Dedication

This book is dedicated to our mothers (Thankamma and Margaret) who gave us life
and the encouragement to write, and to our families for keeping us sane during the
preparation of this book.

Commissioning Editor: Louise Crowe

Development Editor: Fiona Conn
Project Manager: Beula Christopher
Designer: Kirsteen Wright
Illustration Manager: Gillian Richards
Illustrator: Jennifer Rose
Specialist Training in
ONCOLOGY
Dedication
This book is dedicated to our mothers (Thankamma and Margaret) who gave us life
and the encouragement to write, and to our families for keeping us sane during the
preparation of this book.

Commissioning Editor: Louise Crowe

Development Editor: Fiona Conn
Project Manager: Beula Christopher
Designer: Kirsteen Wright
Illustration Manager: Gillian Richards
Illustrator: Jennifer Rose
Specialist Training in
ONCOLOGY

TV Ajithkumar MD FRCP (Edin) FRCR

Consultant in Clinical Oncology
Norwich and Norfolk University Hospital
Norwich, UK

Helen M Hatcher PhD MRCP

Consultant in Medical and Teenage and Young Adult Oncology
Cambridge University Hospital
Cambridge, UK

Edinburgh London New York Oxford Philadelphia St Louis Sydney Toronto 2011
© 2011 Elsevier Ltd. All rights reserved.

No part of this publication may be reproduced or transmitted in any form or by any means, electronic or
mechanical, including photocopying, recording, or any information storage and retrieval system, without
permission in writing from the publisher. Details on how to seek permission, further information about the
Publisher’s permissions policies and our arrangements with organizations such as the Copyright Clearance Center
and the Copyright Licensing Agency, can be found at our website: www.elsevier.com/permissions.

This book and the individual contributions contained in it are protected under copyright by the Publisher (other
than as may be noted herein).

ISBN 978 0 7234 3458 0

British Library Cataloguing in Publication Data

A catalogue record for this book is available from the British Library

Library of Congress Cataloging in Publication Data

A catalog record for this book is available from the Library of Congress

Notices
Knowledge and best practice in this field are constantly changing. As new research and experience broaden our
understanding, changes in research methods, professional practices, or medical treatment may become necessary.

Practitioners and researchers must always rely on their own experience and knowledge in evaluating and using
any information, methods, compounds, or experiments described herein. In using such information or methods
they should be mindful of their own safety and the safety of others, including parties for whom they have a
professional responsibility.

With respect to any drug or pharmaceutical products identified, readers are advised to check the most current
information provided (i) on procedures featured or (ii) by the manufacturer of each product to be administered,
to verify the recommended dose or formula, the method and duration of administration, and contraindications.
It is the responsibility of practitioners, relying on their own experience and knowledge of their patients, to make
diagnoses, to determine dosages and the best treatment for each individual patient, and to take all appropriate
safety precautions.

To the fullest extent of the law, neither the Publisher nor the authors, contributors, or editors, assume any
liability for any injury and/or damage to persons or property as a matter of products liability, negligence or
otherwise, or from any use or operation of any methods, products, instructions, or ideas contained in the
material herein.

The
Working together to grow publisher’s
policy is to use
libraries in developing countries paper manufactured
from sustainable forests
www.elsevier.com | www.bookaid.org | www.sabre.org

Printed in China
Contributors

TV Ajithkumar MD FRCP (Edin) FRCR Ruheena Mendes MRCP, FRCR

Consultant in Clinical Oncology Consultant Clinical Oncologist
Norwich and Norfolk University Hospital University College London Hospitals NHS Trust
Norwich, UK London, UK

Mark Beresford MA, MRCP, FRCR, DM Christine Parkinson PhD, MRCP

Consultant Clinical Oncologist Associate Clinical Lecturer
Bristol Oncology Centre and Department of Oncology
Honorary Senior Lecturer Cambridge University Hospitals NHS Foundation
University of Bristol Trust
Bristol, UK Cambridge, UK

Ellen Copson BSc, MB BS, MRCP, PhD Christopher Williams FRCP, DM

Consultant Medical Oncologist Consultant Medical Oncologist
Southampton University Hospitals Trust and Salisbury Bristol Haematology and Oncology Centre
Foundation Trust Bristol, UK
Southampton, UK
Jessica Wrigley MB BChir (Cantb), MRCP
Emma de Winton BSc, MRCP, FRCP Academic Clinical Fellow
Consultant Clinical Oncologist Department of Medical Oncology
Royal United Hospital Cambridge University Hospitals NHS Foundation
Bath, UK Trust
Cambridge, UK
Albert A Edwards BSc MBBS MRCP
Specialist Registrar in Clinical Oncology
St Bartholomew’s Hospital
London, UK

Helen M Hatcher PhD MRCP

Consultant in Medical and Teenage and Young Adult
Oncology
Cambridge University Hospital
Cambridge, UK

ix
 Preface

It is a startling fact that one in three people have tried to explain the practical elements of
will develop cancer in their lifetime and one in treating cancer patients from radiotherapy plan-
four people will die of cancer. It is therefore ning to chemotherapy prescription, the rationale
important to most people in the health sector to behind them and what the patients are likely to
have a basic understanding of cancer and its ask about these treatments.
treatments. Oncology is one of the most rapidly changing
When we started our training in oncology and areas of medicine with the developments of new
were faced with new patients every day, what we therapies constantly evolving. With the modern
felt was needed was a book which summarized computer-literate patient, we are repeatedly chal-
the most common cancers and their treatments. lenged to be up to date, which is difficult in such
There are many books which discuss the scien- a dynamic specialty. In some instances, we have
tific basis of cancer, but we wanted to know what included website addresses, which are useful
to tell the patient about what treatments they either for your patients or yourselves.
may have and what their outcome might be. This In essence, this is a handbook of practical
is true for many health professionals, both those guidance and knowledge for all those who come
in training (including students) and those whose into contact with patients going through their
main speciality is not cancer management, but cancer journey. It is the culmination of years of
which brings them into contact with cancer teaching and our own knowledge journey, which
patients regularly, e.g. general practitioners, we hope provides the reader with rapid access to
specialist nurses and pharmacists. essential information.
We wanted to provide an overview of clinical
presentation, required investigations and treat- TV Ajithkumar and
ment options according to stage and fitness. We HM Hatcher

x
Acknowledgements

We are indebted to those who took time in their • Dr Evis Sala, Cambridge University Hospital,
busy lives to provide their expert comments on Cambridge.
the manuscript: • Varian Medical Systems.
• Professor Ann Barrett We thank Sue Shadbolt for her excellent organi-
• Professor Ian Judson zational and computer skills in assisting with the
• Dr Mike Shere preparation of figures.
• Dr Sharon Straus We are grateful to Timothy Horne, Janice
Urquhart and Fiona Conn at Elsevier for com-
We owe thanks to several of our colleagues for
missioning this book and supporting us through-
the provision of figures and illustrations:
out its development and production.
• Dr Matt Beasley, Dr Priyanka Mehta, Neil Finally, we thank all those who helped us
Ogborne, Henry Lawrence, Alison Stapleton through our training and the knowledge from
and Helen Appleby at Bristol Oncology senior colleagues to students whose questions led
Centre. us to search deeper.
• Dr Andrew Medford at Glenfield Hospital.
• Mr Rob Grimer at Royal Orthopaedic Hos-
pital, Birmingham.

xi
Clinical approach to
cancer patients
TV Ajithkumar and HM Hatcher
1
Introduction Investigations for
Cancer is a global healthcare problem. In a suspected cancer
the year 2000, cancer accounted for 12% of Initial investigations are to establish a histologi-
approximately 56 million deaths worldwide cal diagnosis of cancer, to assess the extent of
from all causes. It is estimated by 2050 more local disease, and to look for metastatic disease.
than 27 million cancer cases per year will be Further investigations are done to evaluate suit-
diagnosed and result in 17.5 million deaths. In ability for standard or trial treatment and to
the UK, 1 in 3 adults will develop some form of assess the severity of any co-morbid medical
cancer during their lifetime and 1 in 4 die from conditions.
cancer.
A suspicion of cancer or diagnosis of cancer is Diagnostic investigations
the beginning of a difficult journey. In many Diagnostic investigations are undertaken in a
ways it is like climbing a mountain for the first logical order, with blood tests including relevant
time; a journey filled with uncertainty and chal- tumour markers and simple imaging, and proceed
lenges which carries no guarantees (Figure 1.1). to the diagnostic imaging of choice for particular
Patients often carry additional anxieties if there tumour types. Imaging helps to determine local
have been perceived delays so that a knowledge and distant metastatic staging. Confirmation
of warning signs of cancer and an understanding of the diagnosis can be obtained by cytology
of referral and treatment is essential for any or biopsy. Many tumours require biopsy for
healthcare professional.
Patients presenting to their primary care physi-
cian with warning signs of cancer (Box 1.1)
Box 1.1: Warning signs of cancer
should be referred to a specialist centre for an
• Rapid weight loss
urgent evaluation. In the UK and many parts of
• Haemoptysis/persistent cough/hoarseness of voice
the World, cancer treatment is organized around for >3 weeks
a multidisciplinary team which consists of physi- • Rectal bleeding/melaena/altered bowel habit
cians, surgeons, cancer specialists, radiologists, • Haematuria
pathologists and clinical nurse specialists. Many • Breast lump
investigations for suspected cancer are done • Progressive dysphagia
either in ‘one-stop’ (e.g. for breast cancer) or • Persistent headache
‘two-stop’ clinics (e.g. lung cancer) to expedite • Persistent non-specific symptoms
diagnosis and treatment.

© 2011, Elsevier Ltd 3

DOI: 10.1016/B978-0-7234-3458-0.00006-3
 I BASIC PRINCIPLES OF CANCER MANAGEMENT

Figure 1.1
The diagnosis of cancer can be a lonely and challenging
experience. Figure 1.3
CT scan abdomen shows bilateral adrenal metastasis in
small cell lung cancer.

cancer. The choice of investigation depends on

the primary and pattern of metastasis. For
example, the common sites of metastasis in lung
cancer are regional lymph nodes, adrenals and
liver; hence all patients with a lung cancer have
CT scan of chest and abdomen (Figure 1.3). All
patients who are planned to undergo curative
treatment, particularly an extensive surgical
resection, need additional investigations to assess
their suitability for radical treatment. Functional
imaging is more sensitive than anatomical imaging
in detecting distant metastasis (e.g. PET scan
staging alters conventional staging in up to 25%
Figure 1.2
CT guided biopsy from vertebral body.
of patients). Endoscopic ultrasound and thora-
coscopy and laparoscopy are also used in staging
in appropriate situations (Chapters 9, 11).
further characterization and immunohistochemi-
cal assessment. Biopsies can be obtained by core Staging
biopsies, and guided biopsies using imaging or
endoscopic visualization (Figure 1.2). All patients The purpose of staging is to assess the extent
need a definite histological diagnosis if specific of disease, choose the appropriate treatment
cancer treatment is contemplated. Rarely, treat- and to assess likely outcome of the disease.
ment can be undertaken when the radiological Staging is also important in the comparison of
appearance and tumour markers are typical (e.g. results between treatment centres. The TNM
choriocarcinoma, germ cell tumours). system has been developed for many cancers.
TNM staging denotes tumour, node and meta-
Staging investigations static status. T staging is generally based on the
Once the histological diagnosis is established, size of the tumour (usually according to defined
further investigations are undertaken to stage the size criteria, e.g. in breast cancer) or depth of
4
 CLINICAL APPROACH TO CANCER PATIENTS 1

Stage 0 Box 1.2: TNM staging descriptors

Urothelium
Stage I Lamina propria Prefix
• c – clinical staging: based on physical examination,
Stage II Muscle imaging and endoscopy.
Bladder • p – pathological staging: after surgery and
histopathological examination. Some tumours
Stage III Peritoneum have different c and p staging (e.g. breast cancer)
Fat whereas others have only p staging (e.g. colon
cancer).
Stage IV • y – denotes staging after neoadjuvant therapy
(p. 163).
• r – recurrent tumour: restaging following a disease
free interval.
Figure 1.4
Staging of cancer. • a – autopsy staging.
Grading (G)
• Gx – cannot be assessed.
• G1 – well differentiated.
• G2 – moderately differentiated.
• G3 – poorly differentiated.
invasion in hollow organs (e.g. oesophageal
• G4 – undifferentiated.
cancer, bladder cancer) or local spread to neigh-
bouring organs or subsites (e.g. supraglottic L – lymphatic invasion
• Lx – cannot be assessed.
cancer) (Figure 1.4). N staging is based on
• L0 – no lymphatic invasion.
pattern of spread along the lymphatic chain, or
• L1 – lymphatic invasion.
number of nodes involved or size of nodes
involved. It may be clinical or pathological. M1 V – venous invasion
• Vx – cannot be assessed.
denotes distant metastasis. Composite staging
• V1 – microscopic invasion.
involves grouping various T, N and M combi-
• V2 – macroscopic invasion.
nations into 4 stages and each site has different
stage grouping (e.g. see p. 80). Other descrip- R – residual tumour after surgery
• R – no residual tumour.
tors of TNM staging are shown in Box 1.2.
• R1 – microscopic residual tumour.
Other cancers are staged by slightly different
• R2 – macroscopic residual tumour.
systems such as FIGO for many gynaecological
cancers (Chapters 13, p. 197). Multiple tumours
• Multiple tumours in one organ – the tumour with
highest T category should be identified and the
Prognostic factors multiplicity of the number of tumours is indicated
in parentheses, e.g. T1 (m) or T1 (3).
Many factors influence the prognosis of cancer • In simultaneous bilateral cancers of paired organs,
each tumour is classified independently.
apart from staging. Two generally important
prognostic factors are performance status (see
below) and significant weight loss (≥10% weight
loss in last 3 months). A poor performance status Consultation with patients and
(WHO 3–4) and significant weight loss suggest
poor prognosis.
breaking the news
When patients attend oncology clinics many of
them may have some idea about the details of
Multidisciplinary management their cancer and a rough outline of their further
In the UK, all patients with suspected cancer are management. However, most patients are in
managed within the multidisciplinary team. This shock and may take a long time to come to terms
journey starts from the referral with suspected with a diagnosis of cancer. This gets particularly
cancer to the end of the treatment and into difficult for an inquisitive patient, who will search
follow-up or death. for more information on the internet and some
5
 I BASIC PRINCIPLES OF CANCER MANAGEMENT

Box 1.3: Tips on consultation

Dos
• Introduce yourself to the patient and family – mention your role in the care.
• Get a precise and focused history to understand the current symptoms, performance status and weight loss.
• Get a clear idea of their support at home, which will be required to physically and mentally help them through
treatment.
• Take a good family history as this may affect the chances of further malignancies or screening for other family
members.
• Do a relevant clinical examination.
• Ask patient and family what they know so far (the usual answer is ‘not much’ – they are not trying to trick you,
but haven’t taken in everything they have been told – be patient and sympathetic).
• Reiterate the situation – discuss the details of investigations. Offer them an opportunity to look at their scan
pictures, if they wish to.
• Discuss the treatment options and their relative advantages and disadvantages.
• Be clear and realistic about the aim of treatment (e.g. cure, improving chances of cure, prolonging life,
improving symptoms).
• Many patients would like you to give them some suggestions regarding what do you think is the best option
and why (though it is the era of informed consent, you may need to help them to make a decision regarding
their treatment!).
• Formulate a simple plan of treatment and explain this to the patient.
• Always encourage patients and their relatives to ask questions and be candid in giving an answer.
• If you need any extra tests or investigations, explain how it is going to affect the treatment plan (make sure
you chase the results of the tests you requested and let the patient know the result in time).
• Discuss details and logistics about treatment and get their consent.
• Give them contact details if they need further clarification and emergency numbers if things go wrong.
• Introduce them to your team, particularly clinical nurse specialists.
• Keep a positive, caring, sympathetic and professional attitude.

Don’ts
• Don’t give life expectancy in fixed terms. Though many patients on palliative treatment ask about their life
expectancy, it is better to refrain from giving some answers like 4–5 weeks or less than 6 months. It is always a
good idea to ask patient whether they would like to get some figure or just a rough idea. It is better is put in
terms like ‘weeks to months’ or ‘months to years’. If you are forced to give a figure, give a broad range and
explain that the figure is an average. For example, for some with lung cancer with disseminated liver metastasis
the estimated life expectancy will be around 3–6 months, but explain that in the best case scenario it might be
more than 6 months and in the worst case less than 3 months.
• Don’t be too authoritative.
• Don’t try to answer a question if you don’t know the right answer.
• Don’t give equivocal results or bad news over phone – you don’t know what is going on the other end of the
phone or what support the patient has. If you have good news, just let the patient know as soon as possible.
Anxiety for the patient is often greatest when awaiting a scan result. Some centres have a policy of
telephoning with good results, but beware that an intelligent patient will know when there is bad news if a
result is not given (patients talk to each other as well as to professionals).

of the information overload can add to the morbidities at the diagnosis, likely responsive-
anxiety. A clinician role is to help the patient to ness of the particular tumour type and calculating
cope with the situation, and give them clear direc- the tolerance to any planned treatment.
tions on further management and aim (Box 1.3). Performance status (PS): Performance status
helps to quantify the physical well-being of
patients and helps to determine optimal treat-
Assessing fitness for treatment ment, make treatment modifications (including
Assessing fitness for treatment is an important dose modification of chemotherapy) and to
part of decision making. It is mainly based on measure the intensity of supportive care required.
the performance status of patient, active co- It should be clearly documented at the beginning
6
 CLINICAL APPROACH TO CANCER PATIENTS 1

Table 1.1: Karnofsky performance status (KPS) and WHO score

KPS WHO (KPS)
Score (%) Description Score Description
100 Normal, no signs of disease 0 Asymptomatic, fully active and able to
(90–100) carry out all predisease activities
without restriction
90 Capable of normal activity, a few symptoms 1 Symptomatic, restricted in physically
or signs of disease (70–90) strenuous activity but ambulatory and
able to carry out light or sedentary
80 Normal activity with some difficulty. Some
work
symptoms or signs
70 Self-caring, not capable of normal activity or 2 Capable of all self-care but unable to
work (50–70) carry out any work activities ; <50% in
bed during day
60 Needs some help with care, can take care of
most personal requirements
50 Help required often, frequent medical care 3 Capable of only limited self-care; >50%
needed (30–50) in bed during the day
40 Disabled, requires special care and help
30 Severely disabled, hospital admission needed 4 Completely disabled and cannot do any
but no risk of death (10–30) self-care. Totally confined to bed or
chair
20 Very ill, needs urgent admission and required
supportive care
10 Moribund, rapidly progressive fatal disease
0 Death 5 Death

and throughout treatment. There are a number small and potentially curable. Similarly, many
of scoring systems and the two most commonly chemotherapy drugs have systemic organ effects
used are Karnofsky performance status (KPS) which need to be taken into account when plan-
and WHO score (Table 1.1). Patients are gener- ning anticancer treatment.
ally eligible for curative treatment only if PS
is 0–1, palliative anticancer treatment when PS Implementing planned
is 0–2 and generally no anticancer treatment is
given if PS 3–4. However, in certain situations, treatment
when the disease is very responsive to treatment For many early stage cancers, delay in treatment
and rapid deterioration is due to the current is proven to compromise the chances of cure (e.g.
disease process, modified curative treatment germ cell tumours), and in tumours with rapid
is considered (e.g. germ cell tumours). If per- proliferation (e.g. Burkitt’s lymphoma which has
formance status deteriorates rapidly during anti- a doubling time of <24 hours) even a few day of
cancer treatment, treatment is either stopped or delay in initiating treatment can be detrimental.
modified. Hence it is important to start curative treatment
A proper assessment of active co-morbidities as soon as possible.
is important in predicting side effects to proposed
cancer treatment. For example, patients with
severe COPD with poor pulmonary function
Follow-up during treatment
tests (FEV1 <1) are not considered for surgery or Follow-up during treatment is to assess response
radical radiotherapy even if the tumour is very to treatment, monitor toxicity and modify further
7
 I BASIC PRINCIPLES OF CANCER MANAGEMENT

treatment. Toxicity should be monitored along- practitioners will have a key role in coordinating
side treatment so that patients on a 3 weekly some of this care and providing additional
cycle of chemotherapy will be seen every 3 weeks necessary services such as physiotherapy and
prior to each treatment to modify the dose or occupational therapy.
adjust supportive treatments. For patients who At the time of diagnosis, an individual should
have had significant toxicities on a previous therefore be provided with sources of informa-
cycle, they may be seen in between the cycle tion to help them through all these areas to facili-
dates. Patients undergoing radiotherapy will tate their treatment and return to health. The key
often be seen at least once throughout their treat- areas are:
ment to assess acute toxicities and prescribe sup-
• Psychosocial support.
portive measures as necessary.
• Income support.
The optimal timing to assess tumour response
• Macmillan team.
to treatment varies depending upon the type of
• Cancer care in the community.
cancer treatment. For example, radiotherapy and
hormonal agents generally take a 3–4 months to The potential sources of this support can be in
show any response to treatment, whereas chemo- the form of documents from helpful websites or
therapy response is faster (6–9 weeks). Hence, organizations, local cancer support groups, and
investigations to assess response to treatment named key workers such as specialist nurses or
should be planned according to the appropriate Macmillan nurses. It should be emphasized at the
time scale. However if there is any clinical suspi- start of diagnosis and treatment that it is natural
cion of progression while on treatment, prompt to require the help of others at some point in the
investigations are required prior to planned journey and that it will only help their overall
investigations. outcome. The special needs of children diagnosed
with cancer and their family is discussed on
p. 320.
Support during treatment
From the moment of diagnosis of cancer, a per- Cancer screening
son’s life is changed forever. It affects not only
Several cancers now have proven screening pro-
their physical health, but their mental health is
grammes which have been seen to improve either
also challenged. Different individuals deal with
the incidence or outcome of invasive cancers, e.g.
this process in different ways but each should be
breast and cervix. For other cancers screening
offered appropriate support for their needs. This
programmes are in development to try to mini-
may involve psychological support or something
mize the mortality from this disease.
more practical such as directing them to possible
sources of financial support. Many people are
working at the time of diagnosis and their future Genetic screening
employment may be affected depending on their Patients with a suspected genetic component to
job and employer. Laws exist to protect individu- their cancer need referral to a clinical genetics
als, but those who are self-employed will only be department. Chapter 5 (p. 45) deals with the
protected if they had pre-existing insurance. recommendations for referral to clinical genetics
Relationships are frequently challenged by the and further management for the patient and their
diagnosis of cancer and the journey through its family.
treatment, and it is not uncommon for couples
to split up at this time. Financial worries may Follow-up after treatment and
continue after treatment has completed as it
affects the ability to gain new life insurance or a
management of recurrence
mortgage. Those living in countries which require Almost all patients who have been treated with
health insurance will notice an increase in premi- curative intent need some regular follow-up to
ums or difficulty obtaining further health insur- detect an early potentially curable recurrence
ance. Local health providers such as general and a second cancer. The frequency and mode of
8
 CLINICAL APPROACH TO CANCER PATIENTS 1

Beyond cure and survivorship

For many patients treatment will be possible and
they will succeed in climbing the mountain of
diagnosis, treatment and its complications (Figure
1.5). However the long-term impact of this on
their lives must not be underestimated and many
patients feel at their most lost at the end of treat-
ment or when follow-up is discontinued (see also
p. 58, late effects). An understanding of this
process will help facilitate any further care that
is necessary to return them to a functional life.

Further reading
Figure 1.5 Referral guide for suspected cancer, NICE. Available from
Successful treatment of cancer is often a cause for http://guidance.nice.org.uk/CG27/Guidance/pdf/English
celebration, but people will also need help getting
down from the mountain at the other side.

follow-up depend on the pattern of recurrence of

individual cancers, which are dealt with individu-
ally. It is still debatable whether early detection
of a metastatic recurrence improves overall sur-
vival in most cancers.

9
 Principles of
surgical oncology
TV Ajithkumar
2
Introduction nodes, aspiration of cysts, diagnosis of thyroid
nodule and confirmation of recurrent or meta-
Surgery remains the major mode of cure for static disease.
many cancers. The majority of solid tumours are Core biopsy helps to visualize architecture as
treated initially with a curative resection if pos- well as to perform immunohistochemical studies.
sible. The proportion of patients who can undergo It is useful in the diagnosis of solid masses such
a curative resection depends on the stage at pres- as breast lumps or liver metastases. However,
entation and tumour site. Curative surgery may core biopsy should not be used in lymphoma
result in disruption of cosmesis and function. (which requires extensive immunohistochemical
Hence surgery also has an important role in stains) or for soft tissue or bone sarcoma.
reconstructive surgery to maintain body image Incisional biopsy is used when core biopsy is
and ability to return to normal functioning life. non-diagnostic and excision biopsy is not appro-
The potential role of surgery in the manage- priate. The common indication is a suspected
ment of cancer includes: sarcoma needing neoadjuvant treatment or defi-
• Diagnosis and staging. nite resection. Care should be taken when plan-
• Curative. ning incision biopsy to ensure that the site of
• Palliative. biopsy is within the area definite surgery and
• Reconstructive (oncoplastic) surgery. should only be undertaken by surgeons who will
• Risk reduction surgery. undertake the final surgery. A poorly planned
• Minimal access and robotic. incision biopsy can lead to unnecessary morbid
surgery.
Excision biopsy involves removal of the entire
Diagnosis and staging mass or skin lesion. It is important to make sure
that this procedure does not compromise a later
Diagnosis wider excision if necessary. The specimen needs
Histological diagnosis is obtained from tumour to be oriented in three dimensions for the pathol-
tissue by fine needle aspiration cytology, core ogist to determine surgical margins.
biopsy, incisional biopsy and excisional biopsy. Frozen section is occasionally used preopera-
Choosing the right technique is based on the tively to confirm diagnosis when previous histo-
location of tumour, anticipated type of the logic diagnosis is not available (e.g. solitary lung
tumour and reliability of the method to make a lesions), to decide need for further surgery (e.g.
definite diagnosis. lymph node dissection) and ensure adequate sur-
Fine needle aspiration (FNA) yields quick gical margins.
result and shows cellular characteristics but
not architecture. FNA serves as good screening Staging
tool prior to more definitive diagnostic methods. Various surgical procedures such as endoscopy
FNA is useful for diagnosis of enlarged lymph and staging laparotomy aid in defining the extent
10 © 2011, Elsevier Ltd
DOI: 10.1016/B978-0-7234-3458-0.00007-5
 PRINCIPLES OF SURGICAL ONCOLOGY 2
of disease as well as obtaining histological con- abdominal hysterectomy with bilateral
firmation of metastatic disease. These are covered salpingo-oophorectomy).
in detail for specific malignancies. One example
At the time of surgery exposure and shedding
is the use of laparoscopy as an adjunct to detect
viable tumour cells should be avoided if possible.
small peritoneal and liver metastases reduces the
Certain tumours have a propensity to recur
number of ‘open and close’ laparotomies by less
along surgical incision lines or drainage sites e.g.
than 5% in stomach cancer.
mesothelioma and sarcoma. A curative resection
is aimed at a gross visible margin as imaging
Curative surgery modalities will not identify microscopic disease.
Surgery plays a significant role in curative treat- This gross margin depends on the type of malig-
ment of cancer. For many cancers surgery is the nancy and pattern of local spread. An adequate
primary modality of treatment. A decision regard- gross margin helps to ensure adequate micro-
ing curative surgery is made after careful consid- scopic margin of resection. Table 2.1 shows
eration of various patient and tumour related examples of the gross resection margin and
characteristics at a multidisciplinary meeting with microscopic resection margin for some common
surgeons, oncologists, radiologists and patholo- tumours.
gists. At this meeting staging and diagnosis will be Multimodality treatment has affected the
reviewed along with information concerning the surgical approach to many cancers. The use of
patient. Patient-related factors which influence the radio­therapy, chemotherapy or both has led to
choice of curative surgery include age, perform- the use of less radical procedures with an improve-
ance status and co-morbidities. Tumour-related ment of quality of life.
factors include chances of long-term benefit and
potential surgical risks and complications. Surgery of regional lymph nodes
Surgery of the primary tumour Some tumours spread to regional lymph nodes
in a predictive fashion. In these cancers, local
Curative surgery is aimed at removal of the
lymph nodes in continuity with lymphatics are
malignant tumour with a clear margin of normal
removed along with the primary tumour. This
tissue (‘R0’ resection) with reconstruction of the
provides important staging information as well
surgical defect if appropriate. Based on the extent
as a therapeutic advantage to minimize the risk
of removal of cancer, resections are classified as
of a regional recurrence, preventing more exten-
follows which is part of the TNM staging:
sive surgery in the future. Various methods are
• R0 – all margins are histologically free of used to screen pathological involvement of lymph
tumour. nodes before extensive lymph nodes dissection is
• R1 – microscopic residual disease after undertaken. These include:
resection.
• FNA of enlarged regional lymph nodes.
• R2 – gross residual disease after resection.
• Node sampling – involves cherry picking
The tumour should be orientated and marked of 4–5 regional lymph nodes (e.g. breast
at the time of surgery such that any positive cancer).
margins can be identified anatomically should • Sentinel node biopsy – is based on the princi-
the need for re-excision arise. ple that tumour spread to a single node (sen-
Depending on the type of cancer and anatomi- tinel) prior to spreading to other nodes in an
cal site, curative surgery can be: ‘ordered’ fashion and lymph nodes can be
identified by using blue dye or radioisotopes
• Wide local excision (e.g. breast cancer).
(Figure 2.1).
• Removal of part of the organ and sur­
• Lymph node dissection
rounding tissue at risk of spread (e.g. partial
gastrectomy). However, in many situations the role of lymph
• Removal of an entire organ with or without node dissection in overall survival remains
important adjacent structures (e.g. total controversial. In practice, patients with involved
11
 I BASIC PRINCIPLES OF CANCER MANAGEMENT

Table 2.1: Gross resection margin and minimal microscopic resection margin for curative resection
Tumour type Local spread pattern Gross margin Microscopic margin
Breast cancer Circumferential 1 cm 1–5 mm
Lung cancer Within the same lobe Lobectomy
Oesophageal cancer Longitudinal submucosal 5 cm 1 mm
Stomach cancer Submucosal and towards serosa 1 cm 1 mm
Colon cancer Submucosal and towards serosa 3 cm 1 mm
Rectal cancer Towards serosa 3 cm 1 mm
Squamous cell carcinoma Peripheral 1 cm 1 mm
skin
Malignant melanoma Deep 1–2 cm 1 mm
Head and neck cancer Within the anatomic Anatomic compartment 1 mm
compartment

A B

Figure 2.1
Sentinel node biopsy. Sentinel node is identified by either use of blue dye (A) or radioisotope (Tc-99m albumin
nanocolloid). Picture B shows an intense uptake above the injection site with smaller less distinct nodes.

lymph nodes undergo node dissection whereas disease at presentation or in a very select group
the role of elective lymph node dissection is of patients with good performance status with a
dependent on the site of cancer, type of cancer long disease-free survival after treatment of the
and other prognostic factors. Benefits of nodal primary tumour. In the absence of proper
dissections in different cancers are discussed in random­ized studies it is not known whether the
the corresponding chapters. observed therapeutic benefit is actual or due to
the strict selection process (selection bias). The
common situations are resection of isolated or
Metastatectomy as part of limited liver metastases in colorectal cancer
curative surgery which results in 20–40% 5-year survival
Resection of isolated metastatic lesions is (p. 164). Pulmonary metastatectomy in sarcomas
useful for a selected group of patients in certain leads to a 5-year survival of 20–25% (p. 259).
cancers (Box 2.1). In general this is undertaken An alternative is the evolving use of radio­
for patients with surgically resectable metastatic frequency ablation.
12
 PRINCIPLES OF SURGICAL ONCOLOGY 2

Box 2.1: Role of metastatectomy Box 2.2: Potential indications for risk
reducing surgery
• Liver – selected patients with colorectal cancer.
• Lung – selected patients with colorectal, kidney Surgery Indication
and testicular cancers and sarcoma.
Bilateral mastectomy BRCA1/2 mutations
• Adrenal – selected patients with resectable lung Familial breast cancer
cancer and isolated adrenal disease. Unilateral breast cancer in
• Brain – solitary metastasis with controlled/ <40 years
potentially curable systemic disease. Bilateral oophorectomy BRCA1/2 mutations
Familial ovarian cancer
Total proctocolectomy Familial adenomatous
polyposis or APC
mutations
Salvage surgery
Hereditary non-polyposis
Surgery is useful as a salvage measure after colon cancer – germline
primary treatment failure or recurrence after mutations
definitive treatment. It is only appropriate for Thyroidectomy RET oncogene mutation
MEN 2
fit patients with a good chance of prolonged
survival. Examples include abdomino-perineal
resection after chemoradiotherapy for anal
cancer, and exenteration in cervical cancer after
chemoradiotherapy. In patients with prior limited
surgery or chemoradiotherapy, a second chance Risk reduction surgery
of cure is aimed with surgery. Examples include
Less than 5% patients have a genetic component
mastectomy for local recurrence after conserva-
to their cancer (p. 45). Increasing understanding
tive surgery for breast cancer and neck node
of the development of genetically associated
dissection for isolated nodal recurrence after
cancers has led to prophylactic surgery for some
chemoradiotherapy for head and neck cancer.
patients. Box 2.2 shows the indications for
common prophylactic surgeries. Appropriate
Palliative surgery genetic testing and counselling is, however, an
The aim of palliative surgery is to improve or absolute pre-requisite prior to any prophylactic
prevent significant symptoms (e.g. pain, bleeding surgery. Women with BRCA1 and BRCA2 muta-
and obstruction) which are likely to occur tions have a high risk of breast cancer which is
without intervention. It can also enhance the reduced by 90–95% with bilateral mastectomy.
effect of chemotherapy (e.g. in ovarian cancer However, the decision to undergo prophylactic
where it improves survival). Debulking surgery mastectomy should be done after careful discus-
of the primary tumour can produce good sion on explaining the future quality of life,
symptom control and improve quality of life by potential surgical risks and wishes of the patient.
preventing complications due to uncontrolled Alternative risk reduction methods such as use of
disease (e.g. loco-regional surgery in breast tamoxifen and prophylactic oophorectomy after
cancer prevents fungation and symptomatic axil- completion of family should also be considered.
lary disease). Another example is FAP and prophylactic colec-
tomy (p. 50).
Reconstructive (oncoplastic)
surgery Minimal access and
Extensive resection often results in disruption of
robotic surgery
normal anatomy and subsequent cosmesis and The role of minimal access surgery is being
function. Plastic surgical techniques are useful in increasingly studied in the management of solid
correcting the anatomical defects and improving tumours. It is being more often used in abdomi-
cosmesis (e.g. reconstructive breast surgery) and nal malignancies and studies show that laparo-
function (e.g. in head and neck surgery). scopic surgery results in the same long term
13
 I BASIC PRINCIPLES OF CANCER MANAGEMENT

survival as that of open surgery, with no increased Robotic assisted surgery is being studied in
risk of abdominal wall recurrence, less surgical prostate and renal cell cancers. This technique
morbidity and quick return to normal function. may result in minimal surgical trauma with better
Laparoscopic surgery is an accepted modality toxicity profile.
of surgical treatment in gastric, kidney, adrenal
and colorectal cancers. Video-assisted thoracic Further reading
surgery for stage I lung cancer is a particularly Sabel M, Sandak V and Sussman J. Essentials of surgical
attractive option for elderly patients. Oncology. 2006, Elsevier.

14
Principles of radiotherapy
TV Ajithkumar
3
Introduction apy given either alone or in combination with
chemotherapy or biological agents) or adjuvant
After surgery, radiotherapy is the most effective radiotherapy (given after definitive treatment of
curative treatment for cancer, contributing up to tumour, usually surgery). Palliative radiotherapy
25–30% of cure. At least half of the patients with is intended to improve symptoms (e.g. bone pain)
cancer require radiotherapy at some time in their or prevent tumour related complications (e.g.
illness of which about 60% are treated with cura- ulceration in breast cancer).
tive intent, often in combination with surgery
and chemotherapy. Radiotherapy involves use of
various types of ionizing radiation, and X-ray is Methods of delivery
the commonest type of radiation used. Other of radiotherapy
forms of radiation include electrons, protons,
neutrons and gamma radiations from radioactive Radiotherapy is either delivered by a radiation
isotopes. This chapter intends to review the prin- source placed away from the body (teletherapy
ciples of practical radiotherapy (Box 3.1) and a or external beam radiotherapy), by placing a
detailed discussion on radiobiology and mathe- radiation source into the tumour (interstitial
matical modelling are beyond the scope of this brachytherapy, e.g. small tongue cancer) or in a
chapter. body cavity containing the tumour (intracavitary
brachytherapy, e.g. cervical cancer) or by intra-
venous or oral administration of nonsealed
Indications for radiotherapy radionuclides. Depending on the site and type of
cancer, radiotherapy is delivered by either one of
Radiotherapy is indicated if it cures or improves
these techniques or a combination. Sometimes
the chances of cure, improves local tumour
radiotherapy is delivered concurrently with
control, achieves symptom control or improves
chemotherapy or biological agents to improve
the quality of life. There are already adequate
the chances of cure (see below).
data on these various indications for radiother-
apy for different neoplasms. With current under-
standing of radiation biology and improved
External beam radiotherapy (EBRT)
techniques, more indications are evolving, par- EBRT commonly utilizes X-rays and electrons.
ticularly for tumours previously thought to be Before the 1950s, radiotherapy units were kilo-
radioresistant (e.g. liver and pancreatic cancer). voltage machines which produced X-rays with
limited penetrability. These machines, which are
still used in some centres, can be one of the
Intent of radiotherapy following:
Radiotherapy treatment is given with either • Superficial X-rays – operate at a potential of
curative or palliative intent. Curative treatment 50–150 kVp and tube current of 5–10 mA
involves either radical radiotherapy (radiother- and useful to treat superficial skin cancers.

© 2011, Elsevier Ltd 15

DOI: 10.1016/B978-0-7234-3458-0.00008-7
 I BASIC PRINCIPLES OF CANCER MANAGEMENT

Box 3.1: Steps in practical radiotherapy Box 3.2: Linear accelerator (Figure 3.1)
1. Indication for radiotherapy Electrons from gun are accelerated before they hit
2. Intent of radiotherapy the target. The X-rays produced from the target are
collimated by primary collimators in the direction of
3. Which is the best way to deliver radiotherapy? patient. This beam is further modified by flattening
• External beam radiotherapy alone (e.g. head filter, secondary collimation and multileaf collimators
and neck cancer) before reaching patient’s surface.
• Brachytherapy alone (e.g. early stage cervical
cancer)
• External beam radiotherapy and brachytherapy
(e.g. advanced stage cervical cancer)
• External beam radiotherapy with concurrent Modern radiotherapy is based on megavoltage
chemotherapy (e.g. squamous oesophageal X-rays (photons) and electrons. Megavoltage
cancer)
X-rays are produced by artificial acceleration of
• External beam radiotherapy with target agents
(e.g. advanced head and neck cancer) electrons through a vacuum to impact on a target
• Radioisotopes (e.g. well-differentiated thyroid in machines called linear accelerators (LINACs)
cancer) (Box 3.2). The energy of the X-rays is propor-
4. Obtaining informed consent tional to the speed of electrons. Electrons are
• Benefit of radiotherapy produced when the target in a linear accelerator
• Explaining the process is removed from the path of the electron beam
• Expected side effects – short-term and (Box 3.2). Modern LINACs have facilities to
long-term
produce both photons and electrons. Electrons
5. Radiotherapy planning and delivery
have a predictable penetrability and hence are
• Position of patient and immobilization
useful when it is important to limit the radiation
• Localization of tumour (CT or MRI)
dose to a deeper organ. Characteristics of photons
• Target volume definition
that are useful in their clinical use are:
• Tumour volumes (GTV, CTV, PTV)
• Normal organs • Greater penetration compared to lower energy
• Planning technique X-rays, which helps in delivering a higher
• Conventional (2D) proportion of dose to the deep tumour com-
• Conformal planning (3D) pared to the surface dose.
• Intensity-modulated radiotherapy (IMRT) • Skin sparing effect – the maximum absorbed
• Image guided radiotherapy (IGRT) dose is deposited a few millimetres beneath
• Treatment planning the skin. This helps to deliver higher dose to
• Beam arrangement depth without causing significant damage to
• Beam size and shape skin and subcutaneous tissue (Box 3.3).
• Energy of beam
• Wedges, shields, bolus Brachytherapy
• Evaluation of treatment plans – homogenous Brachytherapy involves placing radioactive
dose to PTV and dose to critical organs sources at a very short distance from or in contact
• Prescription of radiotherapy treatment with, the tumour. Rapid fall off of radiation dose
• Treatment verification and corrections at increasing distance from the source permits
6. Supportive care during radiotherapy delivery of a high dose of radiotherapy to the
7. Treatment modifications during treatment (e.g. tumour with sparing of surrounding normal
bank holidays, toxicities and interruptions)
tissue. Short half life and high specific activity of
8. Care after radiotherapy and survivorship issues
isotopes allow delivery of the dose over a short
period of time. The spatial distri­bution of sources
• Deep (ortho – ‘orthodox’) X-rays – operate at is based on a complex set of rules.
a potential of 150–500 kVp and tube current The previous problems of radiation safety for
of 10–20 mA. These are useful to treat thick patients and staff, and prolonged treatment time,
skin cancers and rib lesions. In many centres, have become history with modern brachytherapy
these machines are being replaced by electron machines (Figure 3.3). Clinical applications of
16 beam treatment. brachytherapy are as follows:
 PRINCIPLES OF RADIOTHERAPY 3
Electron
Target

Primary collimator

Bending magnet assembly / target X-ray beam

Flattening filter Scattering foil

Electron accelerator for x-rays for electrons
Electron gun Ion chamber
Asymmetric jaw
Secondary collimator

Multileaf collimator
Multileaf collimator

A B

Figure 3.1
A & B, Linear accelerator. (Courtesy of Varian Medical Systems.)

Box 3.3: Choosing the energy (Figure 3.2)

• Palliative treatment – e.g. intracavitary treat-
ment for bronchial cancer and oesophageal
Electrons have a definite range (range in centimeters
is approximately half of beam energy in MeV) and cancer.
selection of electron is based on the depth needed to
treat (effective treatment depth in centimeters, as Radionuclide treatment
defined by 90% isodose in centre, is approximately
one-third of the beam energy in MeV ). With
Systemic administration of radionuclides, which
increasing energy, the surface dose decreases and emit gamma-radiation, is a useful treatment for
hence if higher dose is needed at the surface, a bolus cancer. In well differentiated thyroid cancer, 131I
is used (p. 23). Bolus is also used to bring up high
dose region to surface to avoid radiation to
is given to patients after thyroidectomy (p. 282).
underlying critical structure. Higher energy electron Strontium-89 and samarium-153 are used for
beams exhibit a lateral constriction of 90% isodose palliation of bone metastases, particularly from
line (Figure 3.2B) which need to be taken into
consideration while deciding the field size at surface.
prostate cancer.
Photons have a skin sparing effect and maximum
dose is deposited at a depth from surface. Dose at a
depth increases with energy of photos. 6–10 MV is Informed consent
generally used, however in large patients with very
deep seated tumours >10 MV yields a better dose Once a decision is made to treat with radiother-
distribution. apy, this decision should be communicated to the
patient. The patient should be informed of the
intention of treatment, potential benefits and side
effects, both short term and long term. It is also
an obligation to explain to the patient the poten-
• Curative treatment as a single modality – e.g. tially serious short and long term consequences
prostate cancer, cervical cancer. of treatment in order to obtain truly informed
• Adjuvant after surgery – e.g. breast consent. Often patients would like to know
cancer. details of how radiation works (Box 3.4), dose
• Curative treatment with external beam radio- and length of treatment, rationale for a number
therapy – e.g. cervical cancer, prostate cancer, of treatments (fractionation – the process of
anal cancer. giving the total dose of radiation as small doses 17
 I BASIC PRINCIPLES OF CANCER MANAGEMENT

100 Beam size at surface

Beam size defined by 90%
isodose near surface
80

60
% depth dose

40

20
95%

0 90%
0 5 10 15 20 25
80%
Depth (cm) 10 MeV
6.53 cm
15 MeV 50%
18 MeV 30%
22 MeV
6 MV Beam size defined by
A 10 MV 90% isodose at depth
B
Figure 3.2
A, The percentage of depth dose of electrons (MeV) and photons (MV). B, Electron beam isodose curves – Note the
constriction of 90% isodose at depth which necessitates addition of wider margins to beam width for adequate
coverage of tumour at depth.

A B

Figure 3.3
Brachytherapy machine and its application. A, High dose rate (HDR) afterloading brachytherapy machine which is
fully computer controlled and completes treatment in a few minutes. B, Interstitial brachytherapy in breast cancer
(Courtesy of Varian Medical Systems).

over a period of time) (Box 3.5) and side effects Radiotherapy planning
(p. 348). Side effects of radiotherapy depend on
the area of treatment, total dose and dose per and delivery
fraction. These can be acute (occurring during
radiotherapy and within 3 months of completion Position and immobilization
of radiotherapy) or chronic (occurring 3 months Radiotherapy aims to deliver a uniform (homog-
after completion of radiotherapy). enous) therapeutic dose of radiation to the tumour
18
 PRINCIPLES OF RADIOTHERAPY 3

Box 3.4: How does radiation work? • Direct damage causes single or double strand break
• Hydroxyl group leads to single strand break
Therapeutic use of radiotherapy is born out of
empiricism. Science caught up with empirical clinical
use later to provide explanations for various patterns X-rays γ-rays
of response to treatment. The cancer cell has an
unlimited capacity to multiply and radiotherapy is H2O
aimed to prevent this unlimited multiplication. The
conventional explanation of radiation effect is based Ionization
on radiation damage to DNA caused directly by
photons and indirectly by free radicals which are
H+ + OH•
produced when photons interact with water
molecules in the tissue (see Figure 3.4). There are
three different types of radiation damage to DNA:
• Lethal – irreversible, irreparable leading to cell
death.
• Sublethal – under normal circumstances cells can A G A A C G T
be repaired in a few hours unless additional
sublethal damage (another dose of radiation)
occurs which makes the damage lethal. T C T T G C A
• Potentially lethal – the component of radiation
damage can be modified by the post radiation
environment.
After DNA damage the following changes can occur:
However, DNA damage is not the only mechanism of • DNA repair
radiotherapy action. Radiotherapy can also influence
• Loss of unrestricted cell division and later cell death
genes controlling the cell cycle (e.g. RB gene, p53)
• Programmed cell death (apoptosis)
and alter the expression of various genes resulting in
expression of cytokines, growth factors, structural
proteins or enzymes. Radiation damage to cell
membrane sends signals to the nucleus and these
signals affect cell behaviour. Sensors

and areas of microscopic spread with minimal

possible dose to the adjacent organs. This neces- Transducers
sitates accurate reproduction of treatment posi-
tion on a daily basis. Patients are positioned and
immobilized to ensure optimal beam delivery
while maintaining a comfortable position. The
common positions are either supine or prone. Effectors
Immobilization depends on the site of treat-
ment and intent. Radical treatment needs better
immobilization techniques as the dose delivered
is often very high. Examples of site specific immo­
bilization devices used are as follows: G1
• Brain tumours – for radical treatment: Perspex M S
shell or stereotactic frame and for palliative
G2
treatment: thermoplastic shell.
DNA repair Cell cycle Transcription Apoptosis
• Head and neck cancers – Perspex shell. transitions
• Breast cancer – chest board with cross bar to
Figure 3.4
fix the arms above the head. Mechanism of radiation induced cell damage.
• Chest – head support and knee support or
stereotactic body frame.
• Abdomen and pelvis – knee support or
stereotactic frame or vacuum bags.
• Limbs – vacuum bags.
19
 I BASIC PRINCIPLES OF CANCER MANAGEMENT

Box 3.5: Rationale for fractionation Box 3.6: Volumes in radiotherapy (Figure 3.5)
Radiotherapy usually results in equal damage to both The following are the volumes in radiotherapy:
normal cells and cancer arising from them. However, • GTV – Gross tumour volume – is the gross disease
normal cells and cancer cells differ in their ability to or radiologically visible tumour – this area has 109
recover from radiation damage. This differential cancer cells. In the figure, the T2W MRI shows
capacity of normal cells to repair and re-grow is hyperintense low grade brain tumour.
exploited in eradication of tumour cells. Radiation
sensitivity of cells is dependent on the phase of cell • CTV – Clinical target volume – is the volume
cycle they are in: G2 and M are radiosensitive which contains GTV and/or subclinical microscopic
whereas S phase is radioresistant. At the time of disease (106 cells) which need to be treated to an
radiotherapy, the cancer cells are in various phases of adequate dose to achieve the aim of treatment.
cell cycles; some of them will be in the sensitive The CTV depends on the pattern of local spread of
phase when there is a good chance of cell kill and specific tumours. In the figure, note the outer
some will be in the resistant phase. border of CTV merges with that of PTV as there is
no possibility of microscopic spread beyond the
Rationale of fractionation is explained by 5 Rs. Some inner layer of the skull.
of the Rs lead to more cancer cell kill, whereas others
lead to better repair of normal cells. • PTV – Planning target volume – is a geographical
concept which denotes the CTV and margins for
• Redistribution of cells – delivering radiotherapy as geographic variations and inaccuracies during
multiple treatments allows tumour cells to reassort treatment. The margin added to CTV to derive
into more radiosensitive phase leading to more PTV depends mainly on the immobilization device
cancer cell damage. (e.g. 2–3 mm with stereotactic frame). PTV has
• Reoxygenation – many cancers have hypoxic areas two components:
within the tumour and normal cells do not have • IM (internal margin) – is a margin added to
any hypoxic areas. Hypoxic areas are relatively CTV to compensate for normal anatomical
resistant to radiotherapy. With each fraction, movements and variations in size, shape and
radiotherapy reduces the number of cancer cells position of CTV during treatment. In the figure,
and allows some of the hypoxic areas to become there is very little anatomic movement of CTV
more oxygenated leading to better cancer cell and hence IM is almost zero, whereas in a lung
radiation damage. tumour, it may be around 1–4 cm depending
• The inherent radiosensitivity of the tumour is on the location of the tumour and depth of
important in achieving a cure or control of breathing.
tumour. Some tumours are very radiosensitive (e.g. • SM (set up margin) – a number of factors can
lymphoma and seminoma) whereas others are cause uncertainties such as daily variation in
relatively radioresistant (e.g. melanoma, sarcoma). position of the patient, mechanical
Most tumours are moderately radiosensitive. Cure uncertainties of the equipment, transfer set up
can be achieved with a smaller dose of errors etc. In brain tumour treatment, if a
radiotherapy in very radiosensitive tumours (e.g. Perspex shell is used a 5 mm margin is added.
germinoma, p. 275)
• TV – treated volume – is the volume enclosed by
• Repair of sublethal damage – reducing the dose an isodose surface, selected and specified by the
per fraction helps to repair damage of normal oncologist as being appropriate to achieve the
tissues more effectively than tumours. Normal purpose of treatment.
tissue may be able to repair sublethal damage if
the interval between two fractions of radiotherapy • IrV – irradiated volume – is that tissue volume
is at least 6 hours. However, some types of cancers which receives a dose that is considered significant
also have quick ability to repair radiation damage in relation to normal tissue tolerance.
leading to radioresistance (e.g. melanoma). • PRV – planning organ at risk volume – refers to
• Repopulation – fractionation helps rapidly the definition of margins around organs at risk for
populating normal tissues such as skin and gut to injury by radiation.
repopulate and hence recover from radiotherapy Please note, even if the actual tumour (GTV) is small,
damage. Again, cancer cells also have the capacity after adding various margins as above the irradiated
to repopulate especially when radiation treatment volume is much bigger. This is one of the limiting
is very prolonged or interrupted (gap correction, factors in delivering a high dose to tumour without
see later). having significant irradiation to normal tissue. Studies
show that a 4–5% increase in dose increases the
tumour control probability by 10% and hence newer
developments are aiming at better localization of
tumour and reduction of various margins to increase
Localization of tumour the dose to the actual tumour.
Localization of tumour is to define various treat-
ment volumes (Box 3.6). Conventional localiza-
tion (2-dimensional, 2D) is with orthogonal
X-rays using special treatment planning machines
20
 PRINCIPLES OF RADIOTHERAPY 3
called simulators. These are diagnostic X-ray accuracy of GTV delineation. Planning CT scan
machines, which can mimic all the positions and is usually taken at a slice interval of 1.5–5 mm.
movements of a treatment machine (Figure 3.6A) A slice thickness of <3 mm helps to get better
and some of these machines have a CT scan facil- resolution of digitally reconstructed images
ity. 2D localization is appropriate for palliative (DRRs) which are used to check accuracy of
treatment. Radical radiotherapy utilizes a plan- treatment delivery (see later in Box 3.12).
ning CT scan or advanced techniques to define
the various tumour volumes in 3-dimensions. Planning technique
Modern computer software allows co-registra- Conventional (2D) simulator planning uses
tion of the planning CT scan with an MRI or simple beam arrangements such as single field
PET scan (Figure 3.6B), which improves the radiotherapy or parallel opposed beams. In con-
formal (3D) planning various volumes and organs
at risk (OAR) are delineated individually on
every slice of cross-sectional imaging and a treat-
ment plan produced by a planning computer.
Intensity modulated planning (IMRT) is a further
improvement of 3D planning, which is aimed at
ensuring homogeneous dose to the tumour with
less dose to organs at risk. This technique has
particular advantage with concave-shaped target
volumes with OAR located in the concavity. The
technique is also useful in sparing critical organs
from radiotherapy toxicity (e.g. parotid gland
sparing in head and neck cancer).
Image guided radiotherapy (IGRT) is a further
advance in radiotherapy planning and delivery
where the real time position of the tumour is
taken into consideration (Figure 3.7). 3D, IMRT
Figure 3.5 and IGRT use multiple beams to obtain the
Volumes in radiotherapy. optimal treatment plan.

A B

Figure 3.6
Localization of tumour. A, Simulator used for conventional localization as well as for plan verification (courtesy
Varian Medical Systems). B, Co-registered planning CT with PET scan showing primary tumour (arrow head) and PET
positive right paratracheal node (arrow).
21
 I BASIC PRINCIPLES OF CANCER MANAGEMENT

A B

Figure 3.7
A&B, IMRT and IGRT. A, IMRT is a conformal technique which helps to selectively avoid/limit radiotherapy dose to
critical structures. This IMRT plan aims to give 70 Gy to ethmoid cancer (yellow line represents 70 Gy) while keeping
the dose to the optic chiasma (arrow) to less than 50 Gy. B, IGRT – specialized radiotherapy machine with on-board
imaging system (arrows) allows real time imaging and correction of error. (Courtesy Varian Medical Systems.)

Box 3.7: Radiotherapy planning (see Figure 3.8) Box 3.8: Beam shaping (Figure 3.9)
Three fields are used and the dose is prescribed at In the early 1950s radiotherapy beams used to be
the intersection point as 100% of prescribed dose either square or rectangular. There was an option to
Note the beam arrangement – shield part of the field with lead or equivalent
material. When conformal radiotherapy started
• Only one beam passes directly through the spinal evolving, individual blocks were made based on the
cord so as to keep cord dose within tolerance BEV of individual beams to shape the radiotherapy
• Beams enter only through the side of disease. No fields using cerrobend (an alloy of bismuth, lead, tin
beams are entering through the normal lung side and cadmium with a melting point of 70°C and hence
• Beams are sized according to the beam’s eye view easy to make different shapes). Currently beam
and are of different dimension shaping is achieving with MLCs (see Figure 3.9).

Treatment planning (Box 3.7)

Direction of beam
The direction of beam depends on the location
of PTV and OARs. Generally beams are placed
so that they are equi-angled, entering the body
through the side of disease and avoiding passing
directly through the OARs if possible.

Beam size and shape

Conventional radiotherapy uses either rectangu-
lar or square fields with appropriate blocking of
beams over critical organs (by shields, see below).
Conformal radiotherapy shapes every beam
according to the ‘beam’s eye view’ (BEV). The
exact shaping of the beam used to be attained Figure 3.8
by shaped blocks. With the advent of multileaf Radiotherapy planning.
22
 PRINCIPLES OF RADIOTHERAPY 3
Figure 3.9
Beam shaping using BEV
(A) and MLCs (B&C).

A C

collimators (MLC), shaping of beams becomes Bolus (a tissue-equivalent material placed

increasingly easy (Box 3.8). directly on the patient’s skin surface) is used to
bring up the radiation dose to the surface. The
Energy of the beam
commonly used tissue equivalent materials are
For superficial lesions and lesions lying within a slabs of paraffin wax, gauze coated with petro-
limited depth, electrons are used and energy of latum or synthetic-based substances. Megavolt-
the electron beam depends on the depth which age radiotherapy has a skin sparing effect (i.e.
needs to be treated (Box 3.3). For deep seated delivering maximum dose at a point deep to the
tumours, megavoltage energy is used, usually skin) which may be a disadvantage when treating
6 MV photons; in some patients a higher energy a superficial PTV (e.g. chest wall after mastec-
with high penetration is necessary to improve the tomy). Hence in order to bring up the maximum
dose homogeneity. dose to the surface bolus is placed on the surface
Wedges, shields and bolus of the treatment volume. Bolus is also used to
bring up the high dose radiation towards the
In multifield radiotherapy, wedges are necessary surface to avoid higher doses to the deeply situ-
to alter the beam profile, thereby ensuring a ated OARs.
homogeneous dose to the target volume (Box
3.6). Wedges also act as a tissue compensator for
sloping external surface. Evaluation of treatment plan
Shields are used to avoid irradiation of part of Once treatment is planned, it is necessary to
the radiotherapy field. In the modern machines evaluate the treatment plan before it is accepted
it is achieved by individual leaves of multileaf for treatment. In difficult situations, such as
collimators. when an OAR is lying near the PTV, the planning
23
 I BASIC PRINCIPLES OF CANCER MANAGEMENT

physicists come up with more than one plan for prescribed dose. This is confirmed by looking
the oncologist to evaluate and choose one for at the dose distribution at every slice of plan
treatment. Evaluation of the plan takes the fol- or looking at the dose volume histogram
lowing steps (Box 3.9): (DVH). DVH plots the total dose against the
percentage of target volume or OAR irradi-
• Homogenous dose to the PTV – ideally, the
ated (Box 3.9). Hotspots are areas outside the
whole of the PTV should be covered by 95%
PTV which receive a dose >100% of the speci-
isodose and the recommendation is that PTV
fied PTV dose. Hotspots are considered sig-
dose should be within –5% and +7% of the
nificant only if they exceed >15 mm in
diameter, except in small organs (e.g. eye,
Box 3.9: Evaluation of a treatment plan optic nerve) where <15 mm diameter has to
(Figure 3.10)
be considered significant.
Treatment plan evaluation is to ensure that the PTV • Dose to OAR – dose to the OAR should not
receives a homogenous dose and the doses to the
OAR are within tolerance. Spatial distribution displays exceed their tolerance dose. Tolerance dose
ensure that 95% isodose encloses the PTV (Figure (TD) is the dose beyond which there is a risk
3.10A & B). Dose volume histogram (Figure 3.10C) is of dose limiting toxicity. TD is stated as TD5/5
helpful to indicate underdosage to PTV as well as
excessive dose to OAR. (dose at which there is 5% risk of occurring
dose limiting toxicity at 5 years) and TD5/50

PTV

95% isodose
(red shade)

B
A

100
90 PTV receives >95% dose,
80 there are areas receiving
>105% dose, there is no PTV
70 receiving underdosage
Volume (%)

60
50 Maximum dose to spinal cord
40 is less than 40% of
prescribed dose
30
20
10
0
0 20 40 60 80 100

Dose (%) Spinal cord

Both lungs
PTV Figure 3.10
C
24 A–C, Evaluation of a treatment plan.
 PRINCIPLES OF RADIOTHERAPY 3

Table 3.1: Normal tissue radiation tolerance dose (treated with 2 Gy per fraction)
TD5/5 (Gy)
Organ Whole 2/3rd 1/3rd Dose limiting toxicity
Brain 45 50 60 Necrosis
Brain stem 50 53 60 Necrosis
Colon 45 – 55 Obstruction, perforation and ulceration
Heart 40 45 60 Pericarditis
Kidney 23 30 50 Renal failure
Lens 10 – – Cataract
Liver 30 35 50 Hepatitis
Lung 17.5 30 45 Pulmonary fibrosis
Oesophagus 55 58 60 Stricture
Optic apparatus 50 – – Blindness
Parotid 32 32 – Xerostomia
Rectum 60 – – Necrosis, fistula, stenosis
Retina 45 – – Blindness
Spinal cord 47 50 50 Myelitis
Small intestine 40 – 50 Obstruction, perforation
Stomach 50 55 60 Ulceration, perforation

(dose at which there is 50% risk of occurring The prescription should indicate the total
dose limiting toxicity at 5 years. The aim of dose, number of fractions, dose per fraction, and
treatment plan evaluation is to limit the dose duration of treatment (e.g. 50 Gy in 20 fractions
to OAR below TD5/5. Table 3.1 gives the over 4 weeks). Conventional fractionation is to
approximate TD of various organs. deliver one radiotherapy fraction per day for 5
• Dose to other normal tissue – it is important days a week. There are a number of alternate
to check that there is no increased dose to the fractionation regimes (Box 3.10). The total dose
entry and exit of the beam and there are no of radiotherapy depends on the type of cancer,
sensitive structures in the path of the radia- site and bulk of disease (Box 3.11). Gray (Gy) is
tion beams. the usual measure of radiotherapy which is
defined as 1 joule of energy per 1 kg of material.
Dose prescription for The subunit is centigray (cGy) which is 1/100 of
radiation treatment a Gray. Radiotherapy alone for cure needs a dose
The prescription point of radiotherapy depends of >60–65 Gy as 1.8–2 Gy per day whereas adju-
on the type of plan. For a single beam, the prescrip- vant radiotherapy uses 50–60 Gy. Most studies
tion point either lies in the point of maximum dose indicate a direct relation between the dose and
(dmax) or at a depth. For parallel opposed beams chances of control and cure.
the prescription point is mid-plane whereas for all
3D and 4D planning the prescription point is often Treatment verification and corrections
at the isocentre or at the intersection of points. Accurate position and immobilization during
For electrons, dose is prescribed at 100%; planning and treatment are important in accurate
however, it is necessary that 90% isodose covers delivery of radiotherapy. In spite of this, treat-
the PTV. ment delivered can be different from the planned 25
 I BASIC PRINCIPLES OF CANCER MANAGEMENT

Box 3.10: Fractionation schedules Box 3.11: Tumour control probability (TCP),
normal tissue complication probability (NTCP)
• Conventional fractionation – delivers 1.8–2 Gy
and therapeutic ratio (Figure 3.11)
single fraction per day, 5 times weekly.
• Accelerated fractionation – aims to shorten the For many types of cancer, a higher dose of
treatment time by delivering larger than standard radiotherapy produces better tumour control. After
size fractions five times weekly or more than five fractionated radiotherapy, the total number of
fractions per week of 2 Gy. Multiple fractions may cancer cells surviving depends on the initial number
also be given daily. The acute toxicity is greater of cells and the proportion of cancer cells killed with
with this and late toxicity is either the same as (if each treatment. Studies show that visible disease
complete repair of sublethal damage occurs) or needs more dose than microscopic disease (to
greater than conventional fractionation. It is pathologically detect microscopic disease, cell
useful for tumours with a rapid growth rate. aggregates of ≥106/cm3 are needed) and subclinical
disease (cannot be detected microscopically). For
• Hyperfractionation – aims to improve tumour example a dose of >65 Gy is needed to control visible
control probability with the same late effects as epithelial tumours, whereas the dose needed to
conventional fractionation. It delivers a larger control microscopic disease is 60–65 Gy and 50–60 Gy
number of smaller than conventional dose for subclinical disease.
fractions per day and the total dose is 10–20%
higher than standard fractionation while total The aim of radiotherapy is to deliver a dose of
treatment time remains the same. It is useful for radiation to destroy the tumour without leading to
tumours with slow growth. serious normal tissue complications. Therapeutic ratio
is used to represent this concept where it is the ratio
• Accelerated hyperfractionation – combines the of the tumour control probability (TCP) and normal
principles of hyperfractionation and accelerated tissue complication probability (NTCP) at a specified
fractionation. level of response (usually <5% or 0.05) for normal
• Continuous accelerated hyperfractionation tissue.
(CHART) – treatment is given as 1.5 Gy per The probability of tumour control without normal
fraction, three times daily 6 hours apart for 12 tissue complications is highest in the therapeutic
continuous days. Proved to improve local control window. The further the NTCP curve to the right of
in lung cancer. the TCP (see Figure 3.11) cure it is easier to achieve a
• Hypofractionation – delivers more than 2 Gy per tumour control with minimal toxicity (A) and a larger
fractions and less than five fractions per week. therapeutic ratio. When NTCP and TCP (C) get closer
the therapeutic ratio gets smaller.
In practical radiotherapy a better therapeutic ratio
treatment. Hence it is important to ensure that can be achieved by:
treatment delivery is within the tolerance limit • Advanced treatment planning (3D, IMRT or IGRT)
of accepted variation from the planning. The • Accurate target localization which helps to reduce
safety margins
accepted tolerance generally depends on the
• Sophisticated dose delivery
immobilization method; e.g. a variation of
<5 mm is acceptable with Perspex. The accuracy
of planned treatment can be verified by:
Box 3.12: Verification of treatment (Figure 3.12)
• Verification of treatment position before DRR (Figure 3.12A) is used to verify treatment
treatment using simulator – the simulator accuracy. This is commonly done by comparison of
X-rays are compared with DRRs for accuracy DRR with the treatment verification film (Figure
3.12B). The treatment set-up is checked by comparing
in terms of isocentre and comparison of bony the position of isocentre, bony landmarks and the
landmarks if feasible and comparison of indi- positions of MLCs or beam shaping block for the
vidual fields (Box 3.12). same beams. If a systemic error is found during
verification, it needs to be corrected before
• Verification of treatment during treatment proceeding with further treatment and the corrected
with portal imaging – a comparison is made treatment plan should be verified for accuracy of
with DRR to assess the position of isocentre treatment set-up.
in at least two views (anterior and posterior),
position of beam in relation to bony or other
visible landmarks (Box 3.12) and shape of During the process of verification two types of
individual fields. errors in treatment set up can occur:
• Real time verification of treatment with cor- • Systemic Σ – error between planning and
rection for variation is the back bone of image treatment. This needs correction before pro-
guided radiotherapy. ceeding with further treatment.
26
 PRINCIPLES OF RADIOTHERAPY 3
100 100
‘Radiosensitive’ tumour
90 A TCP 90 Standard tumour
80 C NTCP 80 ‘Radioresistant’ tumour
Tumour control without
70 70 normal tissue complications
Tumour control (%)

Complications (%)
Normal tissue complication
60 60
50 50
40 40
30 30
20 20
10 10
Accepted complication rate
0
0 10 20 30 40 50 60 70 80 90 100

Dose (Gy)
Figure 3.11
TCP and NTCP (see Box 3.11).

Figure 3.12
A&B, Verification of
treatment.

B
A

• Random ∂ – variations and uncertainties that and check blood counts. Studies have shown that
arise between each fraction of treatment. It is during radical radiotherapy of head and neck,
difficult to correct this error as this does not lung, oesophageal and cervical cancer, it is
occur consistently. important to maintain a haemoglobin level of
During determination of PTV, these errors are >12 gm/dl (a level lower than this may result in
taken into consideration to add a margin to PTV. 10–12% less chance of disease control). The
The suggested margin is 2.5 Σ + 0.7∂. importance of level of haemoglobin is less clear
in other cancers. However, symptomatic anaemia
Supportive care during radiotherapy needs to be corrected. It is also important to
It is important to follow up patients regularly make sure that the blood counts remains safe (i.e.
during radiotherapy to assess and manage radio- platelet count of >100 × 109/dL and neutrophil
therapy toxicities, to monitor nutritional status count of >1.5 × 109/dL) during radiotherapy
27
 I BASIC PRINCIPLES OF CANCER MANAGEMENT

especially when it is given concurrently with In the long term, there are a number of side
chemotherapy or when a significant amount of effects needing special attention. Patients receiv-
bone marrow bearing area is being irradiated. ing radiotherapy to whole or part of the brain
Blood counts below the safe threshold necessitate are at risk of cognitive impairment, cerebrovas-
either withholding chemotherapy or suspending cular accidents, hormonal deficiency and second
chemotherapy until the blood count recovers. cancer (p. 58, late effects). Radiotherapy to the
chest is associated with increased risk of second
Treatment modifications cancer and radiation damage to heart, particu-
larly in patients receiving radiotherapy for left
during treatment
breast cancer. Pelvic radiotherapy often results in
Gap correction menopause and infertility in women and sexual
One of the common situations is an interruption dysfunction and infertility in men. Radiotherapy
during radiotherapy due to holidays, non-attend- induced or promoted second cancer is an impor-
ance or intolerable toxicity. This might need tant survivorship issue. After cancer treatment,
modification of treatment. Studies have shown people often face an array of challenges including
that tumours exhibit accelerated repopulation psycho-social functioning and economic well-
during radiotherapy. Accelerated repopulation being. As physicians, our triumph is not just in
implies an increase in multiplication of cancer curing or controlling cancer, but also in helping
cells which often starts with partial shrinkage cancer survivors to lead a high quality life in the
of tumour after radiotherapy or chemotherapy. society. For a detailed discussion on cancer sur-
Prolonged interruption of radiotherapy results in vivorship, see p. 58.
decreasing efficacy of radiotherapy due to accel-
erated repopulation. Using modelling analysis, an Advances in radiotherapy
increase of total treatment duration by 1 day may
reduce local control by 1.4%. Hence attempts Based on experimental studies, there is a direct
should be made to avoid prolongation of overall correlation between the radiation dose and
treatment. Still, occasionally treatment gets pro- chances of control of cancer, though not linear.
longed, when adjustment should be made to com- However, various uncertainties in the radiother-
plete the treatment in the planned overall time by: apy planning process often lead to a large treat-
ment volume (see Box 3.6). Advances in
• delivering twice daily fractions, at a minimum radiotherapy are aimed at understanding and
of a 6-hour interval controlling these uncertainties in radiotherapy
• treating over the weekend planning. By doing so, we will be able to give
• use of biologically equivalent dose in fewer a much higher dose to the tumour and areas
fractions to achieve planned overall time. of possible spread with minimal dose to the
If treatment still cannot be completed within surrounding normal organs. The areas under
the planned overall time additional fractions may research include advanced immobilization,
be considered. A rough estimate is an additional improved radiotherapy with image guidance and
dose of 0.6 Gy per every day of increase in incorporation of molecular imaging for tumour
overall treatment time. volume delineation.

Care after radiotherapy Measures to improve efficacy

and survivorship of radiotherapy
Some patients have persistent acute radiotherapy Various measures are being studied to improve
side effects up to 3 months after completion of the efficacy of radiotherapy. These include alter-
radiotherapy. Management of these side effects native fractionations (Box 3.10), use of radio-
is multidisciplinary, involving a number of therapy with concurrent chemotherapy, radiation
healthcare professionals including an oncologist, sensitizers and recently, biological agents. The
nurse specialists, therapeutic radiographers, die- examples of alternative fractionation proven to
tician and speech and language therapists (SALT). improve tumour control include CHART for
28
 PRINCIPLES OF RADIOTHERAPY 3
non-small cell lung cancer, 6 fractions per week tumour oxygenation, decreased vessel density,
in head and neck cancer and radiosurgery. increased tumour cell loss and radiosensitiza-
Concurrent chemotherapy is proven to have a tion of endothelial cells. Examples of anti-
role in the primary management of oesophageal, angiogenesis inhibitors under study include
cervical and anal cancers (see corresponding bevacizumab and thalidomide.
chapters). Chemotherapy improves local control
by tumour kill as well as acting as a radiation Re-irradiation
sensitizer.
With more effective systemic treatment, the
Biological agents overall life expectancy of cancer patients is
Based on the current evidence, radiotherapy (as increasing. This often results in recurrence of
well as chemotherapy) causes logarithmic kill of disease with symptoms (such as bone pain, cough
cancer cells and as we know a logarithmic kill etc.) at a previously irradiated site. The conven-
does not end in zero cells, but in at least one cell. tional thinking has been that a heavily irradiated
To achieve permanent tumour control, this last tissue will not tolerate further treatment.
tumour cell which is capable of producing a However, recent data suggest that re-irradiation
recurrence (so called tumour rescuing unit or is often possible. Modern techniques help in re-
clonogenic tumour cell) must be killed. Clinical irradiation with optimal sparing of critical struc-
use of radiotherapy is based on inactivation of tures. Examples are re-irradiation for head and
clonogenic cells. Addition of biological agents is neck tumours with spinal cord sparing and
thought to improve the radiation effect as well re-irradiation with radiosurgery or partial brain
as cause a direct tumour kill. The following radiotherapy after whole brain radiotherapy for
biological agents are being studied as radiation recurrent brain metastasis.
modulators:
• Inhibitors of epidermal growth factor recep-
Future directions
tor (EGFR) – EGFR is expressed in solid Progress in radiotherapy is driven by advances in
tumours such as head and neck squamous cell computer technology. In contrast to the advances
cancer, glioblastoma and non-small cell lung in chemotherapy, based on a structured evalua-
cancer. Overexpression of EGFR is associated tion of efficacy and side effects of new drugs,
with poor prognosis and radioresistance. advances in radiotherapy are often based on
Hence EGFR inhibition is thought to improve technological safety for clinical use rather than
radiosensitivity and these agents also have a its proven clinical benefit compared with the
direct cell kill effect. An example of success existing method of radiotherapy delivery. A
of such a combination is a recently reported better physical dose distribution of radiotherapy
randomized study of radiotherapy with or delivery is often a surrogate measure of clinical
without cetuximab (an EGFR inhibitor) in benefit of a new technology. However, just a
locally advanced head and neck cancer which good radiotherapy plan itself is not capable of
has shown that addition of cetuximab delivering a better clinical result. Hence it is
improves local control (median duration of important in future to critically evaluate the true
24.4 months vs. 14.9 months p = 0.005) and clinical benefits of very costly technological
median survival (49 months vs. 29.3 months advances compared with the existing less costly
p = 0.03). Cetuximab is also being studied in alternatives.
lung cancer.
• Anti-angiogenesis inhibitors – anti-angiogen- Further reading
esis molecules have an indirect cell kill effect. Barrett A, Dobbs J, Morris SL, Roques T. Practical
They are also thought to modify radiation Radiotherapy Planning, 4th Edition. London: Hodder
effect by various mechanisms such as improved Arnold, 2009.

29
 Principles of systemic
therapy
HM Hatcher
4
Introduction Chemotherapy
Systemic therapies form the basis for medical Chemotherapy involves the treatment with cyto-
oncology and a significant amount of clinical toxic chemicals to kill cancer cells. Its benefit
oncology in the UK. The description is broad and depends upon the high proliferation rate of
can be thought to include any treatment which cancer cells compared with the non cancer cells
is given to a patient which will be absorbed sys- in the body. The discovery of nitrogen mustard
temically and could potentially affect the whole and its effects on proliferating cells was discov-
body. Traditionally this would be thought to be ered in both World Wars, but only put into prac-
chemotherapy but the definition also includes tice to treat leukaemias and lymphomas in the
hormonal treatments, chemical adjuncts, immu- 1940s (Figure 4.1). Later that decade aminop-
notherapy, biological agents and systemic radio- terin was shown to induce remissions in leukae-
therapy treatments. Each will be discussed and mia, although the majority of patients relapsed
examples given with reference to the appropriate and died. In the following 10 years different
chapters for more detail. classes of chemotherapeutic agents were discov-
This chapter gives an overview of the practical ered. Most of these were directed against DNA
aspects of various systemic therapies (Box 4.1). synthesis or cell division. In the 1970s cytotoxic
A detailed pharmacological discussion is beyond agents were seen to impact significantly on the
the scope of this book but further reading is sug- cure of specific cancers such as testicular cancer
gested for those interested. and leukaemia (Box 4.5). This improvement in
survival was due not only to the development of
Aim of systemic treatment new drugs but also to the understanding of how
Before recommending or prescribing a systemic to combine them.
treatment the aim of the treatment has to be
understood (Box 4.2). This, in addition to a
knowledge of the specific disease and treatments Classes of chemotherapy drugs
that are effective for that tumour, will dictate the Chemotherapy agents are divided into different
type of treatment offered and its likely intensity categories according to their mechanism of
(Box 4.3). Treatment intensity should be greatest action. The rationale behind chemotherapy is
in those conditions where the intention is cure, to inhibit or kill rapidly dividing cancer cells.
and there is some evidence in certain tumours This may be due to the drug acting at a par-
(e.g. bone tumours) that increased toxicity during ticular point in the cell cycle (cell cycle-specific)
chemotherapy is related to improved survival. or is independent of the cell cycle (cell cycle-
When the treatment is not curative significant non specific) (Figure 4.2). Boxes 4.6 and 4.7
toxicity is unacceptable. give examples of different classes of drugs in
In acute leukaemias the curative chemother- each of these categories with some specific
apy is given in various phases (Box 4.4). examples.
30 © 2011, Elsevier Ltd
DOI: 10.1016/B978-0-7234-3458-0.00009-9
 PRINCIPLES OF SYSTEMIC THERAPY 4

Box 4.1: Types of systemic treatments Box 4.4: Phases of chemotherapy treatment in
• Chemotherapy (single agent or in combination) haematologic malignancies (p. 310)
• Targeted treatments: Induction
• hormonal treatments e.g. tamoxifen, arimidex, Initial intense chemotherapy designed to rapidly
goserelin reduce tumour burden and aim for remission.
• antibodies e.g. rituximab, cetuximab Consolidation
• small molecules e.g. imatinib, erlotinib Continued treatment to reduce the tumour burden
further to the point of remission where no tumour
• Other agents:
cells are detectable.
• bisphosphonates, e.g. pamidronate, zoledronic
acid Maintenance
• immunological agents, e.g. interleukin-2, Ongoing lower dose treatment to maintain remission.
interferon Evidence from ALL studies show improved survival
with prolonged low-dose chemotherapy and
intrathecal methotrexate (p. 310).

Box 4.2: Aim of systemic treatment

Curative Discovery of nitrogen mustards
Chemotherapy is given as the definitive treatment for 1940s
in world wars
cure, e.g. acute leukaemia, choriocarcinoma.
Adjuvant Use of aminopterin in leukaemias
Treatment is given after a definitive treatment such 1950s
to induce temporary remission
as surgery or radiotherapy with the aim of destroying
micrometastatic residual disease, and thereby
increasing the chances of cure, e.g. chemotherapy Combination chemotherapy
after surgery for breast cancer. 1970–1980s cures some cancers e.g.
leukaemia, testicular tumours
Neoadjuvant
A treatment is given before a definitive treatment
such as surgery to facilitate the procedure and/or Combination chemotherapy
improve chances of cure, e.g. chemotherapy is given Late 1980s significantly improves survival
to patients with osteosarcoma prior to resection and e.g. osteosarcoma, breast cancer
replacement with prosthesis. This has the benefit of
assessing pathological response to chemotherapy
such that adjuvant chemotherapy can be modified if First targeted antibody,
necessary. 1997 Rituximab, is highly effective in
B cell lymphomas
Palliative
A treatment is given to improve the quality of life
and symptoms of a patient without the intention of Targeted treatments expand to
cure. It may prolong the life of the individual but this include (1) the small molecule
is not necessarily the case. Quality of life is the prime (tyrosine kinase inhibitor)
assessment. imatinib for CML and then GIST
2000s
(2) Herceptin (trastuzumab)
for breast cancer (3) Use of
adjuncts improves outlook e.g.
bisphosphonates in breast cancer
Box 4.3: Dose intensity and dose density
Dose intensity refers to the total amount of drug Figure 4.1
delivered to the patient over a week. This may be
Milestones in the development of systemic therapy for
given as a single bolus or in a number of treatments
over a few weeks but intensity reflects the actual cancer.
average dose per week. Maintaining the intended
dose intensity (as prescribed on the chart) has been
shown to be important in the survival of certain How does chemotherapy work?
types of cancers (e.g. breast cancer). In those patients
whose treatment was delayed or dose reduced Tumour cells are detectable by conventional
(resulting in reduced intensity) relapses occurred means at 109 cells (equivalent to 1 g tumour or
more frequently. 1 cm tumour) and continue to grow without
Dose density refers to the method of giving a drug treatment. Patients usually die if they remain
in small repeated amounts frequently rather than as
a single high dose less often. untreated or after unsuccessful treatment when
the tumour load reaches 1012 cells. When a
31
 I BASIC PRINCIPLES OF CANCER MANAGEMENT

Box 4.5: Examples of tumours in which Box 4.6: Cell cycle specific chemotherapy drugs
chemotherapy has a significant impact
Antimetabolites S phase e.g.
Cured with chemotherapy
methotraxate,
• Childhood acute leukaemia capecitabine
• Testicular cancer Vinca alkaloids M phase e.g. vincristine,
• Ovarian germ cell tumours vinorelbine
Taxanes M phase e.g. paclitaxel,
• Choriocarcinoma
docetaxel
• Wilms’ tumour Epipodophyllotoxins G2, S, e.g. etoposide
premitotic,
Associated with improved survival
topo II
• Breast cancer Camptothecans S phase, e.g. irinotecan,
• Osteosarcoma topo I topotecan
• Ewing’s sarcoma
• Ovarian cancer
• And several others

Box 4.7: Cell cycle non-specific

chemotherapy drugs

Antitumour e.g. doxorubicin, mitomycin-C

Antitumour antibiotics
antibiotics
Alkylating agents e.g. ifosfamide, chlorambucil
Antimetabolites Nitrosoureas e.g. lomustine, carmustine

S
(2–6h) G2 Vinca alkaloids
(2–32h)
tumours receive additional courses of chemother-
M Mitotic inhibitors
(0.5–2h) apy to bring down the number of tumour cells to
an absolute minimum. However this does not
Taxoids necessarily result in complete removal of tumour
Alkylating agents
cells at the end of chemotherapy and it is believed
that the normal body immunosurveillance will
G1 help to achieve a cure in some instances. In some
(2-∞h) patients, cancer can grow back at any point of
time (relapse) during the conventionally undetec-
G0 table phase (see Box 4.8). In some other patients,
Figure 4.2 the tumours do not respond to chemotherapy
Cell cycle showing phases of cell replication and division. (resistance to treatment) which requires change
Cancer cells progress rapidly through this but may be of treatment (Figure 4.3).
inhibited at various points.
Rationale for combining
chemotherapy agents
chemotherapy regime is given to a sensitive In clinical practice cancer cells tend to develop
tumour it causes cell death in a proportion of the resistance to a single drug by further gene muta-
cancer cells (log kill). In a chemo-sensitive tumour, tions, or development of cellular pumps which
each course of chemotherapy (see Box 4.9) results reduce the dose of drug received by the tumour
in a proportional cell kill and with a few courses cells. Consequently the tumour will have a period
of chemotherapy, tumour may not be detectable of sensitivity followed by a rebound tumour
by conventional means (called complete response regrowth. This may be partly due to the fact that
to treatment). At this point there is a possibility not all tumour cells are passing through the same
of <109 cells remaining and stopping treatment at point of the cell cycle at the same time. Combin-
this point may lead to an early progression/relapse ing drugs allows the oncologist to direct agents
of disease. Hence patients with chemo-sensitive with different activities or against different parts
32
 PRINCIPLES OF SYSTEMIC THERAPY 4

1012 Resistant to treatment Death

Chemo
Chemo Progression, (tumour burden
Chemo relapse of 1–4 × 1012 cells)

Chemo
109
Detectable cancer
No of cancer cells

(tumour burden
of 109 cells equal to
Chemo 1 gm or 1 cm tumour)

Cancer not
detectable by
conventional means
(less than 109 cells)

Carcinogenesis Cure
Point of clinical diagnosis
Time 0 Start Rx 3 weeks 6 weeks 9 weeks 12 weeks
Figure 4.3
Cancer growth and response to treatment.

Box 4.8: Why not give treatment more often to With G-CSF No G-CSF
prevent tumour regrowth?
Neutrophils (x109/L)

Unfortunately giving treatment at an increased

frequency (or intensity) also increases the toxicity of
the treatment. Although some regimens have been
able to achieve increased dose frequency with
additional drugs to support the patient (e.g. use of 0.5
granulocyte-colony stimulating factor [G-CSF] to
avoid life-threatening neutropenic sepsis).
Figure 4.4 shows response of the bone marrow to
chemotherapy after chemotherapy given on day 1.
Neutrophils fall to their minimum between days 10 7 14 21
and 14 in a standard 21-day cycle. If G-CSF is given
the neutrophils may not drop to such a low number. Day of chemotherapy cycle
Figure 4.4
Neutrophil response during a cycle of chemotherapy.

of the cell cycle simultaneously. The idea is that

this increases cell kill at the time of each treat- Actions of specific drug classes
ment but also reduces the development of drug (Figure 4.6)
resistance. Cell cycle phase specific drugs act on cells within
Planning a combination chemotherapy regimen a particular phase of the cell cycle.
requires some knowledge of the mechanisms of
action of the individual drugs, their dosing for Antimetabolites
particular cancers and their toxicities (see Box These drugs are developed to mimic naturally
4.10). produced metabolites, purines, pyrimidines or
33
 I BASIC PRINCIPLES OF CANCER MANAGEMENT

Box 4.9: Cycles of chemotherapy Box 4.10: How do you decide which drugs to
combine for a given cancer?
What is a cycle?
A cycle is a complete treatment from the first day of • Activity and scheduling: Each drug must have
one cycle to the first day of the second cycle. For shown activity for that type of cancer when given
many regimens this means a 3 or 4 week period of as a single agent and be given in a similar
time (depending on the dose determining toxicity scheduling and dosing (synergistic activity).
and its recovery period). Over that time drugs may all • Mechanism of action: Ideally the drugs should
be given on day 1 only or can be given at several have different, complementary mechanisms of
time points in those few weeks. action (a measure to prevent resistance).
How many cycles of chemotherapy? • Toxicities: The toxicities of the drugs should also
be different to minimize overall toxicity.
For curative treatment, further cycles of
chemotherapy are needed after a conventional e.g. Combination of gemcitabine and carboplatin in
clinical response, to tackle the clinically undetectable lung cancer:
tumour burden (Figure 4.3). Hence the amount of Activities and scheduling
chemotherapy may vary from a few cycles to months
• Carboplatin and gemticabine – each has a single
to years depending on the specific cancer (e.g. acute
agent response of ≤20% in lung cancer and is
lymphatic leukaemia needs more than a year of
given 3-weekly.
chemotherapy, whereas in choriocarcinoma two more
courses of chemotherapy is given after a complete Mechanism of action (Figure 4.5)
tumour marker response). • Carboplatin (cell cycle non-specific) act by forming
For many adjuvant treatments, traditionally 6 cycles DNA adducts which prevents DNA synthesis
of chemotherapy are given. (e.g. breast cancer • Gemcitabine (cell cycle specific) – pyramidine
usually 6–8 courses of chemotherapy depending on antimetabolite
the regime).
In palliative treatments it is important to assess Toxicity
response (usually after 2–3 courses of chemotherapy) • Carboplatin: dose limiting toxicity is
before continuing with treatment but if responding thrombocypenia
patients may continue for up to 6 (to 8) cycles • Gemcitabine: dose limiting toxicity is neutropenia
depending on toxicity and the drugs involved. Combination of carboplatin and gemcitabine results
The concept of a cycle does not fit with certain in 30–50% response rate and the dose limiting
therapies such as hormonal treatments or with toxicity is thrombocytopenia.
tyrosine kinase inhibitors as these drugs are
continued for a finite number of years or until
progression.
Gemcitabine

S
folates essential to the synthesis of nucleic acids (2–6h)
G2
and DNA (S phase) preventing the correct incor-
poration of purines or pyrimidines in the DNA M
structure. They therefore prevent DNA replica-
tion and lead to cell death. They are most effec-
tive against tumours with a high growth fraction Carboplatin
and similarly have predominant toxicities on
normal tissues with high cell turn over (e.g. G1
mucosal epithelium and gastrointestinal tract).
Examples are methotrexate, cytosine arabino-
side, capecitabine, gemcitabine and 5-fluorour- G0
acil (5-FU). Figure 4.5
Rationale for the combination of gemcitabine and
Vinca alkaloids and taxanes carboplatin.
Either derived from plant alkaloids or synthetic
derivatives of them, they interfere with mitotic spindle of dividing cells. Taxanes cause mitotic
spindle assembly in M phase causing metaphase arrest by forming abnormal spindle fibres. One
arrest. Vinca alkaloids are extracts of the peri- of the common toxicities of these agents is
winkle plant. They bind to microtubular proteins peripheral neutropathy. Examples are vincristine
which are essential to the formation of the mitotic and paclitaxel.
34
 PRINCIPLES OF SYSTEMIC THERAPY 4
Purine synthesis Pyramidine synthesis
Box 4.11: Sanctuary sites

6-Mercaptopurine Systemic treatments by definition are thought to act

6-Thioguanine Ribonucleotides at all areas of the body via the bloodstream.
However there are areas which have been referred to
Methotrexate as sanctuary sites as traditionally chemotherapy is not
5-Fluorouracil thought to access them via the bloodstream. These
Hydroxyurea are the central nervous system and the testes. The
Deoxyribonucleotides
central nervous system is separated by tight junctions
Cytarabine from the cerebral vasculature such that most drugs
Alkylating agents do not cross the blood–brain barrier. For this reason
DNA disease in this area often has to be treated directly
Antibiotics
by the intrathecal route or using radiotherapy. Some
Etoposide
fat soluble drugs e.g. nitrosoureas are thought to be
able to cross this barrier. It is also possible that in
RNA advanced disease where the vasculature is abnormal
and friable that many drugs will be able to enter the
brain even if not lipid soluble.
Proteins L-asparaginase
The testes are also a sanctuary site such that
testicular biopsies may be performed to assess
involvement in acute leukaemia and in testicular
Enzymes Microtubules Vinca alkaloids
Taxoids tumours, the cancerous testicle needs to be removed
even after intensive chemotherapy.
Figure 4.6
Sites of action of various chemotherapeutic agents.

icities include mucositis and myelosuppression.

Epipodophyllotoxins Examples are epirubicin and bleomycin.
A plant derived compound (from the mandrake Alkylating agents
plant) which acts at several parts of the cell cycle.
They prevent entry into G1/2 and the S phase but These bind to DNA adding alkyl groups to the
also have activity on topoisomerase II. Topoi- cancer cells which results in cross-linking and
somerases are the enzymes responsible for main- strand breakage of the DNA with destruction of
taining the topology of DNA. Common toxicity the DNA template. Destruction of the DNA tem-
is myelosuppression. An example is etoposide plate stops replication and leads to cell lysis.
(VP-16). Examples are chlorambucil and platinums such
as cisplatin and carboplatin.
Camptothecans
Nitrosoureas
This group inhibit topoisomerase I, a nuclear
enzyme responsible for maintaining nuclear Nitrosoureas are lipid soluble alkylating agents
structure, which interferes with both transcrip- which also destroy DNA preventing any further
tion and replication of DNA by preventing DNA DNA synthesis. Due to their lipid solubility
supercoiling. They act in S phase. Their name is they can cross the blood–brain barrier into
derived from the tree Camptotheca acuminata. the CNS (see Box 4.11) and are used in several
Examples are irinotecan and topotecan. CNS protocols. Examples are lomustine and
Cell cycle phase non-specific drugs act at any carmustine.
point in the cell cycle. Delivery of chemotherapy
Antitumour antibiotics Consent
This group of drugs interfere with DNA-directed Prior to the prescribing and administration of
RNA synthesis by intercalating between the base chemotherapy, a definite histological diagnosis
pairs of DNA and generating toxic oxygen-free (exceptions include germ cell tumours and chorio­
radicals, causing single or double stranded carcinoma where elevated tumour markers in the
breaks. Most of these drugs are isolated from a appropriate clinical setting is sufficient) and
number of Streptomyces bacteria. Common tox- informed consent is necessary. Informed consent
35
 I BASIC PRINCIPLES OF CANCER MANAGEMENT

Box 4.12: What do your patients want to know

is obtained after detailed discussion of benefits
about their systemic treatment? and side effects of the treatment (Box 4.12).
• The intended benefits (improvement in survival or
symptoms)
Prescribing chemotherapy
• Names of the drugs Prescribing and reviewing chemotherapy charts
• Major and frequent side effects is an important role of an oncologist. Many hos-
• What to do and who to call with problems and pitals now have charts which have preprinted
when chemotherapeutic and supportive drugs on the
• How the drugs will be given (oral, IV bolus, IV charts (Figure 4.7) which require only a dose
infusion)
calculation, patient details and test results to be
• How long it will take to give the drugs
added. Others have electronic systems with that
• How often will they have treatment and for how
many cycles
information included. Some of these charts are
• When they need to come back to hospital for very simple with all supportive drugs included.
treatment and for an appointment In some hospitals however the entire chart has
to be written by hand and safety checks are

Oncology Centre: Chemotherapy Prescription Chart Carboplatin

DATE: Dose Modifications/Other Addressograph or

Instructions:
Hb Neuts Wt Name:
WBC Serum Creat SA Date of Birth:
Platelets Cr/Cl or EDTA Height Hosp Number:
Cockcroft formula - please complete to show workings: Calvert formula:
Male: [1.25 x (140-age) x weight (kg)] = Female: [1.05 x (140-age) x weight (kg)] = Dose (mg) for AUC5 =
Serum creatinine (µmol/l) Serum creatinine (µmol/l) (EDTA GFR (ml/min) + 25) x 5 = Performance status 0 1 2 3 4

Consultant:

Cycle 1 of 6 ALLERGIES: Ward/Dept:

Date PREMEDICATION Dose Route Rate Special Instructions Drs sig Time Check Admin

Ondansetron 8mg po Stat ≥ 30 mins pre chemo

Dexamethasone 8mg po Stat ≥ 30 mins pre chemo

Date CYTOTOXIC DRUGS Dose Route Rate Volume Special Instructions OP Pharm Batch Number Start Time Admin
Cyto Pharm Date Stop Time Check

Day 1

Carboplatin AUC 5/6/7 mg IV 30 mins 500ml

5% Dextrose

Date TTO’s Dose Route Freq Instructions Instructions continued

Domperidone 20mg po QDS PRN for 5 days post chemotherapy

Ondansetron 8mg po OM For 5 days post chemotherapy

NB: Next cycle due in 21 days

Figure 4.7
A sample chemotherapy prescription chart.
36
 PRINCIPLES OF SYSTEMIC THERAPY 4

Box 4.13: Pre-prescribing chemotherapy checks Box 4.14: Prescribing carboplatin: AUC and
the Calvert formula
• Is the allergy box filled in and does it contain
anything which causes concern for the The required dose is calculated by the following
chemotherapy or supportive drugs? formula:
• Is this the correct chart for that treatment? Dose = AUC × (GFR + 25)
• Is the performance status appropriate for the type where AUC is the area under the curve. It refers to
and intent of treatment? increasing dosages which have an increasing effect
• Are the height and weight accurate and up to until the effect plateaus and any increase in dose
date? results only in increased toxicity. In general AUC
• Is the body surface area correct? (Have your own values are in the range 5–7 in adults but up to 9 in
calculator or check on a computer). children.
• Has the baseline imaging been performed and the
mid treatment imaging booked to allow
assessment of response?
• Has a GFR been performed (for drugs such as
carboplatin, ifosfamide)?
dose for an individual, but for most drugs the use
• Has a MUGA been performed (for anthracyclines
of surface area calculations continue.
and herceptin)? Does the next MUGA need to be Some drugs are not metabolized in the same
booked? way. Carboplatin is the classical example of
• Has the patient previously received a similar drug this type of drug. During the original phase I
which limits the dose and (e.g. anthracyclines) has
the cumulative dose been recorded?
studies the dose limiting toxicity of carboplatin
• Are the appropriate blood results available and was thrombocytopenia. However, unlike other
are they in the correct range for the drugs being drugs, there appeared to be no relationship
given? Has there been a significant deterioration between the dose administered according to mg/
in a blood result which could be attributable to
one of the chemotherapy drugs? m2 and the degree of thrombocytopenia. It was
• Does the dose need modifying on the next cycle known that carboplatin is excreted almost
due to toxicity? (you may only know this after entirely by the kidney and Calvert and colleagues
reviewing the patient). then realized that the drug’s toxicity was related
• Does the patient have significant co-morbidities to the glomerular filtration rate (GFR). This gave
which due to the toxicities of the chemotherapy
may require dose reduction? rise to the Calvert formula which is used to pre-
scribe carboplatin (Box 4.14). It requires knowl-
edge of the GFR, ideally calculated by nuclear
medicine scan.
Some recent drugs, especially the small mole-
especially important in that case. Before the chart cules such as the tyrosine kinase inhibitor, imat-
is written, given that chemotherapy is toxic, a inib, are given as a standard dose which is the
number of calculations and checks have to be same for all patients. For imatinib the standard
made. These are summarized in Box 4.13. dose is 400 mg per day.
Chemotherapy is generally calculated based
on the surface area of an individual. This is an Routes of chemotherapy administration
historic phenomenon based on the extrapolation Systemic treatments can be given by a number of
of doses administered to animals (given as dose routes. Chemotherapy is usually given intrave-
per surface area) in preclinical models. However nously (IV) but some drugs can be given orally
the initial human surface area calculations were and some as both IV and orally. For some intra-
based on hemi-body moulds created from wrap- venous drugs there are several ways to administer
ping brown paper around a small number of it. For example, 5-fluorouracil (5-FU) can be
cadavers some of whom were children. In addi- given as a daily bolus for 5 days every 3 weeks
tion many other drugs are given to adults in a (Mayo regimen) or as a 48 hour continuous
flat (or standard) dosing such as paracetamol. infusion every 2 weeks (modified de Gramont)
Some studies suggest that giving everyone the (p. 165). This drug needs prolonged or repeated
dose calculated for the average surface area of exposure as it acts in S phase but these two
1.7 m2 was as effective as calculating the specific methods produce different toxicity profiles with
37
 I BASIC PRINCIPLES OF CANCER MANAGEMENT

the Mayo regimen producing more significant monitored. It also allows the clinician to record
stomatitis and myelosuppression whereas modi- dates of future scans which can be reviewed prior
fied de Gramont produces significant palmo- to further treatment. Toxicity should be scored
planter erythema. Although many clinicians according to an internationally accepted system
believe the two methods to be equally effective, such as the National Cancer Institute Common
randomized trials have not been performed for Toxicity Criteria and Adverse Events version 3
all cancer types so that some oncologists will only (NCI CTCAE v3) which can be found at: http://
prescribe the method used in the original trials. www.fda.gov/cder/cancer/toxicityframe.htm.
Some drugs can also given either intrathecally
Dose adjustment
(Box 4.15 and Figure 4.8) or via the intraperi-
toneal route (Box 4.16 and Figure 4.9). Although supportive drugs to minimize side
More recent drugs again have a range of effects are usually given prophylactically signifi-
administration routes from intravenous, e.g. cant toxicity can occur. Initially the aim would
monoclonal antibodies, to subcutaneous, e.g. be to change or add to the supportive drugs to
vaccines, to oral, e.g. tyrosine kinase inhibitors. reduce toxicity, e.g. different or additional anti-
Patients often prefer an oral route of administra- emetics for nausea control, or use of G-CSF to
tion or a short intravenous infusion to minimize prevent neutropenic sepsis. If the toxicity has
their time in the hospital but they need to under-
stand that toxicities from oral drugs (e.g. capecit-
abine) can be as great as those from intravenous Ommaya reservoir tap
drugs and that oral chemotherapy is not a ‘gentle
option’. Scalp Syringe
Toxicity recording Brain
Needle
In order to minimize side effects and to evaluate Reservoir tap
how changes in treatment have affected these
side effects or the patient’s symptoms due to the
cancer, accurate recordings of drug toxicity (Box
Cerebrospinal
4.17) must be made. Ideally this should be fluid
recorded on a flow chart so that progress can be

Box 4.15: Intrathecal (IT) chemotherapy.

WARNING – this route can be hazardous!
Drugs delivered directly into the CSF via the
intrathecal route can be used to prevent or treat
meningeal disease. Prophylactic treatment is given
commonly in ALL and in high grade lymphomas likely Figure 4.8
to involve CNS. Ommaya reservoir.
It can be given via lumbar puncture or a central
reservoir (Ommaya reservoir) placed by a
neurosurgeon in the ventricles.
Extreme care must be taken to prevent Box 4.16: Intraperitoneal chemotherapy
administration of a drug not licensed for intrathecal Surgical placement of a catheter directly into the
administration as this can be, and has been, fatal. peritoneum to administer chemotherapy via the
Strict policies should therefore be adhered to and IT peritoneal fluid has been used in several
chemotherapy should not be given on the same day malignancies, notably ovarian cancer and
as intravenous chemotherapy. mesothelioma. It allows for large concentrations of
Drugs safe to give intrathecally: drugs to be placed in close contact with peritoneal
• Methotrexate metastases. Much lower concentrations will also enter
the bloodstream. It has shown to be effective in
• Cytosine arabinoside ovarian cancer but is associated with increased
• Thiotepa toxicity (both systemic and local) and abdominal pain.

38
 PRINCIPLES OF SYSTEMIC THERAPY 4

Box 4.17: Chemotherapy toxicities

Acute toxicities are those which occur within a
treatment cycle in contrast to late effects which can
occur many years later and are covered in (p. 58).
Each drug will have its own specific acute toxicities
but the following are common to many classes of
drugs:
• Nausea and vomiting: tend to occur within hours
or days of the chemotherapy but should be
controlled with appropriate anti-emetics.
• Diarrhoea and constipation: can occur due to
chemotherapy, e.g. diarrhoea after ifosfamide or
due to anti-emetics, e.g. constipation with 5HT3
antagonists such as ondansetron.
• Mucositis: inflammation of the gastrointestinal
tract is common with some antimetabolites and
anthracyclines. It tends to peak the week after day
1 of treatment.
• Myelosuppression causing anaemia or
Port neutropaenia is common to many classes of
chemotherapy. It usually occurs 7–10 days after
treatment but in some drugs such as nitrosoureas
it occurs later (3–4 weeks) which accounts for the
longer treatment cycle.
Chemotherapy
drugs • Infection: is a common source of morbidity for
chemotherapy patients but the risks should be
Peritoneal minimized by avoiding treating with neutrophil
cavity counts which are too low. Dental assessment
Catheter should also be made before treatment to reduce
the risk of oral sepsis and invasive dental
procedures should be avoided during
chemotherapy. Infection risk is greatest 7–15 days
after treatment but can occur at any time which is
why fever in a patient on chemotherapy should
always be taken seriously.
• Fatigue: a common side effect of many treatments
Figure 4.9 which tends to become more significant over the
Diagram to show intraperitoneal port and catheter. course of a treatment. It can occur at any time in
the cycle but tends to be worse within the first
few days of treatment. Patients given steroids as
part of their antiemetics can experience increased
fatigue the day after the steroids stop.
been significant, such that it has not resolved • Hair loss: is common with many (but not all)
drugs. It starts within two weeks of the first
with adjustment of supportive drugs, a dose treatment so wig referrals should be made before
reduction should be made. For example recur- treatment to best match hair colour and style.
rent neutropaenic sepsis which occurs even after Alternative is use of scalp cooling which only
works for selected chemotherapy regimes.
prophylactic G-CSF requires dose reduction. For
• Taste change: is very common and can add to
clinical trials there will also be specific instances problems with appetite.
when this should occur and the protocol must When consenting patients, do not forget the late
be followed in this case. In general, a reduction effects (p. 58) as these can be significant. Figure 4.10
of 20–25% is made but this depends on the gives an example of a toxicity chart.
drugs being given, whether all or only one of
them is likely to be the cause. It also depends
on the intended outcome of the treatment and However if the patient has suffered a life-threat-
the likely effect that dose reduction will have on ening infection associated with the treatment,
the outcome. For example it is known that the the risk of death as a complication of continuing
survival benefit from adjuvant chemotherapy the same dose of treatment may be greater than
can be reduced by a reduction in dose intensity. that of recurrence of the cancer.
39
 I BASIC PRINCIPLES OF CANCER MANAGEMENT

Toxicity chart
Trial name:
Treatment protocol: Date: Cycle:

Toxicity: 0 1 2 3 4 0 1 2 3 4
Performance status Neuropathy
Fatigue Stomatitis (oral)
Nausea/vomiting Alopecia
Diarrhoea Cardiac
Constipation Bilirubin
Haematological (max) ALT

Transfusions since last Plts Blood pressure

cycle (units) Red cells Height (if myeloma)
Days in hospital Weight
Days on IV antibiotics Days on antifungals

Figure 4.10
Example of a toxicity chart.

Complementary therapy interactions cific to the cancer, whereas others have broader
Many patients, especially with advanced cancer, actions.
take additional treatments or complementary
therapies. Each hospital has a different policy Hormone treatments (Table 4.1)
about whether patients are allowed to take com- The observation that breast cancer can regress
plementary medicines alongside their chemother- after oophorectomy and that prostate cancer can
apy. However it is important to take a full history be controlled by orchidectomy suggested that
of these and ensure that certain complementary some cancers may be hormone sensitive. Since
treatments which can interact with chemother- the observation that surgical measures to reduce
apy or other drugs. A specific example is St hormone levels were effective, drugs were devel-
John’s wort which many patients take for mild oped which would achieve a similar effect. In the
depression. It is metabolized by the cytochrome 1990s dramatic improvements in breast cancer
p450 isoenzymes, especially CYP 3A4 and can survival were seen with the introduction of the
significantly interfere with the doses of several anti-oestrogen, tamoxifen, to women with oes-
systemic treatments including etoposide and the trogen receptor positive breast cancer. This led
tyrosine kinase inhibitor, imatinib. to the developments of other drugs which target
the production of oestrogen (such as the aro-
Other classes of matase inhibitors) as well as examining the role
of hormone treatments in other hormone sensi-
systemic therapy tive cancers such as prostate cancer. These are
Although chemotherapy has been the mainstay discussed in more detail in the breast and pros-
of systemic therapy, the development of alterna- tate chapters (Chapters 10 and 12). In general
tive methods of treatment has occurred in the last these treatments are taken for many years to
20 years, many of which have made significant prevent recurrence or control the disease and
improvements in survival. Some of these have can be effective without chemotherapy. In fact
been developed against a particular target spe- there is evidence to suggest that they should not
40
 PRINCIPLES OF SYSTEMIC THERAPY 4

Table 4.1: Medical hormone treatments

Example Mechanism of action
Breast cancer
Anti-oestrogen Tamoxifen Binds with oestrogen receptor
Aromatase inhibitors Arimidex, exemestane Inhibits peripheral conversion of androgens to oestrogens
by the enzyme aromatase
Prostate cancer
LHRH antagonists Goserelin Negative feedback inhibition of LH from pituitary which
decreases testosterone from testis
Corticosteroid Hydrocortisone Suppression of adrenal androgen production

be given alongside chemotherapy, particularly Other antibodies have been developed with a
for anti-oestrogen therapies in breast cancer as wider range of action such as bevacizumab which
it is thought that these cytostatic agents (e.g. targets the vascular endothelial growth factor
tamoxifen) causes cell cycle arrest preventing the receptor. This has shown some improvement in
action of chemotherapy which is dependent on survival in several cancers, which are covered in
rapidly dividing cells for its action. appropriate chapters. The toxicities of these
drugs are different to cytotoxics with allergic
Bisphosphonates reaction being one of the most significant.
Bisphosphonates represent a good example of an
adjunct in the treatment of cancer. These agents Immune therapy
were originally developed to treat osteoporosis In addition to antibodies, which may be consid-
but have been shown to be active in stabilizing ered an immune treatment, there are also a group
bony metastases in a number of malignancies and of drugs which act by modifying the immune
have also been shown to reduce visceral metas- response of the host (patient) in general, rather
tases in breast cancer. The exact mechanism for than targeting a specific molecule or receptor.
this latter activity is unknown. They can be given Examples in this group include interferons
intravenously or orally. Examples include pamid- and interleukins. High dose interferon has been
ronate and zoledronic acid. used in melanoma (p. 235) and interleukin-2 has
some efficacy in renal cell carcinoma (p. 176).
Antibodies Interferon and interleukin both produce systemic
Antibodies are immunoglobulins produced by side effects of an immune response which resem-
plasma B cells in response to antigens. Several ble a viral infection, e.g. fever, fatigue, myalgia
tumour cells express specific antigens which are and headache.
not produced by normal cells and these have been
the target for the development of monoclonal Small molecules
antibodies to these specific antigens. To date the Small molecules are drugs developed with a
most successful drugs in this class are rituximab specific target, usually to a cellular pathway or
and transtuzumab. Rituximab is directed against molecule within that pathway. Examples include
CD20 found on B cells and the addition of tyrosine kinase inhibitors (TKIs) and mTOR
rituximab to standard chemotherapy for B cell inhibitors. TKIs can be specific to a particular
lymphomas has significantly improved survival. tyrosine kinase, e.g. imatinib, or may have activ-
Transtuzumab has been developed to target the ity across a number of kinases, e.g. sunitinib.
HER-2 receptor which is found in 25% of breast Figure 4.11 shows an example of a tyrosine kinase
cancers. Initially used in metastatic disease but signalling pathway using c-KIT. Once the recep-
then in the adjuvant setting for women with tor is bound it sets off a cascade leading to further
HER-2 receptor positive breast cancer, this has cell proliferation. Some of the cascade steps are
also seen a significant improvement in survival. common to pathways involved in many cancers
41
 I BASIC PRINCIPLES OF CANCER MANAGEMENT

such that effective inhibitors to one protein could However for some tumours or in the adjuvant
be useful drugs in a range of cancers. setting RECIST terms may not adequately
describe response. In adjuvant treatment where
Systemic radiotherapy the aim is to cure, the overall survival and some-
In general radiotherapy is directed against a spe- times the progression free survival are the key
cific site in the body. Generally a radioisotope indicators of success. For clinical trials this may
scan is done to assess the uptake by the specific take many years to assess so sometimes other
tumour prior to giving definitive radioablative indicators are used. These include pathological
dose (for example, see p. 282). Doses can be response for tumours such as bone tumours or
repeated several times but there is a risk of late breast cancer in whom the patients have been
myelodysplastic syndromes. given neoadjuvant treatment. The degree of cell
necrosis or pathological response reflects progno-
Assessment of response sis in these groups. For gastrointestinal stromal
tumours which have been treated with a targeted
to treatment treatment, imatinib, the response assessed by
Systemic treatments are often given to treat meta- RECIST criteria may not reflect the true response.
static disease or neoadjuvantly prior to surgery. For these tumours, and other sarcomas there may
In these cases an assessment needs to be made not be an obvious reduction in the size of the
to ensure that the treatment is effective (Figure tumour, and yet the patient feels better. Radio-
4.12) so that an alternative treatment may be logically this is usually accompanied by a change
considered and to avoid inappropriate toxicity. in the density of the tumour becoming more
Most often this assessment is made radiologically cystic and less dense. For gastrointestinal stromal
(e.g. by CT or MRI) by Response Evaluation tumours new criteria (Choi criteria) have been
Criteria in Solid Tumours (RECIST) criteria applied to these tumours to take these changes
(Boxes 4.18 and 4.19, Table 4.2). An under- into account (p. 263).
standing of these terms is necessary in the man- In addition, particularly in the context of clini-
agement of all cancers, even if alternative means cal trials the term Clinical Benefit is used. This
of assessment may also be used (e.g. see section takes into account not only the obvious CR and
on gastrointestinal stromal tumours, p. 261). PR RECIST responses but also those tumours

Figure 4.11
Receptor C–KIT
Simplified diagram to show signalling
pathway of the tyrosine kinase c-KIT
and the cascade that follows once
Cell membrane the receptor is bound. Targets are
being developed to several proteins
Cytoplasm along this pathway including raf,
Tyrosine kinase 1 SHP2 MEK, P13K and AKT.

Tyrosine kinase 2 GRB2 SOS Ras

Shc

P13K JAK2 Lyn

Raf

AKT STAT

Inhibition of apoptosis Proliferation pp90rsk ERK MEK

42
 PRINCIPLES OF SYSTEMIC THERAPY 4

A B

Figure 4.12
CT scan showing a large recurrent uterine sarcoma prior to chemotherapy (A) and after 6 cycles of treatment
demonstrating a complete response (B). The patient went on to have radical radiotherapy and remains free of disease
6 years later.

Box 4.18: Definition of lesions for RECIST Box 4.19: Confirmation of response by
evaluation RECIST criteria
• Measurable lesions – lesions that can be accurately • The main goal of confirmation of objective
measured in at least one dimension with longest response is to avoid overestimating the response
diameter ≥20 mm using conventional techniques rate observed. In cases where confirmation of
or ≥10 mm with spiral CT scan. response is not feasible, it should be made clear
• Non-measurable lesions – all other lesions, when reporting the outcome of such studies that
including small lesions (longest diameter <20 mm the responses are not confirmed.
with conventional techniques or <10 mm with • To be assigned a status of PR or CR, changes in
spiral CT scan), e.g. bone lesions, leptomeningeal tumour measurements must be confirmed by
disease, ascites, pleural/pericardial effusion. repeat assessments that should be performed no
less than 4 weeks after the criteria for response
are first met. Longer intervals as determined by
the study protocol may also be appropriate.

which may be stable by RECIST, but treatment

has also been associated with an improvement in
symptoms. For palliative treatments this is clearly Box 4.20: The future of systemic therapies
important. • Finding new targeted molecules especially for
those cancers with few treatments.

The future of systemic • Finding the best way to assess response for new
therapies.
treatments (Box 4.20) • Learning the best way to combine new therapies
either with other new agents or with
This chapter has highlighted the growth and chemotherapy.
growing diversity of systemic treatments for
cancer from early fortuitous discoveries of chem-
otherapeutic agents to the idea of targeted treat- combine drugs, e.g. cytotoxic with a small mol-
ments. The future of systemic therapies lies in the ecule or a number of targeted small molecules
development of more specific and less toxic drugs, without chemotherapy. This, along with the
and the methods to best assess them. It also changing arena of clinical trials, represents one of
remains to be discovered how is the best way to the great challenges for the future oncologist.
43
 I BASIC PRINCIPLES OF CANCER MANAGEMENT

Table 4.2: RECIST response criteria

Evaluation of target lesions
Complete response (CR): Disappearance of all target lesions
Partial response (PR): At least a 30% decrease in the sum of the longest diameter (LD) of target lesions,
taking as reference the baseline sum LD
Progressive disease (PD): At least a 20% increase in the sum of the LD of target lesions, taking as reference
the smallest sum LD recorded since the treatment started or the appearance of one
or more new lesions
Stable disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for
PD, taking as reference the smallest sum LD since the treatment started

Evaluation of non-target lesions

Complete response (CR): Disappearance of all non-target lesions and normalization of tumour marker level
Incomplete response/ Persistence of one or more non-target lesion(s) or/and maintenance of tumour
stable disease (SD): marker level above the normal limits
Progressive disease (PD): Appearance of one or more new lesions and/or unequivocal progression of existing
non-target lesions

Further reading Brighton D, Wood M (eds). The Royal Marsden Hospital

Book of Cancer Chemotherapy. Edinburgh: Elsevier,
Eisenhauer EA, Therasse P, Bogaerts J, et al. New response 2005.
evaluation criteria in solid tumours: Revised RECIST Arkenau H, Carden C and De Bono S. Targeted agents in
guideline (version 1.1). Eur J Cancer 2009;45:228–247. cancer therapy. Medicine 2007;36(1):33–37.

44
Cancer genetics
E Copson
5
Introduction Inheritance of two alleles each carrying a
mutation within the same tumour suppression
The last two decades have seen rapid expansion gene is extremely rare and can result in a differ-
in our understanding of the genetic origins of ent and more severe phenotype than monoallelic
cancers. Between 5–10% of cancers are due to mutation inheritance. For example, inheritance
inheritance of alterations in genes that confer a of one BRCA2 mutation from a single parent is
high life-time risk of certain malignancies, such associated with breast/ovarian cancer whilst bial-
as breast, colorectal cancer (see Table 5.1), and lelic BRCA2 mutations are a cause of Fanconi’s
very rare tumours. anaemia.
Most of these so-called ‘hereditary cancer pre-
disposition syndromes’ are due to mutations
within a single allele (copy) of a tumour suppres- Diagnosis
sor gene inherited in an autosomal dominant A hereditary predisposition towards developing
fashion. malignancy is characterized by young age at
presentation, an increased incidence of bilateral
Mechanisms of inherited cancer tumours, more than one primary tumour site and
Tumorigenesis involves contributions from two a family history of specific cancers. The first step
classes of genes. Oncogenes control cell growth requires a detailed family history containing all
and proliferation under normal circumstances, maternal and paternal cases of malignant disease,
but once inappropriately activated or overex- with particular emphasis on age of onset and the
pressed can promote rapid clonal expansion. site of the primary tumour. Wherever possible,
Tumour suppressor genes normally inhibit verification of these diagnoses should be gained
abnormal cell proliferation; reduced expression from pathology records.
of these genes can result in uncontrolled cell Analysis of DNA for mutations in known
division. Almost all hereditary cancer predisposi- cancer predisposition genes is performed in a
tion syndromes are due to the inheritance of a limited number of specialist molecular genetics
germline mutation in a tumour suppressor gene. laboratories using DNA derived from a periph-
The inherited mutation inactivates one copy of eral blood sample. The gold standard is direct
the gene and the subsequent development of a sequencing of the whole gene but this is generally
mutation in the remaining ‘normal’ copy of the not commercially viable for very large genes such
gene results in failure of a cell to produce the as BRCA1/2. Screening for pathogenic mutations
tumour suppressor protein (Knudson ‘two-hit’ is therefore often limited to analysis of coding
hypothesis – see Figure 5.1). regions only, or regions of the genes which carry
The concept of heritable cancer predisposition the greatest density of reported mutations. Addi-
was originally developed from observations of an tional tests are required to detect gene deletions.
earlier age of onset of retinoblastoma in patients A full screen for unknown mutations will take
with a positive family history. several weeks to process. ‘Predictive testing’, in

© 2011, Elsevier Ltd 45

DOI: 10.1016/B978-0-7234-3458-0.00010-5
 I BASIC PRINCIPLES OF CANCER MANAGEMENT

Table 5.1: The risk of common cancers associated with inherited cancer syndromes
Genes associated with
Tumour site relative risk of >5.0 Cancer syndrome
Breast BRCA1/2 Hereditary breast/ovarian cancer syndrome
TP53 Li–Fraumeni syndrome
PTEN Cowden syndrome
CDH1 Hereditary diffuse gastric cancer syndrome
STK11 Peutz–Jeghers syndrome
Colorectal APC Familial adenomatous polyposis
MUTYH
MLH1 Lynch syndrome (hereditary non-polyposis colon cancer)
MSH2
MSH6
PMS2
Pancreatic BRCA2 Hereditary breast/ovarian cancer syndrome
BRCA1
MSH2 Lynch syndrome (hereditary non-polyposis colon cancer)
MLH1
STK11 Peutz–Jeghers syndrome
TP53 Li–Fraumeni syndrome
PRSS1 Hereditary pancreatitis
SPINK1 Familial atypical mole malignant melanoma syndrome (FAMMM)
CDKN2A
Prostate BRCA2 Hereditary breast/ovarian cancer syndrome
Endometrial MLH1 Hereditary non-polyposis colon cancer
MSH2
MSH6
PMS2
Ovarian BRCA1/2 Hereditary breast/ovarian cancer syndrome
MLH1 Lynch syndrome
MSH2

which genetic testing is directed at establishing cancer predisposition syndrome receives expert
whether or not an individual has a specific muta- counselling prior to testing and on receiving
tion carried by another family member, is faster. their result. Patients must be advised that failure
to detect a mutation does not always mean
that no mutation is present and that further results
Genetic counselling may become available in the future when genetic
It is essential that any individual considering testing may become more sophisticated. The roles
undergoing genetic screening for an inherited of genetic counselling are summarized in Box 5.1.
46
 CANCER GENETICS 5
One parent carrying Figure 5.1
mutation in tumour Comparison of tumourigenesis
suppressor gene pathways in carriers and non-
carriers of a mutation in a tumour
Tumourigenesis suppressor gene – the Knudson
Non-carrier “sporadic” ‘two hit theory’.

“1st hit” “2nd hit”

2nd parent with

normal tumour Tumourigenesis
suppressor gene Mutation carrier “inherited”

Box 5.1: The roles of the genetic counsellor Box 5.2: Women at increased risk of breast
cancer
• Explaining the difference between sporadic and
inherited cancer risk. Women are generally considered to be at increased
• Facilitating the documentation of a detailed risk of breast cancer if they have:
family history. • One close relative diagnosed with breast cancer
• Explaining alternative options to genetic testing, under the age of 40, or
i.e. approximation of personal risk on basis of • Two close relatives (in same blood line) diagnosed
family history. under the age of 50, or
• Explaining the risk of passing on a mutation to • Three or more close relatives diagnosed at any
offspring. age
• Identifying the most appropriate family member
to undergo genetic testing.
• Ensuring individuals understand the implications
of a positive finding of a mutation in a cancer condition (Box 5.2). Approximately 5% of all
predisposition gene result, including current
recommendations for screening and prophylactic breast cancer cases are thought to be due to
interventions. highly penetrant autosomal dominant cancer
• Ensuring individuals understand the implications predisposition syndromes (Figure 5.2). The two
of a negative result, including population most frequent highly penetrant breast cancer sus-
screening for common cancers.
ceptibility genes are BRCA1 and BRCA2 where
• Ensuring individuals understand the implications
of an ambiguous result. in some families lifetime penetrance for breast
• Helping to communicate test results to other cancer can reach 80% but penetrance is clearly
members of the family. modified by other genetic and environmental
• Ensuring individuals understand that genetic factors. Much rarer syndromes including Li–
testing may result in discrimination by insurance Fraumeni, Cowden, Peutz–Jeghers and heredi-
companies.
tary diffuse gastric cancer (HDGC) syndromes
• Focusing on family health.
can be recognized either by other clinical mani-
festations or by the pattern of cancers in the
family (Table 5.2). Lifetime breast cancer risk for
The remainder of this chapter will look in
carriers of these mutations is in the order of
more detail at inherited breast and colorectal
20–100%. It is likely that most familial clusters
cancer, and the most common cancer predisposi-
of breast cancer are the consequence of multiple
tion syndromes.
low penetrance cancer susceptibility genes acting
in conjunction with environmental factors.
Inherited breast cancer Within the last few years a number of large case-
Studies indicate that 20–30% of breast cancer control studies have identified variants in DNA
patients report a positive family history of this repair genes (e.g. CHEK2, ATM, BRIP1 and
47
 I BASIC PRINCIPLES OF CANCER MANAGEMENT

Figure 5.2
No family history of breast The importance of inherited factors in
cancer (sporadic) the aetiology of breast cancer.

Unidentified genetic factors

Low penetrance genetic

variants

Moderately penetrant genetic

variants e.g. CHEK2, ATM

Highly penetrant hereditary

cancer syndrome
e.g. BRCA1/2, Li Fraumeni

Table 5.2: Cancer predisposition syndromes associated with an increased risk of breast cancer
Clinical syndrome Gene Population frequency Breast cancer risk Other component tumours
Hereditary breast BRCA1 1 : 1000 40–80% Ovarian
cancer lifetime risk
Hereditary breast BRCA2 1 : 750 40–80% Ovarian
cancer lifetime risk Prostate
Pancreatic
Li–Fraumeni TP53 <400 families 30–60% Sarcoma
worldwide by age 45 Brain tumours
Adrenocortical tumours
Leukaemia
Cowden PTEN 1: 300,000 25–50% Thyroid
lifetime risk Endometrial

Peutz–Jeghers LKB1/ 1 : 8900–1 : 280,000 30–55% Colon

STK11 lifetime risk Small bowel
Pancreatic
Ovarian
HDGC CDH1 Unknown 20–40% Gastric
lifetime risk Colorectal
Ataxia ATM 1 : 250 RR 2.3 Leukaemia
Telangiectasia Lymphoma
(homozygotes)

PALB2), which double the risk of breast cancer. Genetics and pathology
The population prevalence of these variants BRCA1 and BRCA2 act as classical tumour sup-
seems to be in the order of 1–5%. pressor genes; inheritance of mutations occurs in
Hereditary breast/ovarian cancer an autosomal dominant fashion and loss of the
unmutated allele is found in tumour specimens.
syndrome
The precise functions of the BRCA1 and BRCA2
Clinical features gene products remain unclear but evidence indi-
See Table 5.3. cates that these proteins are involved in DNA
48
 CANCER GENETICS 5

Table 5.3: Clinical features of BRCA1 and BRCA2 hereditary breast/ovarian cancer syndrome
Feature BRCA1 BRCA2
Gene locus Chromosome 17 Chromosome 13
Population frequency 1 in 400 1 in 400
Increased to 1 in 50 in Ashkenazi Jews Increased to 1 in 50 in Ashkenazi
Jews
Inheritance Autosomal dominant Autosomal dominant
Lifetime risk of breast cancer 40–80% 40–80%
(females)
Pathological features of breast Typically high grade with lymphocytic No typical phenotype
tumours infiltrate and pushing tumour margins,
ER, PR, HER-2 negative
Lifetime risk of ovarian cancer 40–60% 10–20%
Other associated tumours Pancreatic Male breast cancer
Pancreatic
Prostate

repair and transcription regulation, with addi- Box 5.3: Clinical features indicative of a possible
tional roles in cell cycle checkpoint control and underlying BRCA1/2 mutation in breast cancer
cytokinesis. Sporadic breast cancers do not patients
contain BRCA1 mutations and very rarely dem- • Young age at diagnosis (<35 years)
onstrate BRCA2. • Strong family history of breast cancer, e.g.
• 2 first degree relatives with breast cancer, with
Diagnosis average age at diagnosis <50 years
A number of scoring systems exist to estimate the • ≥3 first or second degree relatives with breast
cancer, diagnosed an average age of <60
likelihood of a family carrying BRCA1 or BRCA2
• Family history of breast and ovarian cancer
mutations, e.g. the Gail model. Most cancer
• Family history of male breast cancer
genetic units recommend screening for BRCA 1/2
• Askenazi Jewish ethnicity
mutations if the chance of carrying a mutation is
• Bilateral breast cancer (if first diagnosed at <50
estimated at more than 20%. Oncologists should years)
consider the possibility of an underlying BRCA1/2 • (High grade ER/PR/HER2 negative tumour)*
mutation in breast cancer patients with the clini-
cal features listed in Box 5.3. *BRCA1 only.

Both BRCA1 and BRCA2 are extremely large

genes but screening of all coding regions of the
BRCA1 and BRCA2 genes for nonsense muta- the most effective preventative measure, reducing
tions can be done within 8 weeks, whilst predic- the risk of breast cancer by up to 90%. More
tive testing for known mutations can be acceptable to many women is prophylactic
accomplished within a week. Pre-natal and pre- oophorectomy which reduces breast cancer rates
implantation genetic diagnosis is now available. by 60% and ovarian cancer rates by 95%. The
Over 20% of BRCA1 and BRCA2 screens iden- use of chemoprevention with tamoxifen remains
tify missense mutations. controversial.
Primary prevention Secondary prevention
For individuals with known BRCA1 or BRCA2 Regular breast screening by mammography,
mutations, prophylactic double mastectomy is together with clinical breast examinations, has
49
 I BASIC PRINCIPLES OF CANCER MANAGEMENT

Known family history of Clinical features suggestive of

BRCA1/2 mutations inherited breast/ovarian cancer

Refer to cancer genetics unit

Genetic counselling

Predictive genetic testing for Testing for BRCA1/2 Declines testing for
known BRCA1/2 mutation mutation BRCA1/2 mutation

Mutation not present BRCA1/2 mutation No BRCA1/2 mutation

identified identified

Enter breast screening Further Consider testing for Offer breast cancer
as per general population genetic counselling other hereditary screening as appropriate
cancer syndromes for family history

Commence annual Consider prophylactic risk Consider prophylactic Consider

breast screening reducing mastectomy bilateral salpingo- screening for
oophorectomy ovarian cancer**

Cancer Offer predictive genetic Consider clinical trials

detected testing to family members of chemoprevention

Standard management
of breast cancer /
clinical trials

** See text

Figure 5.3
Algorithm for management of potential BRCA1/2 mutation carrier.

been recommended for all patients with known Treatment of BRCA associated breast cancer
BRCA1 or BRCA2 mutations for some years. The management of potential BRCA1/2 muta-
The 2006 National Institute for Health and Clin- tion carriers is summarised in Figure 5.3 and
ical Excellence (NICE) guidelines for the man- discussed in Chapter 10 on breast cancer.
agement of familial breast cancer include a
recommendation for annual MRI surveillance of
all BRCA1/2 mutation carriers aged 30–49 as
Inherited colorectal cancer
this method of screening has proved more sensi- Approximately 5% of cases of colorectal cancer
tive then mammography. Screening for ovarian are due to an underlying hereditary cancer syn-
cancer remains under investigation. drome, with an increased representation amongst
50
 CANCER GENETICS 5

Box 5.4: Clinical features suggesting underlying

young colorectal cancer patients. Any features
inherited predisposition to colorectal cancer* listed in Box 5.4 should raise the suspicion of a
• Early age onset (<50 years) colorectal cancer or familial colorectal cancer syndrome.
endometrial cancer Most familial cases are due to either hereditary
• Multiple colorectal carcinomas or >10 non-polyposis colon cancer (HNPCC), also
adenomatous polyps in same individual known as Lynch syndrome, which accounts for
• Individual with an HNPCC related tumour who has an estimated 2–3% of all colorectal cancers
either:
• ≥ One 1st degree relative with an HNPCC-
or familial adenomatous polyposis coli (FAP),
related cancer at <50 years which accounts for less than 1% of all colorectal
OR cancers. The key features of these two syndromes
• ≥ Two 1st or 2nd degree relatives with an are summarized in Table 5.4.
HNPCC-related cancer at any age In addition, an increased risk of gastrointesti-
• History of multiple HNPCC related tumours in nal cancer is also observed in Peutz–Jeghers syn-
same individual
drome, caused by the inheritance of mutations in
• Family with known cancer predisposition
syndrome
STK11.

* See Table 5.4 for HNPCC related cancers. Familial adenomatous polyposis
Clinical features
FAP is characterized by the development of
hundreds of colonic adenomatous polyps by the

Table 5.4: Clinical features of FAP and Lynch syndrome

Clinical syndrome Familial adenomatous polyposis (FAP) Lynch syndrome
Incidence 1 in 8000 1 in 1700
Clinical features Extensive gastrointestinal High risk of early onset colon cancer associated
adenomatous polyps from young with elevated risk of distinct spectrum of
age with extremely high rate of extra-colonic tumours.
malignant transformation.
Risk of colon cancer Almost 100% by age 40 70–90%
80% by age 70 in ‘attenuated FAP’
Extra-colonic tumours Desmoid tumours (12–17%) Endometrial carcinoma (30–60%)
Upper gastrointestinal carcinomas Ovarian carcinoma (9%)
(3–5%) Stomach (19%)
Osteomas Duodenum
Thyroid carcinomas Pancreas
Hepato-pancreatic tumours Urological (18%)
Brain
Sebaceous adenomas/carcinomas
Inheritance Autosomal dominant Autosomal dominant
Genes APC hMLH1
hMSH2
hMSH6
Pathogenesis Activation of Wnt pathway and Defective DNA mismatch repair
chromosomal instability (see text)
Pathological features Adenomatous polyposis Microsatellite instability

51
 I BASIC PRINCIPLES OF CANCER MANAGEMENT

age of 20, with a risk of malignant transforma- Secondary prevention

tion of almost 100%. The average age of diag- Long-term surveillance of the small intestine by
nosis of colon cancer is 39 years. Patients are upper endoscopy, starting from age 25–30 years,
also at increased risk of other tumours listed in is also required as peri-ampullary carcinoma is
Table 5.4. the commonest cause of death in FAP patients
who have undergone prophylactic colectomy.
Genetics and pathology Regular abdominal examination and/ or imaging
In more than 90% of FAP cases mutations are should also be considered it there is a family
found within the APC gene on chromosome 5. history of desmoids or hepatoblastoma.
Loss of the APC protein results in chromosomal
instability due to loss of cytoskeleton control and Hereditary non-polyposis
activation of the Wnt pathway which promotes colorectal cancer
tumorigenesis. Clinical features
Diagnosis HNPCC is a hereditary cancer syndrome consist-
ing of a high risk of early onset colorectal cancer
A clinical diagnosis of FAP can be made by flex-
with an increased frequency of endometrial,
ible sigmoidoscopy at an early age. Genetic
ovarian, gastric, duodenal, gastric and urological
screening for APC mutations is recommended
malignancies. Characteristically, the colonic
from the age of 10–12 years. Pre-natal diagnosis
tumours are predominantly right sided (70%)
and pre-implantation genetic diagnosis is avail-
and there is an increased rate of synchronous and
able for this condition.
metachronous tumours.
Primary prevention Genetics and pathology
Carriers of APC mutations should undergo sur- In up to 70% of patients with HNPCC, the
veillance colonoscopy annually from the age of underlying genetic defect is a germline mutation
10 to 15 years. Prophylactic colectomy by the age in one of three genes: hMLH1, hMSH2, hMSH6.
of 20 years is recommended for those found to These genes all encode DNA mismatch repair
have multiple adenomas on surveillance. The type proteins. Defective mismatch repair promotes
of operation performed is dependent on the malignant transformation by permitting rapid
polyp load within the rectum and the age of the accumulation of mutations in other genes, such
patient (see Table 5.5). The cyclo-oxygenase-2 as those that regulate the cell cycle.
inhibitor celecoxib and non-steroidal anti-inflam-
matory agent sulindac may both reduce duodenal Diagnosis
adenoma formation but severe duodenal polypo- The National Comprehensive Cancer Network
sis will require a Whipple’s resection. guidelines currently state that a clinical diagnosis

Table 5.5: Surgical options for patients with FAP

Age of patient and Recommended
rectal polyp load operative procedure Advantages Disadvantages
Teenagers with modest Total colectomy with Can be performed Surveillance of rectum
rectal polyp load ileorectal laparoscopically required
Older patients with low anastomosis Rapid recovery and lower May require conversion
rectal polyp load and complication rate to ileal pouch a few
attenuated polyposis Better bowel control decades later
>20 years with classic Procto colectomy Reduction of rectal Frequent defecation
FAP and high rectal with ileal pouch carcinoma risk and risk of leakage
polyp load Pelvic infection

52
 CANCER GENETICS 5

Box 5.5: Criteria for clinical diagnosis of HNPCC

advocated secondary prevention option for car-
riers of HNPCC associated gene mutations.
At least three relatives must have a tumour
associated with hereditary non-polyposis colorectal Regular upper endoscopy screening should also
cancer (see Table 5.4) + all of the following criteria be considered for HNPCC families with a history
should be present: of gastric cancer and urine cytology for patients
• One must be a first-degree relative of the other with a family history of urological tumours. All
two
other surveillance recommendations are not
• At least two successive generations must be
affected evidence-based.
• At least one of the relatives should have the Female HNPCC mutation carriers should be
relevant cancer diagnosed before the age of screened for ovarian and endometrial tumours by
50 years pelvic ultrasonography with annual transvaginal
• FAP should be excluded
measurements of endometrial thickness and/or
endometrial aspirates.
Management of colonic carcinoma
of HNPCC requires the following minimum Subtotal colectomy can be offered to HNPCC
criteria, based on the Amsterdam II criteria patients presenting with a colonic carcinoma,
(Box 5.5). because of the high rate of synchronous tumours
Analysis of tumour tissue for high microsatel- in these patients although this must be weighed
lite instability (MSI), using a panel of five or six against the functional consequences of extensive
polymorphic markers, will be positive in more colonic resection.
than 80% of patients fulfilling the Amsterdam
criteria. Patients with evidence of MSI should be Li–Fraumeni syndrome
offered genetic screening for germ line mutations
of hMLH1, hMSH2 and MSH6. Alternatively, First described in 1969, classic Li–Fraumeni syn-
immunohistochemical staining of colorectal drome (LFS), is a rare cancer susceptibility syn-
tumours for the hMLH1, hSMH2 and hSMH6 drome characterized by an autosomal dominant
proteins has been shown to be highly sensitive pattern of diverse neoplasms in children and
and specific in predicting an underlying MMR young adults with a predominance of soft tissue
gene defect. The Bethesda guidelines can be sarcomas, osteosarcoma, and breast cancer and
used to identify patients with colorectal cancer an excess of brain tumours, leukaemia, and
where there is young onset or less striking famil- adrenocortical carcinomas (see Box 5.6 for defi-
ial clustering of cancers and in whom testing nition of classic LFS). Many additional tumours
tumour samples for MSI can help direct genetic have also been reported in LFS families (see
counselling and testing since less than 15% Table 5.6).
of sporadic tumours display MSI, but the vast
majority of HNPCC related tumours show this
Genetics
phenomenon. Germline mutations of the TP53 gene (chromo-
some 17), are found in approximately 70% of
Primary prevention families meeting the criteria for classic LFS crite-
The role of prophylactic colectomy in the ria, but the detection rate drops as the criteria
management of patients with HNPCC remains become less stringent. The protein product of
controversial. Some specialists do recommend TP53 is a regulator of the cell cycle and apopto-
prophylactic hysterectomy and bilateral salp- sis. Loss of p53 results in cells with mutated
ingo-oophorectomy on completion of child-bear- DNA dividing in an uncontrolled fashion to form
ing for female carriers of HNPCC associated tumours.
gene mutations.
Incidence
Secondary prevention TP53 germline mutations have an estimated inci-
Annual colonoscopy screening from the age of dence of 1 in 5000. Penetrance is at least 50%
20–25 years is currently the most commonly by age 50.
53
 I BASIC PRINCIPLES OF CANCER MANAGEMENT

Box 5.6: Clinical features of classic LFS Diagnosis

Definition of classic LFS according to TP53 mutations can be detected by sequencing
Chompret criteria of the TP53 gene.
Proband with sarcoma, brain tumour, breast cancer
or adrenocortical carcinoma aged <36 Clinical management
+ ≥ one 1st- or 2nd-degree relative with cancer (other
than breast cancer if the proband has breast Females with a proven TP53 mutation should be
cancer) < age of 46 years screened for breast cancer according to the NICE
OR guidelines for high risk individuals, with annual
a relative with multiple primaries at any age breast MRI from age 30 (NICE recommend an
OR individualized schedule for very high risk women
a proband with multiple primary tumours, two of and it may be appropriate to start MRI as young
which are sarcoma, brain tumour, breast cancer, as 20 years in these rare cases).
and/or adrenocortical carcinoma, with the initial
cancer occurring <36 years, regardless of the family There is no clinical evidence that tumours
history in LFS patients behave differently to sporadic
OR tumours, although there has been concern
a proband with adrenocortical carcinoma at any age that LFS patients are at a particular risk of
of onset, regardless of the family history second tumours following both chemo and
radiotherapy.

Cowden syndrome
Cowden syndrome is an autosomally dominant
Table 5.6: Component tumours of classic inherited cancer predisposition syndrome charac-
Li–Fraumeni syndrome and other tumours terized by multiple hamartomas and a high risk
associated with LFS
of thyroid and breast cancers, with other tumours
Classic Li–Fraumeni Other tumours
component tumours associated with LFS also at increased frequency.
A clinical diagnosis of Cowden syndrome is
Breast carcinomas Leukaemia
Soft tissue and bone Lung currently made according to the International
sarcomas Gastrointestinal Cowden Consortium operational criteria (see
Brain tumours Ovary Table 5.7).
Childhood adrenal cortical Lymphomas
carcinoma Paediatric tumours Genetics
(Choroid plexus tumours) Melanoma
Prostate
In 80% of Cowden syndrome families, the under-
Pancreatic lying mutation is in the PTEN (protein tyrosine
(+ many others) phosphatase with homology to tensin) gene,
located on chromosome 10. PTEN encodes
a phosphatase which mediates cell growth,

Table 5.7: Criteria for clinical diagnosis of Cowden syndrome

Pathognomonic criteria Major criteria Minor criteria
Mucocutaneous lesions: Include: Include:
Facial trichilemmomas Breast carcinoma Genito-urinary tumours
Acral keratoses Thyroid carcinoma Lipomas
Papillomatous papules Endometrial carcinoma Fibromas
Mucosal lesions Macrocephaly Fibrocystic breast disease

54
 CANCER GENETICS 5
proliferation, cell cycle arrest and/ or apoptosis, tions. Pre-implantation genetic testing has been
hence acting as a tumour suppressor. performed for this condition.
Incidence Management
The incidence of Cowden syndrome is estimated Early identification of a RB1 mutation in the
to be 1 in 200,000. Inheritance of a germline child of an affected parent can permit early diag-
PTEN mutation is associated with a 25–50% nosis of retinoblastoma (with the aim of salvage
lifetime risk of breast cancer in females. of the eye), by regular fundoscopic examinations
from birth. An increased frequency of second
Clinical management tumours has been associated with irradiation.
There is currently no consensus on screening.
Individuals with known or suspected PTEN muta- Von Hippel–Lindau syndrome
tions should be referred to their local cancer
Von Hippel–Lindau (VHL) is a rare hereditary
genetics unit to seek up to date advice about
cancer syndrome consisting of haemangioblasto-
surveillance.
mas of the retina and central nervous system
(particularly cerebellar, medullary and spinal
Retinoblastoma sites), associated with phaeochromocytomas
Retinoblastoma is a rare primary malignant and clear cell renal carcinomas. It is inherited
tumour of the retina. Unilateral tumours usually in an autosomal dominant fashion. Hereditary
present before the age of 4 years (median age 18 phaeochromocytomas present earlier and are
months) whilst bilateral tumours present even more frequently multiple than sporadic phaeo-
earlier (median age 13 months). Only 5–10% of chromocytomas but are less likely to undergo
patients have a positive family history. Second malignant transformation. Renal tumours occur
primary tumours are seen in a quarter of surviv- in 25% of VHL families, presenting at a median
ing patients with hereditary retinoblastoma, age of 45 years. They are also more likely to be
occurring up to 40 years after the initial event. bilateral than sporadic renal carcinomas.
These include sarcomas, melanoma, brain
tumours, breast cancers and leukaemia. Genetics
The VHL gene is sited on chromosome 3. Muta-
Genetics tions or deletions of the VHL gene are found in
Germline mutations of the RB1 gene on chromo- virtually all clinically diagnosed VHL families
some 13 are found in over 80% of hereditary or using modern genetic diagnostic methods.
bilateral cases of retinoblastoma and are inher-
ited in an autosomal dominant fashion. The RB1
Incidence
gene encodes a protein which acts as a transcrip- VHL syndrome is estimated to affect 1 in 35,000
tion regulator, suppressing the expression of individuals.
genes required for cells to progress through the
Clinical management
cell cycle and into mitosis. Penetrance of RB1
mutations is variable and ‘skipping’ of genera- Screening for VHL tumours should be as set out
tions may be observed. in Table 5.8. Pre-natal and pre-implantation
genetic diagnosis is now available for VHL when
Incidence a mutation has been identified in a family.
Retinoblastoma is very rare, with an incidence of
1 in 20,000 births worldwide. Approximately Multiple neuroendocrine
45% of cases are hereditary.
neoplasia syndromes
Diagnosis The multiple endocrine neoplasia (MEN) syn-
Identification of mutations within the retinoblas- dromes are autosomal dominant disorders char-
toma gene is complicated by the large size of this acterized by the development of multiple benign
gene, with numerous different reported muta- and malignant tumours of endocrine glands. The
55
 I BASIC PRINCIPLES OF CANCER MANAGEMENT

Table 5.8: Onset of clinical features of VHL and recommended surveillance

Age (years) Clinical feature Surveillance
1–10 Retinal angiomas Retinal screening (from age 5)
11–20 Retinal angiomas Retinal screening
Cerebellar haemangioblastoma Consider CNS imaging
Phaeochromocytomas Urinary/plasma catecholamines
Start renal imaging by age 20
21–30 Cerebellar haemangioblastoma Consider CNS imaging
Phaeochromocytomas Urinary/plasma catecholamines
Renal cysts Renal imaging
31–40 Renal cysts Renal imaging
Renal carcinomas Consider CNS imaging
Endolymphatic sac tumours
41–50 Renal carcinomas Renal imaging

Table 5.9: Clinical features of multiple neuroendocrine neoplasia syndromes

Syndrome Component tumours Comments Genetic defect
MEN1 Parathyroid adenomas Present in up to 95% of cases Mutation in MEN1 gene,
Pancreatic islet cell tumours Present in 50–75% of cases chromosome 11.
Pituitary adenomas 25–65% of cases
Carcinoid tumours
Thyroid tumours
MEN2A Medullary thyroid carcinoma Up to 100% of cases Mutation in extracellular
Phaeochromocytoma Usually multifocal, bilateral cysteine codon of RET
Parathyroid hyperplasia 40% of cases gene, chromosome 10
10–35% of cases
MEN2B Medullary thyroid carcinoma Up to 100% of cases Mutation in tyrosine
Gangliomas Usually multifocal, bilateral kinase codon of RET
Phaeochromocytoma Up to 100% of cases gene, chromosome 10
Also 40–50% of cases
– skeletal abnormalities
– megacolon

key clinical features of MEN1, MEN2A and oncogene RET which codes for a transmembrane
MEN2B are summarized in Table 5.9. receptor tyrosine kinase. The position of the
mutation within the RET gene seems to deter-
Genetics mine whether the clinical features of MEN2A or
MEN1 is caused by mutations in the menin gene MEN2 develop.
located on chromosome 11. Menin is a tumour
suppressor gene which interacts with a number of
nuclear proteins including transcription factors. Incidence
Both MEN2A and MEN2B are associated The incidence of MEN is between 0.2–2 per
with mutations of the chromosome 10 proto- 100,000.
56
 CANCER GENETICS 5

Diagnosis hereditary cancer predisposition syndrome for

Direct mutation detection is now available for expert assessment and advice.
both the MEN and RET genes.
Acknowledgement
Clinical management With thanks to Professor Diana Eccles for her
Regular screening of individuals from MEN1 helpful comments.
families or known MEN mutation carriers should
commence before the age of 10 and should Further reading
consist of serum calcium and prolactin measure- Eng C. Will the real Cowden syndrome please stand up:
ments. Consideration should also be given to revised diagnostic criteria. J Med Genet
measurements of pituitary, parathyroid and 2000;37:828–830.
Callender GG, Rich TA, Perrier ND. Multiple endocrine
pancreatic hormones as well as imaging of the
neoplasia syndromes. Surg Clin North Am.
pituitary gland. 2008;88:863–895.
RET mutation carriers benefit from prophy- Foulkes WD. Inherited susceptibility to common cancers.
lactic thyroidectomy performed between the ages N Eng J Med 2008;359:2143–2153.
of 3 to 5 years. Screening for phaeochromocyto- Garber JE and Offit K. Hereditary cancer predisposition
syndromes. J Clin Oncol 2005;23:276–292.
mas should be performed from adulthood.
Gonzalez KD, Noltner KA, Buzin CH, Gu D, Wen-Fong CY
et al. Beyond Li Fraumeni Syndrome: clinical
Summary characteristics of families with p53 germline mutations.
J Clin Oncol. 2009;27:1250–1256.
In any oncology clinic, a patient with an inher- Guillem JG, Wood WC, Moley JF, Berchuck A, Karlan BY,
ited cancer syndrome will be a rarity. However, et al. ASCO/SSO review of current role of risk-reducing
surgery in common hereditary cancer syndromes. J Clin
identification of the correct underlying high risk
Oncol 2006;24:4642–4660.
genetic mutation can have significant conse- Kim WY and Kaelin WG. Role of VHL gene mutation in
quences for both the patient and their family by human cancer. J Clin Oncol 2004;22:4991–5004.
ensuring that the appropriate clinical interven- NCCN clinical practice guidelines in oncology: Colorectal
tions are adopted to minimize their morbidity cancer screening. www.nccn.org
NCCN clinical practice guidelines in oncology: Genetic/
from malignant disease. It is therefore essential
familial high-risk assessment: breast and ovarian.
to document a full family history for all patients www.nccn.org
presenting with cancer and to refer all patients NICE clinical guideline 41: Familial breast cancer (issue date
that do have clinical features suspicious of a October 2006). www.nice.org

57
 Late effects of cancer
treatment and survivorship
HM Hatcher
6
Introduction Medical late effects
In the UK the estimated numbers of people living Late effects are dependent upon the original
after a cancer diagnosis range from 1–1.5 million. cancer, its treatment, the family genetics and
With increasing cancer incidence and survival it the developmental stage of the individual when
is thought that this will rise to represent 1.5– treated for cancer. Box 6.1 lists some of the
2.5% of the adult population. The 5-year sur- major effects that can occur.
vival for children diagnosed with cancer is now
79% and for adult cancers is 64%. There are a Second malignancy
number of medical, psychological, social and Second malignancies are the second most
economic issues which can significantly contrib- common cause of death (after the primary cancer)
ute to a patient’s morbidity and mortality after in those diagnosed with cancer, and can either be
a diagnosis of cancer. This chapter aims to over- a solid tumour or haematological (leukaemia or
view these issues. myelodysplastic syndromes). The risk of second
malignancy is increased with combinations of
Paediatric oncology and chemotherapy and radiotherapy but is also
dependent upon the underlying genetics of the
the history of survivorship individual and the sensitivity of the tissue irradi-
The median age of diagnosis of cancer in the ated (Table 6.1).
general population is 70 years but the most sig- In general secondary solid tumours arise in
nificant increase in survival rates in the past 30 sites of previous radiotherapy, especially if chem-
years has been in the area of paediatric oncology. otherapy was also given. The total dose of radio-
Many children were treated in a clinical trial therapy delivered as well as the type and energy
such that the initial survivorship data was gained of the treatment and treated volume determine
from paediatric patients. The medical sequelae the risk. The tissues most likely to give rise to a
of cancer treatment as a child have profound secondary malignancy following radiotherapy
consequences due to the current average life are bone marrow, thyroid, breast and soft tissues
expectancy. (sarcomas) (Box 6.2).
Given the dependence of children upon their Leukaemias and myelodysplastic syndromes
parents and the developmental needs of a growing have been found to relate to previous chemo-
child some of their psychosocial survivorship therapy treatment, especially with etoposide,
issues are different to those of adults. In addition anthracyclines and alkylating agents. These leu-
the families of children treated for cancer are kaemias are characterized by a chromosomal
significantly affected and many parents or sib- abnormality at 11q23, tend to occur within 2
lings of childhood survivors suffer long-lasting years of primary treatment and have a poor prog-
psychological and social consequences even when nosis. Intensive regimens for Ewing’s sarcoma or
the clinical outcome has been good. rhabdomyosarcoma have a risk of up to 20% at
58 © 2011, Elsevier Ltd
DOI: 10.1016/B978-0-7234-3458-0.00011-7
 LATE EFFECTS OF CANCER TREATMENT AND SURVIVORSHIP 6

Box 6.1: Medical late effects of treatment Box 6.2: Learning points
• Secondary tumours are often very aggressive and
Second malignancy e.g. leukaemia, sarcoma
do not respond as well to treatment as primary
Chronic health e.g. breathlessness, fatigue
tumours of the same histology.
conditions
Cardiological e.g. arrhythmias • In Ewing’s sarcoma, radiotherapy with greater
Neurological e.g. peripheral neuropathy than 54 Gy is associated with second malignancy
Pulmonary e.g. fibrosis but treatment with less than 45 Gy is associated
Endocrine e.g. GH deficiency with local recurrence.
Fertility e.g. premature ovarian failure
Bone e.g. osteoporosis
Renal e.g. hypomagnesaemia

Example box 6.1:

A 21-year-old woman was treated for Ewing’s

sarcoma of the right pelvis with neoadjuvant
Table 6.1: The most common second chemotherapy, debulking surgery, radiotherapy and
malignancy after treatment for cancer further chemotherapy. She had a good response to
and some of the identified or proposed treatment with only a small mass remaining which
causative agents remained stable on CT scans for 5 years. With
Type of increasing symptoms of pelvic and groin pain at 8
secondary Identified or potential risk years an X-ray then MRI was performed which
malignancy factors showed a mass in the left acetabulum (Figure 6.1).
The appearance of the mass was not typical for a
Leukaemia Chemotherapy, e.g. etoposide, Ewing’s sarcoma and a biopsy was performed. The
anthracyclines pathology showed an osteosarcoma. Despite staging
showing no distant disease and treatment with
Sarcoma Radiotherapy for e.g. previous chemotherapy, the tumour progressed rapidly, lung
sarcoma or retroperitoneal metastases developed and the patient died within
lymph nodes a year.
Genetics, e.g. Li–Fraumeni,
hereditary retinoblastoma
Lung Radiotherapy especially in
smokers 30 years following treatment for Hodgkin’s
Potential risk from multiple CT disease. The increased risk of breast cancer in
scans for follow-up patients treated with mantle radiotherapy for
Breast Radiotherapy, e.g. mantle or Hodgkin’s disease led to the removal of radio-
hemithorax especially if given therapy in the treatment of the majority of cases.
in late teens or early twenties The relative risk of second malignancy is greatest
(up to 4–7 times the
when treated at a younger age at time of diagno-
standardized mortality ratio)
sis and decreases with older age at the time of
Uterine Tamoxifen (risk 1 in 100,000), treatment. In another study, the 15-year cumula-
increased in those with HNPCC
tive risk of a second malignancy was 11.2%
Colorectal Pelvic or abdominal radiotherapy overall, with the greatest number of cases in lung
Bladder Pelvic radiotherapy cancer (2.8%), leukaemia (1.5%), colorectal
Possibly some alkylating agents cancer (1.5%) and breast cancer (1.2%).
(with radiotherapy)
Infertility
Infertility as a consequence of cancer or its treat-
ment remains a significant issue for young people
who have not yet completed their families (Figure
20 years of secondary haematological malig- 6.2). The risk depends on the gender of the
nancy. Myelodysplastic syndromes have been patient and the type of therapy administered as
associated with previous alkylating agents. well as the type of cancer (Box 6.3). Overall the
The cumulative incidence of any second malig- fertility of childhood cancer survivors when com-
nancy increases with time from primary treat- pared with their siblings is 0.76 for men and 0.93
ment, e.g. from 10.6% at 20 years to 26.3% at for women.
59
 I BASIC PRINCIPLES OF CANCER MANAGEMENT

Figure 6.1
Coronal T2 weighted MRI through the pelvis showing
abnormal bony texture in the left acetabulum with an
irregular margin (arrow) in contrast to the normal right
side which shows normal marrow architecture. The left
sided mass is an osteosarcoma.

Box 6.3: Risk of infertility in cancer survivors

The greatest risk to fertility in adult survivors is
• Alkylating agents, e.g. ifosfamide
• Procarbazine
• Abdominal/pelvic radiotherapy
Figure 6.2
• Increasing age, in that women greater than 30
Result of successful pregnancy after treatment for
have an increased risk of infertility after
chemotherapy (compared with <30) but there is a cancer!
significant increase in infertility after the age of
40. For example, cyclophosphamide at 5 g/m2 can
cause amenorrhoea in women over 40 but
adolescents may continue to menstruate after
Fibrosis of the uterus can occur following
20 g/m2 pelvic radiotherapy and may cause growth
restriction of a developing foetus even if the
patient becomes pregnant.
In the UK, guidelines have been developed by Premature ovarian failure can occur in response
a working party to highlight possible manage- to pelvic (or spinal) radiotherapy or certain (but
ment strategies and risks of infertility with dif- not all) chemotherapy agents. The risk of meno-
ferent cancer treatments (Box 6.4). These are pause is associated with the type of therapy
available from the Royal College of Radiologist rather than the type of cancer. The highest risk
website (http://www.rcr.ac.uk/publications.aspx? for women is those who had radiotherapy below
PageID=149&PublicationID=269). the diaphragm combined with alkylating agents.
Infertility in men commonly occurs after High-dose treatments (including total body irra-
alkylating agents or radiotherapy to the gonadal diation) and alkylating agents will usually render
region or after total body irradiation. For this a woman infertile. Even in those cases where
reason all men who are capable of producing fertility is preserved after treatment, the timing
sperm should be offered sperm banking. Sperm of the menopause is likely to be several years
aspiration may be considered for those unable to earlier than the patient’s peers.
ejaculate e.g. pelvic Ewing’s which has affected Treatment with anthracyclines as a young
the sacral nerves. Some men will retain their fer- adult may require an echocardiogram during
tility. This can occur up to 2 years after treatment pregnancy as cardiac function may be impaired
is completed. Retrograde ejaculation can occur with increased cardiac output requirements due
in men who have had bilateral retroperitoneal to the developing foetus.
lymph node dissection e.g. following chemother- There appears to be no significant increase in
apy for a testicular tumour with residual lymph congenital abnormalities in the offspring of sur-
node masses. vivors, nor any increase in childhood cancers in
60
 LATE EFFECTS OF CANCER TREATMENT AND SURVIVORSHIP 6

Box 6.4: Fertility options for women Box 6.5: Timing of pregnancy after
cancer treatment
Currently options are limited for women who require
intensive treatment or pelvic radiotherapy and many Timing of pregnancies for women after treatment for
are costly and not provided by the NHS. Examples cancer is problematic. If the patient remains fertile
include: they will be advised to start their families earlier
• In some cases ovarian suppression with LHRH rather than later. However, as the risk of relapse
(leuteinizing hormone releasing hormone) during occurs in the first few years after treatment for most
treatment, e.g. alongside hormonal treatment for cancers, and the general advice is to wait at least 2
their breast cancer (e.g. tamoxifen) rather than years after completion of treatment. However a large
removal of the ovaries, allows preservation of study showed no increase in rates of relapse for
fertility for some women. breast cancer patients who became pregnant within
a few years of diagnosis.
• Frozen embryos can be successful but the woman
needs to be well enough to defer treatment for a Patients still on maintenance therapy such as
few weeks to complete an IVF cycle and egg tamoxifen should be advised that pregnancy is not
retrieval. Problems associated with this include the recommended whilst taking these drugs due to the
need for a long-term partner to donate sperm to risk for the developing baby.
create the embryos, which is often not the case
for younger patients. An additional problem is
that if the father later withdraws consent for
the embryos to be implanted they must be
destroyed. Box 6.6: Risk factors for hormone induced bone
loss and fracture
• Oocyte removal after an IVF cycle has also been
used, without immediately creating an embryo. • Treatment with hormone manipulation, e.g.
Frozen eggs have now given rise to a very few aromatase inhibitor or anti-androgen
pregnancies and the process is still experimental • Smoking
but the technique is improving so should be
discussed if available. • Heavy alcohol use
• Research is ongoing using extracted frozen • Family history
immature eggs which do not require the time • Bone metastases
delay of a fertility treatment cycle but have yet to • Increasing age
be proven to be a reliable option.
• Still in the experimental stages is the storage of
ovarian tissue which can later be reimplanted into
the patient after treatment.
chemotherapy such that calcium supplementa-
• Surrogacy can be considered if the woman
remains fertile but the uterus is unable to carry a
tion or bisphosphonates are frequently required
full-term pregnancy due to surgery or to prevent fractures. To minimize the risk of
radiotherapy. fractures from significant osteoporosis patients
• Egg donation may be a possibility with or without should be screened for osteoporosis prior to com-
surrogacy.
mencing hormonal treatment using a risk assess-
• Adoption can always be considered.
ment and bone mineral density scan. Patients
should be reassessed after 6–12 months on hor-
monal therapy. Those at significant risk should
the offspring, including after bone marrow trans- be advised about calcium in their diet and/or
plantation (Box 6.5). prescribed calcium supplements. At very high
risk or after a fracture, bisphosphonates (orally
Bone late effects or intravenously) should be prescribed.
Bone growth is affected by steroids, chemother- Osteoradionecrosis can occur after high-dose
apy or radiotherapy (Box 6.6). In addition hor- radiotherapy particularly to the head and neck
monal manipulation with aromatase inhibitors region. Pre-treatment dental assessment and cor-
or anti androgen therapy can have profound con- rective procedures are important in preventing
sequences on bone loss. Osteopenia occurs fre- this side effect.
quently at the end of treatment with combination Osteonecrosis is a known complication of
chemotherapy. In ER positive breast cancer treatment for leukaemia, lymphoma or bone
where patients may have chemotherapy followed marrow transplantation and is thought to be due
by an aromatase inhibitor, the hormonal treat- to high-dose steroids. It tends to occur most in
ment compounds the osteoporotic effect of the weight bearing bones e.g. femur such that arthro-
61
 I BASIC PRINCIPLES OF CANCER MANAGEMENT

plasty of the hip joint may be carried out in up neuropathies are most commonly associated with
to 20% patients with femoral head osteonecro- these drugs, especially vincristine. For cisplatin,
sis. Osteonecrosis of the jaw is a recognized com- the symptoms and signs of peripheral neuropathy
plication of treatment with zolendronic acid. can progress even after treatment has finished
Patients should see a dental surgeon prior to which highlights the importance of detecting
starting treatment and zolendronic acid should deterioration.
be stopped and further dental assessments made
if there is any suspicion of dental abscess.
Example box 6.2:
Neurological
A 17-year-old man with medulloblastoma (Figure
Neurological damage can occur either centrally 6.3A) was treated successfully with combined
to the brain itself or to the peripheral or chemo-radiotherapy followed by further
autonomic nerves depending on the tumour and chemotherapy. Although one of his presenting signs
was of unsteadiness this deteriorated significantly
treatment given. For those with CNS tumours, part way through his chemotherapy such that he was
cranial radiotherapy may be given in combina- unable to stand or walk unaided. Recurrence was
tion with chemotherapy which can produce suspected but the MRI (Figure 6.3B) showed no signs
of this but showed scarring consistent with previous
combined peripheral and central neurological radiotherapy. On examination of the nervous system,
deficits. there had been no change in the central features.
Certain chemotherapeutic agents are known However, a significant peripheral neuropathy had
developed with loss of proprioception below the
to be neurotoxic such as platinums and vinca ankles and wrists. Unfortunately, although his MRI
alkaloids. The risk is greater with increasing age, shows no evidence of recurrence 5 years later he has
particularly over the age of 50 and unless specifi- been left unable to walk out of the house unaided
and is unable to work due to his peripheral
cally assessed during treatment, the damage may neuropathy (Box 6.7).
be permanent and debilitating. Painful peripheral

A B

Figure 6.3
MRI FLAIR sequence showing medulloblastoma in right cerebellum prior to radiotherapy (A) and MRI of brain after
radiotherapy when the patient presented with worsening neurological symptoms (B).
62
 LATE EFFECTS OF CANCER TREATMENT AND SURVIVORSHIP 6

Box 6.7: Learning points Box 6.8: Examples of gastrointestinal

late effects
• Never assume a progressive neuropathy is due to
the most obvious cause. Examine all possible • Diarrhoea (increased frequency)
causes and monitor neurotoxicity throughout • Incontinence
treatment.
• Malabsorption
• Neurotoxic late effects are worse in adults and
those with more than one cause (central and • Abnormal liver function tests
peripheral). • Bacterial overgrowth
• Strictures
• Polyps
Hearing loss due to damage to the auditory • Second malignancy
nerve can occur with platinums, especially cispla-
tin, so that audiometry should be performed
prior to and after treatment. prove effective in symptomatic patients in the
Neurocognitive impairment can also occur longer term.
and the risk is greatest amongst survivors of ALL From the available literature it is difficult to
and CNS tumours. Many of these patients are make recommendations on the management and
treated at a young age so the impact of neuro- follow up of cardiac and pulmonary complica-
cognitive impairment reduces their chance of tions. It would seem prudent however to reduce
further education or employment. The effects are other known cardiac risk factors (smoking cessa-
worse in those treated under the age of 5 and in tion, and blood pressure and cholesterol control)
females. as part of the suggested lifestyle modifications
after treatment.
Gastrointestinal
Following radiotherapy to the pelvis, or abdomen, Pulmonary
acute toxicity to the bowel is well known due Long-term pulmonary toxicities are wide ranging
to inflammation of the intestinal organs. Late and account for a significant amount of morbid-
toxicity is often underestimated but accounts ity and later mortality. The types of damage
for significant morbidity (Box 6.8). Intermittent that can occur include fibrosis (from radiother-
subacute bowel obstruction also occurs. All apy or bleomycin), pneumonitis (radiotherapy,
these symptoms can have a range of causes so gemcitabine), asymptomatic abnormalities of
referral to a gastroenterologist is recommended lung function tests (radiotherapy and combina-
for appropriate investigation. Rectal bleeding in tion chemotherapy) or lung cancer (especially
particular must not be ignored as this may rep- after radiotherapy and chemotherapy in patients
resent a second malignancy, especially in those who continue to smoke). Patients given hemi-
who have had pelvic radiotherapy. thorax radiotherapy for metastatic Wilms’
tumours in childhood are at particular risk.
Cardiological
Cardiac toxicity can take several forms following Endocrine
treatment including cardiac failure, arrhythmias Endocrine abnormalities can occur in any endo-
and increased risk of myocardial infarction crine organ. The most frequently affected are
(Table 6.2). The major risk factors are mediasti- those who have received radiotherapy close to
nal or left chest wall radiotherapy, anthracyclines the pituitary or thyroid (Table 6.3). Hormonal
and vincristine. Asymptomatic arrhythmias are replacement may be necessary for these patients
common. Children treated with anthracyclines as the hormones involved have significant sys-
have reduced left ventricular wall thickness and temic functions. Abnormalities do not occur
reduced left ventricular function which can con- immediately after treatment, particularly those
tinue to deteriorate many years after treatment. from the pituitary or thyroid, so they should be
Treatment with angiotensin converting enzyme screened for starting at least 1 year post treat-
inhibitors has been shown to improve left ven- ment or earlier with symptoms. Adrenal insuffi-
tricular function in the short term but did not ciency should always be considered in patients
63
 I BASIC PRINCIPLES OF CANCER MANAGEMENT

who have received high-dose steroids, particu- cranial prophylaxis with radiotherapy and the
larly during a period of infection. high doses of corticosteroids used.
Endocrine input is essential in the assessment
of late effects in the follow-up clinic. Chronic health conditions
In addition to specific toxicities the overall health
Obesity of an individual is likely to be affected after treat-
Obesity is a significant problem for survivors of ment for cancer. Chronic health conditions can
cancer, especially those treated in childhood. The include overall health, or any of the above
risks are greatest for those treated with cranial medical conditions which have a chronic effect
radiotherapy, females and those aged 0–4 years on an individual’s health. It also includes symp-
at diagnosis. Survivors of ALL have the greatest toms of chronic fatigue which can cause limita-
risk, thought to be due to a combination of tions of everyday life and persist for many years
after treatment is complete. In a study of child-
hood survivors, chronic health conditions
occurred in almost all patients with 27.5% expe-
Table 6.2: Major cardiac problems associated riencing severe or life-threatening health effects.
with cancer treatments Multiple chronic conditions were also more fre-
Nature of cardiac quent with 37.6% experiencing at least 2 and
problem Causative agent(s) 23.8% experiencing at least three significant
Arrhythmias (many Radiotherapy, multiple co-morbidities.
asymptomatic with chemotherapy agents
impact unknown) e.g. anthracyclines,
taxanes
Causes of death after cancer
Cardiac failure Radiotherapy
treatment
Anthracyclines The main cause of death following a diagnosis of
Trastuzumab
cancer is the cancer itself even after surviving
Coronary artery disease Supra diaphragmatic over 5 years from diagnosis. After recurrence the
and myocardial radiotherapy greatest risk of death is from a second malig-
infarction Anthracyclines
Vincristine
nancy followed by pulmonary then cardiac prob-
lems. In one study the standardized mortality
Note:
hypercholesteralaemia
ratio was 19.4 for second malignancy, 8.2 for
is common after cardiac death and 9.2 for pulmonary death with
chemotherapy other causes at 3.3. The risk of death was great-
est for women, those diagnosed before age 5 and
those with an initial diagnosis of leukaemia or

Table 6.3: Overview of most common endocrine abnormalities and their cause
Endocrine organ
affected Hormones affected Causative agent
Pituitary Growth hormone Radiotherapy to brain (pituitary region)
TSH
FSH/LH
Thyroid Thyroxine Radiotherapy to neck or upper chest >15 Gy (scatter effect)
Gonads Testosterone Radiotherapy
Oestrogen Alkylating agents, radiotherapy to pelvis/TBI
Adrenals Cortisol High-dose steroids (mostly haematological malignancies)

64
 LATE EFFECTS OF CANCER TREATMENT AND SURVIVORSHIP 6
CNS tumour. Given the recent change in treat- Mental health issues must not be underesti-
ment to reduce mediastinal radiotherapy (a major mated and addressing them throughout treat-
cause of these sequelae in Hodgkin’s disease) it ment will aid with patients seeking help if
is hoped that these will reduce in the future. necessary, even many years later. Recognizing
that this is a potential problem and consequence
Psychological impact of cancer of losses associated with cancer and its treatment
allows it to be seen as a normal process which,
diagnosis and treatment like the rest of oncology supportive care, should
Following a diagnosis with cancer patients and be appropriately managed.
their families make psychological adjustments to
cope with the treatment and potential outcome. Relationships
Stress is, not surprisingly, very common and
On average cancer survivors are less likely to be
occurs in over 95% of patients. The majority of
married and have a higher incidence of divorce
these will have anxiety and mild depression
than their peers.
which may not require treatment. However
some will have more significant psychological
symptoms and needs including depression, post- Social consequences
traumatic stress disorder, suicidal ideation and When compared with age matched controls
various psychoses. cancer survivors have a lower income. They are
In survivors of childhood cancer there is a more likely to have difficulties obtaining life and
greater degree of some aspects of psychological health insurance or a mortgage after surviving
distress in the parents than in the patient them- cancer.
selves. Parents were more concerned about their
child’s health and thought more often of the Further reading
cancer and its diagnosis than the patient.
Ganz PA. Cancer survivorship. Today and Tomorrow.
Suicidal ideation and previous attempts at Springer Press. 2007. ISBN-10: 0-387-34349-0.
suicide have been shown to be present in up to Mertens A, Yasui Y, Neglia J et al. Late mortality in
12.83% of childhood cancer survivors. Stand- Five-year survivors of childhood and adolescent cancer:
ardized mortality ratios for deaths as a result of The childhood cancer survivor study. J Clin Oncol
suicide in cancer patients are in the order of 2001;13:3163–3172.
Expert guidance on fertility: The effects of cancer treatment on
1.35–2.9 compared with the general population. reproductive functions. Guidance on management. Report
Risk factors include male sex, older age, higher of a Working Party. Available from: http://www.rcr.ac.uk/
disease stage, poor prognosis, poor performance publications.aspx?PageID=149&PublicationID=269.
status, alcoholism, other psychiatric illness,
fatigue, pain, loss of function and previous or Helpful websites
family history of suicide attempts. Lack of family The USA National Action Plan for Cancer Survivorship:
or social support also correlates with increased http://www.cdc.gov/cancer/survivorship/pdf/plan.pdf
suicide risk. SEER survival data: http://seer.cancer.gov/csr/1975_2005/

65
 Palliative care
TV Ajithkumar
7
Introduction Management of pain
Palliative care is the active holistic care of patients The management of pain includes analgesics
with advanced progressive illness and includes as well as non-pharmacological measures. The
areas other than oncology. Apart from, managing World Health Organization (WHO) analgesic
pain and other symptoms, palliative care is aimed ladder (Figure 7.1) has been the gold standard in
at delivering psychological, social and spiritual the management of pain and has been shown to
support to patients and their family to achieve the eliminate pain in 80% of patients. The remaining
best quality of life. Development of cancer pallia- 20% have complex pain which may require spe-
tive care and hospices has gained momentum in cialist interventions. Measures used in complex
the UK since the opening of the World’s first pain include neuro-anaesthetic interventions,
hospice in London in 1967 by Cicely Saunders palliative surgery, radiotherapy, chemotherapy,
and colleagues. Today, palliative care and end-of- physiotherapy, occupational therapy, and psy-
life care are growing areas of research worldwide. chosocial care.
This chapter deals mainly with symptom manage- Analgesics
ment in cancer patients and a detailed discussion
of the principles of multidisciplinary palliative Commonly used analgesics are given in Table
care is beyond the scope of this chapter. 7.1. Strong opioids are started at a low dose and
titrated according to the clinical need (Box 7.2).
Morphine is the strong agent of choice and oral
Pain management administration is preferred. Transdermal prepa-
Pain control is an important component of cancer rations are useful only in stable pain. Some agents
management and uncontrollable pain is the major may only be prescribed by specialists in palliative
fear for many cancer patients. More than 80% of care medicine or anaesthetia.
patients with advanced cancer suffer pain and Opioid side effects, toxicity and management
around 20% of pain in cancer patients may be All patients feel some degree of drowsiness when
attributed to surgery, radiotherapy and chemo- starting or increasing their dosage. This usually
therapy. Pain control involves two important wears off 3–5 days after being on a stable dose.
steps: assessment of pain and management of pain. Constipation is inevitable and 30–50% patients
develop nausea and vomiting; these symptoms
Assessment of pain should be managed prophylactically. Intolerable
It is important to assess the multidimensional side effects necessitate switching to an alternative
nature of pain. Intensity of pain, location, dura- opioid (Figure 7.2).
tion and factors that modify pain should be Opioid toxicity usually manifests pseudo-
assessed. There are various tools to assess the hallucinations (shadows at the peripheries of the
pain and the commonly used ones are shown in field of vision), myoclonic jerks, cognitive impair-
Box 7.1. ment, and visual and auditory hallucinations.
66 © 2011, Elsevier Ltd
DOI: 10.1016/B978-0-7234-3458-0.00012-9
 PALLIATIVE CARE 7

Box 7.1: Numerical rating score (NRS) – Wong-Baker FACES Pain Rating Scale.*

0–5 coding 0 1 2 3 4 5
0-10 coding 0 2 4 6 8 10

No hurt Hurts little Hurts little Hurts even Hurts whole Hurts worst
bit more more lot

Verbal descriptor score

0. None 1. Mild 2. Moderate 3. Severe 4. Very severe

*From Hockenberry MJ, Wilson D: Wong’s essentials of pediatric nursing, ed. 8, St. Louis, 2009, Mosby. Used with permission. Copyright Mosby.

Figure 7.1
Interventional measures
The WHO analgesic ladder. *NRS –
numberical rating score using 10
Step 3: strong opioids point coding.
First line: Morphine
Alternative: diamorphine, fentanyl

± step 1 ±adjuvant

Step 2: weak opioids

Codeine, dihydrocodeine

± step 1 ±adjuvant

Step 1: non-opioids Choice of initial step depends

Paracetamol, aspirin, NSAIDs on intensity of pain
• Mild pain (NRS* 1–4) step 1
• Moderate pain (NRS 5–7) step 2
±adjuvant • Severe pain (NRS 8–10) step 3

Initial management includes adequate hydration managed by reducing doses of opioids over a
(dehydration is often a precipitant of toxicity), few days.
reduction of opioid and haloperidol (1.5–3 mg
oral) for cognitive impairment. If the patient has Adjuvant analgesics
persistent toxicity without adequate analgesia, Adjuvant analgesics (Table 7.2) are a useful
opioid switching is needed (Figure 7.2). Though complement to regular analgesics in complex
there is no best choice, oxycodone and hydro- pain. These include anticonvulsants, antidepres-
morphone are the usual alternatives. Naloxone sants, antispasmodics, bisphosphonates, steroids,
is a short acting opioid antagonist used intrave- muscle relaxants and N-methyl-D-aspartate
nously for reversing accidental severe opioid antagonist (ketamine).
overdose.
If pain is relieved rapidly, for example after a Complex pain
nerve block, opioids can be stopped abruptly in Neuropathic pain is often difficult to control.
many patients without any side effects. However, Agents useful to control neuropathic pain are
up to 10% may experience a withdrawal syn- shown in Table 7.2. Amitryptyline along with
drome due to physiological dependence which is regular analgesics is the first line management. If
67
 I BASIC PRINCIPLES OF CANCER MANAGEMENT

Table 7.1: Analgesics in pain management

Relative effectiveness
compared with oral
Drug Dose Precaution morphine
Step 1
Paracetamol 1 g 4-hourly oral Hepatotoxicity
Diclofenac 50 mg 4–6-hourly GI and renal toxicity
Other NSAIDS GI and renal toxicity
Step 2
Codeine 60 mg 4-hourly oral Max 240 mg daily 0.1
Dihydrocodeine 60 mg 4-hourly oral Max 360 mg daily 0.1
Tramadol 50–100 mg 4-hourly Max 400 mg daily 0.1–0.25
Confusion in elderly
Step 3
Oral morphine: immediate Starting dose 2.5–10 mg Hallucinations and 1
release 6-hourly confusion
Parenteral morphine Starting dose 5–10 mg Accumulate in renal
efficiency
12-hour sustained release – MST 12-hourly; dose
continues calculated based on oral
morphine requirement
24-hour release – MXL
Diamorphine Parenteral 3
Oxycodone: Starting dose 20 mg Less hallucination and 1.5–2
Immediate release (Oxynorm) confusion compared
Sustained release (Oxycontin) with morphine
Hydromorphone: Starting dose 8 mg 7.5
Immediate release (Palladone)
Sustained release (Palladone
SR)
Fentanyl: 12–100 mcg/h over 3 Takes 48 hours to reach +4 (12 mcg/h equal to
Transdermal days steady state. Used only morphine 40 mg/d)
Transmucosal for stable pain and
Buccal relatively safe in renal
Nasal failure
Buprenorphine:
Oral 0.4 mg 75
IV 0.3–0.6 mg 100
Transdermal 17.5–35 mcg/h +4 (calculated with
conversion from mg/day
morphine to mcg/h)
Methadone 10 mg Useful in neuropathic 4 if daily morphine is
pain/can be used in <90 mg, 8 if 90–300 mg
renal failure and 12 if >300 mg

68
 PALLIATIVE CARE 7

Box 7.2: Titration of opioid dose

clinical assessment including detailed history and
examination to establish the cause and severity
Step 1
• Start with immediate release opioid (e.g. oral is important. Possible causes include treatment
morphine 2.5–10 mg depending on age and related (chemotherapy, radiotherapy or other
intensity of pain) 4 hourly. drugs), gastrointestinal pathology (e.g. obstruc-
• Break through analgesia (immediate release) is tion), electrolyte abnormalities (e.g. hypercalcae-
given at the same dose as regular dose.
mia), and brain metastases. Investigations are
Step 2 governed by findings from history, clinical
• Calculate total analgesic requirement (after 48–72
hours).
examination, and a review of the drug chart and
chemotherapy prescription. First-line treatment
Step 3
• Start controlled release preparation at the
depends on the possible cause and examples are
equivalent daily dose of immediate release (e.g. if given in Table 7.3. Levomepromazine (6.25–
oral morphine requirement is 120 mg/day, MST 25 mg subcutaneous per day) and dexametha-
started as 60 mg 12-hourly).
sone are used as second line treatment.
• Breakthrough analgesia is the same analgesia at
one-sixth of the regular total daily dose (e.g. oral
morphine 20 mg from the previous example).
Step 4 Constipation
• If patient needs >4 breakthrough doses per day, Around 50% of cancer patients will develop con-
the baseline controlled release dose needs to be
increased by following steps 2 and 3. stipation, which is due to a number of disease
and treatment related causes. Assessment is to
evaluate the possible cause(s). Prevention is
important, particularly those starting on opioids.
pain is not adequately controlled, gabapentin can Adequate fluid intake should be encouraged
be either added to amitryptyline or used as sub- except when associated with vomiting related to
stitute. In nerve compression pain steroids or small bowel obstruction. A combined stimulant/
TENS (transcutaneous electrical nerve stimula- softener is preferred e.g. co-danthramer (2 caps
tion) can be considered. Ketamine is useful if once or twice daily) or movicol is the choice in
these measures fail to control pain. If pain con- advanced cancer. Osmotic laxatives are useful in
tinues to be a problem neuro-anaesthetic inter- patients who have sufficient oral intake. Rectal
ventions such as neural blockade (nerve block, preparations are indicated when oral laxatives
epidural opioids) or neurodestruction (as a last fail. Glycerol suppositories soften stools while
resort) are considered. bisacodyl suppositories stimulate the rectum.
Radiotherapy is useful in controlling bone Resistant cases require an enema.
pain. 41% of patients achieve a 50% pain relief
within 4 weeks of treatment. Bone pain associ-
ated with mechanical instability is difficult to Diarrhoea
control and often precipitated by movement. In Diarrhoea in cancer patients can be due to chem-
patients with extensive bone metastases, bisphos- otherapy (e.g. 5-fluorouracil, docetaxel), pelvic
phonates are shown to reduce skeletal events radiotherapy, infection or other medical condi-
whereas its analgesic benefit is less clear. tions. Clinical evaluation should be aimed at
Non-pharmacological interventions establishing the cause and severity. Treatment is
essentially supportive aimed at improving hydra-
Non-pharmacological interventions such as
tion and correct electrolyte imbalance if any.
TENS, acupuncture, relaxation techniques and
Infections are treated with appropriate antibiot-
massage may all be useful.
ics. Diarrhoea due to chemotherapy and radio-
therapy is treated with dietetic management
Nausea and vomiting and loperamide. Octreotide is useful in severe
Nausea and vomiting are the most common diarrhoea (200–1200 micrograms per day
symptoms in cancer management. A thorough subcutaneously).
69
 I BASIC PRINCIPLES OF CANCER MANAGEMENT

Oral morphine
mg/24 hour

Cannot take oral morphine Cannot tolerate morphine due to side effects

Divide by 3 Divide by 2 Divide by 3 Divide by 7.5

First line Oral oxycodone Oral hydromorphine

subcutaneous diamorphine mg/24 hour mg/24 hour
mg/24 hour

Subcutaneous morphine Divide by 2 Divide by 2

mg/24 hour if diamorphine
not available

• Stable opioid-responsive pain Subcutaneous Subcutaneous

• Cannot take oral medication oxycodone mg/24 hour hydromorphone mg/24 hour
• Need to improve compliance

Equivalent Divide by 2 Divide by 3.6

Fentanyl patch mcg/hr

Divide by 10
Breakthrough analgesia
• Same opioid and same route – 1/6th of 24 hour dose
Subcutaneous alfentanil • Fentanyl patch – 1/5 patch dose as diamorphine mg dose
(for breakthrough analgesia and safe in renal failure) • Alfentanil – 1/10 of 24 hour

Figure 7.2
Conversion of opioids.

Table 7.2: Adjuvant analgesics

Indication Drug Dosage
Neuropathic pain Dexamethasone 8–16 mg daily
Gabapentin 100–300 mg (nocte) Titrate to 600 mg TDS
Amitriptyline Starting dose 25 mg (nocte)
In elderly start at 10 mg
Pregabalin 150–600 mg
Carbamazepine 100 mg BD up to 1200 in divided doses daily
Sodium valproate 200–500 mg nocte
Muscle spasm Diazepam 2–10 mg daily
Baclofen 5 mg TDS increased up to max 100 mg daily
Smooth muscle spasm Hyoscine SC 20 mg stat or SC infusion 60 mg up to 120 mg in 24 hours
butylbromide
Tenesmus Nifedipine 5/20 mg BD oral

70
 PALLIATIVE CARE 7
intestinal motility and colic (octreotide 600–
Table 7.3: Agent of choice in nausea and 800 mcg/day subcutaneously).
vomiting based on cause
Treatment – first line
Cause anti-emetic
Oral infections
Chemotherapy Granisetron 1 mg BD PO
Ondansetron 8 mg PO BD Mouth care is important in cancer patients.
Dexamethasone 4–8 mg Immunosuppression and steroids predispose to
OD PO oral candidiasis, which manifest as white-yellow
Metoclopramide 20 mg
QDS PO
plaques or as a painful bleeding red area. Treat-
ment is with anti-fungals, e.g. oral fluconazole
Radiotherapy Granisetron 1 mg BD PO and may be given prophylactically with high risk
Ondansetron 8 mg OD
Haloperidol 1.5 mg OD or
treatments. Herpes simplex virus presents as
BD PO painful, yellow lesions on the oral mucosa. Sys-
Raised intra-cranial Cyclizine 50 mg tds PO
temic anti-viral agents and strong opioid analge-
pressure sics are usually needed. Bacterial infections are
treated according to culture results.
Delayed gastric Metoclopramide 10–20 mg
emptying QDS PO
Domperidone 10–20 mg
QDS PO Hiccups
Drug induced Haloperidol 1.5 mg OD or Hiccups are a reflex spasm of the diaphragm
BD PO. causing sudden movement of the glottis. Common
Metabolic e.g. uraemia Haloperidol 1.5 mg OD or causes include gastric distension, raised intra-
or hypercalcaemia BD PO. abdominal pressure, high dose steroids and elec-
trolyte imbalance (e.g. hyponatraemia, uraemia).
Metoclopramide (10 mg qds PO) is useful in
gastric distension. Dimethicone which is an anti-
foaming agent which eases flatulence and disten-
sion (Asilone 5 ml qds) can be effective. Baclofen
Intestinal obstruction (5 mg tds PO) or nifedipine (5 mg tds) can act as
Intestinal obstruction is common with colorectal smooth muscle relaxants. When these measures
and ovarian cancers. Treatment depends on a fail, chlorpromazine can be used as a central
number of factors. Surgery is the treatment of hiccup reflex suppressant (12.5–25 mg daily).
choice if feasible; however, many patients are only
suitable for conservative management. Depend-
ing on the level of obstruction, surgical interven-
Breathlessness
tion includes bypass surgery, stent or surgical Breathlessness is the subjective experience of dis-
excision. In general surgery is only recommended comfort in breathing. Common causes include
if there is a single focus of tumour or adhesion disease affecting the lungs, increased intracranial
causing compression. Multiple areas of involve- pressure, anaemia and pulmonary embolism.
ment or extensive peritoneal involvement is best Supportive measures include breathing exercises,
managed by conservative measures. Conservative a stream of air, either from a fan or through an
management is by bowel rest, nasogastric tube (in open window, and treatment of infections,
case of persistent vomiting), parenteral steroids cardiac failure, effusion, COPD and anaemia.
(to control nausea, bowel oedema and extrinsic Radiotherapy is useful for large tumours and
compression, control of nausea and vomiting bronchial obstruction. Lymphangitis carcinoma-
(cyclizine when there is complete obstruction) tosis is treated with dexamethasone 16 mg daily.
and metoclopromide (in partial obstruction) and Oxygen therapy is useful in patients with SaO2
somatostatin analogues to reduce gastrointestinal <90%. Morphine 5 mg 6-hourly is also useful in
secretions, promote absorption of fluid and reduce breathlessness.
71
 I BASIC PRINCIPLES OF CANCER MANAGEMENT

Cough causes include metabolic abnormalities (hyponat-

raemia, hypercalcaemia), drug toxicity (opioids,
Cough in cancer patients can be either due to steroids), infection and metastatic brain disease
underlying malignancy or due to co-existing non- or its treatment. Antipsychotic medications are
malignant conditions. Treatment depends on the often needed and the commonly used agent is
type of cough and underlying cause. Treatable haloperidol 5–30 mg daily.
causes should be appropriately treated. Physio-
therapy aids expectoration and repositioning Cancer-related fatigue
may alleviate the cough (e.g. lying on same side
as pleural effusion). Codeine linctus and strong Cancer-related fatigue has been defined as ‘a per-
opioids (e.g. oral morphine sulphate) are also sistent subjective sense of tiredness related to
beneficial in symptomatic relief. cancer or cancer treatment that interferes with
usual functioning’. The aetiology is multifacto-
Haemoptysis rial. Treatment includes relaxation, stress man-
agement, regular exercise and psychological
Haemoptysis is managed with oral haemostatic interventions.
agents (e.g. tranexamic acid), local radiotherapy
or bronchoscopic intervention. Massive terminal Cancer cachexia
exanguination requires appropriate sedation.
Cachexia has been defined by a triad of weight
Depression loss >10%, reduced food intake (<1500 kcal/
day) and systemic inflammation (CRP >10 mg/l).
Depression is common in cancer patients. In a All reversible causes of anorexia should be
physically well patient, depression usually mani- identified and treated. Nutritional support may
fests as poor appetite, weight loss, and even be helpful. Progestogens are commonly used to
fatigue. The Hospital Anxiety and Depression improve appetite and weight. The commonly
Scale (HADS) is useful in diagnosing anxiety and used agents are megestrol acetate (160–320 mg/
depression. Management is with counselling, day) and medroxyprogesterone acetate (200 mg
psychological interventions and antidepressants. tds). Steroids may help to improve appetite and
Some cancer centres have a designated psycho- give a sense of wellbeing but caution should be
oncology service to assist in the management of used if given for prolonged periods as they can
these patients. The commonly used antidepres- exacerbate proximal weakness.
sants are:
• Citalopram, an SSRI used as first line treat- Symptom cluster
ment of depression at a dose of 20 mg which A symptom cluster is defined as three or more
can be increased to 40 mg. concurrent symptoms that are related to each
• Mirtazapine, a noradrenaline and specific other. Commonly occurring symptom clusters
serotonin antagonist (NaSSA) given at a dose are:
of 15–45 mg daily.
• Venlafaxine, a serotonin-noradrenergic re- • fatigue, pain and drowsiness
uptake inhibitor (SNRI), the starting dose is • poor appetite and nausea and anxiety and low
75 mg daily. mood
• pain, fatigue, low mood and function.
Treatment is usually started with one class
of agent and if a patient does not respond in These symptom clusters highlight the impor-
4 weeks, it is changed to another class of tance of treating several symptoms in unison,
antidepressant. rather than individually.

Delirium End-of-life care

Delirium (acute confusional state) is a common End-of-life care of the cancer patient is most chal-
psychiatric disorder in cancer patients. Common lenging. Management of the primary illness is no
72
 PALLIATIVE CARE 7
longer the priority and the focus of care shifts to tion is treated initially with haloperidol and
optimize symptom control. An important aspect midazolam. Severe uncontrolled agitation may
of this is recognition of end-of-life and it is often need titrating doses of methotrimeprazine. Res-
difficult to make a decision to stop anticancer piratory secretions, which produce ‘death rattle’,
treatment. This needs a very sensitive approach should be treated with anti-muscarinic agents
involving patients, their families and all con- such as hyoscine hydrobromide, hyoscine butyl-
cerned parties in the care of patients. bromide and glycopyrronium.
In patients with advanced cancer the following An important psychological aspect of end-of-
signs and symptom suggest that the patient is life care is patient dignity. Place of death should
dying: be discussed with the patient and their carers
whilst they are still able to make the decision.
• bedbound or immobile
Although the majority of patients die in hospital
• difficulty managing medication
many would prefer to die in a hospice or home
• confusion
environment. This may take time to organize so
• marked generalized weakness
should be considered early in the outcome is poor
• drowsy or comatose
so that there is sufficient time to make the neces-
• poor appetite and decreased fluid intake.
sary arrangements.
The Liverpool Care Pathway for the Dying After death, the death certificate should be
Patient (LCP) is a framework for the care of issued with appropriate advice on the necessary
the dying patient. This framework emphasizes legal requirements and process of arranging a
the need to discontinue all inappropriate inter­ funeral. Bereavement care is often offered either
ventions including monitoring of vital signs, actively or passively to family members. The
use of IV fluids and antibiotics. All the clinical family should be offered an opportunity to
measures are to improve comfort for the patient. discuss any unanswered questions which may
The minimum medications are used to ease dis- ease the process of bereavement.
tress and pain and medications are given by a
syringe driver. Further reading
Principles of management of specific symp- Fallon M & Hanks G. ABC of Palliative care. 2nd Edition.
toms are as discussed previously. Terminal agita- Wiley Blackwell, Oxford, 2006.

73
Head and neck cancer
AA Edwards and RL Mendes
8
Introduction HPV and about 90% of these are positive
for HPV-16. HPV-16 is particularly asso-
Head and neck oncology is challenging. It ciated with oropharyngeal SCC.
demands a thorough knowledge of head and • Epstein–Barr virus has been implicated in
neck anatomy to guide multi-modality treatment nasopharyngeal carcinoma. Plasma levels
and the treatment itself can lead to significant of EBV DNA before treatment and after
impairment in important functions such as swal- radiotherapy have been correlated with
lowing, facial expression and speech. Tumours outcome and survival.
arising within various head and neck subsites can • Other risk factors:
differ in presentation, clinical course and thera- • Lower socioeconomic status is associated
peutic options. with SCC of the oral cavity and larynx.
Cancers of the head and neck account for • Chewing betel quid – a mixture of tobacco,
around 6% of malignancies worldwide. It is slaked lime and areca nut, wrapped in
more common among men, with a male-female betel pepper leaf – is popular in India and
ratio of 2–3 : 1. Squamous head and neck cancers parts of South East Asia. It is associated
tend to affect patients between the ages of 40–70 the development of oral submucous fibro-
years. The incidence varies geographically – for sis and leucoplakia and is a risk factor
instance, nasopharyngeal carcinoma is most fre- for developing carcinoma of the oral
quent in the Far East. cavity.
• Occupational risk factors include: asbestos
Aetiology (larynx), wood dusts (nasal cavity, nasal
sinuses, nasopharynx and larynx), nickel
The important aetiological factors in squamous
(maxillary sinus) and pesticides (larynx).
cell carcinomas of the head and neck include:
• UV exposure is a risk factor for SCC of
• Tobacco – smoking or chewing tobacco is the the lip.
strongest risk factor for squamous cell carci- • Previous head and neck irradiation
nomas (SCC) of the head and neck, with more increases the risk of subsequent head and
than 90% of patients having a history of neck malignancies.
tobacco use.
• Alcohol – increased alcohol consumption is
associated with an increased risk of head and
Pathogenesis and pathology
neck SCC, and has been shown to have a SCC is thought to develop in a stepwise progres-
synergistic effect with tobacco in the develop- sion from squamous metaplasia to dysplasia,
ment of SCCs. through carcinoma-in-situ to invasive squamous
• Viral infections: cell carcinoma. These histological changes are
• Human papilloma virus – About a quarter accompanied by molecular alterations which
of head and neck SCC specimens contain disrupt the regulation of cell proliferation, by

© 2011, Elsevier Ltd 77

DOI: 10.1016/B978-0-7234-3458-0.00013-0
 II SITE-SPECIFIC CANCER MANAGEMENT

inactivating tumour suppressor genes and acti- lymphatic drainage for head and neck subsites,
vating oncogenes. which are important in planning surgery and
The majority (90%) of malignant tumours of radiotherapy. In the unoperated neck, the pattern
the head and neck are squamous cell carcinomas. of lymph node drainage is relatively predictable
The WHO classification of head and neck cancers for different tumour subsites. The risk of occult
is outlined in Box 8.1. lymph node metastasis varies according to the
primary site and the size of the primary tumour.
Clinical assessment of this risk of cervical nodal
Anatomy metastasis dictates subsequent decisions on inclu-
Figure 8.1 shows the anatomical sites in the head sion of lymph node groups within a neck dissec-
and neck. Figure 8.2 demonstrates the anatomi- tion or radiotherapy target volume during the
cal levels of neck nodes and the typical regional definitive treatment.

Box 8.1: WHO Classification of malignant head Nasopharynx

and neck tumours Oropharynx
• Squamous cell carcinoma and variants such as Hypopharynx
verrucous carcinoma Larynx
• Nasopharyngeal carcinoma Oral cavity
• Salivary gland tumours – acinic cell carcinoma, Sinonasal complex
mucoepidermoid carcinoma, adenoid cystic
carcinoma
• Adenocarcinoma
• Lymphoma
• Small cell carcinoma
• Carcinoid
• Sarcoma
• Metastasis
Figure 8.1
Anatomy of the head and neck region.

Figure 8.2
IA – Submental Anatomical levels of neck nodes.

IB – Submandibular

II – Upper deep cervical

III – Middle deep cervical

IB IV – Lower deep cervical

IIB
IA IIA VA – Posterior triangle

VB – Supraclavicular
III VI – Anterior compartment
nodes
VA
VI

IV VB

78
 HEAD AND NECK CANCER 8

Presentation • to exclude synchronous tumours of the upper

aerodigestive tract
Most patients with head and neck cancer present • determine fitness for radical treatments.
with local symptoms due to the growth and
depend on the site of tumour (see later). Tissue diagnosis
• Fine needle aspiration/core biopsy may be
Evaluation of patients with used to sample enlarged lymph nodes.
head and neck cancer • Examination under anaesthesia (EUA) with
panendoscopy is often used to obtain biopsies
Important features in the history for head and to establish a histological diagnosis, and to
neck cancer patients are: clinically stage the tumour.
• Duration and intensity of symptoms and signs
• Age Imaging
• Socioeconomic status • Suspicious cervical nodes may be further
• Tobacco and alcohol use characterized by ultrasound examination of
• Co-morbid conditions: smoking-related the neck.
illness, respiratory disease, cardiac disease, • CT and/or MRI of the head and neck region
diabetes, liver disease, peripheral vascular are used to assess the extent of the primary
disease, immunodeficiency, poor nutrition tumour and the regional lymph nodes (Figure
• History of previous malignancy or pre-malig- 8.3). MRI is superior for assessing soft tissue
nancy (especially in the head and neck region). infiltration, cartilage invasion and perineural
In patients with recurrent disease or second spread. CT is useful for assessing bone involve-
malignancy, details of previous surgery and/ ment and has the advantage of being better
or radiotherapy should be sought to guide tolerated by patients with swallowing difficul-
further treatment ties because of its faster speed of acquisition.
USS of the neck also has a role in neck staging.
Clinical examination • CT chest (or chest X-ray) may be needed to
rule out pulmonary metastases in locally
The whole oral cavity and teeth should be
advanced disease. Chest X-ray, however, may
inspected carefully (after removing any dentures).
not detect small volume metastatic disease.
The tongue, cheeks, and floor of mouth should
• 18FDG PET-CT has a role in assessing sus-
be palpated bi-manually. The ears and nose
pected tumour recurrence and in detecting
should be examined for mass lesions, discharge
occult primary tumours.
or bleeding. The pharynx and larynx should be
examined using flexible fibreoptic nasoendos- Staging
copy or indirect laryngoscopy and the mobility
of the vocal cords assessed. The neck should be TNM staging is based on the primary tumour
palpated for enlarged lymph nodes or thyroid size and/or extent, regional lymph node metasta-
masses. In patients presenting with metastatic sis and distant metastatic spread (Box 8.2).
carcinoma in a cervical lymph node, an occult
primary should be sought, with particular atten- Management of head and
tion paid to the base of tongue, tonsil, nasophar- neck cancers
ynx and piriform fossae.
Pre-treatment assessment
Investigations and staging Management of head and neck cancers is
complex, and needs a multidisciplinary approach.
The objectives of the clinical assessment of a
All patients require assessment of performance
patient with a suspected head and neck cancer are:
status, dentition, swallowing and nutrition.
• to establish a histological diagnosis Dental assessment is important in minimiz-
• to stage the disease ing late side effects of radical radiotherapy such
79
 II SITE-SPECIFIC CANCER MANAGEMENT

A B

Figure 8.3
MRI of nasopharyngeal cancer.

Box 8.2: A general TNM staging of head and

aged to stop smoking and minimize alcohol
neck tumour intake during radiotherapy.
Stage I T1N0M0 tumour of ≤2 cm
Stage II T2N0M0 tumour of >2–4 cm Principles of treatment
Stage III T3N0M0 tumour of >4 cm Early stage disease (stages I–II/T1–2N0M0)
T1–3N1M0 ipsilateral single node
≤3 cm Early stage disease is usually managed with either
Stage IV T4N0–1M0 involving adjacent surgery or radiotherapy. The choice of treatment
structures
Any T N2M0 ipsilateral single node is based on location of tumour and anticipated
>3–6 cm (N2a) morbidity. Radiotherapy results in a local control
ipsilateral multiple rate of 85–95% for T1 and 70–85% for T2
nodes <6 cm (N2b)
contralateral or lesions. Treatment of the neck should be consid-
bilateral nodes ered in addition to the treatment to the primary
<6 cm (N2c) site. Node negative head and neck cancers with
Any T N3M0 nodes >6 cm
Any T, any Distant metastasis a >15–20% risk of occult cervical node metasta-
N, M1 sis (all cancers except <2 cm lesions in oral cavity
T4 tumours are divided into T4a (resectable) and T4b and T1 glottic cancers) need elective manage-
(unresectable). Hence stage IV can be IVa (T4a), IVb ment of neck nodes – either by a neck dissection
(T4b) or IVc (M1). or neck irradiation. The level(s) of nodes to be
Larynx and pharynx has T staging based on local treated depends on the primary site of tumour
spread, whereas nasopharynx has separate T and N
staging. and T stage, and the choice of treatment modal-
ity depends on the treatment of the primary site
(Box 8.3).

as dental caries and osteoradionecrosis. Main- Locally advanced disease

taining adequate nutrition is a challenge in (Stage III–IVb/T3–4N1–3M0)
patients with head and neck cancer. Patients who
Patients with locally advanced disease are treated
are malnourished or at risk of becoming mal-
with combined modality treatment. The treat-
nourished need dietetic assessment and often
ment decision is based on chance of local control
intervention is needed. All patients with locally
and outcome. The options are:
advanced head and neck cancer need a swallow-
ing and language therapy (SALT) assessment • Surgery followed by postoperative radiother-
80 prior to radical treatment. Patients are encour- apy or chemoradiotherapy
 HEAD AND NECK CANCER 8

Box 8.3: Recommended elective node treatment

Alternate fractionation schedule studied in
in stage I–II (T1–2N0) head and neck cancer head and neck cancer include hyperfractionation
(80.5 Gy in 70 fractions over 7 weeks using two
Nodal Selective node
irradiation in dissection in 1.15 Gy fractions per day), accelerated fractiona-
Primary site N0 disease N0 disease tion (68 Gy in 34 fractions giving six fractions
Oral cavity: per week). The CHART trial failed to improve
T2 well Ipsilateral level I–III local control in locally advanced head and neck
lateralized I–II
T2 reaching Bilateral level cancer. Though generally hyperfractionation and
midline I–III acceleration improve local control by a modest
Oropharynx: amount compared with conventional fractiona-
T1 Tonsil Ipsilateral Ib–II II–IV
T2 lateralized Ipsilateral Ib–IV tion, these are not universally adopted in clinical
tonsil practice because of practicality of delivery and
All other N0 Bilateral Ib–V the advent of chemoradiotherapy.
Larynx:
T1–2 Glottic No nodal II–IV and if Role of primary chemoradiation (Box 8.5)
radiotherapy extends
below glottis, A meta-analysis showed that concurrent cisplatin
II–V with conventional radiotherapy fractionation
T1/2 Bilateral level
Supraglottic Ib–III results in an absolute 5-year survival improve-
All other N0 Bilateral Ib–V ment of approximately 10% compared with
Hypopharynx: radiotherapy alone. This potential survival
All N0 Bilateral I–V II–V
Nasopharynx: benefit needs to be carefully weighed against its
T1N0 squamous No neck – increased acute toxicity of adding concurrent
carcinoma irradiation chemotherapy to radiotherapy for each individ-
All N0 Bilateral I–V
ual patient.
Role of postoperative chemoradiation
Two randomized studies (one North American
• Radical chemoradiotherapy – option for and another European) showed differing benefit
organ preservation and hence its role is not clear.
• Nodal dissection followed by chemoradio-
therapy New treatment approaches
Metastatic disease Intensity modulated radiotherapy (IMRT) (Figure
8.5) – the role of IMRT in head and neck cancer
The management of patients with distant metas- is evolving, whereby radiation dose can be
tases is essentially symptomatic and supportive. reduced to critical structures e.g. spinal cord and
Palliative radiotherapy, surgery and chemother- side effects can be modified, e.g. minimizing sali-
apy are options in an otherwise fit patient. vary gland toxicity with additional scope for
Radiotherapy in head and neck cancer increasing the dose to gross disease.
(Box 8.4) Role of brachytherapy
Conventional fractionation involves delivering a Brachytherapy using low-dose rate iridium
total dose of 66–70 Gy in 2 Gy daily fraction, 5 implantation or high-dose rate after loading may
days a week. Elective irradiation of the clinically be used in a few head and neck subsites at spe-
node-negative neck requires a dose of 44–50 Gy cialist centres. Brachytherapy may be considered
in 22–25 fractions. for some early tumours of the lip, base of tongue,
The indications for postoperative radiother- floor of mouth and anterior tongue, as well as
apy are based on risk factors (Table 8.1). The certain small volume tumour recurrences within
treatment target is generally the tumour bed and a previously irradiated site.
involved neck to a dose of 60–66 Gy in 30–33
fractions (Box 8.4). Consideration may be given Role of chemotherapy
to prophylactic nodal irradiation to a lower dose The use of neoadjuvant (induction) and adju-
depending on risk. vant chemotherapy in the treatment of locally 81
 II SITE-SPECIFIC CANCER MANAGEMENT

Table 8.1: Risk factors for predicting locoregional recurrence in the postoperative setting
Primary site Neck nodes
Major risk factors Positive resection margins Extracapsular spread
Minor risk factors Close resection margins (<5 mm) 2 or more involved nodes
Invasion of soft tissues More than one lymph node level involved
Multifocal primary Involved node >3 cm in diameter
Perineural invasion
Vascular invasion
Poorly differentiated
T3 or T4 disease
High risk of recurrence is associated with the presence of one major risk factor or two minor risk factors.
Intermediate risk of recurrence is associated with the presence of one minor risk factor.
Factors of less importance in predicting risk of recurrence include: oral cavity primary site; presence of
carcinoma-in-situ or dysplasia at the resection margin; and uncertain surgical or pathological findings.

advanced head and neck cancer has been Role of biological agents
controversial. A large meta-analysis of trials Epidermal growth factor receptor (EGFR) inhib-
studying the role of chemotherapy in locally itors have been studied in head and neck cancer.
advanced head and neck SCC showed no signifi- Over 80% of head and neck SCC tumours
cant benefit for induction or adjuvant chemo- overexpress EGFR. This is associated with
therapy. More recent studies have supported a aggressive tumours, resistance to cytotoxic
role for induction chemotherapy in improving agents and irradiation, hence a poor prognosis.
laryngeal preservation in locally advanced SCC Cetuximab combined with radical radiotherapy
of the larynx. A study comparing cisplatin-5-FU is proven to improve both 3-year local control
with docetaxel, cisplatin and 5-FU showed a (41% vs. 34%) and overall survival (55% vs.
better survival with three drugs (Box 8.5). 45%) in locally advanced head and neck SCC
Palliative compared with radiotherapy alone. Hence NICE
recommends the use of cetuximab with radio-
Palliative chemotherapy provides a modest
therapy in patients with locally advanced head
benefit in advanced head and neck cancer with
and neck cancer with good performance status
objective response rates of 30–40% and median
in whom platinum-based chemoradiation is
survival around 6 months. Cisplatin/5-FU com-
contraindicated.
binations are most commonly used although
capecitabine, taxanes and biological targeting
agents are all being studied. Patients who fail to
respond to first line chemotherapy should be con-
Care during and after treatment
sidered for phase 2 experimental studies. Head Radiotherapy toxicity is discussed on p. 348.
and neck cancer provides an ideal template for Rehabilitation of the patient after completion
the study of novel agents as its accessibility of treatment involves input from a multi­
permits scrutiny of both tumour control and disciplinary team including clinical nurse special-
normal tissue effects. The EXTREME study ists, speech and language therapists, dietitians,
showed that addition of cetuximab to cisplatin physiotherapists, occupational therapists, dental
and 5-FU improves overall survival compared to surgeons, dental hygienists and prosthetic
chemotherapy alone. specialists.
82
 HEAD AND NECK CANCER 8

Box 8.4: Radical radiotherapy in head and neck cancer

Radical radiotherapy
• Position – All patients supine with the head in the neutral position, except nasopharyngeal cancer and parotid
tumours and tumours of the ear (neck extended). Mouth bite for oral cavity, nasal cavity and sinus tumours will
facilitate normal tissue sparing.
• Immobilization – customized shell
• Localization – CT planning
• Target volume definition:
• GTV – all radiologically visible tumour
• CTV – with 1–2 cm margin depending on the anatomic area. CTV may need editing in the areas of
anatomical barriers to spread
• CTV – Figure 8.2 shows anatomical boundaries of nodes and Box 8.2 shows nodes need to be treated for N0
disease. For node positive disease, patients generally receive radiotherapy to bilateral level I–V nodes; the
exceptions beings well lateralised T2N1 tongue tumours and T1–2N1 tonsil tumours when just the ipsilateral
level I–V nodes may be treated
• PTV – depends on the method of immobilization and ranges from 3–5 mm
• Radiation dose:
• Phase I (see Figure 8.4)
– Photons – 44 Gy in 2 Gy per fraction with a lateral parallel opposed beam to the primary tumour and
upper neck nodes
– Photons – 44 Gy in 2 Gy per fraction to anterior neck split with cord and lung shielding
• Phase II
– Photons – 22–26 Gy in Gy per fraction with lateral opposed beam moved anterior to spinal cord
– Photons – 0–6 Gy in 3 fractions to anterior neck split
– Electrons – if posterior neck nodes, need treatment. A total dose of 44–50 Gy to elective nodes and
66–70 Gy to involved nodes is delivered
• Bolus is indicated if:
– there is skin involvement
– close superficial margin
– primary electron treatments e.g. pinna
– postoperative tracheostome site
• Monitoring
• Follow-up to assess and treat toxicity
• Haemoglobin should be maintained above 12 g/dl
• Tolerance dose of organs at risk in Gy (at 2 Gy per fraction)
• Lens 8–10 Gy, cornea 40 Gy, retina 50 Gy, optic nerve 50 Gy, optic chiasm 50 Gy, spinal cord and brain stem
44–48 Gy, hypothalamus 44 Gy
Postoperative radiotherapy
• CTV – surgical bed and areas at risk+1–2 cm
• PTV – dependent on set up error
• Dose – 60–64 Gy in 30–32 fractions to areas at risk 44–50 Gy in 25 fractions to elective nodes

Patients who developed recurrent disease follow-

Treatment of recurrent disease ing previous radical radiotherapy or chemoradia-
The common pattern of recurrence is loco­ tion would be considered for salvage surgery.
regional. The options for managing recurrent The management options for advanced, recur-
disease depend on the initial treatment. Patients rent or metastatic head and neck cancer depend
who were treated initially with surgery, may be on factors such as co-morbid conditions, previ-
considered for salvage surgery, radiotherapy or ous treatment, performance status, patient pref-
palliative chemotherapy or best supportive care. erences and the nature of their symptoms.
83
 II SITE-SPECIFIC CANCER MANAGEMENT

Advanced head and neck cancer can have a dev-

astating impact on personal appearance and vital
functions such as speech and swallowing. Quality
of life is of paramount importance when deciding
management in recurrent disease.

Box 8.5: Systemic treatment in head and

neck cancer
Cisplatin with concurrent radiotherapy
• Cisplatin 100 mg/m2 IV 3-weekly on days 1, 22 and
43 (if GFR is >50 ml/min). This is the regimen
employed in the EORTC and RTOG trial of
postoperative chemoradiotherapy.
• Cisplatin 40 mg/m2 (max 70 mg) IV weekly for 6
courses (if GFR is <55 and >40 substitute with
carboplatin AUC 5 and no platinum if GFR <40).
This regimen is also used in some UK centres.
Cetuximab (when concurrent cisplatin is
contraindicated).

The initial dose is 400 mg/m2 IV followed by weekly

doses are 250 mg/m2 for 2–8 weeks.
Neoadjuvant chemotherapy
• Docetaxel 75 mg/m2 IV day 1 Figure 8.4
Illustration of phases of radiotherapy in locally advanced
• Cisplatin 100 mg/m2 day 2
laryngeal cancer: Phase I treatment volume (green
• 5-Fluorouracil 1000 mg/m2/day days 1–4 rectagle) includes posterior triangle nodes and during
Cycle duration 3 weeks. phase II, spinal cord is shielded (red shade). Note
Maximum 3 courses, assessment after 2 courses. shielding of oral mucosa (yellow shade) to minimise
mucositis.

A B

Figure 8.5
An axial CT slice of the neck shows an IMRT plan with (A) concave isodose patterns around the spinal cord, sparing it
from the high-dose region and (B) another plan shows sparing of parotid.
84
 HEAD AND NECK CANCER 8

Prognosis with an aggressive surgical approach. Middle ear

tumours are usually squamous cell carcinoma
The overall 5-year survival for head and neck and evaluation should include high resolution
cancer is around 50%. Prognosis is adversely CT scan to assess the extent of disease. Treat-
affected by cervical node involvement. The ment is with radical surgery followed by post­
number of involved lymph nodes, the extent of operative radiotherapy. Small tumours may be
involved nodal levels and the presence of ext- treated with radical radiotherapy alone. 5-year
racapsular spread all impact overall survival. survival rate is around 10% for advanced disease
and 80% for early disease.
Follow-up
Tumours of the nose, nasal cavity and
Ninety percent of recurrences occur in the first 2
years. A second primary tumour is the leading paranasal sinuses
cause of death of patients successfully treated for Malignant tumours from this region are a diverse
early cancers of the head and neck, e.g. lung group. 50% of sinonasal tumours arise from the
cancer or other head and neck cancers. Patients maxillary sinus, 25% from the ethmoid and 25%
are followed up for 5 years to detect recurrent from the nasal cavity. Squamous cell carcinoma
disease and second primary tumours, and in order accounts for 50% of these cancers and the
to manage late morbidity following treatment. remainder include adenocarcinoma, adenoid
cystic carcinoma, melanoma, olfactory neurob-
Management of specific cancers lastoma and undifferentiated carcinoma.

Tumours of the eye Clinical features and evaluation

Malignant tumours of the eyelids include basal cell Presentation can be complex, often with features
carcinoma and squamous cell carcinoma, which of infection and inflammation, resulting in
are managed similarly to skin cancers (p. 237). advanced disease at presentation. Symptoms
Malignant melanoma is the most common depend on the site of origin and include epistaxis
primary intraocular tumour in adults, which and nasal obstruction for nasal tumours, eye
behaves similarly to melanoma elsewhere. In signs for ethmoidal tumours, unilateral cheek
localized disease, treatment is by surgical exci- swelling, trismus, oro-antral fistulas and prob-
sion and management of advanced disease is the lems wearing dentures for maxillary tumours.
same as melanoma arising from skin (p. 231). Around 5% of patients have neck node disease
A variety of malignant tumours, such as sar- which indicates a poor prognosis.
comas and lacrimal gland cancers, can arise in Evaluation includes history and examination
the orbit. Sarcomas are managed with exentera- including eye and cranial nerves I–VI, endoscopy
tion of the eye, with adjuvant radiotherapy and biopsy and imaging. CT scan is useful in
with or without chemotherapy (p. 254). Lacrimal local staging and MRI scanning is beneficial
gland tumours are treated with complete surgical particularly to assess skull base and orbital
excision if possible and radiotherapy is indicated involvement.
for inoperable tumours and for close/positive
margins postoperatively. Management
The treatment approach is usually a combination
Cancers of pinna of total surgical excision followed by postopera-
Management of basal cell carcinomas and tive radiotherapy. The surgical approach varies
squamous cell carcinomas is dealt within with the location of tumour. Patients with clini-
Chapter 14 (p. 231). cally involved lymph nodes need node dissection.
In those with clinically negative nodes, an elec-
Cancers of external ear canal and tive node dissection may be indicated for patients
middle ear with high risk of nodal spread (e.g. soft palate).
Cancers of the external ear canal have a high Patients with inoperable loco-regional disease
risk of local recurrence and are therefore treated can be treated with radical chemoradiotherapy.
85
 II SITE-SPECIFIC CANCER MANAGEMENT

Prognosis of recurrence after first surgery and after second

With the combined approach the reported 5-year and subsequent recurrences.
survival rates are around 30–50%. Prognosis
Salivary gland tumours Overall 5-year survival of T1–2 tumours is 60–
75% while that of T3–4 is less than 50% with
Salivary gland tumours are a heterogeneous group
postoperative radiotherapy. Poor prognostic fea-
of tumours which usually present in the sixth
tures include high grade tumour, nodal metasta-
decade of life. These can arise from the major
sis, and perineural invasion.
(parotid, submandibular and sublingual) and also
the minor salivary glands of the oral cavity and Nasopharyngeal cancer
oropharynx. Around 20% of parotid, 50% of Nasopharyngeal cancer (NPC) is common in
submandibular and 80% of sublingual and minor south-east Asia. Factors such as Epstein–Barr
gland tumours are malignant. The most frequent virus infection, genetic predisposition and diets
malignant tumour is mucoepidermoid, followed including salty fish are thought to increase the
by adenoid cystic, adenocarcinoma, acinic cell risk of NPC in south-east Asia. Smoking also
carcinoma and squamous cell carcinoma. increases the risk. Most of the cancers are vari-
Presentation and evaluation ants of squamous cell carcinoma.
A common presentation is painless swelling. Presentation and evaluation
Pain, nerve palsies, nodal metastasis and fixity of The majority of patients present with a neck
mass can occur in malignant lesions. Minor sali- node mass (70%). Other presenting symptoms
vary gland tumours often present as painless sub- depend on the direction of spread of the local
mucosal masses. tumour. For example spread through the Eus-
Clinical assessment includes detailed examina- tachian tube can result in unilateral middle ear
tion of the mass, oral cavity and oropharynx, problems and postero-lateral spread leads to
assessment of facial nerve and other cranial cranial nerve involvement. Multiple cranial
nerves and examination of regional nodes. nerves can be involved in NPC which include III,
FNA is useful to establish diagnosis. Imaging IV, VI and IX–XII.
with CT and/or MRI helps to assess the anatomi- Evaluation is to assess local tumour spread
cal extent of the tumour and lymph node status. including cranial nerve involvement and nodal
Management involvement. All levels of neck nodes can be
involved in NPC. Local staging is with endo-
The aim of treatment is complete surgical removal
scopic examination which also helps to obtain
with minimal morbidity. This involves total
tissue biopsy. CT of the head and neck is obtained.
parotidectomy for parotid cancers and wide
MRI is better in demonstrating soft tissue and
surgical excision of tumours in other glandular
submucosal involvement.
tumours. Neck dissection is needed in those with
enlarged nodes but as the risk of nodal recur- Management
rence is low in node negative patients it is not Concurrent chemoradiotherapy is the treatment
routinely advised. A selective neck dissection of choice. The target volume for radiotherapy
may be advised in high-grade aggressive tumours. encompasses both the primary tumour site and the
Postoperative radiotherapy is indicated in bilateral neck nodes. Neck dissection may be indi-
cases of close or positive margins, high-grade cated for nodal recurrence after radiotherapy.
tumour, advanced disease and those with carti-
lage, bone, muscle, or perineural involvement. Prognosis
The radiotherapy target volume encompasses the Stage is the most important prognostic factor.
tumour bed with adjacent nodal areas. Overall 5-year survival is around 80% for stage
Pleomorphic adenoma is a benign tumour of I disease and 30% for stage IV disease. Poor
the parotid gland with a long natural history and prognostic factors include skull base involve-
variable chances of local recurrence. Radiother- ment, advanced age, and supraclavicular node
86 apy may be indicated for patients with high risk involvement.
 HEAD AND NECK CANCER 8

Oral cavity Presentation and evaluation

Oral cavity tumours account for 30% of all Presenting features include painful swallowing,
head and neck cancers. Anatomically the oral sore throat, muffled speech and referred ear ache.
cavity is divided into lip, anterior two-thirds of Up to 20% patients present with neck nodes
tongue, buccal mucosa, floor of mouth, gingival, which can be cystic mimicking a branchial cyst.
retromolar trigone and hard palate. The com- Evaluation includes history, examination of
monest site is lip followed by the lateral border the upper aerodigestive tract and neck and a flex-
of tongue and floor of mouth. 90% of cancers ible nasal endoscopy. Biopsy of the primary is
are SCC. essential as well as FNA of suspicious nodes.
MRI is indicated for loco-regional staging.
Presentation and evaluation
Management
Early cancers present as a white or red patch
which can progress to an ulcerative lesion. Other Early disease is usually treated with radiother-
presenting features include difficulty in eating apy, which results in better function compared
and ill fitting dentures. with surgery.
Evaluation includes detailed history, examina- Patients with advanced disease need a com-
tion of the lesion including palpation to assess bined approach with neck dissection followed by
local deep tissue infiltration. Trismus indicates chemoradiotherapy if the lesion is midline or
pterygoid muscle involvement with retromolar involving both sides. Patients with lateralised
lesions. Cranial nerve examination and regional lesions may be considered for radical resection
nodal examination should also be performed. with reconstruction followed by postoperative
radiotherapy. Alternatively, these patients can be
treated with primary chemoradiotherapy which
Management
may give local control rates comparable to
Early cancers (T1–2N0) of the lip and oral cavity surgery and less morbidity.
are curable either by surgery or by radiotherapy.
The choice is dictated by anticipated cosmetic Prognosis
outcome and availability of local expertise. In
Prognosis depends on site and stage. With
patients with positive margin or deep tumour
primary radiotherapy the local control rate is
(>5 mm), postoperative radiotherapy minimizes
>80% for early stage disease.
the risk of local recurrence.
The majority of advanced cancers (T3–T4N+)
Hypopharynx
are treated with a combination of surgery and
radiotherapy. The anatomical divisions of the hypopharynx are
pyriform fossa, postcricoid, and posterior pha-
ryngeal wall. More than 95% of cancers are epi-
Prognosis
thelial, predominantly SCC. The most frequent
The prognosis depends on the stage and site of site is pyriform fossa (60%) followed by postcri-
the tumour. Early lip cancers have cure rates of coid (30%) and posterior pharyngeal wall (10%).
90–100% with surgery or radiotherapy. Tumours Hypopharyngeal cancers are aggressive with
without lymph node involvement have a survival diffuse locoregional spread and early metastasis.
rate 65–90% depending on the site of the lesion. 60% of patients present with locoregional disease
and 15–25% have distant metastasis. The most
Oropharynx common site of metastasis is lung (80%) fol-
Anatomical divisions of the oropharynx include lowed by liver and bone.
the tongue base, the faucial arch, the tonsil
and tonsillar fossa, and the pharyngeal wall. Presentation and evaluation
The majority of tumours are SCC (85%) and Presenting features include progressive dys-
NHL can also occur in the tonsils (10% of phagia, odynophagia, hoarseness and a neck
tumours). The most frequent sites are the tonsils mass. Some patients present with a metastatic
and tongue base. neck node from an occult primary. 87
 II SITE-SPECIFIC CANCER MANAGEMENT

Evaluation includes endoscopy and biopsy. Prognosis

Local staging is with CT and MRI. Glottic cancers have the best prognosis with local
Management control rates of 90% for T1, 75% for T2 and
60% for selected T3 tumours. In patients who
Most patients present with locally advanced
recur, salvage surgery yields a 5-year cancer spe-
disease. Surgery involves total pharyngolaryngec-
cific survival of 95–100% for T1 and 85–90%
tomy with reconstruction, which is associated
for T2 tumours.
with significant morbidity. An alternative treat-
ment is chemoradiotherapy (with or without neo- Uncommon tumours of head and neck
adjuvant chemotherapy) which improves the
These tumours include adenoid cystic carcinoma,
chances of laryngeal preservation. Patients with
sarcomas and paragangliomas. Adenoid cystic
early disease can be treated with radical
carcinoma is characterised by perineural invasion
radiotherapy.
and late recurrences including lung metastasis.
Prognosis Surgery followed by radiotherapy is the treat-
Overall prognosis is generally poor (5-year sur- ment of choice.
vival of 15–65%). Sarcomas are treated with surgical excision
followed by postoperative radiotherapy if high
Laryngeal cancer grade or close/positive margins (p. 254).
Laryngeal cancer is the most common malig- Paragangliomas arise from neuroectodermal
nancy within the head and neck. 90% are SCC. tissue and the most frequent sites are carotid
The anatomical divisions are glottis, supraglottis body and jugulo-tympanic region. Surgery is the
and subglottis. Glottic cancers often present as treatment of choice and in patients who decline
T1 disease and have the best prognosis. surgery, radiotherapy is an option.
Presentation and evaluation Further reading
Hoarseness is the most common presentation. Argiris A, Karamouzis MV, Raben D, Ferris RL. Head and
Other features include pain, dysphagia, and neck cancer. Lancet. 2008;371:1695–1709.
odynophagia and referred earache. Presentation Grégoire V, Levendag P, Ang KK et al. CT-based delineation
as metastatic neck node can occur in supraglottic of lymph node levels and related CTVs in the node-
tumours. negative neck: DAHANCA, EORTC, GORTEC,
NCIC,RTOG consensus guidelines. Radiother Oncol.
Management 2003;69:227–236.
Machtay M, Moughan J, Trotti A t al. Factors associated
Early stage disease (T1–T2N0) is generally with severe late toxicity after concurrent chemoradiation
managed with either surgery or radiotherapy. for locally advanced head and neck cancer: an RTOG
Preservation of the voice is an important factor analysis. J Clin Oncol. 2008;26:3582–3589.
in determining treatment. In early stage disease Baujat B, Audry H, Bourhis J et al. Chemotherapy in locally
both conservation surgery and radiotherapy advanced nasopharyngeal carcinoma: an individual patient
data meta-analysis of eight randomized trials and 1753
offer similar survival. Radiotherapy is preferable patients. Int J Radiat Oncol Biol Phys. 2006;64:47–56.
where the extent of surgery will result in poor Emami B, Lyman J, Brown A et al. Tolerance of normal
voice. tissue to therapeutic irradiation. Int J Radiat Oncol Biol
Advanced stage patients are treated with an Phys. 1991;21:109–122.
organ preserving approach using chemoradio- Rivera F, García-Castaño A, Vega N, Vega-Villegas ME,
Gutiérrez-Sanz L. Cetuximab in metastatic or recurrent
therapy, provided there is no breach of the car- head and neck cancer: the EXTREME trial. Expert Rev
tilages of the larynx. Surgical management Anticancer Ther. 2009;9:1421–1428.
involves a total laryngectomy, with permanent Corry J, Peters LJ, Rischin D. Optimising the therapeutic ratio
tracheostomy. Voice rehabilitation is an essential in head and neck cancer. Lancet Oncol. 2010;11:287–291.
component of treatment in patients who undergo Dirix P, Nuyts S. Evidence-based organ-sparing radiotherapy
in head and neck cancer. Lancet Oncol. 2010;11:85–91.
a total laryngectomy. The options of voice Bernier J, Bentzen SM, Vermorken JB. Molecular therapy in
rehabilitation include voice prosthesis, oesopha- head and neck oncology. Nat Rev Clin Oncol. 2009;6:
geal speech and an electrolarynx. 266–277.
88
Cancers of the thorax
TV Ajithkumar and HM Hatcher
9
Lung cancer • Asbestos increases the incidence of mesothe-
lioma as well as lung cancer, particularly in
Epidemiology smokers.
• Radon, a radioactive gas released from granite
Lung cancer is the most common cause of death rock, accounts for around 2000 lung cancer
from cancer in the industrialized world. There deaths (6% of total) per year in the UK.
are 37,000 new patients per year in the UK and • Other industrial carcinogens include uranium,
170,000 per year in USA. Lung cancer is rarely arsenic, nickel and vinyl chloride.
diagnosed below 40 years, but the incidence rises
steeply thereafter with a peak at 75–84 years. Other risk factors
The median age at diagnosis is 60 years. The life • Lung diseases – previous tuberculosis, silicosis
time risk is 1 in 13 in men and 1 in 20 in women and fibrosing alveolitis may increase the
in the UK. Lung cancer is responsible for 25% risk of lung adenocarcinomas (called ‘scar
of all cancer deaths in the UK and 28% in USA. carcinomas’).
• Genetic factors – relatives of patients with
Aetiology lung cancer have a two-fold higher risk of
Smoking developing lung cancer than the general popu-
Smoking accounts for up to 92% of lung cancer lation. An increased lung cancer risk is
deaths in men and 80% in women. The age- observed in carriers of mutations of the TP53
adjusted relative risk of developing lung cancer gene and retinoblastoma (RB) gene and in
for people who smoke more than 20 cigarettes xeroderma pigmentosum, Blooms’s syndrome
per day is 20 times that compared with life-long and Werner’s syndrome.
non-smokers. This risk remains the same until • Previous malignancies – long-term survivors
approximately 5 years after smoking cessation of lung cancer are at risk of developing a
and even 15–20 years after stopping smoking second lung cancer. The risk of lung cancer is
there is 2–3 times the risk of developing lung also increased in breast cancer patients who
cancer, compared to life-long non-smokers. had radiotherapy and are smokers.
Passive smoking causes an average 24%
Pathogenesis and pathology
increase in the incidence of lung cancer compared
to non-smokers living with non-smoking part- Pathogenesis
ners. Passive smoking causes about 3% of the Lung cancer arises in the mucosa of the bronchi
lung cancers. or more rarely in the lung parenchyma. It has
been hypothesized that invasive lung cancer is the
Environmental and occupational hazards endpoint of a multi-step process as a result of
It has been suggested that up to 15% of cases in cumulative genetic abnormalities involved in the
men (5% in women) may be attributable to occu- regulation of epithelial cell growth and division
pational factors in conjunction with smoking. caused by carcinogens in tobacco smoke.

© 2011, Elsevier Ltd 89

DOI: 10.1016/B978-0-7234-3458-0.00014-2
 II SITE-SPECIFIC CANCER MANAGEMENT

Pre-invasive lesions Non-small cell lung carcinoma (NSCLC)

The two well-known pre-invasive lesions are NSCLC consist of the following types:
atypical adenomatous hyperplasia (AAH) and • Squamous cell carcinoma – which accounts
diffuse idiopathic pulmonary neuroendocrine cell for 30% of lung cancer, presents with large
hyperplasia (DIPNECH). AAH manifests as central lesions with associated atelectasis,
localized ground glass areas of less than 5 mm pneumonitis and hilar and mediastinal lym-
on high resolution CT scan and progresses to phadenopathy. Cavitation is seen in up to
invasive adenocarcinoma at an unknown rate. 10% of cases. Microscopically these tumours
DIPNECH manifests as small nodules and thick- show presence of keratin production and/or
ened bronchiolar walls associated with a mosaic intercellular bridges.
pattern of air trapping on CT scan, and is a pre- • Adenocarcinoma (30–35%) – the proportion
cursor of pulmonary carcinoid. of adenocarcinoma has been increasing over
Malignant lesions time with a relative decrease in squamous
cell and small cell carcinomas, and this trend
Box 9.1 shows a classification of lung tumours, is expected to continue. Adenocarcinoma
which is based on light microscopic assessment usually presents as small peripheral lesions
of patterns of differentiation. The most impor- with a high propensity for nodal and distant
tant distinction is between small cell carcinoma spread. A variant of adenocarcinoma called
(SCLC: 15–25% of lung cancers) and other bronchoalveolar carcinoma grows diffusely
carcinomas, collectively called non-small cell and has a characteristic appearance on chest
carcinoma (NSCLC). These subgroups behave X-ray mimicking slowly progressive or non-
differently in their presentation, natural history resolving ‘pneumonia’. Histological diagnosis
and response to treatment. is based on presence of neoplastic gland forma-
Small cell carcinoma (SCLC) tion or intracytoplasmic mucin. Immuno­
SCLC is a highly malignant neuroendocrine histochemical staining with TTF-1 (thyroid
tumour and typically presents as large central transcription factor-1 which is expressed by
masses with atelectasis and extensive mediastinal lung adenocarcinoma and thyroid cancer)
lymphadenopathy. Two-thirds of the patients helps to distinguish metastastic adenocarci-
have detectable metastases at diagnosis and there noma (TTF-1 negative) from lung carcinoma.
is a high risk of brain metastases. Microscopi- • Large cell carcinoma (10–20%) tends to be
cally these tumours consist of small round cells a relatively large peripheral lesion and has
with round or oval nuclei and nuclei and scant high propensity for regional lymph node and
cytoplasm. Immunohistochemically these stain distant metastasis. Microscopically this
for cytokeratin as well as neuroendocrine markers tumour is diagnosed by exclusion of all other
(e.g. neuron specific enolase). types of lung cancer.

Other neuroendocrine tumours

Box 9.1: Malignant tumour of lung These tumours have immunohistochemical (e.g.
• Squamous cell carcinoma and variants
chromogranin) or electron microscopic (neurose-
• Small cell carcinoma
cretory granules) evidence of neuroendocrine dif-
• Adenocarcinoma and variants including ferentiation. They represent 2% of lung tumours
bronchoalveolar carcinoma and have heterogeneous behaviour.
• Large cell carcinoma and variants
• Typical carcinoid can occur centrally or
• Adenosquamous carcinoma
peripherally, are not linked to smoking and
• Carcinomas with pleomorphic, sarcomatoid and
sarcomatous elements have an excellent prognosis. Microscopically
• Carcinoid tumours these tumours are composed of polygonal
• Carcinomas of salivary gland type cells arranged in distinct organoid, trabecular
• Unclassified or insular growth pattern. There will be <2
mitotic figures per 10 HPF and no necrosis.
90
 CANCERS OF THE THORAX 9
• Atypical carcinoid shows morphological fea- features of raised intracranial tension, focal neu-
tures of carcinoid with 2–10 mitotic figures rologic deficits, fits and mental and personality
per 10 HPF and/or necrosis. These are thought changes.
to be intermediate in behaviour between Paraneoplastic syndromes occur in up to 10%
typical carcinoid and SCLC. There is no evi- of patients. Box 9.2 lists the paraneoplastic
dence that there is progression from typical syndromes. SCLC is the most common type asso-
carcinoid to atypical carcinoid and SCLC. ciated with paraneoplastic neurologic syndromes.
• Large cell neuroendocrine carcinoma has a
worse prognosis than atypical carcinoid.
These tumours have features of neuroendo- Box 9.2: Paraneoplastic manifestations of
lung cancer
crine tumour but do not meet the criteria of
carcinoid, atypical carcinoid or small cell car- Nervous system
Multifocal encephalopathy1
cinoma. There will be prominent necrosis and
Cerebellar degeneration1
more than 10 mitotic figures per 10 HPF.
Limbic encephalitis1
Presentation Extrapyramidal syndrome1
Stiff-person syndrome1
More than 90% of patients are symptomatic at
Opsoclonus-myoclonus1
presentation of which approximately 30% are
Optic neuritis1
due to tumour, 30% are due to non-specific sys-
Sensorimotor polyneuropathy1
temic symptoms (anorexia, weight loss or fatigue)
Lambert–Eaton syndrome1
and 30% due to metastatic disease. Five percent Chronic gastrointestinal pseudo-obstruction1
of patients are asymptomatic and are detected
Endocrine
incidentally.
Syndrome of inappropriate ADH secretion (SIADH)1
Respiratory symptoms Humoral hypercalcaemia of malignancy2
Ectopic Cushing’s syndrome1,3
Cough is the most common presenting symptom
Ectopic hCG syndrome4
(70%), followed by dyspnoea (60%), chest pain/
Growth hormone excess3
discomfort (50%) and haemoptysis (41%).
Cardiovascular
Other symptoms Thromboplebitis2
Arterial thrombosis
Symptoms due to compression of recurrent laryn-
Marantic endocarditis
geal nerve (hoarse voice), phrenic nerve (breath-
lessness), brachial plexus (shoulder pain and/or Musculoskeletal and dermatological
Hypertrophic osteoarthopathy2,5
arm pain, sensory changes and muscle wasting in
Clubbing2,5
the distribution of C8 and T1–2 nerves) and sym-
Dermatomyositis
pathetic plexus (Horner’s syndrome) can occur.
Acanthosis nigricans5
Four percent of lung cancer patients present with
Erythema gyratum repens
superior venacaval obstruction (SVCO) and is
Acquired hypertrichosis lanuginosa2
most common with small cell lung cancer. Pleu-
Pruritus2,5
ritic chest pain and pleural effusion occurs in
Raynaud’s syndrome
pleural involvement. Pericardium involvement
Haematological
can present with pericardial effusion and rarely,
Haemolytic anaemia
tamponade. Rarely, dysphagia due to massive
Red cell aplasia
nodal disease compressing the oesophagus can
Thrombocytosis
occur.
Bone pain is the presenting symptom in up to Others
Nephrotic syndrome
25% patients. Liver involvement usually leads to
Hypouricaemia
pain if there is massive metastasis. Clinical
adrenal insufficiency is rare. Brain metastases at Commonly seen in 1small cell lung cancer, 2squamous cell
carcinoma, 3carcinoid, 4large cell carcinoma, 5adenocarcinoma.
diagnosis occur in up to 10% and present with
91
 II SITE-SPECIFIC CANCER MANAGEMENT

Hypercalcaemia either due to excess parathyroid nodes. CT is not reliable in assessing lymphaden-
hormone (PTH) or PTH-related peptides is opathy, to distinguish T3 from T4 disease and in
common in squamous cell carcinomas (15%). demonstrating chest wall invasion, which all are
Hyponatremia occurs in up to 10% of patients, important in making treatment decision.
which is either due to syndrome of inappropriate CT scan is useful in assessing resectability.
secretion of ADH (SIADH) or to atrial natri­ Encasement of proximal pulmonary arteries/
uretic factor. SIADH is commonly associated veins, gross mediastinal involvement by tumour,
with SCLC. widespread mediastinal lymphadenopathy and
distant metastasis on CT scan suggest an unre-
Signs sectable tumour (96% accuracy). Tumour inva-
A normal physical examination does not exclude sion of central pulmonary artery and vein,
lung cancer. involvement of main stem bronchus and tumour
extension across the major fissure (anywhere on
General: cachexia, finger clubbing, anaemia,
the left side, above the minor fissure on right),
enlarged supraclavicular lymph node, features
all suggest the need for pneumonectomy for com-
of SVCO and Horner’s syndrome (in upper
plete resection.
lobe tumours).
CT scan of brain is done if there is clinical
Chest: reduction of breath sounds over a lobe,
suspicion of brain metastasis or patient is planned
signs of lobar collapse, inspiratory crackles
to undergo curative treatment.
over a lobe, unilateral wheeze, features of
Bone scan is indicated if there is bone pain or
pleural effusion, rib tenderness.
isolated raised alkaline phosphatase.
Other systems: bone tenderness, hepatomeg-
aly, features of brain metastasis, peripheral
neuropathy and proximal myopathy. Tissue diagnosis
Flexible bronchoscopic biopsy can be obtained
Investigations and staging (Figure 9.1) in 60–70% of lung cancers (central tumours).
Evaluation of a patient with suspected lung Sampling using multiple techniques (biopsy,
cancer is to: brushings and washings) gives the highest diag-
nostic yield (sensitivity of 83–88%).
• establish histologic type
CT guided percutaneous needle aspiration/
• define extent of disease (staging)
biopsy – is useful in peripheral tumours. Core
• assess fitness to undergo the best appropriate
biopsies improve the sensitivity compared with
treatment.
aspirates. Complications include bleeding and
Imaging pneumothorax.
Fine needle aspiration is suitable for sampling
Chest X-ray (Figure 9.2A) may show lung lesion
lymph nodes, skin nodules and liver and adrenal
with or without lymphadenopathy. There can be
metastases. Pleural effusion requires aspiration,
associated lung collapse, pleural effusion, syn-
biochemical analysis and cytology together with
chronous nodules or pericardial effusion. Bone
multiple pleural biopsies.
metastases or bony destruction due to direct
Sputum cytology has wide variation in sensi-
invasion can also been seen.
tivity (10–97%) and should be reserved for
Contrast enhanced CT scan of chest, includ-
patients with central tumours who are unable to
ing upper abdomen (3–10% patients show
tolerate or unwilling to undergo bronchoscopy
asymptomatic liver and/or adrenal metastasis –
or other invasive procedures.
Figure 9.2B&C) should be performed prior
to further diagnostic investigations including
bronchoscopy. Staging
Lymph nodes of >1 cm in short axis diameter, Stage determines prognosis and guides treat-
a central low intensity suggesting necrosis and ment. TNM staging of lung cancer is given in
rounding of the contour of a hilar node where it Box 9.3. Small cell lung cancer can also be staged
meets the lung margin suggest malignant lymph using a simple staging classification (Box 9.4).
92
 CANCERS OF THE THORAX 9

• History – weight loss and performance status

• Clinical examination
• Chest x-ray (PA/lateral)
• FBC, biochemistry including Ca2+ and alk. phos
• Spirometry

• CT scan chest and abdomen

• Bronchoscopy and biopsy/percutaneous biopsy
• Brain CT/MRI (if radically treatable or symptoms)
• Bone scan (if bone pain or increased alk. phos)

Non-small cell lung cancer Small cell lung cancer

Is patient in any of these groups: Manage according to stage

• Candidate for surgery (figure 9.7)
• Candidate for radical radiotherapy
• Candidate for radical combination treatment
• Has limited (1–2 stations) N2/3 disease of Complete staging and manage
No
unknown significance and fit for surgery according to stage (figure 9.6)

Yes

PET scan

Definite distant metastasis or Suspicious of mediastinal disease Negative for mediastinal disease
high probability of N2/3 disease or distant metastasis and distant metastasis

Manage according to stage Histologic confirmation Manage according to stage

(figure 9.6) needed (figure 9.6)

Superior mediastinal nodes Aortic node Inferior mediastinal node Distant

(stations 1, 2, 3 and 4) (stations 5 and 6) (stations 7, 8 and 9) metastasis

Mediastinoscopy VATS Mediastinoscopy FNA/biopsy

EBUS EUS VATS
TBNA EUS

Complete staging and manage according to stage (figure 9.6)

Figure 9.1
Evaluation of lung cancer.

93
 II SITE-SPECIFIC CANCER MANAGEMENT

A B

Figure 9.2
Imaging in lung cancer.

radical chemoradiotherapy, whereas IIIB disease

is unresectable. This necessitates both an accu-
rate distinction of T3 from T4 tumours and an
accurate staging of nodal status. A classification
of mediastinal nodes is shown in Figure 9.3.
Methods of mediastinal staging
Positron emission tomogram (PET) (Figure 9.4)
– PET is scan based on the principle of differen-
tial uptake of 2-[fluorine-18]-fluoro-2-deoxy-D-
glucose (FDG) by cancer cells. FDG is metabolized
at a higher rate by tumour cells than normal cells
and the areas of increased activity can be detected
by a scanner. FDG-PET has higher sensitivity
C (87% vs. 68%), specificity (91% vs. 61%) and
accuracy (82% vs. 63%) at detecting mediastinal
disease than CT scan. PET also has a high nega-
tive predictive value in exclusion of N2/N3
SCLC can be classified as TNM staging or using
disease, which helps to omit further mediastinal
the simplied.
staging in case of a negative PET. Overall, there
is 20% improvement in accuracy of PET over CT
Mediastinal staging in non-small cell for mediastinal staging of NSCLC.
lung cancer PET also detects distant metastases. The inci-
Accurate distinction of stages II, IIIA and IIIB is dence of extra thoracic metastases on PET which
important in deciding optimal surgical treatment are not suspected by CT scan is 9 to 11%. CT
in the potentially operable patients. Stage II false-positive adrenal nodules have been cor-
disease is treated with lobectomy or pneumonec- rectly identified as negative on FDG-PET.
tomy with mediastinal sampling or dissection. One of the limitations of PET is false-positive
Stage IIIA disease may be treated with neoadju- ‘hot spots’ in the mediastinum due to inflamma-
vant chemotherapy followed radical surgery or tory processes (in up to 13 to 17%). It is less
94
 CANCERS OF THE THORAX 9

Box 9.3: Staging of non-small cell lung cancer

accurate when the lesion is <1 cm and in tumours
of low metabolic activity such as carcinoid and
Stage Ia
bronchoalvelolar carcinoma.
T1N0 Tumour ≤3 cm diameter
PET scan is recommended for all NSCLC
Stage Ib
patients being considered for radical treatment.
T2aN0M0 Tumour >3 cm or ≤5 cm OR
Tumour of ≤5 cm with
Patients with no lymphadenopathy on CT scan
involvement of visceral but with PET scan positive nodal disease needed
pleura, main bronchus ≥2 cm mediastinoscopy prior to definitive treatment as
distal to the carina or partial
atelectasis
50% of patients can have false positive PET scan.
Stage IIA MRI scan – has limited role in staging. This
T2bN0M0 Tumour >5 cm or ≤7 cm
may be useful to evaluate vascular and vertebral
T1-T2aN1M0 Metastasis in ipsilateral hilar or body invasion and to assess integrity of brachial
peribronchinal nodes plexus in Pancoast’s tumour.
Stage IIB Endobronchial ultrasound (EBUS) – EBUS is
T2bN1M0 able to penetrate up to 5 cm and can identify
T3N0M0 Tumour of >7 cm OR lymph nodes and vessels. It is helpful in visual-
Tumour invading chestwall,
diaphragm, phrenic nerves, izing paratracheal (stations 2 & 4) and peribron-
mediastinal pleura or parietal chial lymph nodes (see Figure 9.3) and enables
pericardium OR EBUS guided transbronchial needle aspiration
Tumour <2 cm from carina,
atelectasis of entire lung or (Figure 9.5). Sonographic features of malignant
nodule in the same lobe lymph node are round shape, sharp margins and
Stage IIIA hypoechoic texture. The advantage of EUS over
T4N0-1M0 Tumour invading mediastinal CT and PET is that it can characterize lymph
structures or nodule in different nodes smaller than 1 cm. It can also determine
ipsilateral lobe
T1-3N2M0 Metastases in ipsilateral the depth and extent of tumour invasion of tra-
mediastinal and/or subcarinal cheobronchial lesions and helps to define the
nodes relationships to the pulmonary vessels and the
Stage IIIB hilar structures. EBUS has been found to predict
T4N2M0 the lymph node staging correctly in 96% of cases,
anyT N3M0 Metastases in contralateral hilar
or mediastinal nodes with a sensitivity of 95% and specificity of 100%.
Metastases in scalene or Endo-oesophageal US (EUS) with fine needle
supraclavicular nodes aspiration is useful to assess sub-aortic (station
Stage IV 5), subcarinal (station 7), and paraoesophageal
M1a contralateral lung nodule/pleural (station 8) lymph nodes as well as the upper
nodule/malignant effusion
M2b distant metastasis
retroperitoneum, which are not accessed by
mediastinoscopy. It is envisaged that EUS-FNA
and EBUS will not replace but will complement
surgical techniques like mediastinoscopy.
Transbronchial needle aspiration (TBNA) –
TBNA using a flexible fibre optic bronchoscope
Box 9.4: Staging of small cell lung cancer has a sensitivity of 78% and high specificity
Limited stage (stage I-III) (approaching 100%) for identifying mediastinal
Tumour confined to the hemithorax of origin, the metastases. However, the diagnostic yield is
mediastinum, and the supraclavicular nodes, that can
be encompassed within a tolerable radiation therapy operator dependent.
port. Mediastinoscopy is generally regarded as the
Extensive stage (stage IV) gold standard for preoperative mediastinal evalu-
Tumor that is too widespread to be included within ation. CT scan is helpful in guiding selection of
the definition of limited-stage disease above. Patients patients for mediastinoscopy prior to surgery.
with distant metastases (M1) are always considered
to have extensive stage disease. Cervical mediastinoscopy allows better access to
contralateral lymph nodes. It is useful in evaluat-
95
 II SITE-SPECIFIC CANCER MANAGEMENT

Superior mediastinal nodes Brachiocephalic

(innominate artery)
1 Highest mediastinal
2 Upper paratracheal
Mediastinoscopy
EBUS 3 Pre-vascular and retrotracheal
TBNA 4 Lower paratracheal
2R 3
(including azygos nodes)
N2 = single digit, ipsilateral
N3 = single digit, contralateral or supraclavicular Ao
4R
Aortic nodes
Azygos vein 6
5 Subaortic Phrenic
10R nerve
(A-P window) PA
EUS Ao
VATS 6 Para-aortic 5
11R 7
(ascending aorta 11L PA
or phrenic) 10L
8
Inferior
9
mediastinal nodes 12, 13,14R 12, 13,14L
7 Subcarinal Ligamentum
Mediastinoscopy arteriosum
EUS 8 Paraeosophageal
VATS (below carina) Inferior pulmonary Left pulmonary
ligament artery
9 Pulmonary ligament
N1 nodes Right lung Left lung
10 Hilar Upper lobe – 2R, 3 and 4R Upper lobe – 2L, 4L, 5 and 7
11 Interlobar Middle lobe – 4R and 7 Lower lobe – 4L, 7 and 8
Lower lobe – 3, 7 and 8 Central – 3, 5, 6 and 7
12 Lobar Central – 2, 3, 4 and 7
13 Segmental
14 Subsegmental
Figure 9.3
The classification of mediastinal nodes, patterns of nodal spread and method of choice of staging.

ing paratracheal (2 & 4), scalene and inferior and referral to a team specializing in the manage-
mediastinal nodes (7, 8 & 9). It is not useful in ment of lung cancer. Treatment depends on type
evaluating aortic nodes (5 & 6). Mortality rates of lung cancer (NSCLC vs. SCLC), stage, per-
from mediastinoscopy are negligible, but mor- formance status, co-morbidities and cardiopul-
bidity rates especially arrhythmias are reported monary reserve.
to be 0.5–1%. It has to be borne in mind that up
to 30% of patients with lung carcinoma who Non-small cell lung cancer (Figure 9.6)
have a negative mediastinoscopy prove to have Stage I–II
mediastinal nodal metastasis at surgery.
Video-assisted thoracoscopy (VATS) is useful Patients presenting with stage I–II disease are
to evaluate aortic (5 & 6), paraoesophageal (8) generally treated with curative intent if perform-
and pulmonary ligament nodes (9). It is also ance status is good (0–1) and pulmonary func-
useful in assessing the pleural cavity and obtain- tion are adequate. The treatment options include:
ing pleural biopsies. • Surgery alone (if excision complete).
• Surgery followed by radiotherapy (in case of
Management of lung cancer microscopic residual disease).
Patients presenting with symptoms suggestive of • Surgery followed by chemotherapy (in selected
lung cancer need urgent evaluation (Figure 9.1) cases of IB & II).
96
 CANCERS OF THE THORAX 9

Abnormal uptake in lung

PET normal uptake
in brain and heart

Excretion of isotope
through renal system

Figure 9.4
PET scan in lung cancer.

• Radical radiotherapy (in patients who are A complete anatomical resection is achieved
unfit or unwilling for surgery). by one of the following procedures:
Radical surgery • Lobectomy is the most common procedure
Surgery offers the best prospect of cure in stage which carries a postoperative mortality of
I–II disease, but only 10–20% of patients are suit- 2–4%.
able for surgery. Surgery is aimed at complete • Pneumonectomy is indicated if the tumour
resection of the tumour and its intrapulmonary invades hilar structures (e.g. main bronchi,
lymphatics. Patients need careful preoperative main pulmonary artery) and has a higher
evaluation as they are often frail and frequently mortality rate (6–8%).
have cardiopulmonary morbidity due to chronic • Wedge or segmental resection is useful in
smoking. Spirometry is required in all patients. If patients with peripheral tumours and impaired
the FEV1 is less than 1.5 L for lobectomy and less lung function but carries a high rate of local
than 2 L for pneumonectomy, full lung function recurrence (3–5 times) and a lower survival
tests are required. Table 9.1 shows minimal pul- (reduce survival by 5–10%).
monary function required for different curative • Bronchoplastic or ‘sleeve’ resection is designed
treatments. All patients require an ECG and to spare lung tissue as an alternative to pneu-
patients with murmurs should have echocardio- monectomy. This procedure is used to resect
gram. Patients with known ischaemic heart disease endobronchial lesions at or adjacent carina to
should have detailed cardiologic assessment. preserve distal tissue.
97
 II SITE-SPECIFIC CANCER MANAGEMENT

A C

B D

Figure 9.5
Endobronchial ultrasound (A) and its use for FNA (B) of an enlarged lower paratracheal node (C&D).

Radical radiotherapy (Table 9.2) tumour localization and radiation delivery. Early
Patients with medically inoperable stage I/II are results suggest a 2-year local control of >90% in
treated with radical radiotherapy if lung function patients with stage I tumours with <5% signifi-
is adequate (Table 9.1). In the only randomized cant toxicity.
trial, radiotherapy was inferior to surgery (4-year
survival 7% vs. 23%). After conventional radical Postoperative treatment
radiotherapy (60 Gy in 30 fractions over 6 Radiotherapy
weeks), 2-year survival is about 20%. A UK There is no proven role for postoperative
MRC study showed that 2-year survival is better radiotherapy after complete surgical resection of
(20 vs. 29%) with continuous hyperfractionated stage I–II lung cancer. There is some suggestion
accelerated radiotherapy (CHART). This radio- that routine radiotherapy in N0–N1 disease sig-
therapy regime consists of 54 Gy in 36 fractions nificantly decrease survival. Hence radiotherapy
over 12 continuous days giving three fractions may be offered in incomplete resection and/or
per day with a minimum interval of 6 hours unexpected N2 disease (improve local control
between each fraction. with no effect on survival) if performance status
An evolving technique of stereotactic radio- and residual lung function permits. However,
therapy typically delivers high doses of radio- further studies are needed to define the exact role
therapy in 3–5 fractions using precise method of of radiotherapy in the adjuvant chemotherapy era.
98
 CANCERS OF THE THORAX 9

Non-small cell lung cancer

(completely staged)

Stage I and II Stage III A and Stage III B (dry) and • Stage III B (wet) and IV
WHO PS 0-1 WHO PS 0-1 • All stages with WHO PS
2 or more

Neoadjuvant Neoadjuvant
chemotherapy x 3 chemotherapy x 3
cycles cycles

Adequate cytoreduction
to treat with radical radiotherapy No
Fit for surgery
Options
Yes • Palliative chemotherapy*
• Biological agents
• Palliative radiotherapy
Radical • Supportive care
radiotherapy

Adequate cytoreduction No

Yes No Yes

Surgery or radical
radiotherapy

Surgery Radical radiotherapy Recurrence/progression

pT1 N0 pT2–4 and/or pT1-4 N2-3 Options

N1 • Palliative chemotherapy*
• Biological agents
• Palliative radiotherapy
Follow-up Consider adjuvant Consider adjuvant • Supportive care
chemotherapy chemotherapy and
mediastinal radiotherapy

Recurrence

Local recurrence Metastatic recurrence

consider options
chemo-radiotherapy • Palliative chemotherapy*
• Biological agents
• Radiotherapy
• Supportive care

Figure 9.6
Management of non-small cell lung cancer. *palliative chemotherapy is considered only in patients with good
performance status (0-2).
99
 II SITE-SPECIFIC CANCER MANAGEMENT

Table 9.1: Minimal pulmonary function for curative treatment

Test Pneumonectomy Lobectomy Radical radiotherapy
FEV1 ≥2 L ≥1.5 L Stage I & II: >1 L*
Stage III: >1.5 L$
FEV1/FVC ≥50 ≥50
FEF 25–75 ≥0.6 L ≥0.6 L –
PCO2 35–45 mmHg 35–45 mmHg –
PO2 >60 mmHg >60 mmHg –
Predicted postoperative FEV1 ≥1 L or 40% ≥1 L or 40% –
MVO2 >15 ml/kg/min ≥15 ml/kg/min –

*For peripheral tumours and small tumours (planning volume <150 cm3) >0.7 L.
$
For small tumours >1 L.

Table 9.2: Radiotherapy in lung cancer

Indication Technique Target volume Dose*
Incomplete resection CT-planned conformal Known area of residual 50 Gy/20 fractions
tumour identified by surgical (microscopic)
clips + 1–2 cm margin 55 Gy/ 20 fractions
(macroscopic)
Postoperative N2 CT-planned conformal Whole mediastinum + 1–1.5 cm 50 Gy/20 fractions or
disease margin 60 Gy/30 fractions
Radical radiotherapy CT planned conformal Radiological mass with 1–2 cm 55 Gy/20 fractions or
– stage I & II margin 64 Gy/32 fractions or ‘CHART’
Radical radiotherapy CT-planned conformal Radiological residual mass with 55 Gy/20 fractions or
– stage III 1–2 cm margin 64 Gy/32 fractions or ‘CHART’
Palliative Conventional Radiological disease +1–2 cm 39 Gy/13 fractions
margin 10 Gy in single
Thoracic radiotherapy CT-planned conformal Pre-chemotherapy tumour if 40 Gy/15 fractions
– small cell cancer feasible with adjacent
mediastinal nodes + 1.5 cm
margin

*V20 (volume of normal lungs receiving 20 Gy) should be less than 34% and spinal cord dose should be <38–40 Gy with 4 weeks’
treatment and <44 Gy with 6 weeks’ treatment.

Chemotherapy (Box 9.5) tin. 5-year overall survival in NCIC JBR 10 trial
In randomized trials, there is no survival benefit was increased from 54 to 69% in stage IB and II
with adjuvant chemotherapy for stage IA. In disease. In the ANITA trial overall survival was
stage IB and II, an early meta-analysis showed a not significantly different in stage IB (62% vs.
5% overall survival benefit with postoperative 63%) but was statistically significant in stage II
cisplatin-based combination chemotherapy. This (52% vs. 39%) resected NSCLC. More hetero-
has been supported by several recent trials of geneous trials which have allowed a wider range
cisplatin combinations. The NCIC JBR 10 and of tumour stages, more variety in chemotherapy
ANITA trials both used vinorelbine and cispla- combinations within the trial and less stand­
100
 CANCERS OF THE THORAX 9

Box 9.5: Chemotherapy regimes in lung cancer

The treatment options are:
Non-small cell carcinoma • Radical chemoradiotherapy (for T1–3N2
• Cisplatin 80 mg/m2 IV Day 1 + vinorelbine 30 mg/ disease with PS 0-1).
m2 IV Days 1&8. Cycle repeated 3 weekly.
• Surgery alone or with postoperative radio-
This regime is used in adjuvant chemotherapy trials.
therapy and/or chemotherapy (for unexpected
• Carboplatin (AUC 5) IV Day 1 + vinorelbine 25 mg/
m2 IV Days 1 & 8. Cycle repeated 3 weekly. N2 disease after resection).
• Carboplatin (AUC 5) IV Day 1 + gemcitabine • Neoadjuvant chemo-radiotherapy or chemo-
1200 mg/m2 IV Days 1 & 8. Cycle repeated 3 therapy followed by surgery (for T3 N1 and
weekly. small volume N2 disease, both with PS 0–1).
• Carboplatin (AUC 5) IV Day 1 + paclitaxel 175 mg/ • Radical radiotherapy (if chemotherapy con-
m2 IV Days 1 & 8. Cycle repeated 3 weekly.
traindicated, radical RT feasible & PS 0–1).
The above three regimes are equally effective.
• Palliative chemotherapy (not suitable for
• Docetaxel 75 mg/m2 IV Day 1. Cycle repeated
3-weekly. Used as second-line chemotherapy. radical radiotherapy and PS 2 or less).
• Symptomatic treatment and palliative radio-
Small cell lung cancer
• Carboplatin (AUC 5–6) + etoposide – is the usual therapy (PS 2 or more).
first line regime.
The IALT trial and meta-analysis showed at
• CAV (cisplatin, adriamycin and vincristine).
least a 5% survival advantage with adjuvant
• ACE (Adriamycin, cyclophosphamide and
etoposide. chemotherapy in resected stage IIIA disease. Sim-
• CAV & ACE are not given with concurrent ilarly, the ANITA trial also showed statistically
radiotherapy as adriamycin causes ‘radiation significant improved survival with adjuvant
recall’. vinorelbine and cisplatin in completely resected
• Oral topotecan. stage IIIA disease (42% vs. 26%).

Stage IIIB (T4 any N, M0/ any T N3 M0) without

malignant effusion
ardized surgical eligibility have provided less Treatment options are:
obvious benefits in survival (ALPI and European • Radical chemoradiotherapy (if PS 0–1 and
BIG lung trial). The IALT trial did however show disease can be radically irradiated).
a benefit in survival and the trial was closed early • Neoadjuvant chemoradiotherapy or chemo-
when the planned interim analysis showed a sig- therapy followed by surgery (selected group
nificant impact on survival with a median follow- with good PS).
up of 56 months. In summary, fit patients with • Radical radiotherapy (small radically
resected stage IB–II should therefore be offered treatable disease, PS 0–1, chemotherapy
four courses of a cisplatin combination chemo- contraindicated).
therapy within 12 weeks of surgery. • Palliative chemotherapy (not suitable for
Stage III radical treatment and PS not >2).
• Symptomatic and supportive care.
Stage IIIA (T1–3, N2 M0/T3 N1 M0)
Patients with stage IIIA comprise a complex and In young fit patients with stage IIIB disease due
heterogeneous group with varied treatment to involvement of adjacent structures, neoadju-
outcome. The result of surgery alone is poor and vant chemotherapy or chemoradiotherapy can be
the expected 5-year survival is between <10 and used to downstage the tumour and aim for surgi-
40%; it is dependent on the extent of mediastinal cal resection. There is a trend towards increased
nodal involvement. survival at least in the first 2 years for these
The treatment of choice is radical chemoradio- patients particularly when chemotherapy is given
therapy if good performance status (0–1). Patients concurrently with radiotherapy. Trials have
with small volume N2 disease can be considered examined dose and scheduling and concluded
for surgery after neoadjuvant chemotherapy or that full dose chemotherapy concurrently with
chemoradiotherapy. radiotherapy was most beneficial.
101
 II SITE-SPECIFIC CANCER MANAGEMENT

Stage IIIB with malignant effusion/stage IV which cannot be encompassed in a radical radio-
Patients with malignant effusions (IIIB) or meta- therapy field or with co-morbidity. An MRC
static disease (IV) are incurable and both carry study showed that for such patients with per-
a similar prognosis. The treatment aim is pallia- formance status 0–1, high-dose palliative radio-
tive with the intention of improving symptoms therapy (39 Gy in 13 fractions, if no spinal cord
as much as disease control. Treatments will in the field or 36 Gy in 12 fractions, if cord in
be greatly affected by patient fitness as these the radiotherapy field) results in better 2-year
patients will often be frail and suffer several co- survival (13% vs. 9%) compared with 17 Gy in
morbidities. Many trials have examined the role two fractions. Patients who need relief of local
of chemotherapy versus best supportive care in symptoms due to primary tumour or metastases
this group. Overall chemotherapy has a response are treated with palliative radiotherapy. This is
rate of 20–40% with a duration of 6 months and either 10 Gy single fraction (PS >2), or 17 Gy in
a median overall survival of less than 1 year. The two fractions (PS 2). The side effects of large
survival benefit from chemotherapy is in the fractions include nausea, acute chest pain and
range of 6–8 weeks. Response rates for an indi- fever.
vidual reflected overall survival in a meta-analy-
sis. Frequent assessment prior to chemotherapy Relapsed pre-treated NSCLC
with CXR is recommended to assess response. In the small number of stage IIIB/IV patients who
Chemotherapy has been associated with sym­ have received previous platinum-based chemo-
ptomatic benefits such as reduced palliative therapy and relapse whilst still fit, second line
radiotherapy requirements, reduced analgesia, chemotherapy can be considered. Docetaxel has
weight stabilization and maintenance of per- shown good activity and improved median sur-
formance status. Toxicity was frequently seen, vival of 3 months over best supportive care in
worse with combination chemotherapy but this subset of patients. Re-irradiation is an option
quality of life studies showed that these were not if >6 months after previous radiotherapy and it
perceived as worse compared with patients not is possible to avoid spinal cord.
on chemotherapy. Erlotinib has shown a survival advantage of 2
In general, chemotherapy has a greater benefit months and improved symptom control when
in fit patients of good performance status (WHO used in combination with chemotherapy. In the
0 or 1). In these patients combination chemo- UK, erlotinib is recommended as a clinically and
therapy (a platinum and other agent such as cost-effective alternative to docetaxel for the
vinorelbine or gemcitabine) can be offered. A second line treatment of NSCLC.
recent study has shown that a combination of
cisplatin and pemetrexed improves overall sur- New agents
vival in patients with locally advanced or meta- Understanding some of the molecular mecha-
static adenocarcinoma (12.6 vs. 10.9 months) nisms in NSCLC has led to the development of
and large cell carcinoma (10.4 vs. 6.7 months) new targeted therapies. The mechanisms of these
compared with cisplatin and gemcitabine. In the are common to several malignancies (see
less fit or elderly single agent treatments, pallia- Appendis, p. 370). The most successful agents in
tive radiotherapy, biological agents or appropri- NSCLC are those targeted against the epidermal
ate trials can be considered. growth factor receptor (EGFR). Two oral drugs
Recently phase III studies have shown that which inhibit the tyrosine kinase domain of the
maintenance treatment with pemetrexed and EGFR are erlotinib (Tarceva™) and gefitinib
erlotinib are useful in patients who had not pro- (Iressa™). Toxicity with these drugs is unlike
gressed after first line chemotherapy. standard chemotherapy drugs and includes a
characteristic rash which often reflects drug
Palliative radiotherapy activity, diarrhoea and pneumonitis (reported in
A significant number of patients may need radio- gefitinib in a Japanese study). The patients most
therapy to palliate symptoms. There will be a likely to benefit from these drugs are female,
subgroup of patients with large localized NCSLC those with an adenocarcinoma (especially bron-
102
 CANCERS OF THE THORAX 9

Small cell lung cancer

(completely staged)

Limited stage Extensive stage

Palliative chemotherapy
Performance status and/or radiotherapy Performance status
No No
0–2 • 0–2
Supportive care
Yes Yes

Chemotherapy with platinum

Chemotherapy with platinum and etoposide for 4–6 cycles
and etoposide for 4–6 cycles
•
Thoracic radiotherapy begins with Assess response after
1st / 2nd cycle of chemotherapy, 3 cycles
if feasible
•
Prophylactic cranial radiotherapy
with/after last cycle of chemotherapy Complete response (CR) at distant sites
or likely to achieve CR at distant sites

No Yes

Recurrence/progression Continue up to 4–6 Consider

cycles and follow-up thoracic radiotherapy
Options
• Second line chemotherapy
• Palliative radiotherapy
PCI for all patients
• Supportive care
with a response
• Clinical trial

Figure 9.7
Management of small cell lung cancer.

choalvelolar subtype), be non-smokers and be Small cell lung cancer (Figure 9.7)
Asian. At the molecular level, increased EGFR Small cell lung cancer (SCLC) accounts for 20%
protein expression, gene amplification and the of lung cancer. Up to 60% have extensive stage
presence of EGFR mutations in the tyrosine disease at diagnosis.
kinase domain increase patient response. A recent
comparative study of gefitinib with a combina- Limited stage disease
tion of carboplatin and paclitaxel (IPASS study) The standard treatment for patients with good
has shown that gefitinib results in a better pro- performance status (0–2) and no significant co-
gression free survival in patients with EGFR+ morbidity is combination chemotherapy with
tumours. platinum regime with concurrent thoracic radio-
A randomized study (E4599) showed that a therapy and prophylactic cranial radiotherapy.
combination of bevacizumab (anti-VEGF) with In 5–10% of patients with SCLC limited to
chemotherapy improves survival by 2.3 months lung, diagnosis is established only after resection.
in patients with untreated advanced non-squa- These patients need adjuvant chemotherapy as
mous cell lung cancer. there is high likelihood of development of distant
103
 II SITE-SPECIFIC CANCER MANAGEMENT

metastasis. Role of surgery in early stage disease therapy. Some others use a radiotherapy regime
is not well established. Surgery following com- of 50 Gy in 25 fractions. One study shows that
plete or partial response to chemotherapy is not twice-daily concurrent radiotherapy is better
beneficial. than once daily radiotherapy.

Chemotherapy (Box 9.5) Prophylactic cranial irradiation (PCI)

Chemotherapy remains the mainstay of treat- Brain metastases are present at the time of diag-
ment of small cell lung cancer. Randomized trials nosis of small cell lung cancer in up to 10%
have shown that multiple agent chemotherapy is patients. Another 40–50% of patients develop
better than single agent in terms of response rate brain metastases during the course of illness sug-
and survival. gesting that brain metastases are a common
Meta-analysis showed that cisplatin regime cause of treatment failure.
results in higher response rate (69% vs. 62% p < A meta-analysis of PCI for patients with SCLC
0.001) and lower risk of death at 12 months (OR in complete remission showed that PCI reduces
0.80 CI 0.69–0.93; p = 0.002) for both localized the risk of brain metastasis by 54%, the risk of
and extensive SCLC. Platinum based regime has death is reduced by 16%, contributing to an
less mucosal toxicity, less myelo­suppression and increase in 3-year survival of 5.4% (20.7% vs.
is easier to combine with radiotherapy than 15.3%). There is no evidence of differential
anthracycline-based regimes. Though there is no benefit with age or radiation dose. Though,
conclusive evidence that carboplatin-etoposide is optimal timing of PCI is not clear, it is recom-
similar in efficacy to cisplatin-etoposide, the mended that PCI should be administered without
former regime is easier to administer and the delay after primary treatment. There is no con-
current clinical practice resides with using cispla- clusive data on optimal dose of radiotherapy.
tin where survival is the primary aim and carbo- 30 Gy in 10 fractions over 2 weeks is the com-
platin where palliation is the primary aim. monly used regime in the UK. Other regimes
There is no established role for maintenance include 20 Gy in 10 fractions, 30 Gy in 15 and
chemotherapy and patients are treated with 4–6 36 Gy in 18 fractions. Since there is some concern
courses of chemotherapy. Dose intensification about the risk of long term neurological toxicities
leads to increased toxicities with no survival such as cognitive impairment and ataxia, PCI
advantage over standard dose chemotherapy. may be avoided in patients older than 70 years
and those with cerebrovascular disease.
Radiotherapy
Thoracic radiotherapy Extensive stage
Thoracic radiotherapy is indicated for patients Chemotherapy is the main modality of treatment
with limited stage SCLC. A meta-analysis showed and a recent Cochrane review showed that in
that addition of radiotherapy reduced the risk patients with extensive SCLC chemotherapy pro-
of death by 14% which is equivalent to 5% longs survival. One of the regimes shown in Box
absolute increase in 3-year survival. In terms of 9.5 is used.
intra-thoracic control, there is 25% absolute In patients with extensive disease who achieve
improvement with addition of radiation at an complete response at extra-thoracic sites after
expense of 1.2% absolute increase in the risk of primary chemotherapy, thoracic radiotherapy
treatment related mortality. Interruption of radi- improves survival to a similar extent as that of
otherapy results in lower survival (median sur- limited stage disease. A recent randomized study
vival 14 vs. 16 months). Patients who continue has shown that patients with extensive SCLC
to smoke during radiotherapy also have a lower (aged 18–75 years) who had a response to chem-
survival (median survival 14 vs. 18 months). otherapy, would benefit from PCI. Patients who
While the optimal dose and fractionation of received PCI has a lower risk of brain metastases
radiotherapy remains unclear, most clinicians use (1-year risk of 15% vs. 40%), and better 1-year
40 Gy in 15–20 fractions over 3 weeks which is survival (27% vs. 13%). The commonly used
given concurrently with 1st, 2nd cycle of chemo- radiotherapy regime in this study is 20 Gy in five
104 therapy if feasible or at the end of the chemo- fractions.
 CANCERS OF THE THORAX 9
Second-line chemotherapy primary tumour and supraclavicular fossa giving
The median survival following relapse after first- 45 Gy in 25 fractions) reported a complete resec-
line chemotherapy is approximately 4 months. tion of tumour in more than three-fourths of the
There are two groups: the sensitive group who patients and an overall 5-year survival of 44%. In
have previously responded and who have had a this study, surgery was done 3–5 weeks after
relapse-free-interval of at least 3 months and the chemoradiotherapy and additional two courses of
resistant group who do not fit in the sensitive chemotherapy were given postoperatively.
group. The sensitive group may be re-induced Selected series of radical radiotherapy (60–
with same type of first-line chemotherapy. Of 66 Gy) alone report a 5-year survival of up to
patients with sensitive disease 30–40% respond 40%.
to second-line chemotherapy (median survival 6 In summary, patients with operable tumours
months), while less than 10% of patients with and good performance status (0–1) are treated
resistant disease will respond to chemotherapy. with chemoradiotherapy followed by surgery
The commonly used second line chemotherapy and postoperative chemotherapy. Patients with
regimes are CAV or oral topotecan (Box 9.5). medically inoperable or locally advanced tumours
with good PS are treated with either radical radi-
Prognostic factors and survival otherapy or chemoradiotherapy. Patients with
In general, performance status is the best predic- metastatic disease or with poor PS are treated
tor of outcome in lung cancer. In early stage symptomatically.
NSCLC, tumour staging and nodal status are
important prognostic factors. Carcinoid tumours
In advanced stage NSCLC, females have better Localized carcinoid tumour is treated with
prognosis. Significant weight loss (>10% within surgery. Typical carcinoids are low-grade malig-
last 3 months) and large cell histology indicate nancies which are usually treated with excision,
poor prognosis. An early response to treatment with parenchyma-sparing sleeve or bronchoplas-
implies a longer survival. tic resections indicated whenever possible. Atypi-
Good performance status, female gender and cal carcinoids are aggressive malignancies, and
limited stage predict prolonged survival in small radical surgical resection is indicated. Locore-
cell lung cancer. gional failure rates of 8% have been reported for
5-year survival by non-small cell lung cancer typical carcinoids and 23% for atypical carci-
by stage is as follows: noids. Role of adjuvant treatment is unknown.
Stage I 60–80% Up to 64% of patients with atypical carcinoid
Stage II 25–40% can develop systemic metastases at a median time
Stage IIIa 10–40% of 17 months after diagnosis.
Stage IIIb & IV <5%
Combination chemotherapy using the regimes
as in SCLC is used to treat metastasis
30–40% of limited stage SCLC patients survive carcinoid.
2 years median survival 18–20 months). Median
survival of extensive stage SCLC is 10–12 months. Mixed small and non-small cell lung cancer
A small proportion of patients (2%) present with
Special situations
mixed small and non-small cell lung cancer.
Superior sulcus tumour There is no clear recommendation for manage-
Superior sulcus tumour (Pancoast’s tumour) typi- ment of these tumours exists. Hence treatment
cally presents as T3/T4 lesion. Accurate staging is should be individualized based on the stage of
important in the optimal management of these the disease and general condition of patients.
tumours. Recent studies indicate that a subgroup Although, there is no role for surgery for pure
of patients without distant metastasis can be small cell lung cancer; patients with localized
managed with combined modality approach. A mixed tumours may be candidates for aggressive
recent phase II study of concurrent chemoradio- surgery or chemo-radiotherapy (similar to
therapy (two cycles of combination chemotherapy NSCLC as it requires higher dose of radiotherapy
with cisplatin and etoposide and radiotherapy to for optimal long term control). Patients with 105
 II SITE-SPECIFIC CANCER MANAGEMENT

poor performance status or metastatic disease are tion (conflicting results). Patients with meta-
treated with palliative measures. chronous brain recurrence after a curative
resection are also considered for resection ±
Lung cancer in never smokers
WBRT or radiosurgery.
Never smokers are those who have smoked less
than 100 cigarettes in their lifetime. Studies
suggest that environmental tobacco smoke is Palliative care issues
a common cause of these cancers. Other risk Despite recent advances in treatment, many
factors may also contribute. Women are more patients with SCLC and NSCLC will progress
commonly affected than men. Adenocarcinoma and eventually die of their disease. Patients with
is more common, particularly the bronchoalveo- advanced disease can present with a number of
lar carcinoma subtype. Treatment is essentially problems which require specialist services.
the same as that of smokers. However, recent • Bone metastases are very common and can
data suggest that this group of patients have a result in pain and spinal cord compression (p.
higher response rate and better survival with 328). Pain can be improved using radiother-
EGFR tyrosine kinase inhibitors such as erlotinib apy with a single 8 Gy fraction or 20 Gy in
and gefinib (see IPASS study, p. 102). five fractions for spinal cord compression.
Multiple primary lung cancer • Haemoptysis: invasion of vessels by expanding
2–4% patients can present with multiple primary tumours can result in haemoptysis which can
lung tumour which can be either synchronous be significant. Palliative radiotherapy (10 Gy
(detected simultaneously) or metachronous single fraction) may alleviate the bleeding but
(detected after an interval). However it is often other measures can be used, e.g. cryotherapy.
difficult to distinguish this from a metastasis from • Superior vena cava obstruction can occur and
the lung tumour. Patients with multiple primary should be treated as an emergency (p. 337).
cancers are managed as two individual tumours. Steroids should be given in the first instance
and radiotherapy (20 Gy in five fractions) is
NSCLC with solitary metastases successful at reducing symptoms in 60%.
A small subset of patients present with isolated • Hypercalcaemia can be due to bone metas-
extrathoracic metastasis either after radical treat- tases or the production of a PTH like peptide.
ment or at presentation. Studies show that in It should be tested for regularly in advanced
patients with good performance status, resection lung cancer to prevent it presenting as
of the lung tumour and metastasis with or without an emergency (p. 339). It is treated with
systemic treatment result in improved survival. hydration, bisphosphonates and treatment of
In patients with synchronous isolated adrenal the underlying cancer if that is possible.
metastases, this approach results in a 5-year sur- • Stridor is a rare but distressing symptom
vival of 10–23%, whereas in those with isolated caused by compression of the proximal
metachronous adrenal metastasis occurring >6 airways, usually by tumour or lymph nodes.
months after initial curative treatment, the 5-year Initial supportive care includes assessment of
survival is around 38%. Of those with recurrence the airway by otolaryngologist, steroids and
in <6 months, none survive for 2 years. oxygen (p. 339). If severe, heliox, a mixture
In patients with synchronous isolated brain of helium and oxygen where the small particle
metastases with complete resection of all disease, size of helium facilitates delivery of the
the reported 5-year survival is 21%. Hence syn- oxygen, can be given. Treatment of the com-
chronous brain metastasis in a fully staged pressive lesion (e.g. radiotherapy to the nodal
(including PET scan) resectable stage I–II lung mass) may be the only option to prevent pro-
cancer patient with good performance status is gression of stridor.
treated with resection or radiosurgical ablation • Breathlessness is the most common symptom
with complete excision of the primary tumour. in advanced NSCLC and can be debilitating.
They also need systemic treatment as well as Investigations should be done to rule out
whole brain radiotherapy (WBRT) after resec- significant pleural effusion and pulmonary
106
 CANCERS OF THE THORAX 9
emboli as these are both treatable. Assuming lioma. However, smoking combined with asbes-
the breathlessness is due to tumour progres- tos exposure increases the risk of lung cancer.
sion and no further active treatment is pos-
sible, simple measures such as the use of a fan, Pathogenesis and pathology
teaching relaxation techniques and the cau- Pathogenesis
tious use of oral morphine, which causes dila- Amphiobile (blue and brown) asbestos is strongly
tation of smooth muscle walls in blood vessels linked to mesothelioma. It is postulated that the
leading to an improvement in symptoms, can thin and long fibres of amphiboles when inhaled
be helpful. Overall lung cancer patients often could penetrate and scratch the pleural surfaces.
have an array of palliative care needs such The chromosomal changes caused by fibres as they
that specialist in symptom control should be pierce the mitotic spindle as well as free radical
involved at an early stage. formation from the fibres cause malignancy. The
Follow-up possibility of relationship between simian virus 40
(SV40) and mesothelioma is still debatable. Recent
Role of follow-up in patients after curative treat- studies suggest a possible genetic susceptibility to
ment for NSCLC remains controversial. For asbestos-induced carcinogenesis.
patients with potentially curative re-treatment,
it is reasonable to cover routine follow-up 3–6 Pathology
monthly for 2 years and 6–12 monthly there­ There are four histological subtypes of meso­
after, with clinical examination and radiological thelioma:
evaluation. The role of routine follow-up after
treatment for SCLC is less clear. • Epithelial (40%) – associated with pleural
Some evidence suggests that continued smok­ effusions and better prognosis.
ing adversely affects the overall prognosis and • Sarcomatoid (20%) – ‘dry’ mesothelioma.
hence discouraged. • Mixed (35%).
• Undifferentiated (5%).
Mesothelioma The important histopathological diagnosis is
adenocarcinoma, which is differentiated immu-
Introduction nohistochemically. Mesothelioma is positive for
Mesothelioma is an aggressive tumour arising calretinin, WT1 (Wilms’ tumour 1) antigen, epi-
from the cells of pleura and peritoneum. Cur- thelial membrane antigen (EMA) and cytokeratin
rently just over 2000 new cases are diagnosed in 5/6 and negative for cytokeratin 7, 8, 18 & 19,
the UK annually and the number of cases is TTF-1, BER-EP4 (mostly), CEA and MOC. The
expected to peak in 2015. In the USA, 2000 new converse is diagnostic of adenocarcinoma.
cases are diagnosed annually and the incidence Presentation
is declining. Widespread use of asbestos after
World War II correlates with the anticipated The usual presentations are exertional dyspnoea,
increase in Europe within the next 15 years. The chest pain or pleural effusion. Weight loss, fatigue,
median age at diagnosis is 60 years and males are cough and paraneoplastic fever are also common.
five times more commonly affected than females. Right hemithorax (65%) is more often affected
than left (35%) and 3% cases are bilateral.
Aetiology
Investigations and staging
Mesothelioma is the most strongly linked cancer
to occupation. It is estimated that 80–90% of Imaging
mesothelioma cases or deaths in men are caused Chest X-ray and CT scan (Figure 9.8) are the
by occupational exposure to asbestos. The latency initial methods of imaging. Chest X-ray shows
period after exposure ranges from 15–50 years. evidence of pleural thickening, pleural effusion
Shipbuilding and construction are the industries and volume loss. CT scan shows unilateral
which used to involve high exposure of asbestos. pleural effusion, nodular pleural thickening and
Smoking does not increase the risk of mesothe- tumour encasement of the lung (‘rind like’
107
 II SITE-SPECIFIC CANCER MANAGEMENT

Staging
The recommended staging system is the Inter­
national Mesothelioma Interest Group (IMIG)
staging system, which is based on clinico-patho-
logical tumour variables and nodal classification
that of lung cancer (Table 9.3).

Management
There is no standard of care and only a minority
of patients (10–15%) are eligible for any poten-
tially curative treatment. The majority of patients
(85–90%) presents with advanced disease with
medial survival of less than 12 months and 5-year
A survival of ≤1%. Suitable patients with stage I
and II disease may be treated with radical surgery
or multimodality treatment aimed at long-term
survival.

Surgery
There are no randomized data on the benefits of
surgery. Radical treatment involves resection of
the entire parietal and visceral pleura en bloc
with underlying lung, ipsilateral pericardium
and diaphragm called extrapleural pneumon­
ectomy (EPP). Historical series suggest 5-year
survival of 10–20% with EPP. The MARS trial
(Mesothelioma and Radical Surgery) is aimed to
B
determine whether EPP is better than no surgery
Figure 9.8 in terms of survival and quality of life. However
Imaging of mesothelioma. the majority of patients are not suitable for such
extensive surgery. It has a reported morbidity
appearance – seen in 70% of cases) leading to up to 60% and mortality of 3.4% in expert
contraction of hemithorax. Calcified plaques are hands.
found in 20% of patients. Chest wall invasion Palliative surgery involves pleurectomy or
leads to obliteration of extrapleural fat planes, decortication. It is an option for palliation of
invasion of intercostal muscles, displacement of breathlessness caused by effusion when standard
ribs, or bone destruction. treatment options failed. The exact benefits of
PET scan is helpful in distinguishing benign these procedures are not well-defined.
from malignant pleural masses and to detect Radiotherapy
extrathoracic and nodal disease. Recent studies
report increasing usefulness of PET scan in defin- Mesothelioma is not a radiosensitive tumour.
ing prognostic group and to assess response to However, radiotherapy is still used in the follow-
chemotherapy. ing settings:
• Prophylaxis of thoracic tract seeding – to
Tissue diagnosis avoid mesothelial cell seeding down the tracts
Histopathological diagnosis should be made in after thoracoscopies and drains. There is no
all cases using cytological analysis of pleural fluid convincing evidence for this indication (three
or pleural biopsy done either under radiological small trials; one showed benefit and two did
guided or by VATS. A cell block prepared from not). Radiotherapy dose is 21 Gy/3 fractions
108 at least 500 ml of pleural fluid is often helpful. over a week using electrons.
 CANCERS OF THE THORAX 9
Chemotherapy
Table 9.3: IMIG staging system
for mesothelioma Although chemotherapy is used a part of multi-
modality treatment, many regimes have poor
Stage
response to treatment and severe toxicity. Many
Ia
chemotherapy studies using single or combina-
T1aN0M0 Limited to parietal pleura; no
involvement of visceral
tion regimens showed an objective response rate
pleura. of <20% with no impact on survival. A system-
Ib atic study suggested cisplatin as the most active
T1bN0M0 Limited to parietal pleura: single agent. The antifolate agent, pemetrexed,
scattered foci involving which inhibits enzyme thymidylate synthetase,
visceral pleura. represents the recent advance in chemotherapy.
II A recent randomized study of 456 patients with
T2N0M0 Ipsilateral pleura with (i) PS 0–1, cisplatin with pemetrexed vs. cisplatin
involvement of diaphragmatic alone showed a superior response rate (41.3 vs.
muscle or (ii) confluent
16.7%; p < 0.001), median survival (12.1 vs. 9.3
visceral pleural tumor or
extension from visceral pleura months; p = 0.02), and time to progression (5.7
into the lung parenchyma. vs. 3.9 months; p = 0.001). Neutropenia was the
III
commonest toxicity in the combined arm. The
T3N0M0 Ipsilateral pleura with recommended dose of pemetrexed is 500 mg/m2
involvement of the given IV on day 1 followed by cisplatin 75 mg/
endothoracic fascia, or m2 of each 21 day cycle for 4–6 cycles. There are
extension into mediastinal no data on benefit of chemotherapy beyond six
fat or solitary resectable
extension of chest wall or
courses.
non transmural involvement In elderly patients, carboplatin is often substi-
of pericardium. tuted for cisplatin and data from phase II studies
T1–3N1M0 Ipsilateral bronchopulmonary suggest similar efficacy.
or hilar nodes.
T1–3N2M0 Ipsilateral mediastinal or
internal mammary nodes/
Palliative care
subcarinal nodes. Recurrent pleural effusion is a debilitating
IV problem. Talc pleurodesis seems to give the best
T4N0M0 Diffuse or multiple chest results with low morbidity. Alternate option is
wall involvement; PleurX catheters with repeated drains.
transdiaphragmatic extension Management of other symptoms follows the
to peritoneum; direct
extension to contralateral
same principle of any advanced cancer.
pleura; mediastinal organ
extension; extension to spine; Prognostic factor and survival
extension to internal surface
There are two prognostic predictive models:
of pericardium or involvement
of myocardium. EORTC and Cancer and Leukaemia group-B
Any T, N3M0 Contralateral mediastinal (CAL-B). EORTC system (Table 9.4) distin-
nodes; contralateral internal guishes patients with mesothelioma as good
mammary nodes or any (median survival 10.8 months) and poor (5.5
supraclavicular nodes.
months) prognostic groups, where as CAL-B
Any T, Any N, M1 Distant metastases present.
distinguishes six groups with median survival
ranging from 1.4 months to 13.9 months. Table
9.4 shows the EORTC prognostic index.
• Palliative radiotherapy –to relieve pain.
• Adjuvant radiotherapy following EPP – no Medicolegal implications
randomized trial data. One phase II trial Mesothelioma is a notifiable disease. Patients
reported reduced local recurrence and pro- diagnosed to have mesothelioma are automati-
longed survival. cally eligible for some benefits and allowances. 109
 II SITE-SPECIFIC CANCER MANAGEMENT

survival 13.1 months). Surgery alone may be

Table 9.4: EORTC prognostic index adequate for indolent well-differentiated tumours
of mesothelioma
and multicystic mesothelioma variants (both
Prognostic factor Score
variants are common in young women and arise
Sex Male +0.60 from the pelvic peritoneum).
Performance status 1 or 2 +0.60 Patients with poor performance status are
Histological diagnosis Possible or probable +0.52 treated with symptomatic and supportive care.
The overall median survival is around 12 months.
Sarcomatous type Yes +0.67
WBC count >8.5 × 109/L +0.55 New agents and future direction
Calculate total score by adding all the individual Since the success of pemetrexed, there have been
scores which can be 0–2.94 attempts to improve survival with targeted agents.
Most mesotheliomas overexpress EGFR and
Good prognosis Poor prognosis there have been phase II trials with two EGFR
Outcome (total score (total score
measures ≤1.27) >1.27) small molecules, gefitinib and erlotinib. Gefitinib
Median survival 10.8 months 5.5 months
showed limited activity in less than 10% and erlo-
tinib did not produce any responses. TKIs which
1-year survival 40% 12%
act on the VEGF pathway have also been exam-
2-year survival 14% 0% ined (p. 372). Both sorafneib and vatalanib have
shown a small number of responses in pretreated
patients. However, bevacizumab, the monoclonal
antibody against VEGF, showed no improvement
in survival or response when compared with
Peritoneal mesothelioma chemotherapy alone in a randomized trial.
Mesothelioma can also arise from peritoneal There is some interest in the antineoplastic
and pericardial cavities. Malignant peritoneal ribonuclease, rapirnase, which is isolated from
mesothelioma consists of up to 10–15% of all frogs’ eggs. In 81 patients who had evaluable
mesotheliomas and presents with abdominal disease and progressed after chemotherapy, there
symptoms due to ascites and tumour mass. The were four partial responses, two minor responses
majority of patients present with diffuse perito- and 35 patients achieved stable disease with a
neal mesothelioma which is characterized by median overall survival of 6 months.
multiple nodules involving the entire peri­toneal
surface. Tissue diagnosis is by biopsy and it is Thymoma
important to rule out associated pleural disease.
Treatment options include systemic chemo- Introduction
therapy, cytoreductive surgery with or without Thymoma is an epithelial tumour arising from the
intraperitoneal chemotherapy and radiotherapy. thymus accounting for nearly half of all primary
Patients with good PS (0–1) with diffuse disease mediastinal tumours. It presents with a spectrum
and no extraperitoneal spread are considered of manifestations and has a wide ranging progno-
for maximal cytoreduction and intraperitoneal sis from benign to highly malignant.
hyperthermic chemotherapy. The chemotherapy The peak incidence if thymoma occurs at
agent used is mitomycin C. A systematic review 40–60 years, with no predilection for gender.
reported a median survival ranging from 34–92 There is no known aetiological factor.
months and a 5-year survival ranging from 29%
to 59% with this approach. The perioperative Pathology
morbidity varied from 25% to 40% and mortal- WHO classification (Box 9.6) which correlates
ity ranged from 0% to 8%. with prognosis, is based on the histological
Other patients with good PS and inoperable assessment of morphology of the neoplastic epi-
tumours may be considered for chemotherapy thelial cells and the non-neoplastic lymphocytic
with cisplatin and pemetrexed (reported median component.
110
 CANCERS OF THE THORAX 9

Box 9.6: WHO classification of thymoma

10-year
Type Description Characteristics survival
A Medullary thymoma 4–7% of thymoma; 17% associated with 100
myasthenia; epithelial cells are spindle or oval
with a few lymphocytes
AB Mixed thymoma 28–34%; 16% associated with myasthenia; foci 100
with type A thymoma admixed with foci rich
lymphocytes
B1 Predominantly cortical thymoma 9–20%; 57% associated with myasthenia; 83
tumour resembles normal functional thymus
with large number of cells
B2 Cortical thymoma 20–36%; 71% associated with myasthenia; 83
scattered plump cells with vesicular nuclei and
distinct nucleoli with heavy population of
lymphocytes
B3 Well differentiated thymic carcinoma 10–14; 46% associated with myasthenia; 35
epithelial cells are round or polygonal
admixed with a minor component of
lymphocytes
Carcinoma Thymic carcinoma – various subtypes Histologic features not specific to thymus but 28
Thymic neuroendocrine tumors those of carcinomas of other organs
Combined thymic epithelial tumours At least 2 distinct areas each corresponding to –
one hisological thymoma and/or thymic
carcinoma; commonest combination B2&B3
New entities Micronodular thymoma 1–5%; not usually associated with myasthenia; –
good prognosis
Biphasic metaplastic thymoma Males common; not associated with myasthenia; –
good prognosis
Hepatoid carcinoma Features that of hepatoid carcinoma –
Carcinoma with t(15;19) translocation Aggressive cancer with survival only a few weeks

Presentation Tissue diagnosis

Nearly 50% are asymptomatic with diagnosis CT guided FNA is less reliable. CT-guided core
being made incidentally. Common symptoms biopsy can be safely performed for large tumours.
include chest pain, cough, dyspnoea, dysphagia, When CT guided biopsy is inconclusive or when
hoarseness, respiratory tract infections and not feasible, anterior mediastinotomy is the next
superior vena caval obstruction. Various para- choice. Although VATS helps to provide a tissue
neoplastic syndromes can be associated with diagnosis, a theoretical risk of pleural seeding
thymoma. About 30–40% of thymoma patients exists. For small tumours excisional biopsy is
have myasthenia gravis and conversely, 10–15% advisable.
of patients with myasthenia have underlying
thymoma. Staging
Thymoma is staged according to Masaoka
Investigations and staging staging (Box 9.7), which is a postoperative
Imaging staging. Invasion is the most important prognos-
In chest X-ray, large tumours are seen as medi- tic factor.
astinal widening or anterior mediastinal mass
(Figure 9.9A). The typical appearance in CT scan Management (Figure 9.10)
is a well-defined homogenous anterior mass Successful treatment of thymoma depends on
lesion (Figure 9.9B) within a well-defined fibrous complete surgical resection. The majority of thy-
capsule. MRI scan is useful to evaluate medias- momas confined to the thymus are amenable to
tinal, cardiac and pericardial spread when CT curative resection. Stage-wise management of
findings are unequivocal. thymoma is shown in Figure 9.10.
111
 II SITE-SPECIFIC CANCER MANAGEMENT

A B

Figure 9.9
Imaging in thymoma.

Box 9.7: Masaoka staging of thymoma

from 26% to 5% in invasive disease. However,
more recent studies challenge this approach as
Stage Description
the most common mode of failure is pleural
I Macroscopically completely encapsulated
with no microscopic capsular extension recurrence rather than mediastinal. Hence some
IIa Microscopic invasion through the capsule recommend radiotherapy only if the resection
IIb Macroscopic invasion into mediastinal fat margin is <1 mm and suggest histology should
or pleura
III Invasion into adjacent structures also be taken into account.
(pericardium, lung or great vessels)
IVa Pleural or pericardial metastases Chemotherapy
IVb Lymphatic or haematogenous metastases A subgroup of patients with pleural disease (IIb)
are at risk of pleural relapse. These patients
cannot be considered for radiotherapy because of
the extensive radiation field, and hence may be
Early stage (stage I and II) considered for adjuvant chemotherapy.
Surgery
Locally advanced disease (stage III and IVA)
En bloc surgical resection through a median ster-
notomy is the treatment of choice. Patients with If stage III or IVA with limited pleural disease
myasthenia gravis or suspected to have myasthe- is suspected preoperatively, patients should be
nia should have appropriate preoperative meas- treated with neoadjuvant treatment. This can be
ures to avoid postoperative myasthenic crisis. either chemotherapy alone (PAC) or chemora-
Recurrence after complete excision of a stage I diotherapy (EP with 45 Gy of radiation) (see
thymoma is less than 2%. 30% people will have below). Surgery is done 4–6 weeks after neoad-
invasive disease at surgery; still a complete resec- juvant treatment. Patients who haven’t had radi-
tion can be achieved in the majority of these otherapy preoperatively, should be considered
cases. However, recurrence of completely resected for postoperative radiotherapy (Box 9.8) pro-
invasive thymoma is approximately 30% with vided the area of risk can be encompassed in a
median time of local recurrence around 3.8 years. radical radiotherapy portal and pulmonary func-
tion tests are adequate.
Radiotherapy
There is no proven role for radiotherapy in stage Metastatic disease
I disease. Previously, radiotherapy was consid- Patients are treated with palliative chemotherapy
ered as a standard adjuvant for stage II disease, if general condition permits. Otherwise treat-
112 as radiotherapy may reduce the risk of relapse ment is essentially symptomatic and supportive.
 CANCERS OF THE THORAX 9

Thymoma – preoperative

Localized Local invasion Metastatic

of adjacent organs

En bloc resection Consider chemotherapy (PAC) Fit for chemotherapy

or chemoradiation (EP with radiotherapy)

Stage I Stage II Stage III Surgery Yes No

(4–6 weeks later)

Follow-up Consider adjuvant chemotherapy PAC or EP Palliative

• Adjuvant radiotherapy Consider RT if area of risk of recurrence Stage IVa – a good response
• If IB, risk of pleural disease – can be encompassed in a radical to chemotherapy – consider
consider adjuvant chemotherapy radiotherapy portal surgery ± radiotherapy
for young or fit patients

Relapse

• Localized – consider salvage surgery or radical RT if not already given

• Metastatic – palliative chemotherapy or symptomatic care

Figure 9.10
Management of thymoma.

Chemotherapy as those with no recurrence. In one series the

Patients who fail surgery and/or radiotherapy or reported 5-year survival is 51% and those who
who present with metastastic disease are candi- had complete resection had a better survival of
dates for chemotherapy (Box 9.9). However, 64%.
there are no randomized trials of chemotherapy Patients who may relapse with metastatic
in thymoma. Studies showed that a combination disease may be managed according to the fitness
of cisplatin, doxorubicin and cyclophosphamide of the patient and prior treatment. Fit patients
(CAP) resulted in an overall response of 50%, who haven’t had any previous chemotherapy
medial duration of response of 12 months and are treated with platinum based regime (PAC or
median survival of 38 months. Another combi­ EP). Patients who relapse 12 months after a pre-
nation regime of etoposide and cisplatin (EP) vious platinum-containing regime, may be rechal-
showed a response rate of 56% with median lenged with the same regime while treatment
response of duration of 3.4 years and median of patients who relapse within 12 months of
survival of 4.3 years. Hence CAP and EP remains initial platinum regime remains investigational.
the standard chemotherapy combination for In patients who are chemotherapy refractory and
thymomas and thymic carcinoma. showing demonstrable uptake on In-labelled
octretide scan, may be candidates for treatment
with somatostatin analogues plus prednisolone.
Salvage treatment The commonly used regime is either octreotide
Often disease recurrence is limited to the thorax. 1.5 mg/day subcutaneously, or lantreotide 30 mg
These patients should be considered for re- intramuscularly every two weeks with pred-
resection as they may have similar 5-year survival nisolone daily until progression. 113
 II SITE-SPECIFIC CANCER MANAGEMENT

Box 9.8: Radiotherapy in thymoma

is the completeness of resection. Presence of
myasthenia does not influence the survival while
Target volume
• GTV – defined by visible tumour and/or surgical autoimmune diseases such as red cell aplasia,
clips on postoperative scan hypogammaglobulinemia and lupus erythemato-
• PTV = GTV + 1.5–2 cm sus appear to have a poor prognosis. 10-year
Critical organs survival of non-invasive (stage I) thymoma ranges
• Lung, heart and spinal cord between 67–80%, while those for invasive (stage
Energy II–IV) ranges from 35–53%. 5-year survival rates
• 6 MV are: 93% for stage I, 86% for stage II, 70% for
Field arrangement
stage III and 50% for stage IV.
• Single anterior Up to 28% patients are reported to develop
• Un-equally weighted (2 : 1) or (3 : 2) second primary cancer and the most common is
Antero-posterior colorectal. The reason for this association is
• Anterior wedge pair unknown.
• Multiple field
Follow-up
Dose
• Complete excision/microscopic disease – 50 Gy in Patients should be monitored up to 10 years,
20–25 fractions over 5 weeks since late metastases are not unusual. Follow-up
• Macroscopic disease – 55 Gy in 20 fractions or should be in the form of clinical examination,
60 Gy in 30 fractions
blood tests and CT staging at appropriate
• Preoperative – 45 Gy in 20 fractions
interval.
Special situation
• Patients with lupus erythematosus may need dose Future direction
modification to minimize late toxicity
There is an evolving role for somatostatin ana-
logues and radiotargeted therapy. Monoclonal
antibodies such as gefinitib and cetuximab are
reported to have therapeutic benefits in thymoma.
Box 9.9: Chemotherapy in thymoma
CAP Further reading
• Cisplatin (50 mg/m2), doxorubicin (50 mg/m2), and
cyclophosphamide (500 mg/m2) given on day 1. Herbst RS, Heymach JV, Lippman SM. Lung cancer. N Engl
• Repeated every 21 days for a maximum of eight J Med. 2008;359:1367–1380.
cycles, if stable or responsive disease after 2 cycles. Bonomi PD. Implications of key trials in advanced nonsmall
cell lung cancer. Cancer. 2010;116:1155–1164.
EP Puglisi M, Dolly S, Faria A et al. Treatment options for
• Cisplatin 60 mg/m2 given on day 1 and etoposide small cell lung cancer – do we have more choice? Br J
120 mg/m2 on days 1, 2, and 3. Cancer. 2010;102:629–638.
• Cycles repeated every 3 weeks for a maximum of Tassinari D, Drudi F, Lazzari-Agli L et al. Second-line
eight cycles treatments of advanced non-small-cell lung cancer: new
evidence for clinical practice. Ann Oncol. 2010;21:
428–429.
Dempke WC, Suto T, Reck M. Targeted therapies for
Palliative care non-small cell lung cancer. Lung Cancer. 2010;67:
257–274.
Management of palliation of symptoms follows Stahel RA, Weder W. Improving the outcome in malignant
the same principles as that of any other advanced pleural mesothelioma: nonaggressive or aggressive
cancer. The common issues are dyspnoea due to approach? Curr Opin Oncol. 2009;21:124–130.
pleural effusion and locally advanced tumour. Ceresoli GL, Zucali PA, Gianoncelli L et al. Second-line
treatment for malignant pleural mesothelioma. Cancer
Prognostic factor and survival Treat Rev. 2010;36:24–32.
Falkson CB, Bezjak A, Darling G et al. The management of
Prognosis is dependent on clinical stage and his- thymoma: a systematic review and practice guideline.
tology and the most important prognostic factor J Thorac Oncol. 2009;4:911–919.

114
Breast cancer
TV Ajithkumar and HM Hatcher
10
Introduction Pathogenesis and pathology
Breast cancer is the most common female malig- Breast cancer arises from the epithelial cells lining
nancy in the UK and USA. In the UK, 30,000 the terminal duct lobular unit. Development of
new cases and 15,000 deaths occur each year due invasive breast cancer is thought to be due to a
to breast cancer. In the USA, there are 192,000 multi-step process. WHO classification of breast
new cases and 43,300 breast cancer deaths every cancer is shown in Box 10.1.
year. The life-time risk of developing breast
cancer for a woman is 1 in 12 in the UK and 1 Precursor lesions
in 8 in the USA. Lobular carcinoma-in-situ is considered as a pre-
cursor of invasive lobular cancer, but in most
cases, it does not progress to the invasive stage.
Aetiology It is regarded as a marker for either lobular or
The reported risk factors include hormonal, ductal carcinoma.
genetic, dietetic and radiation. Table 10.1 shows Atypical ductal hyperplasia is characterized by
these risk factors and protective factors for breast intraductal epithelial proliferation with some of
cancer. The effect of hormones, notably oestro- the features of DCIS. These increase the risk of
gen, is the most significant aetiological factor in invasive cancer 4–5 times.
breast cancer. Genetic factors in breast cancers In ductal carcinoma-in-situ (DCIS) malignant
are dealt with in Chapter 5 (p. 47). BRCA1 epithelial proliferation is confined to a duct with
mutation associated cancers tend to occur at an no stromal invasion. It accounts for 3–5% of
early age, are highly aggressive and are typically palpable breast cancer and 15–20% of screen
negative for oestrogen (ER), progesterone (PgR) detected cancer. It is graded according to the
and human epithelial growth factor receptor 2 appearance of cell nuclei. Low-grade micropapil-
(HER2/neu (’Triple negative’). BRCA2 muta- lary DCIS can occur as a multicentric tumour
tions account for 1% of breast cancers which are whereas high-grade comedo carcinoma DCIS can
often ER and PgR positive. be associated with invasive tumour in the same
Other risk factors include: quadrant.
Microinvasive carcinoma is focus of invasive
• Previous breast cancer – increases the risk of cancer of <1 mm in maximum extent.
a contralateral breast cancer (0.5–1% per
year). Malignant breast lesions
• Prior radiation – to the breast or part of • Invasive ductal carcinoma: 70–80% of all
breast increases the risk of cancer (RR 3) (e.g. invasive carcinomas are classified as invasive
Mantle radiotherapy for Hodgkin’s disease). ductal carcinomas, which are thought to arise
• Some benign conditions of the breast (e.g. from DCIS. They occur most commonly as
atypical hyperplasia). ‘ductal no special type’ (ductal NST). Ductal

© 2011, Elsevier Ltd 115

DOI: 10.1016/B978-0-7234-3458-0.00015-4
 II SITE-SPECIFIC CANCER MANAGEMENT

Box 10.1: Modified WHO classification of

Table 10.1: Risk factors of breast cancer breast cancer
Relative Precursor lesions
risk
Lobular carcinoma-in-situ
Early menarche (before 11 years) 3 Intraduct proliferative lesions
Late menopause (after 54 years) 2 Atypical ductal hyperplasia
First pregnancy after 40 years 3 Ductal carcinoma-in-situ
Microinvasive carcinoma
Nulliparity 3
Intraductal papillary neoplasms
HRT 1.7 Papilloma
Oral contraceptive 1.2 Atypical papilloma
Intraduct papillary carcinoma
One maternal first degree relative 1.5–2
Intracystic papillary carcinoma
Two first degree relatives 3–5
Malignant lesions
First degree relative diagnosed before 3 Invasive ductal carcinoma (NST) and subtypes
40 years Invasive lobular carcinoma
Bilateral breast cancer 4 Tubular carcinoma
Alcohol 1.3 Invasive cribriform carcinoma
Medullary carcinoma
Protective factors
Mucinous carcinoma
Artificial menopause before 35 years 0.5 Neuroendocrine tumours
Increased parity 0.5–0.8 Metaplastic carcinoma
Age at first pregnancy less than 30 0.6–0.8 Sarcoma
years
Breast feeding 0.8

retrieved, number of nodes involved and extent

of involvement (e.g. micrometastasis or metasta-
sis), presence of DCIS and immunohistochemical
NST is a diagnosis of exclusion. Other special status of ER and PgR and HER2. Patients with
subtypes of ductal carcinomas include: an ambiguous HER2 (2+) status on immuno­
• Tubular carcinoma: 1–2% of breast histochemistry, require fluorescent in situ hybrid-
cancer. ization (FISH) to look for gene amplification
• Medullary carcinoma: 4–9% of breast (Box 10.2).
cancer. Molecular profiling has identified five subtypes
• Mucinous carcinoma: 2%. of breast cancer: luminal A, luminal B, HER2+,
• Papillary carcinoma: 1–2%. normal breast-like and basal-like. The luminal
• Invasive lobular carcinoma – constitutes 10– tumours are ER+ whereas others are ER−. The
15% of invasive cancers. These tumours outcome of these types is different. The role of
infiltrate diffusely leading to a discrepancy molecular profiling in routine clinical practice is
between imaging findings and histologic evolving but it is possible in the future that these
tumour size. subtypes will be treated differently.
• Other cancers: include lymphoma, sarcoma,
melanoma and metastasis. Surgical anatomy of breast and
The postoperative pathology report should
lymphatics (Figure 10.1)
include: number of tumours, maximum diameter The adult breast extends from the second rib
of largest tumour, histologic type and grade, superiorly to the sixth rib inferiorly and from
circumferential excision margin and minimal the lateral edge of the body of the sternum
margin, vascular invasion, number of nodes medially to mid-axillary line laterally. There are
116
 BREAST CANCER 10

Box 10.2: Grading and scoring systems

approximately 20–30 axillary lymph nodes
in breast cancer which are surgically defined as:
Nottingham grading of breast cancer • Level I – nodes inferior to pectoralis minor
Characteristics Score 1 Score 2 Score 3 (12–14 in number).
Degree of tubule >75% 10–75% <10% • Level II – nodes posterior to pectoralis minor
formation (6–8 in number).
Nuclear pleomorphism Mild Moderate Severe
Mitoses/10 HPF Score of 1–3 based on the • Level III – nodes superior to the pectoralis
diameter of high power minor (2–4 in number).
field and mitotic
frequency Internal mammary nodes (3–5 nodes on either
Grade I: score 3–5 side) lie 2–3 cm from the sternal edge from the
Grade II: score 6–7
3rd to 5th to intercostal space at a depth of
Grade III: score 8–9
4–6 cm depending on the body habitus.
ER and PgR scoring systems More than 75% of all lymphatic drainage
McCarty’s Semi quantitative H scoring (total score
0–300).
passes through the axillary nodes and the remain-
(Percentage of stained cells multiplied by a der through the internal mammary nodes. There
number, 0–3, reflecting the intensity of staining). is a higher risk of internal mammary node
Negative score ≤50 (−) involvement with medially located tumours and
Weakly positive 51–100 (+) in those with extensive axillary nodes. Apical
Moderately positive 101–200 (++) axillary node involvement leads to blockage of
Strongly positive 201–300 (+++) lymphatics and subsequent retrograde spread of
Her-2/neu scoring cancer to supraclavicular nodes (see Figure 10.1).
Immunohistochemical scoring
Score 0–1+: Negative Presentation
2+: Borderline – needs further testing
3+: Positive Many patients with early breast cancer are
detected during screening by mammography.
FISH score
<2.0, not amplified: Negative The usual presentations are painless lump
>2.0, amplified: Positive (65–75%), distortion of the breast (5%) and
nipple discharge (2%). A small proportion of
patients present with isolated axillary lymphad-
enopathy. Some patients present with metastatic
manifestations such as bone pain, respiratory
Subclavicular nodes
symptoms and features of liver metastases and
Axillary nodes Parasternal nodes brain disease.
Signs
Breast examination may reveal a non-tender,
well or ill-defined lump with or without fixity to
the skin or chest wall. The skin may be dimpled,
invaded, reddened, indurated or with nodular
irregularity.
Axillary and supraclavicular lymph nodes may
be enlarged. Hepatomegaly, pleural effusion and
spinal tenderness (usually thoracic and lumbar)
can occur in metastatic disease.

Initial assessment
Figure 10.1 ‘Triple’ assessment of patients with suspected
Surgical anatomy of breast and lymphatic drainage. breast cancer includes a combination of clinical
117
 II SITE-SPECIFIC CANCER MANAGEMENT

Example Box 10.1 Breast cancer: key points Clinical examination

for a case presentation Clinical examination helps to elicit physical
All patients signs, accurately document the site of lesion, and
• Age, menopausal status, performance status contributes to tumour and nodal staging.
• Previous breast disease, co-morbidities which
affect treatments (cardiac/diabetes/systemic
sclerosis), history of blood clots, other medications
Breast imaging
and allergies Mammogram
• Family history (breast cancer, ovary, prostate,
sarcoma)
The commonest mammographic abnormality of
DCIS is micro-calcification (in 50% cases). Other
New patient with local disease
features include asymmetric density and mass.
• Size and location of tumour
High-grade DCIS is associated with linear and
• Nodal status
branching calcification, whereas low-grade DCIS
• Receptor status
• Patient anxieties about body image and thoughts
is associated with fine and granular calcification.
about reconstruction if appropriate Invasive cancer appears as a speculated mass
• Planned surgery (Figure 10.2). Although calcification can occur in
New patient with metastatic disease
various conditions, a linear small (<1 mm in
• Location and extent (bulk) of metastatic disease diameter), non-uniform size and clustered calci-
• Receptor status fication is suggestive of malignancy.
• Any signs of impending emergencies which affect Mammogram has a low sensitivity in breasts
treatment (e.g. SVCO, SCC) with considerable fibroglandular tissue, particu-
• Any signs of life-threatening visceral involvement larly in young women and those on hormone
Patient with local relapse replacement therapy (HRT). The evolving
• Previous stage and date of original diagnosis digital mammography has the benefits of better
• Details of previous treatments and treatment imaging of dense breast and computer-assisted
related complications and time since completion detection.
of original treatment
• Receptor status
Ultrasound
• Duration of current symptoms/signs hormone
status Ultrasound examination of the breast helps to
• Staging at time of local relapse (current distinguish between solid and cystic lesions of
staging) more than 1 cm in size. Malignancy appears as
Patient with metastatic relapse a hypoechoic lesion with associated distortion of
• Previous stage and date of original diagnosis the surrounding tissues and an acoustic shadow
• Details of previous treatments and treatment on the breast tissue below it (Figure 10.3). It is
related complications and time since completion
of original treatment
also useful to assess axillary nodal status as
• Receptor status
well as to aid in guided FNA and core biopsy.
• Duration of current symptoms/signs hormone
Ultrasound is less sensitive than mammography
status for early detection and hence is not used for
• Current staging screening.
• Any signs of impending emergencies which affect
treatment (e.g. SVCO, SCC) MRI scan
• Any signs of life-threatening visceral involvement MRI can more accurately define the size of the
tumour compared with mammography and is
better in delineating intraductal disease and multi-
focal disease. MRI has a high sensitivity in detect-
examination, breast imaging (mammography ing cancers (almost 100%) and lower sensitivity
and/or ultrasound) and pathologic evaluation in detecting DCIS (80%), but has a higher false
(core biopsy). With this approach, a definite positivity. MRI is more useful for young women
diagnosis of breast cancer can be made in 99% who have dense breast tissue (Figure 10.4). MRI
of cases. is particularly useful in screening women less than
118
 BREAST CANCER 10
Figure 10.2
Mammogram.
Mediolateral oblique
(MLO) view (A) shows an
irregular lesion in the
breast with specks of
calcification (arrows).
Craniocaudal
(superioinferior) view (B)
conventionally represents
the outer or lateral aspect
of breast at the top of the
film and medial aspect at
the bottom of the film
and hence the mass is in
the medial aspect of
breast.

A B

Irregular hypoechoeic mass

Distortion of surrounding area

Acoustic shadow below the mass

A B

Figure 10.3
Ultrasound in breast cancer.

40 years with a high risk of breast cancer, to rule lesions may necessitate image localization using
out multifocal disease prior to conservation, mammography or ultrasound and hook wire
imaging women with implants and to distinguish replacement before open biopsy.
scars from tumour recurrence.
Pathological diagnosis
Investigations after
Pathological diagnosis may be obtained by core
triple assessment
biopsy or open surgical biopsy. Core biopsy can Most patients with early stage disease without
be obtained by conventional or vacuum assisted clinical evidence of metastatic disease will proceed
means such as Mammotome. Vacuum assisted to surgery after preoperative assessment. Patients
core biopsy yields a larger sample and may in who require neoadjuvant systemic treatment
some cases allow complete removal of the target prior to definite surgical management need
abnormality in the breast. Clinically impalpable staging investigations including:
119
 II SITE-SPECIFIC CANCER MANAGEMENT

Box 10.3: Staging of breast cancer

Stage 0
• Tx – primary tumour cannot be assessed.
• T0 – no evidence of primary tumour.
• Tis – carcinoma-in-situ and Paget’s disease with no
tumour
Stage I (T1N0M0)
A • T1 – tumour 2 cm or less in its greatest dimension
• N0 – no regional lymph node metastasis
• M0 – no distant metastases
S Study Time: 10
Stage II
2600
IIA (TxN1M0, T1N1M0, T2N0M0)
• T2 – tumour larger than 2 cm but not larger than
2400
5 cm
• N1 – ipsilateral non-fixed lymph node metastasis
2200
IIB (T2N1M0, T3N0M0)
2000 • T3 – tumour more than 5 cm
Stage III
1800
IIIA (Tx-2N2M0, T2-3N1-2M0)
• N2 – ipsilateral fixed axillary node or ipsilateral
1600
internal mammary lymph nodes

1400 IIIB T4N0-2M0

0 60 120 180 240 300 360 420 • T4 – tumour of any size with direct extension to:
B s. • T4a – Extension to chest wall
• T4b – oedema (including peau d’orange) or
ulceration of the breast skin, or satellite skin
Early post- Intermediate and late post-contrast phase nodules confined to the same breast
contrast
Type 1a – continuous straight enhancement • T4c – both T4a and T4b
phase
• T4d – inflammatory breast cancer
Type 1b – continuous
curved enhancement IIIC (any T, N3 M0)
Intensity

Type 2 – plateau • N3 – metastasis to ipsilateral supraclavicular lymph

nodes or infraclavicular lymph nodes or metastasis
to the internal mammary lymph nodes with
Type 3 – curve washes metastasis to the axillary lymph nodes.
out – decrease intensity after peak
Stage IV (any T, any N, M1)
• M1 – distant metastasis
Time
Type 1 – mostly benign (83%) and 9% malignant
Type 2 – 11% benign and 35% malignant
C Type 3 – typical malignant (57% malignant and 5% benign)

Figure 10.4 Postoperatively, patients with ≥4 positive

MRI showing breast cancer and different time–intensity lymph nodes and T4 disease also need the above
curves. Breast lesion near the chest wall (A) shows a investigations. In those with less than four
time-intensity curve which washes out (B) after the early
positive nodes, normal biochemistry and no
peak suggesting malignancy. C shows different types of
dose–intensity curves. symptoms suggestive of metastasis, the incidence
of metastasis is 2–4% and hence routine staging
is not advised.
• Full blood count, liver function, renal func-
tion tests and serum alkaline phosphatase.
• Chest X-ray and CT scan of chest and
Staging
abdomen – to rule out distant metastasis. TNM staging of breast cancer is given in
• Bone scan. Box 10.3.
120
 BREAST CANCER 10
There is no universally accepted recommendation
Management of for adjuvant hormones. Current studies evaluate
carcinoma-in-situ various hormonal agents (e.g. IBIS II).
With mammographic follow-up, breast cancer
Ductal carcinoma-in-situ (DCIS) disease free survival in DCIS approaches 100%.
Treatment is aimed at preventing local recur- Women with DCIS in one breast are at risk of
rence, particularly of invasive cancer. After a contralateral tumour occurring at a rate of
biopsy alone, 40% will progress to invasive 0.5–1% per annum.
cancer. Surgical management of unicentric DCIS
includes conservative surgery and simple mastec- Lobular carcinoma-in-situ (LCIS)
tomy. These choices should be discussed with LCIS comprises 30–50% of carcinoma-in-situ,
patients. Those who undergo mastectomy can be associated with invasive cancer in 10% and are
considered for immediate reconstruction. There frequently bilateral (35–60%). It is usually unde-
is no recommended optimal margin for DCIS; a tectable clinically and cannot be seen on mam-
margin of >10 mm is adequate and <1 mm in mogram due to the lack of central necrosis.
inadequate (NICE recommends 2 mm). Patients One-third of people develop invasive cancer in
with a persistent positive margin after repeat sur- the same or contralateral breast over 20 years.
gical excision, widespread DCIS (involving two However, the issue of whether LCIS is a direct
or more quadrants), suspicious microcalcifica- precursor of invasive lobular carcinoma has yet
tion throughout the breast and those likely to to be resolved.
have an unacceptable cosmetic result with con- Isolated LCIS following biopsy is managed
servative surgery are considered for simple mas- with close observation. The rate of progression
tectomy. Axillary staging and dissection are to cancer after biopsy alone is approximately 1%
unnecessary for patients with pure DCIS. Some per annum. Mastectomy is generally reserved for
series report up to 2% incidence of axillary patients with the highest risk of invasive recur-
node metastasis due to an unrecognized invasive rence such as young age, diffuse high-grade
cancer. lesions and significant family history. Tamoxifen
Randomized studies show that postoperative is being increasingly used as prophylactic treat-
radiotherapy (45–50 Gy in 1.8–2 Gy per frac- ment which has shown to reduce the invasive
tion) reduces breast recurrence (both in situ and recurrence by 56%.
invasive) with no effect on survival and irrespec- LCIS associated with DCIS or invasive cancer
tive of prognostic factors. However, in a sub- is managed according to the dominant malignant
group with <10 mm, low/intermediate grade histology. There is no need for further surgery to
DCIS with adequate margin, radiotherapy may obtain a clear margin for LCIS.
be safely omitted (<10% local recurrence at 10
years). Though there is no randomized study Management of early stage
looking at the benefit of tumour bed boost radio- invasive cancer (Figure 10.5)
therapy, it may be considered if further excision
to obtain a wider margin is likely to compromise After triple assessment, initial treatment options
cosmetic results. for early stage (non-inflammatory T1–2N0–
Two studies evaluated the benefits of tamoxifen 1M0) include:
in DCIS. NSABP B-24 showed that tamoxifen • Conservative surgery with axillary surgery.
reduced local recurrence of DCIS and invasive • Mastectomy with axillary surgery.
cancer (11% vs. 7.7%, p = 0.02) whereas • Neoadjuvant chemotherapy followed by con-
UKCCCR trial showed that tamoxifen had no servative surgery (when primary surgery is
beneficial effect in reducing local recurrence when likely to result in unacceptable cosmesis).
combined with whole breast radiotherapy (15 vs.
13%, p = 0.42). In the absence of radiotherapy Surgery
tamoxifen reduced the risk of DCIS recurrence Surgery is aimed at removal of the primary breast
(10 vs. 6%, p = 0.03) but not invasive recurrence. tumour and staging and/or treating the axilla.
121
 II SITE-SPECIFIC CANCER MANAGEMENT

Postoperative breast cancer

Node negative Node positive

All of the following: Any of the following: 1–3 nodes positive 4 or more nodes positive
• pT ≤2 cm • pT >2 cm
• Grade 1 • Grade 2/3
• Vascular invasion • Vascular invasion
negative positive HER 2 negative HER 2 positive
• HER2 negative • HER2 positive
• Age ≥35 years • Age <35 years

Low risk Intermediate risk High risk

Endocrine responsiveness

Responsive/uncertain* Unresponsive Responsive Uncertain* Unresponsive Responsive/uncertain* Unresponsive

Hormones or nil Follow-up/discuss HT or CT → HT CT → HT CT CT → HT CT

Treatment recommended for hormone-responsive

Risk group Premenopausal Postmenopausal
Low risk Tam or nil or GnRH Tam or AI or Tam or nil
Intermediate Tam (±OS) (±CT) or CT → Tam (±OS) or Tam alone or OS Tam → AI or AI or CT → Tam → AI or CT → AI
High risk CT → Tam or CT → Tam + OS or CT → (AI+OS) CT → Tam → AI or CT → AI

• Adjuvant chemotherapy for intermediate and high risk should be combination regimen with an anthracycline for a duration
of at least 4 cycles
• Taxanes should be considered for high-risk patients, especially ER negative
• Herceptin should be considered in patients with >1 cm HER2 positive tumour who had adjuvant anthracycline based chemotherapy

* Uncertain – low level of steroid hormone receptor immunoreactivity (<10% cells positive), lack of PgR, HER2 overexpression and
possibly µPA and PAI-1
HT – hormone therapy; CT – chemotherapy; OS – ovarian ablation; AI – aromatase inhibitor; Tam – tamoxifen;
GnRH - gonadotropin releasing hormone agonist

Nottingham Prognostic Index

(= N stage + grade + (maximum diameter cm x 0.2) – Applicable only to patients aged ≤70 years with <5 cm tumour
Excellent prognostic group (2.08–2.4) % 10 year survival – 96 Moderate prognostic group II (4.42–≤5.4) % 10 year survival – 74
Good prognostic group (2.42–≤3.4) % 10 year survival – 93 Poor prognostic group (5.42–≤6.4) % 10 year survival – 50
Moderate prognostic group I (3.42–≤4.2) % 10 year survival – 81 Very poor prognostic group (6.5–6.8) % 10 year survival – 38

Figure 10.5
Adjuvant systemic treatment in breast cancer (based on St. Galen International consensus 2007).

122
 BREAST CANCER 10

Box 10.4: Contraindications to breast

beyond the invasive cancer into the surround-
conservation surgery ing normal breast parenchyma).
• Prior radiotherapy to the breast or chest wall • Lymphovascular invasion – increases the risk
(can’t give more radiotherapy) of recurrence by 1.5 times.
• Radiotherapy during pregnancy (risk of radiation • Grade (grade I tumours have 1.5 times less
to the foetus) risk of recurrence than grade II–III).
• Diffuse suspicious or malignant appearing
microcalcification (difficult to obtain clear margin) Mastectomy: involves complete removal of the
• Widespread disease that cannot be completely breast from the pectoral fascia. Risk factors for
excised with satisfactory cosmesis through a single chest wall recurrence after mastectomy include
incision (result in negative margin and/or poor
cosmesis) tumour of >5 cm, more than 4 nodes involved,
• Persistent positive pathological margin (can’t margin <1 mm. Grade 3 and vascular invasion
obtain clear margin of >1 mm) are not independent risk factors for recurrence.
• Active connective tissue disease involving skin
(scleroderma and lupus) (due to increased risk of Breast reconstruction after mastectomy
radiation toxicity, if patient insists on conservation,
radiotherapy is given at a reduced dose) Reconstruction can be done at the same time
• Tumours of >5 cm (may result in poor cosmesis; as mastectomy (immediate) or at a later date
however conservation can be attempted after (delayed). Immediate reconstruction can be
neoadjuvant chemotherapy) offered to patients with diffuse DCIS and early
• Focally positive disease with extensive intraducal breast cancer who may not require postoperative
component (focally positive disease without
extensive intraductal component can be treated radiotherapy (radiotherapy to a reconstructed
with higher dose of radiotherapy) breast can result in poor cosmetic outcome).
• Women ≤35 years or premenopausal with BRCA1/2 Delayed reconstruction is appropriate when
mutation (higher risk of recurrence) postoperative radiotherapy is planned and there
is concern about tumour clearance.
Methods of reconstruction include:
Primary breast surgery can be either conservative • Tissue expanders – initially the expander is
(wide local excision – WLE followed by radio- placed in the pocket deep to pectoralis muscle,
therapy) or mastectomy. Conservative surgery which is later replaced with a permanent
followed by postoperative radiotherapy offers a implant containing silicone gel or saline after
better cosmetic outcome than mastectomy. a few months. Complications include infec-
However, not all patients are suitable for breast tions, failure of expansion and capsular con-
conservation (Box 10.4). tracture (particularly after radiotherapy).
• Autologous tissue – using either a pediculated
Breast surgery
flap (e.g. latissimus dorsi flap) or a free flap
WLE aims to remove the cancer with at least (free transverse rectus abdominis – TRAM
>1 mm circumferential microscopic disease free flap).
margin. The clinico-pathological factors that
increase the risk of local recurrence after WLE Axillary surgery
include:
Axillary surgery includes sentinel node biopsy
• Positive margin (<1 mm). The risk of recur- (SNB) alone, SNB followed by axillary dissection
rence is 16–21% with a positive margin com- or axillary dissection alone. SNB is not done in
pared with 2–5% with a negative margin and cases of high risk of axillary node involvement
hence all patients need re-excision if techni- (e.g. palpable axillary node >3 cm or T3 or T4
cally feasible. tumours, multicentric tumours), previous history
• Age ≤35 years (2–3 times increased risk of of surgery to breast or axilla, during pregnancy
local recurrence). or lactation (contraindication of dye and radio-
• Extensive intraductal component (defined as isotope) and after neoadjuvant systemic treat-
an infiltrating ductal cancer where >25% of ment outside of clinical trials (role not defined),
the tumour volume is DCIS and DCIS extends where dissection is the norm.
123
 II SITE-SPECIFIC CANCER MANAGEMENT

For SNB the sentinel node is localized by pre- Box 10.5: Radiotherapy in breast cancer
operative intradermal injection of technetium
Indications
labelled colloid and lymphoscintiscan or by
Whole breast
intraoperative injection of blue due or using both • After breast conservation for invasive cancer
techniques. Sentinel node biopsy has >95% • After breast conservation for DCIS (except low risk
detection rate. of recurrence)
Patients who are sentinel node positive will Tumour bed boost
undergo axillary clearance. A current study • All patients <40 years
(ALMANAC) is evaluating the role of axillary • 40–50 years with high risk features
radiotherapy in patients who are sentinel node • Patients with <1 mm margin and further surgery is
positive. not contemplated
Postmastectomy chest wall
Adjuvant radiotherapy • T3/T4 tumour
(Boxes 10.5 and 10.6) • ≥4 positive nodes after dissection

A meta-analysis suggests that adjuvant radio- Supraclavicular fossa

• ≥4 positive nodes after dissection
therapy results in a reduction of local recurrence
by two-thirds and improves 15-year survival by Position
• Supine with arm abducted (for CT plan)
5%. It also suggested that at 15 years one breast
• Supine with angled breast boards (conventional)
cancer death is avoided for every four local recur-
rences prevented. Localization
• Simulator or CT planning
After conservative surgery • Target volume
Radiotherapy reduces the risk of local recurrence Clinical target volume (CTV)
after breast conservation (5-year local recurrence • Whole breast – entire breast tissue and
subcutaneous tissue excluding muscles, rib cage
of 7% with radiotherapy and 26% without and skin
radiotherapy) and is the current standard after • Chest wall – skin including scar extending up to
WLE. However, one study showed that in deep fascia excluding muscles and rib cage
patients over 70 years with good prognostic • Tumour bed – 1.5–2 cm around surgical cavity or
factors ( less than 2 cm tumour, grade 1 or 2, ER haematoma
positive, node negative and no lymphovascular • SCF nodes – SCF node, infraclavicular nodes and
apical nodes
invasion) omission of radiotherapy may not com-
promise survival. Planning target volume
• 1 cm margin around CTV
Addition of radiotherapy to the tumour bed
(boost) after whole breast radiotherapy has Dose
Whole breast, chest wall and supraclavicular fossa
shown to reduce local recurrence (10-year local • 50 Gy in 25 fractions/40 Gy in 15 fractions
recurrence rate of 6.2% with boost and 10.2%
Tumour bed boost
without boost p < 0.001). On multivariate analy- • 16 Gy in 8 fractions (EORTC study)
sis, age was the only significant predictor of local • 9 Gy in 3, 10 Gy in 5, 12.5 Gy in 5 etc
recurrence and the greatest benefit was seen in
those aged <40 years. Boost radiotherapy did not
improve 10-year overall survival. Many centres
now follow a risk adapted policy for boost. high risk of chest wall recurrence (20–30%) and
routine postoperative chest wall radiotherapy is
Postmastectomy radiotherapy advised. This results in less local recurrence (6%
(Boxes 10.5 and 10.6) vs. 23%) and improvement of 15-year survival
There is ongoing debate on the role of radio- by 5%. Postmastectomy radiotherapy may be
therapy after mastectomy. Chest wall recurrence considered in cases of T1 tumour with 1–3 posi-
is thought to arise from tumour that has involved tive nodes or T2 tumours with features of bio-
dermal lymphatics. Patients with a tumour of logical aggressiveness (ER−, HER2+, grade 3 and
≥5 cm size and ≥4 positive lymph nodes are at high proliferative index).
124
 BREAST CANCER 10

Box 10.6: Radiotherapy side effects

making tools (e.g. adjuvant online – https://www.
adjuvantonline.com and Nottingham prognostic
Acute
• Fatigue index) have been developed to help to make adju-
• Skin erythema (100%) and inframammary fold vant treatment decisions. According to the 2007
desquamation (10%) St. Gallen Consensus adjuvant chemotherapy is
Late generally recommended for intermediate and
• Swelling and induration of breast (30%) high-risk patients (Figure 10.5). Patients with
• Telangiectasia (1% severe) HER2+ tumours of >1 cm and/or nodal involve-
• Asymptomatic lung changes (1%) ment are considered for adjuvant trastuzumab
• Sarcoma (<1% risk at 30 years) (see later, p. 128).
• Lymphoedema (3–40% depends on the extent of
axillary surgery) Adjuvant chemotherapy
• Brachial plexopathy (1%) A meta-analysis suggest that 6 months of anthra-
cycline based combination chemotherapy reduces
yearly death from breast cancer by about 38%
in women younger than 50 years and by 20%
Patients with ≥4 involved nodes after axillary for women aged 50–69 years (absolute risk
dissection are at risk of supraclavicular recur- reduction at 5 years of approximately 3% for
rence (>15%) and hence supraclavicular radio- DFS and OS). A recent meta-analysis showed
therapy is advised. Axillary radiotherapy is not that addition of a taxane to anthracycline-based
recommended after axillary dissection as there is chemotherapy results in an absolute risk reduc-
30–40% risk of significant lymphoedema and the tion at 5 years of 5% for DFS (17% relative
risk of isolated axillary recurrence without radio- reduction in relapse) and 3% for OS (15% rela-
therapy is only 1–4%. However, it may be con- tive reduction in death) for high risk early breast
sidered in rare instances of residual macroscopic cancer. Subgroup analysis showed that the DFS
disease in the axilla or positive dissection margin. benefit was present irrespective of ER status,
number of lymph nodes involved, age, menopau-
Adjuvant systemic treatment sal status and HER-2 status. However, it is
Adjuvant systemic therapy is aimed at preventing uncertain whether all subgroups, particularly
recurrences by eradicating micro metastatic those with node-negative disease, derive such
disease which is presumed to be present at the benefit from adjuvant taxanes.
time of diagnosis. Adjuvant systemic treatment is A practical approach is to use anthracycline
recommended when there is a significant reduc- based chemotherapy (e.g. FEC or Epi-CMF) for
tion in calculated risk of recurrence with an patients without high-risk early breast cancer
acceptable level of treatment related toxicity. and taxane-anthracycline chemotherapy for high
However, the optimal strategy for advising sys- risk patients needing chemotherapy (Figure
temic treatment has not yet been determined. 10.5). In the UK, anthracyclines-taxane combi-
Hormone receptor status and HER2 status are nation is licensed to use in patients with node
the most important determinants in the choice of positive breast cancer. Box 10.7 shows the com-
systemic treatment. Patients with ER+ tumours monly used chemotherapy regimes in breast
may receive hormones alone or a combination of cancer
endocrine treatment and chemotherapy. Patients
with ER− tumours are considered for adjuvant Adjuvant endocrine therapy (Figure 10.5)
chemotherapy alone. However, there are no clear The Early Breast Cancer Trialists’ Group over-
guidelines on the threshold of benefit above view of adjuvant tamoxifen has shown that
which adjuvant chemotherapy is advised. Some tamoxifen for 5 years results in a 41% propor-
experts justify adjuvant chemotherapy for tional reduction in recurrence and 34% propor-
patients with <90% 10-year survival and others tional reduction in mortality in oestrogen receptor
use an absolute survival benefit of at least 3–5% positive breast cancer patients irrespective of
at 10 years with chemotherapy. Several decision age, menopausal status, and administration of
125
 II SITE-SPECIFIC CANCER MANAGEMENT

Box 10.7: Chemotherapy regimes in breast cancer

Adjuvant/neoadjuvant
CMF
• Cyclophosphamide 100 mg/m2 po days 1–14
• Methotrexate 40 mg/m2 IV days 1 and 8
• 5 FU 600 mg/m2 IV days 1 and 8
• Folinic Acid Rescue 15 mg 6-hourly × 6 doses po days 2 and 9. Start 24 hours post MTX
28-day cycle × 4–6 cycles
Epi-CMF (efficacy based on preliminary results from the NEAT study, ASCO 2003)
• Epirubicin 100 mg/m2 IV bolus 21-day cycle for 4 cycles
• CMF as below for 4 cycles for 4 cycles
FEC
• 5 FU 600 mg/m2 IV day 1
• Epirubicin 60–75 mg/m2 IV day 1
• Cyclophosphamide 600 mg/m2 IV day 1
21-day cycle. For 6 cycles
FEC100
• Epirubicin 100 mg/m2 IV day 1
• 5 FU 500 mg/m2 IV day 1
• Cyclophosphamide 500 mg/m2 IV day 1
21-day cycle. For 6 cycles
FEC-D
FEC given 3 weekly for 3 cycles (as above) followed by docetaxel 100 mg/m2 IV on D1 every 21 days for 3 cycles.
TAC
• Docetaxel 75 mg/m2 IV day 1
• Adriamycin 50 mg/m2 IV day 1
• Cyclophosphamide 500 mg/m2 IV day 1
21-day cycle for 6 cycles
EC-T (EC given 3 weekly for 4 cycles followed by T given 3 weekly for 4 cycles)
• Epirubicin 90 mg/m2 IV day 1 once in 3 weeks
• Cyclophosphamide 600 mg/m2 IV day 1 once in 3 weeks
• Docetaxel 100 mg/m2 IV day 1 once in 3 weeks
Docetaxel
• Docetaxel 100 mg/m2 IV day 1
21-day cycle for 6 cycles
AC
• Doxorubicin 60 mg/m2 IV day 1
• Cyclophosphamide 600 mg/m2 IV day 1
21-day cycle for 4–6 cycles (there is controversy regarding optimum duration)
Palliative
• Capecitabine 1250 mg/m2 PO twice daily 1-14 given 3 weekly until progression, intolerable toxicity or patient/
clinician choice to stop
And many others including the previous regimes!
Weekly treatments in bone marrow failure
(If bone marrow recovers the patient may be switched to a 3-weekly regimen)
Weekly Epirubicin
• Epirubicin 20 mg/m2 IV day 1 every week for 12 weeks
Weekly docetaxel
• Docetaxel 30–40 mg/m2 IV weekly for up to 12 weeks
Weekly paclitaxel
126 • Paclitaxel 80–100 mg/m2 IV weekly up to 12 weeks
 BREAST CANCER 10
chemotherapy. There is also a proportional oestrogen ceases and extraovarian production
reduction of contralateral breast cancer by 47%. from secondary sources continues. Aromatase
In premenopausal women tamoxifen (20 mg activity also increases with age.
daily for 5 years) or tamoxifen combined with Hormonal treatment is aimed at decreasing
ovarian function ablation achieved either by oestrogenic stimulation of breast cancer cells.
bilateral oophorectomy or gonadotropin releas- This is achieved by either preventing the binding
ing hormone agonists (GnRH) for at least 2 years of oestrogen to cancer cells (e.g. tamoxifen), or
are standard recommendations. Aromatase by inhibiting ovarian and extraovarian produc-
inhibitors (AIs) are not indicated for premeno- tion of oestrogens (e.g. oophorectomy, GnRH
pausal women (see below). A study of GnRH agonists and aromatase inhibitors).
agonist, goserelin for 2 years (ZIPP) showed that
in women who weren’t given tamoxifen, goser- Hormonal agents
elin resulted in 14% less cancer related events Tamoxifen is a non-steroidal antioestrogen which
and prevented 8.5 deaths whereas when given has antagonist activity against breast cancer cells
with tamoxifen, goserelin results in 2.8% fewer and agonist effect on bone, endometrium and
events and 2.6% less death compared with serum lipids. Tamoxifen causes competitive
patients received only tamoxifen. inhibition with oestrogen for oestrogen receptors
In postmenopausal women the adjuvant which results in a G1 block leading to decreased
hormone options are: tumour growth. Other mechanisms include
• Tamoxifen for 5 years. induction of apoptosis, and increasing NK cell
• Tamoxifen for 2–3 years with early switch to activity.
AIs exemestane or letrozole (total 5 years). The side effects of tamoxifen include hot
• AI for 5-years – letrozole or anastrazole (for flushes (50%), vaginal discharge and irregular
large tumours, node positivity or HER2+ menses. Tamoxifen increases the risk of endome-
disease). trial cancer, especially in those above 50 years of
• Tamoxifen for 5 years followed by AI (letro- age (80 excess cases per 10,000 tamoxifen treated
zole) for another 2–3 years (for node positive women at 10 years). Other side effects include
disease). endometrial polyp and hyperplasia, thrombo­
embolism (1–2%) and retinopathy. The benefi-
The optimal duration of tamoxifen currently cial effects of tamoxifen include increase in bone
appears to be 5 years. Early results of the two mineral density and decreased circulating choles-
randomized studies of extended tamoxifen terol and LDL.
(aTTom and ATLAS) did not show any significant Aromatase inhibitors reduce oestrogen levels
benefit but an increased risk of endometrial cancer in postmenopausal women by inhibiting the aro-
and venous thrombosis with 10 years of tamoxifen. matase enzyme in extraovarian tissue. However
Early switch to AI, initial AI and extended use these are ineffective in premenopausal women as
of hormones have all shown improvement in they increase gonadotropin secretion which leads
DFS with a decrease in distant metastasis, breast to reduced feedback of oestrogen on the hypoth-
recurrence and contralateral tumours. alamic–pituitary axis, thereby causing increased
aromatase activity. There are two groups of AIs:
Mechanisms of action of hormonal agents
• Type 1 inhibitor (steroidal analogue–enzyme
Oestrogen stimulates the growth of breast cancer.
inactivator) – irreversibly bind to aromatase,
In premenopausal women 90% of total oestro-
e.g. exemestane.
gen is produced by the ovary which is stimulated
• Type 2 inhibitor – non-steroidal analogue–
by FSH and LH. The remaining oestrogen is pro-
enzyme inhibitor – reversibly bind to the
duced by peripheral conversion of circulating
enzyme, e.g. anastrazole and letrozole.
androgen by the enzyme aromatase which is seen
in extraovarian tissues such as subcutaneous fat, The usual side effects of AIs are hot flushes,
liver, muscle, breast and breast cancer cells. In joint pain and muscular stiffness. The long-term
postmenopausal women, ovarian production of risk of osteoporosis is a concern (see p. 61, late
127
 II SITE-SPECIFIC CANCER MANAGEMENT

effects). All patients need bone mineral density therapy which is aimed at down staging the
assessment by DEXA scan prior to starting AI. primary tumour which may facilitate surgery or
Patients with osteopenia need vitamin D and even avoid the need for mastectomy. Full staging
calcium supplement whereas those with a T-score workup is needed in this group of patients.
less than −2.5 SD (osteoporosis) need bisphos- In older women with receptor positive
phonates. All patients on AI need a 2-yearly tumours, initial hormonal treatment can be used.
DEXA scan. Although studies show that all the AIs result in
a higher response than tamoxifen, letrozole is the
Adjuvant trastuzumab
only licensed drug for neoadjuvant use. Two ran-
In patients with HER2+ disease (immunohisto- domized studies, separately comparing letrozole
chemical score of 3+ or FISH score >2.0) one and anastrazole with tamoxifen, showed that
year of adjuvant trastuzumab is recommended. aromatase inhibitors induce a higher rate of
Trastuzumab (Herceptin) is a humanized mono- regression allowing breast conservation. In the
clonal antibody again the extracellular domain comparative study of 4 months of tamoxifen
of HER2. All the six randomized studies have with letrozole, letrozole has a higher response
shown improved DFS with addition of trastuzu- rate (55%) than tamoxifen (36%). This study
mab to chemotherapy while 4 of the 6 trials also showed that those patients with HER-1
showed an overall survival benefit with adjuvant or HER-2+ tumours had a higher response to
trastuzumab, e.g. HERA study which compared letrozole (88% vs. 21%). In the second study
chemotherapy vs. chemotherapy with trastuzu- anastrazole achieved significantly higher breast-
mab showed a better 3-year DFS (81% vs. 74%) conservation rate than tamoxifen (47% vs. 22%,
and OS (92% vs. 90%). p = 0.03).
Adjuvant trastuzumab is indicated in patients Neoadjuvant chemotherapy is the standard
with >1 cm and/or node positive tumour and treatment for patients with large primary tumours
who received adjuvant chemotherapy. The role aiming for conservation and for inflammatory
of trastuzumab in <1 cm and node negative breast cancer (see p. 132). Chemotherapy results
disease as well as a single modality is not studied. in a 70–90% response with a 20% pathological
A loading dose of 8 mg/kg followed by 17 complete response. NSABP B-27 showed that an
maintenance doses of 6 mg/kg every three weeks initial anthracycline regime followed by docetaxel
is the recommended schedule. If there are more results in a better response rate (90.7% vs.
than 7 days delay treatment needs to be restarted 85.5%, p < 0.001) and pathological complete
with a loading dose. response (64% vs. 40%, p < 0.001). In patients
Common side effects include hypersensitivity with HER2 positive tumours addition of trastu-
and flu-like symptoms. Cardiotoxicity is a zumab results in improved pathological response
concern (<4% symptomatic or severe cardiac (65% vs. 26%, p = 0.016) and it is advisable to
failure). Hence it is not given if the left ventricu- incorporate trastuzumab with the neoadjuvant
lar ejection fraction is <50%. It is not given con- non-anthracycline chemotherapy. One such
currently with anthracyclines, but can be given approach is to give initial 3–4 courses of anthra-
concurrently with taxanes. Cardiac monitoring cycline chemotherapy followed by taxanes with
during treatment is mandatory. A recent study trastuzumab. In breast cancer, type and degree
reported no increase in adverse cardiac events in of response to primary systemic treatment pre-
patients receiving trastuzumab with adjuvant dicts disease-free as well as overall survival.
radiotherapy. After neoadjuvant chemotherapy, inflamma-
tory breast cancer patients undergo total mastec-
Locally advanced disease tomy whereas non-inflammatory breast cancer
(T3 N1, T1–3 N2–3, T4 N0–3) patients undergo mastectomy or conservation if
appropriate. If patients had negative SNB pre-
(Figure 10.6) chemotherapy, no axillary surgery is needed. If
Patients with locally advanced breast cancer axillary nodal status is unknown or positive
are usually treated with neoadjuvant systemic SNB, axillary clearance is needed.
128
 BREAST CANCER 10

Locally advanced Metastatic

>5 cm, skin involvement, fixed axillary nodes,
or inflammatory

Young women or ER – or fixed axillary nodes, Older women, ER+, non inflammatory Hormone negative/life-threatening
or inflammatory or aiming for conservation and no intent for conservation visceral involvement/failed hormones

Neoadjuvant chemotherapy – e.g. FEC –D or TAC, Aromatase inhibitors Yes No

if HER2+, FECx4 followed by Dx4 with trastuzumab for 4 months

Mastectomy* and axillary clearance followed by Chemotherapy with Hormones

postoperative radiotherapy to chest wall and trastuzumab if
supraclavicular fossa HER2+
(*conservation in some patients)

Adjuvant hormones if ER+ Maintenance hormones • ± Palliative radiotherapy

Total 18 courses of trastuzumab (concurrent chemo-hormones • ± Palliative surgery
(including neoadjuvant) if HER2+ is discouraged) • ± Bisphoshphonates if bone metastasis
• + Supportive care

Palliative chemotherapy Hormones

• FEC/EC Premenopausal
• Docetaxel • Tamoxifen and ovarian suppression/ablation
• Vinorelbine • AI and ovarian ablation
• Capecitabine Postmenopausal – a cascade of hormones
• Carboplatin • AI–Letrozole/arimidex
• Trial drugs • Tamoxifen/AI
• Exemestane
• Fulvestrant

Figure 10.6
Management of locally advanced and metastatic breast cancer.

All patients need postoperative radiotherapy Evaluation includes complete history and
to chest wall or breast (Figure 10.6). Adjuvant examination, blood tests including the tumour
systemic treatment depends on hormone receptor marker CA15-3 if available, CT scan chest,
and HER2 status. abdomen and pelvis, bone scan and receptor
status. Imaging of the brain is indicated only if
Metastatic disease symptomatic.
The aims of treatment are symptom control,
(any T, any N, M1) (Figure 10.6) improving quality of life and survival. Treatment
Approximately 6% patients present with distant options include hormones, chemotherapy and
metastasis at diagnosis and 40% of patients biological agents.
with early stage disease will eventually develop Patients with hormone receptor positive
metastases. The survival of patients with meta- disease without life-threatening visceral involve-
static disease varies from months to years. Bone ment are treated with hormonal treatment. In
metastases have the best outcome, followed by premenopausal women who have not previously
lung, liver and brain metastases. had tamoxifen or discontinued for >12 months,
129
 II SITE-SPECIFIC CANCER MANAGEMENT

the standard option is tamoxifen and ovarian significant improvement in time to progression
ablation or suppression. Otherwise, an AI with with capecitabine combined with lapatinib com-
ovarian ablation may be considered. pared with capecitabine alone (6.2 months vs.
In postmenopausal women studies show that 4.3 months, p = 0.00013).
AI have superior results compared with tamoxifen A very small subset of patients present with
so should be the drug of choice, if not received bone marrow failure subsequent to extensive
previously. In one study, letrozole resulted in a bone disease. Modified chemotherapy with low-
significantly longer time to progression (41 vs. 26 dose weekly anthracycline or taxanes is the
weeks, p = 0.0001) and higher response rate (30% option in these patients (Box 10.6).
vs. 20%, p = 0.0006) compared with tamoxifen In patients with metastatic disease, response to
in advanced breast cancer. Since data are in more treatment should be evaluated after 3 months of
favour of letrozole, it is the agent of choice. There endocrine treatment and after 2–3 cycles of
is no definite recommendation for second-line, but chemotherapy.
the options include tamoxifen, anastrazole, letro-
zole, exemestane, fulvestrant and megesterol Recurrent disease
acetate. Unless there is an indication for chemo-
2–20% patients after conservative surgery and
therapy, various hormonal agents are used as
<10% patients after radical surgery will present
a cascade of treatment until all options are
with loco-regional recurrence within 10 years.
exhausted.
10–70% patients present with metastatic recur-
Chemotherapy is used in patients with recep-
rence within 10 years.
tor negative tumours, hormone resistant tumours,
Patients presenting with isolated loco-regional
and life-threatening progressive disease. Chemo-
recurrence need complete staging prior to poten-
therapy results in a 50% response rate usually
tially curative treatment and ‘secondary’ adju-
lasting less than one year. Based on meta-analy-
vant treatment. Patients with systemic recurrence
sis, anthracyclines result in a greater clinical
are treated similarly to those with metastatic
benefit than a CMF regime and should be
disease.
considered as first-line treatment if the patient
has not previously received an anthracycline.
Taxanes are the options after anthracycline
Palliative care
failure. Both docetaxel and paclitaxel have • Bone metastases – treated with pain manage-
proven activity. Other agents used in breast ment as per WHO analgesic ladder (p. 66)
cancer include capecitabine, vinorelbine, gemcit- and local radiotherapy studies show that
abine, carboplatin, etc. (Box 10.6). 8–10 Gy as a single fraction has similar effi-
Patients with HER2 positive disease are cacy to that of prolonged. Women with bone
treated with trastuzumab with or without chem- metastases should be given bisphosphonates
otherapy. In patients who progress on trastuzu- which help to control pain as well as prevent
mab, retrospective data support a change of fractures, need for radiotherapy or orthopae-
chemotherapy with continuation of trastuzu- dic surgery and epidoses of hypercalcaemia.
mab; however, NICE recommends discontinua- Pamidronate, ibandronate, clodronate and
tion if it is systemic progression. Patients with zoledronic acid have all been shown to be
HER2 positive disease have a high risk of brain effective.
metastasis. Trastuzumab need not be discontin- • Brain metastasis – management of brain
ued on isolated progression/relapse in the brain. metastases are dealt with in Chapter 16
In patients after trastuzumab failure, lapatinib (p. 278). Patients with HER2+ disease have a
is a treatment option, though currently not yet high risk of brain metastasis, particularly to
approved in the UK. It is an inhibitor of HER2 the posterior fossa.
and as well as EGFR (ErbB1) receptor. A rand- • Tumour related symptoms of fungation, dis-
omized study in patients who had been previ- charge and bleeding are treated with either
ously treated with trastuzumab showed a palliative mastectomy or radiotherapy.
130
 BREAST CANCER 10
• Management of oncological emergencies such Special situations
as spinal cord compression and hypercalcae-
mia are discussed in Chapter 23 (p. 328). Paget’s disease
This is a pre-malignant condition of the nipple
Prognostic factors and outcome and areola occurring in the 5th or 6th decade.
Clinically there is erythema, dryness and fissuring
Lymph node metastasis is the most important of the nipple.
prognostic factor. The number of lymph nodes Microscopically it is characterized by Paget’s
involved has prognostic implications. Other cells located throughout the epidermis. More
important prognostic factors include tumour size than 95% of patients with Paget’s disease have
(affects the risk of nodal involvement, metastasis an associated ductal carcinoma. Fifty percent of
and survival), grade (affects survival), age (women patients with Paget’s disease have a lump of
aged <35 years have twice the risk of local recur- which more than 90% are invasive carcinoma.
rence and 1.6 times higher risk of distant metas- Of the other half of patients without a lump,
tasis compared with >35 years), hormone receptor 30% will have invasive carcinoma and 70% have
status (patients with ER+ tumours have better ductal carcinoma-in-situ.
survival), lymphatic invasion (presence of which Investigations include breast examination,
increases local recurrence and systemic recur- mammography and biopsy. Prognosis is de­
rence) and HER2+vity (adverse prognosis, more pendent on the characteristics of associated
likely to respond to anthracyclines). malignancy.
Long-term prognosis can be estimated using Conservative surgery followed by radiother-
the Nottingham prognostic index (Figure 10.5) apy is the treatment of choice. The local recur-
or using online programmes such as adjuvant rence with surgery alone is 25–40% from a small
online (www.adjuvantonline.com). series. An EORTC study of complete excision
5-year survival of stage I breast cancer is with nipple-areolar complex with postoperative
85%, stage II 70%, stage III 50% and stage IV radiotherapy showed a local recurrence of 5.2%.
20%. Mastectomy is offered based on patient choice
and for multifocal disease. Management of
Screening and prevention regional nodes and recommendations for sys-
temic treatment are based on the features of
Evidence shows that screening using mammogra- underlying malignancy.
phy reduces death from breast cancer by a third.
In the UK screening is aimed at those with the Inflammatory breast cancer
greatest proven benefit which includes women Two percent of all breast cancers are inflamma-
aged 50–69 years. The benefit of screening tory. Clinically there is ill-defined erythema, ten-
for women aged 40–49 years and >70 years is derness, induration and eczema-like skin changes.
controversial. This is often misdiagnosed as a breast abscess.
Screening mammography is done every 2 years Microscopically it is characterized by the pres-
for the general population and annually for those ence of cancer cells in dermal lymphatics. All
with a strong family history of breast cancer. patients need staging investigations with CT of
In women having screening, the breast cancer the chest and abdomen and bone scan. Patients
prevalence is about 0.5% (i.e. about 1 in 200 without distant metastasis are treated with neo-
women who are screening will be diagnosed adjuvant chemotherapy followed by mastectomy
to have breast cancer). 10% of women recalled and axillary clearance and adjuvant radiother-
for further assessment with a ‘positive’ screening apy. In HER2+ patients, trastuzumab can be
mammogram are found to have a breast cancer. added along with neoadjuvant taxanes. Patients
Assessment and prevention of breast cancer in receive hormones if ER+.
women with family history of breast cancer is 25% of patients present with metastatic
given on p. 47. disease when the aim is palliative and the treat-
131
 II SITE-SPECIFIC CANCER MANAGEMENT

ment principle is the same as metastatic breast Usual presentation is a painless mass (85%)
cancer. and other features include nipple retraction,
ulceration, discharge and pain. Investigations
Triple negative breast cancer include ultrasound, mammography and histo-
Triple negative breast cancer lacks the expression logical confirmation.
of oestrogen, progesterone and HER2 receptors. Primary treatment is total mastectomy with
Up to 15% of breast cancer falls into this cate- an axillary procedure similar to female breast
gory which is associated with a high rate of local cancer. Adjuvant radiotherapy indications are
and systemic recurrence. These tumours are similar to female breast cancer. Adjuvant
similar to BRCA-1 associated breast cancer. Cur- tamoxifen is indicated for ER+ tumours.
rently, these tumours are treated as other breast Metastatic breast cancer can be treated
cancers. Recent understanding of the role of with hormonal manipulation or chemotherapy.
BRCA1 gene pathway dysfunction in these 80% of oestrogen in men is produced peri­
tumours has led to the ongoing research on the pherally and 20% production is from the testis.
role of platinum chemotherapy and poly (ADP- Hence, aromatase inhibitors may not be effec-
ribose) polymerase (PARP) inhibitors as poten- tive. Methods of hormonal manipulation include
tial therapeutic strategies. Data show that these tamoxifen, orchidectomy, anti-androgens and
tumours are sensitive to platinum-based chemo- aminoglutethimide.
therapy and hence a number of studies are under-
way to evaluate various platinum regimes. Breast cancer during pregnancy
Please see p. 292.
Bilateral breast cancer
It occurs in those with a strong family history of Recent advances
breast cancer and those who had breast cancer Several biological and target agents are under
at an early age. It can be either synchronous investigation either as single agents or in combi-
(tumours occur simultaneously or within 6 nation. A randomized study of bevacizumab (an
months of initial diagnosis) which occurs in less anti-VEGF) with paclitaxel showed a better
than 1% or metachronous (tumours diagnosed 6 response rate (37% vs. 21%, p < 0.001) and
months or more after initial diagnosis) which has progression-free survival (11.8 vs. 5.9 months,
an incidence of 1–2% per year on follow-up. p < 0.001) compared with paclitaxel alone.
These should be managed as two separate breast However, overall survival was similar in both
cancers. groups. An ongoing study (BEATRICE) is evalu-
ating the role of 1 year of bevacizumab along
Male breast cancer with standard adjuvant chemotherapy in triple
Male breast cancer accounts for 1% of all breast negative breast cancer.
cancers and 0.1% of male cancer deaths. The Other agents under evaluation include sunitinib
average age at diagnosis is 10 years later than (a tyrosine kinase inhibitor), PARP inhibitors,
women. Alterations in testosterone and oestro- cetuximab (EGFR inhibitor) and ixabepilone (a
gen balance may play a role in the aetiology microtubule inhibitor).
as illustrated by the increased risk in men
with undescended testis, or after orchiectomy. Further reading
Klinefelter’s syndrome has 50-fold increase in Veronesi U, Boyle P, Goldhirsch A, Orecchia R, Viale G.
breast cancer. Other risk factors include obesity, Breast cancer. Lancet. 2005;365:1727–1741.
cirrhosis, family history of breast cancer, Benson JR, Jatoi I, Keisch M et al. Early breast cancer.
BRCA1/2 mutations. Lancet. 2009;373:1463–1479.
Buchholz TA. Radiation therapy for early-stage breast cancer
90% tumours are invasive of which 80%
after breast-conserving surgery. N Engl J Med.
tumours are infiltrating ductal carcinoma, 5% 2009;360:63–70.
papillary and 1% lobular. 10% tumours are Pagani O, Senkus E, Wood W et al. International guidelines
DCIS. 80% tumours are ER+ and 75% PR+. for management of metastatic breast cancer: can
132
 BREAST CANCER 10
metastatic breast cancer be cured? J Natl Cancer Inst. treatment and current lines of research. Cancer Treat
2010;102:456–463. Rev. 2010;36:206–215.
Roy V, Perez EA. Beyond trastuzumab: small molecule Fentiman IS, Fourquet A, Hortobagyi GN. Male breast
tyrosine kinase inhibitors in HER-2-positive breast cancer. Lancet. 2006;367:595–604.
cancer. Oncologist. 2009;14:1061–1069. Dawood S, Ueno NT, Cristofanilli M. The medical treatment
Bosch A, Eroles P, Zaragoza R, Viña JR, Lluch A. Triple- of inflammatory breast cancer. Semin Oncol. 2008;35:
negative breast cancer: molecular features, pathogenesis, 64–71.

133
 Cancers of the
gastrointestinal system
TV Ajithkumar and E de Winton
11
Oesophageal cancer The common malignant tumours are adeno-
carcinoma, squamous cell carcinoma (SCC) or
Epidemiology undifferentiated carcinoma. Most adenocarcino-
Oesophageal cancer is an aggressive cancer with mas occur at or immediately above the GOJ
an overall survival rate of less than 10%. There which are classified (Siewert Classification) as
are over 7000 new patients per year in the UK follows:
and 16,000 per year in USA. The median age at • Type I – distal oesophageal cancer which may
diagnosis is 69 years. The male to female ratio is infiltrate GOJ.
2.5 : 1; but cervical oesophageal cancer is more • Type II – straddles the GOJ (cancer of the
common in women. cardia; also called junctional cancer).
• Type III – subcardial cancer which may infil-
Aetiology trate OGJ and distal oesophagus.
Oesophageal reflux and Barrett’s oesophagus are
Adenocarcinoma – accounts for 65% of
thought to increase the risk of adenocarcinoma.
oesophageal cancers in the UK and the major
Oesophageal reflux may account for the increased
aetiological factor is Barrett’s oesophagus. The
incidence of adenocarcinoma (10% per year) in
incidence of carcinoma arising in Barrett’s
the Western world.
oesophagus is 1 per 100 patient-years.
Box 11.1 shows risk factors for oesophageal
Squamous cell carcinoma (SCC) accounts for
cancer. A diet rich in fruit and vegetables has
25% of oesophageal cancer. Alcohol and smoking
been shown to reduce the relative risk.
are the major etiological factors. SCC is common
in upper and mid third cancers.
Anatomy
Most common sites of metastatic spread are
The oesophagus extends from the cricopharyn- lymph nodes (70%), lung (20%), liver (35%),
geal sphincter to the gastro-oesophageal junction bone (9%) and adrenal glands (2%).
(GOJ) and is 25 cm in length. Figure 11.1 shows
the anatomic sections of the oesophagus. The
majority of tumours (85%) arise in the middle Clinical features
and lower third of oesophagus and 15% arise in Most patients present with progressive dysphagia
the upper third. and difficulty in swallowing liquids indicate an
advanced stage. 50% patients experience painful
Pathogenesis and pathology swallowing and other presentations include
Oesophageal cancer is thought to be the end reflux, regurgitation and vomiting following
result of a multi-step process of carcinogenesis. eating, rapid weight loss. Local invasion of cancer
Adenocarcinoma arising from Barrett’s oesopha- leads to pain, and nerve compression leading to
gus is thought to undergo a stepwise progression Horner’s syndrome, recurrent laryngeal nerve
with associated genetic changes. palsy and a raised hemi-diaphragm.
134 © 2011, Elsevier Ltd
DOI: 10.1016/B978-0-7234-3458-0.00016-6
 CANCERS OF THE GASTROINTESTINAL SYSTEM 11

Box 11.1: Risk factors for oesophageal cancer

Metastatic disease can result in liver capsular
pain, bony metastases, ascites or peritoneal
• Gastro-oesophageal reflux (achalasia – SCC, hiatus
hernia and obesity – adenocarcinoma) deposits. Patients are usually cachectic at this
• Barrett’s oesophagus (adenocarcinoma) stage.
• Nutritional deficiency (vitamins A, C and riboflavin
– SCC) Evaluation
• Oesophageal injury (SCC) History: details of symptoms including per-
• Alcohol (SCC) formance status, weight loss and degree of
• Smoking (SCC) dysphagia.
• Fungal toxins (infected cereals) Examination: cachexia, anaemia, jaundice,
• Plummer–Vinson syndrome (upper third SCC) enlarged supraclavicular nodes, chest (for
• Tylosis palmaris (50% lifetime risk of SCC) pleural effusion) and abdomen (hepatomeg-
• History of head and neck cancer (SCC) aly, ascites).
• Diet – high fat, low-protein and low calorie (SCC)
• Nitrosamines (both adenocarcinoma and SCC)

Cervical
15–18 cm from incisors 15% of cancers
•
Squamous cell carcinoma
Upper third thoracic
common
18–24 cm from incisors

Middle third thoracic 35% of cancers

24–32 cm from incisors

Lower third thoracic 50% of cancers

32–40 cm from incisors Adenocarcinoma common

Figure 11.1
Anatomic section of oesophagus.
135
 II SITE-SPECIFIC CANCER MANAGEMENT

Investigations and staging

Investigations are aimed at establishing the extent
of disease, obtaining histologic diagnosis and
assessing fitness for appropriate treatment:
• Barium swallow is usually the initial investi-
gation of choice which shows the level of
obstruction. Malignant strictures appear as
asymmetric narrowing with abrupt, shelf-like
margins and irregular contours, and may
show proximal dilatation (Figure 11.2A).
• Endoscopy allows visual assessment of the
tumour and biopsy.
• Endoscopic ultrasound (EUS) helps to assess
the depth of invasion through the various
layers of oesophagus (>90% accuracy), adja-
cent structures and neighbouring lymph nodes
(70–80% accuracy). The normal oesophagus
has five alternating hyperechoic and hypo­
echoic layers with inner most hyperechoic
superficial mucosa. Oesophageal cancers
appear as hypoechoic masses that can disrupt A
this layered pattern (Figure 11.2B, arrow).
Malignant lymph node is characterized by
more than 1 cm, round, hypoechoic area with
distinct margins (Figure 11.2B, arrowhead).
EUS guided fine needle aspiration (FNA) of
any suspicious lesions, particularly lymph
nodes of >5 mm, helps to improve the diag-
nostic accuracy.
• CT scan of the thorax, abdomen and pelvis is
routinely done to assess the local extent of the
tumour and local and distant staging.
• Positron emission tomography (PET) is useful
in detecting distant metastases (sensitivity of
90% and specificity of >90%) and has been
increasingly used in oesophageal cancer.
• Laparoscopy is useful in lower third oesopha-
geal and gastro-oesophageal junction tumours
prior to major surgical procedure. This helps B
to visualize and biopsy small peritoneal
metastases, which may not have been detected Figure 11.2
on CT or PET. Up to 20% patients are up- Barium swallow (A) and EUS (B) in oesophageal
cancer. (Weinstein WM, Hawkey CJ, Bosch J. Clinical
staged after this procedure and major surgery Gastroenterology and hepatology, 1st edition, Page 183,
can be avoided. fig 32.7 (Mosby, 2005).)
• Bronchoscopy is useful as a preoperative pro-
cedure in upper and middle third oesophageal
cancer to rule out bronchial invasion.
• Tissue diagnosis is obtained via endoscopic
biopsy.
136
 CANCERS OF THE GASTROINTESTINAL SYSTEM 11

Box 11.2: Staging of oesophageal cancer

ment of fitness for suitable treatment is an essen-
tial component of the decision. A number of
Stage I
• T1 N0 M0 Invasion of lamina propria or treatment options are available depending on the
submucosa stage, location of tumour, and fitness to undergo
Stage IIa treatment, which include:
• T2 N0 M0 Invasion of the muscularis mucosa
• Endoscopic mucosal resection (EMR) – for
• T3 N0 M0 Invasion of the adventitia
superficial cancer limited to the mucosa.
Stage IIb • Radical surgery alone (T1N0M0 tumours
• T1–2 N1 M0 Regional nodal involvement located >5 cm from the cricopharyngeal junc-
Stage III tion and fit for surgery).
• T3 N1 M0 • Radical chemoradiotherapy (tumours within
• T4 N0–1 M0 Invasion of adjacent structures 5 cm from the cricopharyngeal junction,
Stage IVa unresectable/medically unfit patients with T1–
• Any T any N M1a T3N0–1M0 tumours and selected T4N0–
Stage IVb 1M0).
• Any T any N M1b • Preoperative chemotherapy followed by
Tumours of upper third cancer radical surgery (operable and medically fit
• M1a: Metastasis in cervical lymph nodes patients with T1–T4N0–N1M0 cancer located
• M1b: Other distant metastasis >5 cm from the cricopharyngeal junction).
Tumours of middle third cancer • Radical chemoradiotherapy followed by
• M1a: Not applicable surgery (only in those with residual disease
• M1b: Non regional lymph node or other distant after radical chemoradiotherapy and fit for
metastasis
surgery).
Tumours of lower third cancer
• Radical radiotherapy (not suitable for surgery
• M1a: Metastasis in coeliac lymph nodes
and chemotherapy).
• M1b: Other distant metastasis
• Palliative treatment or best supportive care
(PS >2).

Radical surgery
• Other investigations – include full blood Surgery is the best single modality treatment
count, biochemistry and coagulation profile. compared with radiotherapy alone. The best
Patients considered for surgery need pulmo- outcome from specialist centres is 5-year survival
nary function tests, arterial blood gases, ECG of approximately 35% with a postoperative mor-
and an exercise test. tality of less than 5%.
Type of surgery depends on the site of
Staging tumour, histology and the extent of lymphade­
Staging determines prognosis and guides treat- nectomy required. The surgery involves subtotal
ment. TNM staging is given in Box 11.2. oesophagectomy with the upper part of the
stomach and anastomosis of the cervical oesopha-
Management of oesophageal cancer gus and gastroplasty. 60–70% of patients have
(Figure 11.3) involved lymph nodes at the time of surgery and
Localized disease hence need dissection of abdominal and medias-
tinal nodes in middle and lower third cancers (a
This group consists of patients with stages I–III
minimum of 15 nodes should be removed).
oesophageal cancer as well as a subgroup of
The common procedures are as follows:
operable stage IVa (involving pleura, pericar-
dium and diaphragm). However, only one-third • Upper third oesophageal cancer: three-phase
of patients present with localized disease. The approach with complete removal of the
majority of these are stage II or III disease and tumour and mediastinal and supraclavicular
less than half of these patients are curable. Assess- lymphadenectomy.
137
 II SITE-SPECIFIC CANCER MANAGEMENT

• Barium study
• Endoscopy and biopsy
• EUS
• CT scan chest/abdomen/pelvis
• Blood counts and biochemistry

Localized Metastatic

• Cervical oesophagus • Upper third >5 cm from • Palliative chemotherapy

• Upper third <5 cm from cricopharyngeal junction • Palliative radiotherapy
cricopharangeal junction • Middle third • Best supportive care
• Lower third

• Radical chemoradiotherapy Fit for surgery Unfit for surgery or unresectable Unfit for surgery and
• Radical radiotherapy and fit for chemoradiotherapy chemoradiotherapy
• Palliative
• Bronchoscopy if indicated
• Laparoscopy for distal third tumours
• PET scan

Radical surgery Radical chemoradiotherapy • Palliative chemotherapy

• Palliative radiotherapy
• Best supportive care

R0 resection R1/R2 resection No residual Residual

disease disease

Follow-up • Follow-up Follow-up Follow-up

• Local radiotherapy or surgery
• Chemotherapy
• Chemoradiotherapy

Figure 11.3
Management of oesophageal cancer.

• Middle and lower third cancers: two stage apy is contraindicated. The best results are an
Ivor–Lewis approach. The first stage consists overall 5-year survival of less than 10%.
of laparotomy and mobilization of the
Radical chemoradiotherapy (CRT)
stomach, followed by right thoracotomy to
Radiotherapy is given in combination with chem-
remove the tumour and to form an oesoph-
otherapy which is proven to be superior to radical
agogastric anastomosis.
radiotherapy alone. Chemotherapy improves
Minimally invasive surgical approaches are local control by radiation sensitization and helps
evolving. to minimize distant metastatic relapses. This
approach results in an overall 3-year survival of
Radical radiotherapy (Box 11.3) 30%. The commonly used combination is cispla-
Radical radiotherapy is the treatment of choice tin with 5-fluorouracil with radiotherapy at a
in patients with localized disease who are medi- dose of 50 Gy in 2 Gy per fraction (Box 11.3).
cally unfit for surgery and in whom chemother- However, locoregional recurrence remains the
138
 CANCERS OF THE GASTROINTESTINAL SYSTEM 11

Box 11.3: Radiotherapy for oesophageal cancer

Position – supine (with arms above head for middle and lower third, and arms by side for upper third)
Localization – CT planning with information from EUS
Target volume
Radical chemoradiotherapy
• GTV – tumour with enlarged nodes
• CTV:
• Superio-inferior
– Tumours above carina (cervical and upper-third) – GTV + 2 cm and bilateral supraclavicular nodes
– Middle third – GTV + 2 cm margin
– Lower third – GTV + 2 cm margin and coeliac axis basin nodes and gastrohepatic ligament (lesser curve,
paracardial and left gastric nodes)
• Lateral and anterior – GTV + 1 cm
• Posterior – GTV + 0.5–1 cm
• PTV – CTV + 1 cm
• 2 phase treatment – phase I CTV = GTV + 3–5 cm superio-inferior margin and 1.5–2 cm axial margin and phase
II CTV as GTV with 2 cm margin superoinferiorly and 1.5–2 cm axially
Radical radiotherapy
PTV – 5 cm superior inferior margin for phase I and 2.5–3 cm for phase II and 2.5 cm axial margin
Palliative radiotherapy
PTV – tumour and node + 3 cm margin
Dose
Indication Single phase 2 phase
Radical chemoradiotherapy 50–50.4 Gy in 25–28 fractions Phase I – 30 Gy in 15
Phase II – 20 Gy in 10
Radical radiotherapy 55 Gy in 20 or Phase I – 33 Gy in 12 and phase II – 22 Gy in 8
66 Gy in 33 fractions Phase I – 36 Gy in 18 and Phase II 30 Gy in 15
Preoperative chemoradiotherapy 45 Gy in 25 fractions
Palliative 30 Gy in 10 fractions or
20 Gy in 5 fractions
Normal tissue tolerance
• Lung V20 (volume receiving 20 Gy) <25%
• Heart V30 <40%
• Spinal cord total dose below 45 Gy
Care during radiotherapy
• Weekly blood test
• Keep Hb >12 gm%
• Avoid significant weight loss (consider PEG/RIG feeding)

major cause for overall failure with 50% of Preoperative chemotherapy followed
patients developing locoregional disease. by surgery
Attempts to increase the radiotherapy dose to A meta-analysis showed that preoperative chem-
improve local control has resulted in increased otherapy followed by surgery improved 2-year
treatment-related deaths without improvement survival by 7% compared with surgery alone
in local control or survival. Studies comparing (HR 0.90; CI 0.81–1.00). The largest study
CRT with CRT followed by surgery showed (MRC OE02) of 802 patients which compared
similar overall survival, but with high treatment- surgery alone with two cycles of 3-weekly preop-
related mortality with surgery. erative cisplatin (80 mg/m2 on day 1 as 4 hour
139
 II SITE-SPECIFIC CANCER MANAGEMENT

infusion) and 5-fluorouracil (1 g/m2/day continu- study (REAL-2) to explore the role of oxaliplatin
ous infusion for 4 days) followed by surgery instead of cisplatin and capecitabine instead of
showed that chemotherapy improves overall sur- 5-FU (EOX regime) showed that toxicity of 5FU
vival from 34% to 43% at 2-years (p = 0.004). and capecitabine were similar; oxaliplatin resulted
Hence, this is the standard treatment option in in increased neuropathy and diarrhoea but
most UK centres. reduced renal toxicity, thromboembolism, alo-
pecia and neutropenia when compared with cis-
Preoperative CRT followed by surgery platin. Patients receiving EOX survived longer
A meta-analysis showed that preoperative CRT than ECF (38% vs. 47% at 1-year; p = 0.02).
followed by surgery improved 2-year survival
by 13% compared with surgery alone (HR 0.81 Palliative treatment of dysphagia
95% CI 0.70–0.93; p = 0.002). However, this Dysphagia is the predominant symptom which
benefit was only seen with concurrent chemora- needs palliation. The various methods to relieve
diotherapy rather than sequential and treatment- dysphagia are:
related mortality was increased with preoperative
• Endoscopic dilatation – results in immediate
CRT (p = 0.053). Due to concerns about mor-
but short lived (2–4 weeks) improvement and
bidity and mortality, it is not practised in the UK.

Advanced and recurrent disease

(Figures 11.3 and 11.4) Box 11.4: Chemotherapy for oesophageal cancer
Two-thirds of oesophageal cancer patients Preoperative chemotherapy
present with advanced disease and a significant • Cisplatin 80 mg/m2 on day 1 and 5-FU 1 gm/m2/day
continuous infusion for 96 hours. Cycles repeated
number of patients who had initial radical treat- every 3 weeks for 2 cycles.
ment will relapse. The treatment is essentially
Chemoradiotherapy
palliative, aimed to improve symptoms, quality
• Cisplatin 60–80 mg/m2 repeated 3 weekly for 4
of life and possibly to extend life. Pre-treatment cycles with 5-fluorouracil 250 mg/m2/day initially
performance status is important in deciding reducing to 200 mg/m2/day during radiotherapy.
potentially toxic treatment. Palliative
ECF regime
Systemic treatment • Epirubicin 50 mg/m2 day1, cisplatin 60 mg/m2/day1
Chemotherapy for advanced oesophageal cancer and 5-FU 200 mg/m2/day; cycle repeated 3-weekly
improves survival when compared to best sup- ECX regime
portive care alone. In the UK, the combination of • Epirubicin 50 mg/m2 day1, cisplatin 60 mg/m2/day1
and capecitabine 625 mg/m2 orally twice daily ;
epirubicin, cisplatin and 5FU (ECF) has been used cycle repeated 3-weekly
as the standard regime (Box 11.4). A randomized

Figure 11.4
Recurrence
Management of recurrence.

Locoregional Metastatic

Prior chemoradiotherapy Prior surgery • Palliative chemotherapy

• Palliative radiotherapy
• Best supportive care
• Surgery • Chemoradiotherapy (no prior RT)
• Palliative chemotherapy • Chemotherapy (PS <3)
• Best supportive care • Best supportive care (PS >2)
• Salvage surgery
140
 CANCERS OF THE GASTROINTESTINAL SYSTEM 11
hence useful only for those with limited life tyrosine kinase inhibitor which acts by blocking
expectancy. epithelial growth factor receptor (EGFR), has
• Stent – immediate and prolonged improve- been shown to have some benefit in patients with
ment. There are two types of stents: uncov- advanced oesophageal cancer (50% 6-month
ered and covered (has risk of migration). survival). Bortezomib, a proteasome inhibitor, is
• Local therapies – laser, ethanol injection and also being studied along with chemotherapy.
photodynamic therapy. Response is short Another agent under investigation is a mono-
lived. clonal antibody, panitumumab (REAL 3 study).
• Radiotherapy – is delivered by external beam
radiotherapy or brachytherapy. Radiotherapy Screening and surveillance
will not result in immediate relief of dysphagia The role of screening is not fully established. In
and may cause initial deterioration. the UK, high-risk patients (tylosis and Plummer–
• Palliation of other symptoms follows the Vinson syndrome) are regularly screened with
principles that of any other cancer (p. 66). endoscopy. Routine surveillance of chronic reflux
(absolute individual risk of less than 1 in 1000
Prognosis and survival
per annum) is not justified. Patients with Bar-
Stage, particularly depth of invasion of the rett’s oesophagus with mild dysplasia are treated
oesophageal wall, is an important prognostic with acid suppression therapy followed by a
factor. Other prognostic factors include age, repeat endoscopy and multiple biopsies at 8–12
performance status and weight loss (>10% in 3 weeks. If this remains stable, six-monthly repeat
months). Grade and histologic subtypes have no biopsy is recommended. Patients with high-grade
prognostic importance. dysplasia have a 30–40% risk of having invasive
The overall 5-year survival of oesophageal adenocarcinoma and hence full staging is under-
cancer is <10%. Less than a third of patients are taken with a view to oesophagectomy.
suitable for surgical resection. Around 80% of
patients with stage I disease are alive at 5 years Small cell carcinoma of oesophagus
whereas only 15% of stage IIa/III patients are
alive at 5 years. The median survival of patients This accounts for 0.5–2.4% of oesophageal
treated with palliative intent is 4 months. cancers. The usual presentation is dysphagia
(86%) of 1–3 months’ duration and presents in
Follow-up patients in their late 50s. Treatment is similar to
All patients are followed up after curative treat- small cell lung cancer with chemoradiotherapy.
ment. The follow-up involves history and clinical There are some reports suggesting that addition
examination, 4-monthly for one year, 6-monthly of surgical resection may improve long-term
for two years and yearly thereafter. Investiga- survival. The reported median survival ranges
tions are done as clinically indicated. from 12–18 months.

Ongoing studies and new agents Gastric cancer

New chemotherapy regimes and drugs are being
tested to improve the efficacy of CRT. UK SCOPE Epidemiology
1 trial is testing the addition of cetuximab (an Gastric cancer is the second commonest cause of
EGFR inhibitor) to standard CRT. cancer death in the world. There are approxi-
MRC OE05 study is comparing ECF chemo- mately 8200 new patients per year in the UK and
therapy followed by resection versus ECX chem- over 26,000 per year in USA. Although the
otherapy followed by resection in patients with overall incidence has decreased significantly,
resectable adenocarcinoma of the oesophagus. there has been an exponential rise in tumours of
Along with various attempts to improve the the proximal stomach and cardia. The median
loco-regional control of oesophageal cancer, age at diagnosis in men is 70 years and in women
studies are ongoing to assess the benefit of various 74 years. It is common in men (male to female
biological agents. Gefinitib (500 mg daily), a ratio 2.3 : 1).
141
 II SITE-SPECIFIC CANCER MANAGEMENT

Only 20% of patients present with localized Clinical features

disease and the overall 5-year survival is Most patients present with advanced disease.
15–20%. Presenting features are often nonspecific and
Aetiology typically include weight loss, persistent abdomi-
nal pain, nausea, anorexia, and early satiety.
The aetiology of gastric cancer is multifactorial.
Dysphagia can occur with GOJ or proximal
The following factors increase the risk:
gastric tumours, whilst distal tumours can
• Diet: low consumption of fruits and vegeta- produce gastric outflow obstruction. 10–20%
bles and high intake of salts, nitrates and patients have haematemesis. Paraneoplastic fea-
smoked or pickled foods increases the risk. tures include dermatomyositis, acanthosis nigri-
• Smoking. cans, diffuse seborrhoiec keratoses (sign of
• Helicobacter pylori – associated with gastric Leser–Trelat), circinate erythemas and micro­
lymphoma and adenocarcoma (2.8-fold angiopathic haemolytic anaemia.
increase).
• Blood group A (20% increased risk for infil- Evaluation
trative type). • History – detailed history including per­
• Gastric resection, chronic atrophic gastritis formance status, recent weight loss and family
and pernicious anaemia. history.
• Family history of gastric cancer (2–3-fold • Clinical examination:
increase). • General: anaemia, jaundice, cachexia,
• Genetic syndromes: hereditary non-polyposis enlarged left supraclavicular lymph node
colorectal cancer, familial adenomatous poly- (Virchow’s node).
posis, and Peutz–Jeghers syndrome. • Abdomen: epigastric mass, hepatomegaly,
High intake of fruits and vegetables (high in periumbilical nodule (Sister Mary Joseph
vitamin C and E, and antioxidants) and regular nodule), mass on anterior rectal wall on
use of aspirin and non-steroidal anti-inflamma- per rectal examination (Blumer’s shelf) and
tory drugs (NSAIDs) are associated with a ovarian masses (Kruckenberg’s tumour).
reduced risk of gastric cancer.
Investigations and staging
Pathology Evaluation of patients helps to establish histo-
Gastric cancer arises through a multistage and logical diagnosis, to assess the extent of disease
multifactorial process. The intestinal type of (stage) and assess fitness to undergo appropriate
gastric cancer evolves through the stages of meta- treatment.
plasia to dysplasia to carcinoma. However details
of evolution of diffuse type of gastric cancer is Initial assessment
not known. Flexible oesophagogastroduodenoscopy (OGD)
• Adenocarcinoma accounts for 95% of gastric is the diagnostic procedure of choice which
cancers. Histologically these are divided permits direct visualization of tumour and biopsy
into intestinal or diffuse type. The intestinal of any suspicious lesions. However, the diagnosis
subtype usually arises in distal stomach in of the diffuse-type gastric cancer can be difficult
older patients and the diffuse subtype is endoscopically as the overlying mucosa may
common in younger patients. The variant appear normal.
diffuse subtype which extensively infiltrates Double contrast barium studies (Figure 11.5)
the stomach wall is known as linitis plastica. complement endoscopy.
• Primary lymphomas (MALT) are increasing.
• Gastrointestinal stromal tumours (GIST) (p. Further assessment
261). Once histological diagnosis is made, staging
• Other tumours include small cell carcinoma, investigations are necessary to determine the
carcinoid and squamous cell carcinoma. treatment options.
142
 CANCERS OF THE GASTROINTESTINAL SYSTEM 11

Box 11.5: TNM staging of gastric cancer

Stage 0
TisN0M0 carcinoma-in-situ (intraepithelial tumour
without invasion of the lamina propria)
Stage IA
T1N0M0 tumour invades lamina propria or
submucosa
Stage IB
T1N1M0 metastasis in 1–6 regional lymph nodes
T2N0M0 tumour invades muscularis propria (a) or
subserosa (b)
Stage II
T1N2M0 metastasis in 7–15 regional lymph nodes
T2N1M0
T3N0M0 tumour penetrates serosa (visceral
peritoneum)
Figure 11.5
Barium study shows a large circumferential lesion in the Stage IIIA
body of the stomach (with permission). T2N2M0
T3N1M0
T4N0M0 tumour invades adjacent structures
Stage IIIB
T3N2M0
• CT scan of chest, abdomen and pelvis should
be undertaken to establish loco-regional (sen- Stage IV
T1–3N3M0 metastasis in >15 regional lymph nodes
sitivity of 65–80%) and metastatic staging.
T4N1–3M0
High resolution dynamic two-phase multi-
Any T Any N M1
slice CT with contrast and water (600–800 ml)
to distend the stomach has improved the diag-
nostic accuracy. The drawbacks of CT scan
are that it is not very accurate for staging
early cancer and up to 30% of peritoneal • PET scan may be useful for establishing meta-
metastases will not be detectable. static disease and to predict response to neo-
• Endoscopic ultrasound (EUS) is useful in pre- adjuvant treatment, particularly for intestinal
dicting depth of tumour invasion and helps to type cancer.
guide FNA of suspicious perigastric lymph
nodes. The stomach is seen as five layers of Preoperative evaluation
alternating bright (hyperechoic) and dark Includes full blood count, biochemistry, coagula-
(hypoechoic) bands. tion profile, arterial blood gas, pulmonary func-
• Laparoscopy – laparoscopy allows direct vis- tion tests and ECG. All patients should undergo
ualization of the liver surface, peritoneum and nutritional screening prior to surgery. A body
local lymph nodes. Laproscopy alters CT mass index of <18.5, body weight <90% pre-
staging by up to 40% (up or down-staging) dicted, >20% weight loss and a low albumin
and is recommended in all patients with predict an increased risk of perioperative
gastric cancer and GOJ cancer with a gastric complications.
component. Biopsy should be taken from all
suspicious lesions. Intraoperative ultrasound Staging
may further increase the yield of liver metas- Box 11.5 shows the pathological staging of
tasis and is useful in assessing lymph nodes. gastric cancer. Sixteen nodal stations defined by
Cytology of peritoneal washings may be the Japanese Research Society for Gastric Cancer
undertaken, but its sensitivity is limited by help to define the extent of lymph node dissection
contamination with mesothelial cells. in gastric cancer (Figure 11.6 and see below).
143
 II SITE-SPECIFIC CANCER MANAGEMENT

submucosal invasion. With treatment the 5-year

survival is >90%, whereas if untreated up to two-
thirds progress to advanced cancer over 5 years.
2 The treatment options include:
1 • Endoscopic mucosal resection (EMR) – is
9 7 10 appropriate for small well-differentiated poly-
8
poidal or raised lesions.
5 3 • Gastric resection with lymphadenectomy.
4
6 Resectable gastric cancer
All patients should undergo laparoscopy with or
without peritoneal washings for malignancy cells
prior to open laparotomy to assess the extent of
disease and resectability. Surgery is feasible only
in less than half of the newly diagnosed patients
Level 1 1. Right paracardial and only 13–50% patients are cured with surgery.
2. Left paracardial
3. Lesser curvature Surgery
4. Greater curvature Surgery is aimed at complete removal of the
5. Suprapyloric
6. Infrapyloric tumour and lymph nodes. When performing
7. Left gastric gastric resection a 5 cm free margin is required
for infiltrative tumours whereas 2 cm may be
Level 2 8. Common hepatic artery sufficient for expanding tumours. The pylorus
9. Coeliac axis seems to act as a barrier to extension of cancer
10. Splenic hilus
11. Splenic artery and hence 2–3 cm surgical margin for pylorus
may be necessary.
Level 3 12. Hepatic pedicle The extent of gastric resection depends on
13. Retropancreatic the size and location of the primary tumour
14. Mesenteric root (Figure 11.8).
15. Middle colic artery
• Subtotal gastrectomy – for an early or well
Level 4 16. Paraaortic circumscribed T2 cancer, >2 cm away from
GOJ. A 5 cm margin is needed for more infil-
Label 11, Levels 3 and 4 are not shown in the diagram trative lesions.
• Total gastrectomy – for tumour located <5 cm
Figure 11.6 from GOJ or the tumour is diffuse with sub-
Upper abdominal nodal stations.
mucosal infiltration.
• Distal gastrectomy – is the option for distal
gastric tumours which can be completely
Management of gastric cancer excised.
(Figure 11.7)
Lymphadenectomy with recovery of a
All patients should be assessed in a multidiscipli- minimum of 14, and an optimal of 25 lymph
nary setting. Assessment of the performance nodes is recommended. Based on the extent of
status and co-morbidities should be done. lymphadenectomy, dissection is categorized as:
Early gastric cancer (EGC) • D0 – gastric resection with incomplete dissec-
By definition the tumour is limited to the gastric tion of level 1 nodes.
mucosa or submucosa (T1) irrespective of nodal • D1 – gastric resection with complete dissec-
involvement. There is a 10–20% risk of lymph tion of level 1 nodes.
node involvement, depending on the size of • D2 – gastric resection with complete dissec-
the tumour, histologic subtype and presence of tion of level 1&2 nodes.
144
 CANCERS OF THE GASTROINTESTINAL SYSTEM 11
Figure 11.7
Bloods
Management of gastric cancer.
Scopy
CTchest/abdomen/pelvis
EUS

Early gastric cancer Locoregional disease Metastatic gastric

cancer

• Endoscopic resection Medically fit for Medically fit but Medically unfit for
• Gastric resection and resection unresectable resection
lymphadenectomy

Laparoscopy

No metastatic disease Metastatic disease Performance status

0–2

3 courses of
chemotherapy with ECF Yes No

Surgery

Palliative chemotherapy +/– Best supportive

3 courses of ECF supportive care care

Recurrence or progression

Best supportive care, second line chemotherapy, or clinical trial

• D3 – gastric resection with complete dissec- no standard chemotherapy regime. Adjuvant

tion of levels1–3 nodes. chemotherapy is hence not offered except in a
• D4 – gastric resection with complete dissec- clinical trial.
tion of level 1–4 nodes.
Adjuvant chemoradiotherapy
The current UK practice is to perform D2 lym-
A randomized trial showed better 3-year survival
phadenectomy without pancreatico-splenectomy.
with post-operative chemoradiation (50% vs.
Laparoscopic gastrectomy and laparoscopy
41%; p = 0.005) compared with surgery alone.
assisted D2 dissection are shown to be
However, it is not an accepted standard treat-
promising.
ment in the UK and Europe because of the draw-
Adjuvant chemotherapy backs of the study such as only 10% patients had
Meta-analyses showed improved survival benefit D2 dissection, significant radiotherapy error in
with adjuvant chemotherapy (one study reported 30% patients and 30% patients did not complete
HR 0.85–95%; CI: 0.80–0.90); but there was chemoradiotherapy due to toxicity.
145
 II SITE-SPECIFIC CANCER MANAGEMENT

Distal gastrectomy Total gastrectomy Figure 11.8

Gastric resections and
reconstructions.

Bilroth I Bilroth II Roux-en-Y

(gastroduodenostomy) (gastrojejunostomy) oesophagojejunostomy

Perioperative treatment
Box 11.6: Treatment regimes in gastric cancer
A randomized study (UK MRC MAGIC) showed
Perioperative chemotherapy and surgery
that three cycles of pre- and postoperative chem- (UK MRC MAGIC trial)
otherapy with epirubicin, cisplatin and continu- • ECF chemotherapy: Epirubucin 50 mg/m2 IV day 1,
ous infusion 5 fluorouracil (ECF) significantly cisplatin 60 mg/m2 IV day 1 and 5-fluorouracil
200 mg/m2/day continuous IV infusion for 21
improved 5-year survival (36% vs. 23%; days. Cycle repeated 3-weekly. Total 3 cycles
p = 0.009) compared with surgery alone in preoperatively.
resectable gastric and lower oesophageal cancers • Surgery 3–6 weeks after chemotherapy
(Box 11.6). This is the standard of care in most • Postoperative chemotherapy – 3 cycles of ECF
of the UK and parts of the Europe (Box 11.6). started 6–12 weeks after surgery
Metastatic or unresectable cancer
Unresectable gastric cancer ECF regime (see above)
The median survival of patients with unresecta- ECX regime
• Epirubicin 50 mg/m2 day 1, cisplatin 60 mg/m2/day
ble non-metastatic cancer is 6 months without 1 and capecitabine 625 mg/m2 orally twice daily;
treatment. Treatment is aimed at improving cycle repeated 3-weekly
the symptoms and quality of life and possible
extension of life. The various palliative measures
include:
outlet obstruction. Endoscopic stent place-
• Bleeding – endoscopic laser photocoagulation ment offers effective palliative. However,
or argon plasma coagulation is effective in 15–40% with develop recurrent symptoms.
controlling bleeding. If these measures fail, An alternative option is palliative bypass.
palliative resection may be considered. • Radiotherapy – is effective in controlling
• Obstruction – tumours of the proximal bleeding or obstruction in patients who are
stomach may present with dysphagia whereas unsuitable candidates for other interventions.
distal stomach tumours present with gastric Radiotherapy is effective in controlling pain.
146
 CANCERS OF THE GASTROINTESTINAL SYSTEM 11
Systemic treatment of unresectable Screening
gastric cancer Routine screening is not recommended for gastric
Patients with unresectable and/or disseminated cancer. Role of screening of asymptomatic indi-
gastric cancer should be considered for a clinical viduals for gastric cancer from countries with
trial, and those with good performance status high incidence such as Japan shows inconsistent
(0–2) may be offered systemic therapy. Rand- results of benefit.
omized trials suggest that chemotherapy may
improve survival compared with best supportive Gastric stump cancer
care (9–11 months vs. 3–4 months HR 0.39) and By definition this is the cancer developing in the
quality of life. A meta-analysis showed that gastric remnant at least 5 years after surgery for
combination chemotherapy improves survival benign peptic ulcer disease. Patients after distal
by 6 months and the best survivals are achieved gastric resection have a 4–7 fold increase in
by three-drug regimens containing 5-FU, anthra- gastric cancer attributed mainly to gastroduode-
cycline and cisplatin. The standard regime used nal reflux. Treatment is complete removal of
in the UK is ECF (Box 11.6). A recent study gastric remnants with a D2 lymphadenectomy.
(REAL 2) showed that ECF is comparable to The pattern of lymph node metastases in these
EOX. This regimen has the advantage of avoiding cancers may differ from primary gastric cancer
the need for continuous infusion of 5-FU. and the prognosis is the same as primary gastric
Other active agents include taxanes, and cancer.
irinotecan.
Follow-up Cancers of the liver
There is no evidence that regular intensive fol- Introduction
low-up improves outcome and hence symptom
driven follow-up is recommended. Cancers of the liver can be primary (5%) or sec-
ondary (95%). The most common primary liver
Management of recurrence cancer is hepatocellular carcinoma (HCC) which
The role of second-line chemotherapy is not well- accounts for 90% of primary liver cancers. There
established. The commonly used agents include are more than 3000 new patients diagnosed in
taxanes, irinotecan and oxalipatin. In the major- the UK. Males are more commonly affected
ity of patients management is essentially pallia- (male: female ratio is 5 : 3). Median age of diag-
tive aiming at best supportive care. nosis is 64 years.

Prognosis Aetiology
Important prognostic factors in resectable gastric The risk factors include:
cancer include depth of invasion, number of • Chronic liver disease – 80–90% HCC arising
lymph nodes involved and positive resection in patients with cirrhosis.
margins. Estimated 5-year survival by stage is: • Hepatitis infection – hepatitis B and C viruses
• Stage I: 70%. account for 75% cases of HCC. HCV accounts
• Stage II: 40%. for the recent rising trend.
• Stage III: 20%. • Alcohol accounts for 10% of cancers in Asia
• Stage IV: less than 5%. and 20% in Europe and USA.
• Non-alcoholic fatty liver disease (NAFLD) –
Newer agents associated with obesity and type 2 diabetes.
Monoclonal antibodies and various agents tar- 5% patients progress to cirrhosis and have an
geting pathways of cellular proliferation are increased risk of HCC.
being evaluated. However data are still limited • Aflatoxin.
to early phase studies. Examples of molecules • Metabolic disorders – haemochromatosis,
under study are bevacizumab (anti-VEGF), cetix- alpha-1-antitrypsin deficiency, and Wilson’s
umab (anti-EGFR) etc. disease.
147
 II SITE-SPECIFIC CANCER MANAGEMENT

Pathology Box 11.7: Okuda staging of

HCC is the most common primary liver tumour hepatocellular carcinoma
and is multiple in >50% cases. They spread locally Criteria Positive Negative
and invade blood vessels. Commonly metastasize Tumor size* >50 percent <50 percent
to lungs. The other histologic types include Ascites Clinically detectable Clinically absent
cholangiocarcinoma, sarcomas and lymphoma. Albumin <3 mg/dL >3 mg/dL
Bilirubin >3 mg/dL <3 mg/dL
Clinical features Stage
Commonest presentation is an incidental mass I No positive
on USS in cirrhotic patients. Other presentations II One or two positives
include abdominal pain, weight loss, anorexia, III Three or four positives
fever, ascites, jaundice, and paraneoplastic syn-
Prognosis of untreated patients
dromes (hypercalcaemia and hypoglycaemia). • Stage I: 8.3 months
Spontaneous bleeding of HCC can occur in • Stage II: 2 months
5–15% patients who present with abdominal • Stage III: 0.7 months
pain, haemorrhagic ascites or even shock.
*Largest cross-sectional area of tumour to largest cross-sectional
Diagnosis and staging area of the liver.

In a patient with pre-existing cirrhosis, a mass of

≥2 cm has >95% of chance of being malignant. Management (Figure 11.9)
Serum AFP of ≥400 µg/l is diagnostic.
Treatment of HCC depends on tumour stage,
Imaging liver function (Child–Pugh grading; Box 11.8),
and performance status.
Contrast enhanced CT scan and MRI scan are
useful in establishing the diagnosis. Both tests Stage O and stage A
have 80% accuracy. The characteristic feature of Treated radically and treatment options include:
HCC is a specific vascular profile – an intense
contrast intake during the early arterial phase • Resection.
followed by contrast washout during delayed/ • Transplantation.
portal venous phase. • Percutaneous tumour ablation.

Tissue diagnosis Resection

In patients with cirrhosis, >2 cm nodule with Surgical resection is the treatment choice in HCC
characteristic dynamic profile on one imaging, in non-cirrhotic patients. These tumours gener-
biopsy confirmation is unnecessary. In patients ally tend to be solitary and large. The 5-year
with a 1–2 cm nodule, if a characteristic vascular survival is 50% with less than 1% mortality.
profile is seen in two imaging techniques, biopsy Resection is the appropriate treatment for only
confirmation is needed. Lesions of >1 cm with a subset of cirrhotic patients with HCC. Absence
non-specific vascular pattern need biopsy. of portal hypertension and normal bilirubin are
However, biopsy can be delayed or avoided key factors in selecting the best candidates for
depending on the timing of definite treatment. resection. Hence the eligibility criteria include:
Biopsy has the risk of tumour seeding. Nodules
• Single tumour
of <1 cm in size needs close follow-up.
• No jaundice
Staging • No portal hypertension
• No extra-hepatic disease
There are two methods of staging: TNM
and Okuda staging. Barcelona Clinic Liver With appropriate selection of patients a 5-year
Cancer group incorporate Okuda staging (Box survival of 70% can be achieved with less than
11.7) for staging classification and treatment 5% operative mortality. There is no role for any
recommendation. adjuvant treatment after resection.
148
 CANCERS OF THE GASTROINTESTINAL SYSTEM 11

HCC

Stage O Stage A-C Stage D

PST 0, Child–Pugh A, Okuda 1 PST 0–2, Child–Pugh A–B, Okuda 1–2 PST >2, Child–Pugh C, Okuda 3

Very early stage (O) Early stage (A) Intermediate stage (O) Advanced stage (C) Terminal
1 HCC <2 cm 1 HCC or 3 nodules Multinodular Portal invasion stage (D)
Carcinoma in situ <3 cm, PST 0 PST 0 N1, M1, PST 1–2

1 HCC 3 nodules ≤3 cm

Portal pressure/bilirubin

Increased

Normal Associated diseases Portal invasion N1, M1

No Yes No Yes

Resection Liver PEI/ Chemoembolization New agents

transplantation radio frequency

Curative treatments Randomized controlled clinical trials Symptomatic treatment

Figure 11.9
Staging classification and treatment of hepatocellular carcinoma (Llovet JM, Burroughs A, Bruix J. LANCET
2003;362;1907–1917, fig 5, with permission). PST – performance status test, PEI – percutaneous ethanol injection.

Liver transplantation
Box 11.8: Child–Pugh grading of severity of
liver disease Liver transplantation is a treatment option for
HCC in cirrhotic patients. Indications for liver
Score
transplantation (only 10% are eligible) include
Criteria 1 2 3
(Milan criteria):
Hepatic None 1–2 3–4
encephalopathy • Solitary HCC <5 cm.
(grade) • Up to three HCC all <3 cm.
Total bilirubin (mg/dl) <2 2–3 >3
Ascites Absent Mild Moderate In these highly selected patients the reported
or severe 5-year survival is >70%. Liver transplantation
Serum albumin (g/dl) >3.5 2.8–3.5 <2.8
is not an acceptable option for HCC in non-
Prothrombin time <4 4–6 >6
(second prolonged) or or or cirrhotic patients because of the need for intense
or INR 1.7 1.7–2.3 >2.3 immunosuppression.
Child–Pugh Grade A = 5–6 points.
Grade B = 7–9 points. Percutaneous ablation
Grade C = 10–15 points. Percutaneous ablation is a treatment option for
patients with stage 0 & A disease who are not
149
 II SITE-SPECIFIC CANCER MANAGEMENT

suitable for resection or transplantation and • Stage 0 & A after radical treatment – 5-year
those who are waiting for transplantation. Abla- survival 50–75%.
tion is achieved either by: • Stage B – median survival 16 months without
treatment and with TACE 3-year survival is
• Chemical injection (ethanol, acetic acid and
50%.
boiling saline).
• Stage C – median survival 6 months without
• Thermal ablation (radiofrequency, laser and
treatment and with palliative treatment <10%
cryotherapy).
survive for 3 years.
Percutaneous ethanol injection (PEI) and radi- • Stage D – 1 year survival <10%.
ofrequency ablation (RFA) are equally effective
for tumours of <2 cm whereas RAF is more effec- Screening
tive for larger tumours. Surveillance is offered to patients with cirrhosis
and the two most common tests used for
Stage B & C screening are serum alpha-foetoprotein (AFP)
Treatment is palliative and options include: and ultrasonography.

• Transarterial chemoembolization (TACE)

and transarterial embolization (TAE).
Tumours of the biliary tract
• Systemic treatment. Tumours of the biliary tract can occur at any
• Chemotherapy. point between the sphincter of Oddi and the
• Biological agents, e.g. sorafenib. gallbladder.
Chemotherapy results in low response rate Carcinoma of the gallbladder
and has no impact on survival. Sorafenib, a
multi-kinase inhibitor, has been shown to prolong Introduction
survival in patients with advanced HCC with Carcinoma of the gallbladder is the most common
good liver function compared with controls (10.7 malignant lesion of the biliary tract. It is more
vs. 7.9 months) common in females with a 4 : 1 female:male
ratio.
Stage D Gallstones are considered one of the important
risk factors, although the majority of patients
Treatment is essentially symptomatic and
with gallstones never do not develop cancer.
supportive.
65–90% of patients have associated gallstones.
Other reported risk factors include ‘porcelain’
Management of recurrence gallbladder, gallbladder polyps of >10 mm
After surgical resection 70% of cases recur at 5 diameter, and anomalous pancreaticobiliary duct
years. Some of these recurrences are true recur- junction (APBDI).
rences (intrahepatic metastases) and some are de
novo tumours (30–40%). True recurrences typi- Pathology
cally occur within 2 years after resection, and are 90% of patients with gallbladder cancer have
usually associated with vascular invasion, satel- associated dysplasia and carcinoma-in-situ, sug-
lite nodules and poorly differentiated tumours. gesting a multi-step carcinogenesis. 90% tumours
De novo tumours usually occur late. are adenocarcinoma and the remainder are
The treatment options include re-resection squamous cell carcinoma. Spread of tumour is by
(possible in 10–20%), salvage transplantation or local invasion (including liver segments IV and
palliative treatment. V), through lymphatics and venous blood (to
liver).
Prognosis
Prognosis depends on cancer and cirrhosis. 50– Clinical presentation
60% patients die of cirrhosis, 30% with hepatic The usual presentation is an incidental finding at
failure and 10% with gastrointestinal bleeding. cholecystectomy. Other clinical features are that
150
 CANCERS OF THE GASTROINTESTINAL SYSTEM 11
of gallstone disease and unremitting jaundice in • Extensive involvement of hepatoduodenal
some patients. ligament
• Encasement or occlusion of major vessels
Investigations and staging
• Poor performance status
Initial assessment is by ultrasound which may
show a complex mass filling the lumen with The surgical options include:
localized thickening of gallbladder wall. There • Simple cholecystectomy
may be associated liver metastasis, ascites and • Radical cholecystectomy (for tumours in­
dilated bile ducts. vading perimuscular connective tissue and
• CT – useful in local staging, it can establish beyond – ≥T2) (Figure 11.10)
infiltration into adjacent tissues and vessels • Radical cholecystectomy with liver resec-
and nodal or distant metastases. tion – the extent of liver resection is
• MRI is useful in identifying invasion of the controversial.
hepatoduodenal ligament and portal vein • Radical cholecystectomy with extensive node
encasement, both features suggestive of an dissection – the role of node dissection is con-
unresectable tumour. troversial. Para-aortic node dissection does
• ERCP is not useful in diagnosing gallbladder not improve survival.
cancer but can be useful in identifying growth • Radical cholecystectomy with resection of the
in adjacent intrahepatic ducts or in the bile duct or pancreaticoduodenectomy.
common bile duct.
Adjuvant treatment
Staging
There is no proven role for adjuvant treatment.
Staging is given in Box 11.9.
A small retrospective study suggests that in
Treatment patients with completely resected gallbladder
Patients with resectable cancer cancer adjuvant radiotherapy with 5-fluorouracil
Surgery is the only curative treatment and no chemotherapy may improve survival (5-year
more than 10–30% patients are eligible for survival rate of 64% compared with 33% of
surgery. Surgical resection is contraindicated in: historical control).

• Multiple liver metastases

• Ascites Patients with unresectable and
• Multiple peritoneal metastases metastatic cancer
Treatment in this group of patients is essentially
palliative. Jaundice is treated with stent place-
ment or biliary bypass.
Box 11.9: Staging of gallbladder cancer
Stage I Palliative chemotherapy
• T1N0M0 – tumour invades lamina propria or 5-fluorouracil is the most extensively studied
muscle layer
regime. 5-fluorouracil based combination chemo­
• T2N0M0 – tumour invades perimuscular connective
tissue; no extension beyond serosa or into liver therapy yields a response rate of 10–38%.
Combination of gemcitabine and cisplatin gives
Stage II
• T3N0M0 – perforates serosa and invades liver or
a higher response of 61%.
adjacent organ
• T1–3N1M0 – regional lymph node metastasis
Prognosis
Stage III
5-year survival of gallbladder cancer is <5%.
• T4 any NM0 – invades main portal vein or hepatic
artery or multiple extrahepatic organs Stage at diagnosis is the most important determi-
nant of prognosis. Median survival of early stage
Stage IV
• Any T any N M1 – distant metastasis disease is 7–19 months whereas that of meta-
static disease is 2 months.
151
 II SITE-SPECIFIC CANCER MANAGEMENT

Figure 11.10
Extent of dissection in radical
cholecystectomy.

Area of liver resection

Gall bladder

Nodes of hiatus
Nodes along
hepatic artery
Cystic lymph node
Pericholedochal
lymph nodes

Superior pancreaticoduodenal lymph nodes

Posterior pancreaticoduodenal lymph nodes Coelic lymph nodes

Carcinoma of the bile ducts • Thorotrast (a radiological agent which is no

Introduction longer used).
• Smoking increases the risk in patients with
Cholangiocarcinoma (CCA), which comprises PSC.
tumours arising from intrahepatic, perihilar and
distal extrahepatic bile ducts, accounts for 3% of Pathology
all gastrointestinal cancers. There is a slight male CCA can arise anywhere in the biliary tree.
preponderance. Peak incidence occurs around 90% of tumours are adenocarcinoma whereas
65–70 years. tumours arising from choledochal cysts and or
Aetiology gallstones may be adenosquamous or squamous
carcinomas.
Risk factors include:
• Primary sclerosing cholangitis (PSC; life time Clinical features
risk 5–20%) – occurs at an earlier age (30–50 The presentation of CCA depends on the ana-
years) and tends to present as a diffuse, tomical location. 10% tumours arise from intra-
multicentric tumour. hepatic ducts, 50–60% from hilar (called Klatskin
• Liver fluke infestation (Opisthorchis viverrini, tumours) and 20–30% from the distal common
Clonorchis sinensis) – 8–10% cases. These are bile duct. Intrahepatic tumours present as a mass
endemic in Japan and Southeast Asia. lesion detected by abdominal imaging or with
• Chronic typhoid carriers (6-fold increased non-specific symptoms, whereas hilar or extra­
risk). hepatic tumours present with jaundice (>90%),
• Chronic intraductal gallstones (10% risk). pruritus, weight loss and abdominal pain. Patients
• Choledochal cysts (life time risk 3–15%) – presenting with a triad of cholestasis, abdominal
average age for development of CCA is 34 pain and weight loss should be evaluated for
years. Higher risk on those with anomalous cancer.
pancreatico-biliary ductal junction and muta- Diagnosis of malignancy in patients with
tions in p53 and Smad-4 tumour suppressor PSC is challenging. The new development of
genes and K-ras oncogene. jaundice and a dominant bile duct stricture in an
152
 CANCERS OF THE GASTROINTESTINAL SYSTEM 11
individual with previously stable PSC should Tissue diagnosis
raise the suspicion of malignancy. Patients with resectable tumours do not need
preoperative diagnosis whereas tissue diagnosis
Diagnosis and staging is needed for unresectable or metastatic disease.
Blood tests include raised markers of biliary Tissue diagnosis can be obtained by biliary cytol-
obstruction. CA19.9 of >100 U/mL has a sensi- ogy, endoscopic ultrasound or CT guided biopsy
tivity of 89% and a specificity of 86%. depending on the location of tumour.
Laparoscopy and laparoscopic ultrasound are
Imaging useful in identifying patients with superficial liver
• USS is used as a first line test in patients pre- or peritoneal metastases and thus laparotomy
senting with abnormal liver function tests, can be avoided.
jaundice or abdominal pain. USS can differ- Staging
entiate obstructive from non-obstructive
jaundice, detect a mass lesion in intra-hepatic The Bismuth and Corlette classification of proxi-
CCA, and confirm ascites in patients with mal bile duct cancers are shown in Figure 11.11.
advanced disease. Further imaging is always Treatment
needed to evaluate and stage the disease.
Resectable tumour
• CT of the chest, abdomen and pelvis is useful
The aim of surgery in resectable disease is R0
in locoregional and metastatic staging.
resection which involves resection of tumour
• MR cholangiography (MRCP) and endo-
with regional nodes and extended liver resection.
scopic retrograde cholangiopancreatography
Criteria which exclude resectability include:
(ERCP) are useful in accurate local staging.
• MRI is particularly useful for hilar CCA. • Distant metastases
• Cholangiography assesses biliary drainage • Encasement of coeliac trunk
and can be used to obtain a biopsy. • Portal vein occlusion with collaterals

Type 1 Type 2 Type 3 Type 4 Figure 11.11

Classification and treatment of
biliary tumours.
3A 3B

Type 1 – proximal to the bifurcation

Type 2 – involving hepatic duct confluence but not hepatic duct
Type 3 – extending to the right (type 3A) or left (type 3B) hepatic ducts
Type 4 – extends into both the right and left hepatic ducts or with multi-focal duct involvement

Treatment
• Types I and II: en bloc resection of the extrahepatic bile ducts and gall bladder, regional
lymphadenectomy, and Roux-en-Y hepaticojejunostomy
• Type III: as above plus right or left hepatectomy
• Type IV: as above plus extended right or left hepatectomy
• Distal cholangiocarcinomas are managed by pancreatoduodenectomy as with ampullary or
pancreatic head cancers
• The intrahepatic variant of cholangiocarcinoma is treated by resection of the involved
segments or lobe
153
 II SITE-SPECIFIC CANCER MANAGEMENT

• Lymph node metastasis (N2 nodes). Pancreatic cancer

• Poor clinical status and co-morbidities.
Introduction
Type of primary surgery depends on location
of tumour (Figure 11.11). Approximately 7400 new cases are diagnosed in
the UK and 37,000 new cases in USA every year.
Adjuvant treatment The peak incidence is in the 65–75 year age
There is no proven role for adjuvant treatment group with 60% of patients being older than 65
after R0 resection. years of age. The male:female ratio is 1.25 : 1.
Only 10–15% patients present with early stage
Liver transplantation
disease amenable to curative surgery, and 4%
Neoadjuvant chemoradiotherapy followed by
survive more than 5 years.
liver transplantation may be an appropriate
treatment for a subgroup of patients with unre-
sectable localized disease with no lymph node Aetiology
and vascular involvement. The reported 5-year Exact aetiology is unknown and the suggested
survival is 82% from USA. risk factors include:
Management of unresectable tumours • Cigarette smoking – increases the risk by two
Management of unresectable tumours is essen- fold and accounts for 30% of cases.
tially palliative and supportive. Jaundice is • Increasing age – more than 50% pancreatic
managed with stent or biliary bypass. Other evolv- cancers occurring in individuals aged 70 years
ing treatments include photodynamic therapy, or older.
high intensity focused ultrasound (HIFU), radio­ • Chronic pancreatitis – increases risk by
frequency ablation, palliative radiotherapy and 15–25%.
drug coated stents. • Late onset diabetes mellitus.
Palliative chemotherapy with gemcitabine • Hereditary pancreatitis – autosomal domi-
alone or in combination with platinum agents or nant condition, mutation of PRSS1 gene and
capecitabine may be considered for fit patients. results in a 70-fold increase.
The reported response rate is 15–40% with median • Cancer family syndromes – account for 10%
survival of 4–16 months. A recent randomized of cases. Common syndromes associated with
phase III study (ABC-02) has shown that a com- pancreatic cancer include Peutz–Jeghers,
bination of cisplatin and gemcitabine yields a familial atypical multiple mole melanoma,
better median overall survival compared with familial adenomatous polyposis and Li–Frau-
gemcitabine alone (11.7 months vs. 8.1 months meni syndrome.
p < 0.001).
Pathology
New agents
Ductal adenocarcinoma develops through an
Growth factor receptors HER-1 and HER-2 are adenoma–carcinoma sequence of epithelial pre-
overexpressed in biliary tract cancers. New neoplastic lesions called pancreatic intra-epithe-
agents studied include erlotinib (EGFR-1 inhibi- lial neoplasia (PanIN).
tor) and lapatinib (EGFR-1/HER-2 dual inhibi- Ductal adenocarcinoma is the most common
tor) (p. 370). malignant tumour of the pancreas. There are
Prognosis several variants such as undifferentiated (ana-
plastic), adenosquamous, signet ring cell carci-
CCA has a poor 5-year survival of <5%. The
noma, and mucinous non-cystic. 65% tumours
majority (75%) of patients die within 1 year.
are located within the head, 15% in the body,
Surgery is the only curative treatment and
10% in the tail and 10% are multifocal.
outcome depends on completeness of surgical
resection. R0 resection has a 5-year survival of
20–40%, R1 has 5–10% and R2 has 0%. The Clinical features
median survival after palliative chemotherapy is Tumours of the head of the pancreas tend
154 4–16 months. to present with obstructive jaundice or acute
 CANCERS OF THE GASTROINTESTINAL SYSTEM 11
pancreatitis, but the onset is usually insidious. Further investigations include:
Tumours of the body and tail tend to present
• Magnetic resonance cholangio-pancreatogra-
even later and are associated with a worse
phy (MRCP) – useful in assessing cystic
prognosis. Other presenting features include
tumours.
fatigue, back pain, weight loss, late onset
• Endoluminal ultrasonography (EUS) – useful
diabetes mellitus, steatorrhoea and duodenal
in detecting small tumours and biopsy of
obstruction.
small lesions.
• Endoscopic retrograde cholangiopancreatog-
Signs raphy (ERCP) – rarely used in the diagnosis
• General examination – anaemia, jaundice, except to insert biliary stent to relieve
cachexia, enlarged left supraclavicular node obstructive jaundice and obtain biopsy (Figure
(Troisier’s sign). 11.12B).
• Abdominal examination – abdominal mass, • Percutaneous transhepatic cholangiography
ascites, hepatomegaly, umbilical nodule. (PTC) useful to relieve jaundice when ERCP
has failed or not possible.
Diagnosis and staging
Tissue diagnosis
Initial investigations include abdominal ultra-
sound and CT scan. Tissue diagnosis is usually obtained by EUS with
fine needle aspiration (FNA). The technique has
• Abdominal ultrasound – is the initial evalua- a sensitivity of >90% and specificity of almost
tion which can detect biliary and pancreatic 100%. Percutaneous fine needle aspiration (FNA)
duct dilatations, tumours >2 cm and liver biopsy is less sensitive (69%) and carries a risk
metastases. of intraperitoneal seeding (16%).
• CT scan of the chest, abdomen and pelvis is
helpful in local (Figure 11.12A) and distant Blood tests
staging. It can also help to determine the • FBC, biochemistry and clotting profile.
resectability of a tumour with 80–90% • Serum CA19.9 is the commonly used tumour
accuracy. marker which has a sensitivity of 70–90%

A B

Figure 11.12
CT scan and ERCP in pancreatic cancer. Carcinoma pancreas (white arrow) leading biliary obstruction (black arrow)
and duodenal obstruction with gastric dilatation (white asterix) (A) and ERCP shows strictures of common bile duct
and pancreatic duct (‘double duct sign’) (B).
155
 II SITE-SPECIFIC CANCER MANAGEMENT

and specificity of 90%. It is useful to assess Patients with jaundice may be considered for pre-
response and identify tumour recurrence. A operative biliary drainage. The type of surgery
level of <200 u/ml suggests longer survival. depends on location of the tumour:
Further tests prior to surgery • Tumours of head of the pancreas – pan­
creaticoduodenectomy (classic Whipple) or
Laparoscopy with laparoscopic ultrasound alters
pylorus preserving pancreatoduodenectomy
the management of 15% of patients already
(pp Whipple) are considered curative. A meta-
assessed as resectable by CT. Selective laparos-
analysis showed that both procedures carry
copy based on the serum level of CA19-9 and
equal morbidities and survival. There is no
large tumour, is a more efficient strategy, reduc-
survival advantage for extended radical
ing the proportion of patients undergoing laparo-
lymphadenectomy in pancreatic cancer.
scopic ultrasound from 100% to around 45%
• Tumours of the body and tail of pancreas –
while increasing the yield from 15% to 25%.
left pancreatectomy which includes splenec-
Staging tomy and en bloc removal of the hilar lymph
Staging is shown in Box 11.10. nodes.
The postoperative morbidity of radical surgery
Management of pancreatic cancer
is around 40% and the mortality is <5%.
Treatment of resectable cancer
Neoadjuvant therapy
Surgery
Neoadjuvant treatment using a combination
Patients with good performance status and
of external beam radiotherapy with 5-FU or
resectable tumours are treated with radical resec-
Gemcitabine based chemotherapy may improve
tion. Criteria for resectability are given in Box
resectability in a borderline resectable tumour.
11.11. Though the aim of surgery is a complete
Several studies report a resection rate of 60%
microscopic resection (R0), 30–60% of resec-
and negative resection margin of 90%. However,
tions result in microscopic residual disease (R1).
this is not routinely practised in the UK.
Postoperative treatment
• Adjuvant chemotherapy – a meta-analysis
showed that adjuvant chemotherapy improves
Box 11.10: Staging of pancreatic cancer 5 year survival (19% vs. 12%) and median
Stage 0 survival (19 months vs. 13.5 months) com-
TisN0M0 Carcinoma-in-situ pared with no chemotherapy. The recently
Stage IA
reported ESPAC-3 study comparing gemcit-
T1N0M0 Tumour limited to the pancreas, ≤2 cm in abine and 5-FU/FA in patients who had R0/
diameter
Stage IB
T2N0M0 Tumour limited to the pancreas, >2 cm in
diameter
Stage IIA Box 11.11: Criteria for resectable
T3N0M0 Tumour beyond pancreas, but without pancreatic cancer
involvement of coeliac axis or superior mesenteric
artery • No coeliac, hepatic or superior mesenteric artery
involvement
Stage IIB • A patent superior mesenteric-portal venous
T1–3N1M0 Regional lymph node metastasis confluence
Stage III • Portal venous involvement of not more than 2 cm
T4 any NM0 Tumour involving coeliac axis or in length or more than 50% circumference
superior mesenteric artery • No liver, peritoneal or other distant metastases
Stage IV • Absence of portal hypertension and cirrhosis
Any T any N M1 Distant metastasis • No severe co-morbidity to exclude surgery

156
 CANCERS OF THE GASTROINTESTINAL SYSTEM 11
R1 resection showed no difference in survival Symptom control
(median survival of 23.0 months with 5-FU/ • Pain control – measures include analgesics,
FA and 23.6 months with gemcitabine). celiac plexus block or unilateral thoraco-
• Adjuvant chemoradiotherapy – a meta-analy- scopic splanchnicectomy.
sis showed that chemo-radiotherapy did not • Obstructive jaundice – managed with biliary
improve survival compared with no treatment stent or surgical bypass. Plastic stents are used
(median survival 15.8 months vs. 15.2 for patients with metastatic disease and
months). tumours of >3 cm diameter whereas self-
• Adjuvant chemoradiotherapy and chemo­ expanding metal stents are used for patients
therapy – RTOG 9704 trial reported no with good performance status and locally
statistically significant survival benefit advanced disease of <3 cm.
with gemcitabine to adjuvant 5-FU based • Duodenal obstruction – treated with endo-
chemoradiotherapy. scopically placed stents or bypass surgery.

Unresectable and metastatic cancer New agents

70% of patients will present with unresectable Early studies combining gemcitabine with
disease and treatment of these patients is essen- EGFR inhibitor erlotinib has shown some activ-
tially palliative. Treatment options include: ity but the exact role of EGFR inhibitors is still
evolving.
• Palliative chemotherapy (for locally advanced
and metastatic cancer). Prognosis and outcome
• Palliative chemoradiotherapy (locally ad- The most important prognostic factors are
vanced cancer). resectability and performance status. Median
• Symptom control (poor performance status). survival following surgical resection ranges from
Palliative chemotherapy – single agent response 11–20 months. Without active treatment, meta-
rate is seldom more than 10%. A meta-analysis static pancreatic cancer has a median survival
showed that chemotherapy improves survival of 3–6 months and 6–10 months for locally
compared to best supportive care (HR 0.64; 95% advanced disease, which increases to around
CI, 0.42–0.98). Single agent 5-FU results in a 11–15 months with surgical resection. Five-year
median survival of 5–6 months. Single agent survival ranges from 7–25%. Radical resection
gemcitabine has a better median survival (5.7 vs. alone gives a 5-year survival rate of around 10%.
4.4 months, p = 0.0025), 1-year survival (18% Pancreatic endocrine tumours
vs. 2%) and relatively mild toxicity compared
Pancreatic endocrine tumours arise from the
with 5-FU. Hence the current drug of choice is
islet cells of the pancreas and the main types
gemcitabine.
are insulinoma, gastrinoma, glucagonoma and
A recent meta-analysis has confirmed that
VIPoma. The mean age at presentation is 47
gemcitabine combination chemotherapy improves
years. Genetics syndromes of MEN1, Von
survival compared with gemcitabine alone
Hippel–Lindau, neurofibromatosis type 1 and
(HR = 0.91; 95% CI, 0.85–0.97). Capecitabine
tuberous sclerosis are associated with an increased
and platinum are the commonly used drugs with
risk of pancreatic endocrine tumours.
gemcitabine.
Clinical presentation is either due to tumour
Palliative chemoradiotherapy – the role of
mass or from excessive peptide secretion.
external beam radiotherapy given concurrent
with 5-FU or gemcitabine is not clear. However, • Insulinomas present with features of hypogly-
a meta-analysis showed that chemoradiotherapy caemia associated with fasting or vigorous
increases survival compared with radiotherapy exercise, and rapidly relieved by eating a
alone (HR 0.69, 95% CI 0.51–0.94). There was snack or drinking a liquid rich in glucose.
no survival difference between chemotherapy Diagnosis is based on a very low blood sugar
alone and chemoradiotherapy followed by (<2 mmol/l) and a high level of insulin and
chemotherapy. C-peptide (indicative of endogenous insulin).
157
 II SITE-SPECIFIC CANCER MANAGEMENT

• Gastrinoma presents with refractory multiple The clinical presentation of a carcinoid tumour
peptic ulcers and diarrhoea. It is diagnosed by can be a non-specific abdominal symptom,
high gastrin levels (>100 pg/ml, or >200 pg/ although carcinoid syndrome can occur in 25%
ml after secretin stimulation). of cases. CT is the diagnostic image of choice.
• Glucagonoma presents with features of hyper- Surgery is the treatment of choice for resectable
glycaemia, stomatitis, weight loss, diarrhoea tumours. However, 70–80% patients present
and psychiatric disturbances. Necrolytic with advanced disease. Treatment options for
migratory erythema of the skin is a character- advanced disease include:
istic feature. Diagnosis is by high plasma glu-
• Symptom control using octreotide or a long
cagon levels.
acting version.
• Vasoactive intestinal polypeptide tumour
• Radioisotope treatment using 131I-MIBG or
(VIPoma) causes watery diarrhoea and 111
In/90Y octreotide in patients with positive
hypokalaemia. Diagnosis is by high plasma
scans.
levels of vasoactive intestinal polypeptide.
• Palliative chemotherapy – streptozosin plus
Staging investigations of pancreatic endocrine 5-FU/dacarbazine and doxorubicin plus 5-FU.
tumours include CT scan, MRI scan, EUS, 111In-
The overall five-year survival rate is 30–40%
octreotide and selective portal/splenic venous
and the median survival of patients with meta-
sampling and intraoperative ultrasound.
static disease is approximately 7 months.
Surgical resection is the treatment of choice
which may be indicated even in metastatic
disease. 5-year survival following surgical resec- Malignant tumours of
tion is 50–95%. the small intestine
Cystic tumours of pancreas Small intestinal malignancies constitute 2–3% of
all malignant GI cancers. The ileum is the most
These constitute around 15% of all pancreatic
frequent site of tumours and is more common
cystic masses. The common types are:
in males.
• Serous cystic neoplasms predominantly affect
women, are found mostly in the head of the Aetiology
pancreas and represent 30% of cystic neo- The risk factors include:
plasms. Conservative approach with regular
• Familial adenomatous polyposis (FAP) – small
imaging is the management.
intestinal adenocarcinoma is one of the
• Mucinous cystic neoplasms are also common
common causes of death in patients with FAP
in women affecting the body and tail of the
after colectomy.
pancreas, and represent 40% of primary
• Crohn’s disease (adenocarcinoma).
cystic neoplasms. These are treated with
• Coeliac disease (adenocarcinoma and lym-
resection to avoid malignant transformation.
phoma) – type of lymphoma in coeliac disease
• Intraductal papillary mucinous neoplasms
is enteropathy associated T cell variant.
(IPMNs) commonly affect men and constitute
• Tropical sprue (lymphoma).
30% of pancreatic cysts. IPMNs arising from
• MEN type-1 (gastrin producing tumour of
main duct should be resected whereas those
duodenum and jejunum).
from branch duct may be managed with
regular follow-up imaging. Pathology
Carcinoid tumours Tumours of small intestine can be of epithelial,
mesenchymal or lymphoid origin. The following
Carcinoid tumours are neuroendocrine neo-
are the common types of cancers occurring in the
plasms arising from enterochromaffin cells. These
small intestine:
can be functioning or non-functioning. The mean
age at presentation is 49 years and women are • Adenocarcinomas (45%) – occur in ampulla
more commonly affected. of Vater in the duodenum and jejunum.
158
 CANCERS OF THE GASTROINTESTINAL SYSTEM 11
• Carcinoids or neuroendocrine tumours (30%) Staging
– common in terminal ileum. Adenocarcinoma is staged similar to colonic
• Sarcomas (10%) – common in ileum, major- cancer (p. 163). Lymphomas are staged using the
ity of tumours are GIST (p. 261). Ann Arbor staging (p. 299).
• Lymphomas (15%) – B cell NHL is the most
common. Management
• Metastatic cancers – are commoner than Small intestinal adenocarcinoma
primary and usual primaries are GI tract,
In patients with localized adenocarcinoma, resec-
breast, uterus, ovary and melanoma.
tion of visible disease and regional lymph nodes
Clinical features is done. In advanced disease, surgery may help
Clinical presentation depends on the type of with palliation of symptoms.
cancer, site and size. The majority of patients Chemotherapy regime is same as that of
with small intestinal malignancies present with colonic cancer (p. 165). A small study reports a
advanced disease. Nonspecific symptoms include response rate of 50% and a median survival of
abdominal pain, anaemia, nausea, bleeding, and 20 months with a combination of oxaliplatin
weight loss. Patients can also present as a surgical with capecitabine.
emergency with perforation or intussusception. Small intestinal lymphoma
Duodenal tumours can present with obstruction
as well as jaundice. Metastatic liver carcinoid can Stage I and II B-cell NHL are treated surgically
present with carcinoid syndrome. Lymphoma with or without chemotherapy, whereas III–IV
may present with pain, weight loss and features disease is treated with primary chemotherapy
of malabsorption. GIST commonly presents with with or without surgical debulking. Chemother-
anaemia, sometimes with an abdominal mass. apy regimens are similar to NHL (p. 305).

Investigations GIST
The initial investigations depend on the present- Managed similar to GIST occurring elsewhere
ing symptoms. (p. 261).

Imaging Prognosis
• Plain X-rays – useful in suspected Prognosis depends on the type of cancer and
obstruction. stage. Adenocarcinoma usually presents with
• Abdominal ultrasound – useful to detect liver advanced disease and the reported 5-year sur-
metastasis, ascites and biliary dilatation. vival is 30%. Duodenal tumours have a better
• CT scan of chest, abdomen and pelvis can prognosis with 5-year survival of 50%.
delineate primary tumour and disease extent. Lymphomas have a 10-year survival of 60%.
Different histological types exhibit different The prognosis of small bowel GIST depends on
features, e.g. lymphoma appears as diffuse their size and mitotic rate (see p. 262 for NIH
segmental thickening of the small intestine prognostic index).
and GIST as a well circumscribed mass.
• Small bowel follow-through. Colorectal cancer
• Endoscopic ultrasound (EUS).
Epidemiology
• Small bowel endoscopy.
• 111In-octreotide scan – in carcinoid to rule out Colorectal cancer (CRC) is the third commonest
metastatic disease. cancer in the UK after breast and lung. Over
36,000 new cases per year are diagnosed in the
Tissue biopsy UK and 105,500 per year in the USA.
Biopsy confirmation is essential prior to defini- Over 80% of cases occur in people over 60
tive treatment. Tissue diagnosis can be obtained and is rare below the age of 40 (except in heredi-
by endoscopic, CT guided or laparoscopic tary forms). The male:female incidence ratio is
methods or by laparotomy. 1.2 : 1.0. In the UK, the lifetime risk is 1 in 18
159
 II SITE-SPECIFIC CANCER MANAGEMENT

for men and 1 in 20 for women. Two-thirds of • Drugs – females on hormone replacement
primaries are in the colon and one third in the therapy and those using regular aspirin are at
rectum. Left-sided cancers are more common low risk of developing CRC.
than right (sigmoid and rectal cancers account • Lifestyle – long-term smokers are at high risk
for over half). of adenomas and CRC mortality. Regular
physical activity reduces the risk of CRC, par-
Aetiology ticularly in men.
The majority of colon cancers are sporadic and
not associated with known hereditary genetic
mutations. Hereditary bowel cancer is character-
Pathogenesis and pathology
ized by early age at diagnosis, right-sided cancers, Almost all colorectal cancers are adenocarcino-
synchronous/metachronous colorectal tumours mas and arise in adenomatous polyps through a
or other characteristic tumours in same individu- multi-step process (Figure 11.13). Most adeno-
als or families (see below). Up to 25% of patients carcinomas are moderate to well differentiated
with CRC give a positive family history, suggest- with typical morphology. About 80% of primary
ing involvement of genetic factors. colorectal adenocarcinomas and 70% of
metastases will be CK7− CK20+. Rare histologic
• Genetic (p. 50): types include squamous cell carcinoma, small
• Familial adenomatous polyposis (FAP) cell carcinoma, adenosquamous carcinoma and
accounts for 1% of all cases of CRC. medullary carcinoma.
• Hereditary non polyposis colorectal cancer
(HNPCC) accounts for about 5% of all
CRC cases. Presentation
• Familial – those with an affected first-degree About 85% of patients with bowel cancer have
relative are at increased risk of developing these symptoms at the time of diagnosis. Approxi-
CRC (relative risk 2.25). mately one-third presents with altered bowel
• Inflammatory bowel disease – increases the habit or obstructive symptoms (usually left sided
risk. In ulcerative colitis the cumulative risk tumours as the distal bowel is narrower and faecal
of developing CRC is estimated to be 8% at content more solid) and one-third with iron defi-
20 years and 18% at 30 years. ciency anaemia (usually right-sided tumours).
• Diet and supplements – high intake of red For rectal cancers other symptoms include faecal
meat, calorie and high body mass index incontinence, passage of mucus and tenesmus. Up
increase the risk whereas high vegetable intake to 30% present with acute colonic obstruction.
and high-fibre diet are protective. More advanced tumours may cause weight loss,

Figure 11.13
Common genetic mutations Consequences
Pathogenesis of colorectal cancer.

Normal colonic mucosa APC mutations Clonal expansion and proliferation

DNA methylation changes TS suppression/oncogene activation

Adenomatous polyps
K ras mutations Unregulated cell growth
and clonal expansion
Large adenomatous polyps
Bc12 over expression Decreased apoptosis
DCC deletion Confers metastatic capacity
p53 deletion Unregulated cell growth
Invasive carcinoma
160
 CANCERS OF THE GASTROINTESTINAL SYSTEM 11
nausea and anorexia, and abdominal pain and elevated CEA preoperatively, and this can be
distension from ascites or hepatomegaly. used to detect early recurrence in patients
who may be appropriate for further curative
Investigations and staging surgery. It is also useful in monitoring response
Initial investigations include double contrast to treatment in recurrent and metastatic
barium enema (DCBE), sigmoidoscopy (allows disease. It is less likely to be elevated in poorly
visualization up to splenic flexure at 60 cm) and differentiated carcinomas.
colonoscopy (Figure 11.14A & B). The whole • All patients with confirmed CRC need CT
colon should be imaged as approximately 5% of scan of the chest, abdomen and pelvis for
patients have synchronous cancers and up to staging.
40% have synchronous adenomas. CT colonog- • Patients with rectal cancer need locoregional
raphy is an alternative DCBE (Figure 11.14C). staging with pelvic MRI (Figure 11.15);
Endoscopy also allows biopsy confirmation. including T2W image MRI helps to define the
Those patients presenting with suspected extent of the tumour and to identify mesorec-
intestinal obstruction should have cross-sectional tal margin invasion by tumour which helps to
imaging preoperatively unless there are signs of decide need for neoadjuvant treatment.
peritonitis when emergency surgery will take • If MRI suggests a small (<3 cm) early T1 lesion
precedence. endorectal ultrasound is useful to access fea-
sibility of local excision and exclude tumour
Further investigations penetration into the muscle of the bowel wall
• Blood – full blood count, liver function tests, (T2 disease) with an accuracy of 87%.
U&E and serum carcinoembryonic antigen • PET scan is not routinely used in CRC but
(CEA). The majority of patients will have an may be useful in the context of a rising

A B

Figure 11.14
Double contrast barium enema shows a
polypoid cancer with an irregular indrawn
base (A), colonoscopy showing T1 high rectal
cancer (B) and CT colonography showing an
annular carcinoma (C). Parts A and C from
Adam A, et al: Grainger & Allison’s
C Diagnostic radiology, 5th Edition, Volume 1,
2009 (Elsevier), with permission.
161
 II SITE-SPECIFIC CANCER MANAGEMENT

CEA or clinical suspicion of metastatic disease Staging

or local recurrence, where CT is negative Figure 11.17 shows TNM and Dukes’ staging
or equivocal and confirmation of relapse which are postoperative staging. After radical
would alter management. PET scan may also resections, 12 or more nodes should be examined
have a role in potentially resectable metastatic as this correlates with prognosis for Dukes’ B
disease such as lung to rule out extensive cancers. Pathology reports should also inform
metastasis. about presence or absence of tumour perforation,
• In patients with resectable or potentially extramural vascular invasion, radial margins,
resectable liver metastasis, MRI of the liver is lymph nodes (number examined and involved)
done to exclude more extensive disease prior and assessment of completeness of resection.
to perioperative chemotherapy (Figure 11.16).
Management of colon cancer
(Figure 11.18)
Stage I (Dukes’ A)
• Surgery
Seminal vesicle
circumferential Stage II (Dukes’ B)
tumour
• Surgery
• Consider adjuvant chemotherapy in patients
with PS0-2 if:
• high risk factors (vascular invasion,
peritoneal involvement or T4 tumours,
perforation, poorly differentiated adeno-
carcinoma and surgical margins with
tumour cells).
Mesorectal fascia • or young age (<70 years).
Mesorectal fat
Lymph nodes T3b tumour extension threatening Stage III (Dukes’ C)
left posterior margin

Figure 11.15
• Surgery.
T2W MRI of mid rectal cancer shows threatened • Consider adjuvant chemotherapy in all
mesorectal margin. patients with PS 0–2.

A B

Figure 11.16
CT scan of liver in portal venous phase shows resectable liver metastases (A) and MRI liver with hepatocyte specific
contrast reveals more extensive metastases (B).
162
 CANCERS OF THE GASTROINTESTINAL SYSTEM 11
Mucosa • Palliative chemotherapy
• Palliative radiotherapy
• Other palliative treatments
• Active symptom control
Lamina propria Surgery
Muscularis mucosa Surgery is curative and several studies have
shown equal survival with better cosmesis and
Submucosa shorter hospital stays for laparoscopic versus
open surgery for colectomies. Emergency surgery
has higher perioperative mortality than that of
elective surgery. Hence emergency stenting may
Muscularis propria be useful to temporarily decompress an obstructed
lesion prior to definitive surgery.

Adjuvant chemotherapy
Subserosa Table 11.1 shows current recommendations for
Serosa adjuvant chemotherapy. There is no benefit of
adjuvant chemotherapy in Dukes’ A disease. In
Mesorectal tissue/mesorectal stage III (Dukes’ C) disease, 5-fluorouracil/folinic
membrane in rectum acid (5FU/FA) chemotherapy gives an absolute
Tis – confined to mucosa or lamina propria survival benefit of between 8–13%, with 6 months
(no significant metastatic potential) chemotherapy as effective as 1 year. In stage II
T1 – invades submucosa disease, chemotherapy results in a similar propor-
T2 – invades muscularis propria
T3 – invades subserosa/pericolic/mesorectal tissue tional reduction (approximately 33%) in recur-
T4 – invades other organs or tumour on serosal surface rence, but absolute benefits are less because of
lower mortality rates (QUASAR 1 showed an
Stage group TNM stage Dukes stage % Patients absolute increase in 5-year OS of 3.6% for patients
O Tis N0 M0 – less than 70 years). Patients with stage II disease
with adverse features have a higher disease-related
I T1-2 N0 M0 A 11
mortality rate (with >1 risk factor this approaches
IIA T3 N0 M0 that of Dukes’ C cancers) and hence absolute
B 34
IIB T4 N0 M0 benefits of adjuvant chemotherapy are greater.
Capecitabine has been shown to have equal
IIIA T1-2 N1 M0
efficiency with favourable toxicity profiles com-
IIIB T3-4 N1 M0 C1 or 2 26 pared to bolus 5FU in patients with stage III
IIIC T1-4 N2 M0 disease. This is now standard of care for high
IV T1-4 N1-2 M1 D 29
risk Dukes’ B cancers and those patients with
Dukes’ C not fit for combination chemotherapy.
In patients with stage II and III CRC, addition of
N1 = 1–3 lymph nodes (LN) contain metastatic carcinoma,
N2 = ≥4 LN contain metastatic carcinoma, oxaliplatin to 5FU/FA improved 3-year DFS by
C1 = apical LN negative, 5% over infusional 5FU/FA alone at the cost of
C2 = apical LN positive increased neurotoxicity. Absolute benefit was
Figure 11.17 greater for stage III vs. stage II disease (6.9% vs.
Staging for colorectal cancer. 2.7%). Hence oxaliplatin in combination with
5FU/FA is a treatment option for stage III colon
Stage IV cancer.
• Consider radical surgery with perioperative Ideally chemotherapy should begin within six
chemotherapy if resectable liver +/− lung weeks of surgery dependent on wound healing
metastases. and patient recovery. The benefit of adjuvant
163
 II SITE-SPECIFIC CANCER MANAGEMENT

Adenocarcinoma of colon without evidence

of distant metastasis and fit for surgery
Yes No

Radical intent Resectable liver Unresectable Patient unfit

or lung liver/lung metastases for surgery
metastases* or other metastatic due to co-
disease morbidities

Radical segmental Radical intent Palliative intent

surgical resection
•
Consider intra-operative Consider 12 weeks
U/S of liver lesions preoperative No obstructive Obstructive
(do not biopsy) chemotherapy symptoms symptoms

Consider stenting or
palliative resection/by-
pass surgery as
appropriate
(de-functioning stoma
rarely required)

Dukes A Dukes B Dukes C Metastatic WHO

disease PS 0-2

High risk features and/or young age Resectable No Yes No

Performance status 0-2 metastases*

Surgical No Yes
follow-up
alone
Adjuvant Peri-operative Palliative • Best supportive care
chemotherapy chemotherapy chemotherapy • Other palliative treatments

* <4 lung resectable metastases following cardiothoracic surgical review and/or liver metastases resectable or potentially resectable with downstaging Ox/MdG
chemotherapy following liver surgeons review (requires >30% of liver intact post surgery. Note that age, number, size and proximity of metastases to major vessels
are not exclusions to this) Patients WHO PS 0-1

Figure 11.18
Management of colon cancer.

treatment starting beyond 3 months of surgery is their primary disease (Figure 11.16). However,
uncertain. resection is feasible only in 10% of patients with
metastatic disease. Preoperative chemotherapy,
Management of isolated lung or in selected patients whose liver metastases are
liver metastases initially extensive for surgery, can enable curative
Liver or lung metastasectomy should be consid- resection in about 30%. A maximum of 12 weeks
ered in fit patients following radical resection of treatment is recommended prior to surgery as
164
 CANCERS OF THE GASTROINTESTINAL SYSTEM 11

Table 11.1: Chemotherapy regimens for colorectal cancer

Regimen Drugs Doses Schedule Indications PS
Modified Roswell 5FU 500 mg/m2 IV B weekly 6/8 Adjuvant patients <70 years 0–2
Park Folinic acid 20 mg/m2 IV B weekly 6/8 Dukes’ B (equivalent efficacy
to Mayo Clinic regimen with
less mucositis)
Capecitabine Capecitabine 1250 mg/m2 po bd 14 d Adjuvant Dukes’ B (high risk) 0–2
3 weekly Adjuvant Dukes’ C
First line palliative
Modified de Folinic acid 350 mg IV 2 h d1 First line palliative 0–2
Gramont (MdG) 5FU 400 mg/m2 IV B d1 (capecitabine not tolerated
2800 mg/m2 IVI 46 h d1–3 or severe renal impairment)
Oxaliplatin Folinic acid 350 mg IV 2 h d1 Adjuvant Dukes’ C 0–1
modified de Oxaliplatin 85 mg/m2 IV 2 h d1 First or second line palliative
Gramont 5FU 400 mg/m2 IV B d1 Perioperative resectable liver
2400 mg/m2 IVI 46 h d1–3 metastases
Irinotecan modified Folinic acid 350 mg IV 2 h d1 First or second line palliative 0–1
de Gramont Irinotecan 180 mg/m2 IV 90 min h d1
5FU 400 mg/m2 IV B d1
2400 mg/m2 IVI 46 h 1–3
Irinotecan Irinotecan 350 mg/m2 IV 90 min d1 Second line palliative 0–1
2
Concurrent RT Capecitabine 825 mg/m po bd 5 weeks Neoadjuvant locally advanced 0–1
schedules 2 rectal cancer
5FU 350 mg/m IV B d1–5
Folinic acid 20 mg/m2 weeks 1+5
IV B d1–5
weeks 1+5

both oxaliplatin and irinotecan are associated Management of rectal cancer

with liver parenchyma damage and the risks (Figure 11.19)
increase with higher cumulative chemotherapy
Traditionally rectal cancers are defined as tumour
doses.
arising <15 cm from the anal verge (<12 cm in
A recently published trial has shown a 9%
USA). With the advent of MRI imaging, rectal
increase in 3-year PFS (42% vs. 33%) for patients
cancers are defined as those arising below the
undergoing surgery with perioperative oxalipla-
peritoneal reflection.
tin/modified de Gramont (Ox/MdG) chemother-
apy (12 weeks pre- and 12 weeks post-resection) Stage I
in patients with four or less resectable liver metas- • Surgery TME AR or APR
tases without increased postoperative mortality. • Local excision for T1 tumours of mid or
In patients who underwent combined liver lower rectum
and lung metastasectomy the reported 5-year sur- • Short course pre-op RT for T2 low rectal
vival is around 30% whereas that of lung metas- cancers requiring APR
tasectomy is around 50%. Patients who relapse Stage II
with isolated liver disease after a previous resec- • Surgery TME AR or APR
tion of liver metastases, may be considered for • Short course preoperative RT for T3 low
re-resection depending on hepatic reserve and PS. rectal cancers requiring APR
165
 II SITE-SPECIFIC CANCER MANAGEMENT

Figure 11.19
Adenocarcinoma of rectum without evidence
Management of rectal cancer.
of distant metastasis and fit for surgery
Yes No

Radical intent

Consider neoadjuvant
MRI predicts R0 chemotherapy as first Manage as for colon
Radical intent
resection treatment as for colon cancer (Fig 11.18)
cancer

No Yes Mid to high rectal tumour Palliative intent

without risk factors • Manage as Fig 11.18
• Consider early palliative
RT if rectal symptoms
PS 0–2 Palliative intent No

• Long course CRT

• Consider RT alone if contraindication Young age Low rectal cancer
to 5FU or frail/elderly significant nodal requiring APR
involvement
T3b disease
Restaging CT 4–6
wks to exclude metastasis Yes Consider short course RT

TME/AR/APR as TME or AR/Hartmans TME/AR/APR as

surgically indicated as surgically indicated surgically indicated

MDT review of Review of completeness

histology of resection

R0 resection R1/R2 resection at CRM R0 resection

• Long course CRT Manage depending on

*Offer entry into (if no previous RT)
CHRONICLE study or Dukes stage as for colon
• Consider RT alone if
surgical FU cancer Fig 11.18
contraindication to 5FU
or frail/elderly

* In patients not receiving concurrent neoadjuvant fluropyrimidine chemotherapy manage as for colon cancer according to Dukes stage

• Long course preoperative CRT if MRI pre- Stage III

dicts involved or threatened (<1 mm from • Surgery TME AR or APR
tumour) circumferential resection margin • Long course preoperative CRT if MRI
(CRM). predicts involved or threatened CRM (from
• Consider adjuvant chemotherapy as for colon tumour or nodes)
cancer in patients who did not have preopera- • Short course preoperative RT for T1–3 N1–2
tive CRT. low rectal cancers requiring APR
166
 CANCERS OF THE GASTROINTESTINAL SYSTEM 11
• Consider short course preoperative RT in dose than post operative treatment (biologically
patients with rectal cancer at any level if mul- effective dose >30 Gy vs. >35 Gy).
tiple risk factors for recurrence (young age, Preoperative short course radiotherapy has
involved nodes, EMVI, bulky tumour). been shown to reduce the risk of local recurrence
• Consider adjuvant chemotherapy as for colon (LR) by >50% in resectable locally advanced
cancer in patients who did not have preopera- rectal cancer (Swedish study 5-year LR 27% with
tive CRT. surgery alone vs. 12% surgery and radiother-
Stage IV apy). With TME surgery this advantage persist
• As for colon cancer. and there is much lower LR rates (Dutch study
2-year LR 8.2% TME alone vs. 2.4% TME
Surgery with radiotherapy). Side effects of radiotherapy
are increase in early (wound complications)
Local recurrence is a significant risk in rectal
and late (bowel, anorectal and sexual function)
cancer, with rates historically as high as 40%
morbidity.
with surgery alone. Approximately 25% of
The accuracy of preoperative MRI staging
patients fail with locoregional disease alone
in rectal cancer has led to a more selective
which is rarely curable and often associated
approach to the use of RT in the UK with
with distressing symptoms. In recent years
short course treatment being offered to those
strategies have focused on reducing local recur-
patients with predicted R0 resections but signifi-
rence rates in rectal cancer. The most important
cant risk factors for relapse (Figure 11.19).
factor in this is R0 resection, i.e. no tumour cells
Early reports from the MRC CR07 study show
at the circumferential excision margin which
reduced LR rates (4.7% vs. 11.1%) for all stages
reduces the rate of local recurrence by 90% and
and sites of rectal cancer with preoperative
mortality rate by 66% of that if margins are
short course RT compared to selective postop-
involved.
erative RT if CRM was positive, and an improved
Total mesorectal excision (TME), involves
3-year DFS of 4.6%.
careful dissection with the resection plane outside
the mesorectum. It has led to significant improve- Downstaging of locally advanced disease
ments in local recurrent rates, survival and
In patients where MRI identifies risk of CRM
decreased morbidity such as impotence in men.
involvement preoperative long course chemo­
It should be standard for all rectal cancer surgery,
radiotherapy (LCCRT) is used to downstage
with either anterior resection (AR) for mid to
tumours enabling R0 resection in up to 80%.
high tumours or abdominoperineal resection
Concurrent chemotherapy improves pathological
(APR) for low rectal tumours if clearance <1 mm
complete response rates and reduces LR over RT
or there is sphincter involvement or poor anal
alone at the cost of increased acute toxicity.
tone. Since laparoscopic surgery results in higher
rates of CRM involvement and sexual and Adjuvant chemotherapy in rectal cancer
urinary complications compared with open
There is no proven benefit for postoperative
resection, open TME surgery remains the gold
adjuvant 5FU chemotherapy after preoperative
standard.
bolus 5FU CRT schedule, regardless of stage. In
Though there are no randomized studies, local
patients who haven’t had preoperative CRT the
excision is an option for T1 tumours in the
benefit of adjuvant chemotherapy is thought to
absence of risk factors for relapse (nodes, high
be similar to that in colon cancer, although the
grade, vascular invasion, >3 cm). Transanal
number of rectal cancer patients in adjuvant
excision is the commonly used technique.
chemotherapy studies is small.

Radiotherapy (Table 11.2) Local recurrence of rectal cancer

Data show that preoperative radiotherapy is In selected cases exenteration (if not involving
more effective (relative reduction in recurrence pelvic side walls or sacrum) may be curative. In
rates 57% vs. 37%), less toxic and requires lower these cases metastatic disease should be excluded
167
 II SITE-SPECIFIC CANCER MANAGEMENT

Table 11.2: Radiotherapy for rectal cancer

Indication Technique Target volume Dose and timing
Low rectal cancer Simulator PTV borders 25 Gy/5#
requiring APR 2D Sup – L5/S1 over 1 week
(T2–3N0, T1–3N1–2) Patient prone Inf – anal marker/3 cm below disease (spare Preoperative
Anal marker anal canal for mid-high tumours) Surgery within 7 days
3 or 4 field Lat – 1 cm outside bony pelvis
Post – post sacrum
Ant – mid femoral head/2 cm ant sacral
promontory
MRI predicted Involved CT planned PTV = CTV (GTV and mesorectum) + 45 Gy/25#
or threatened CRM 3D conformal 3 cm margin sup/inf/lat over 5 weeks
Patient prone 2 cm ant With chemotherapy
3 or 4 field Post to sacrum Preoperative
Surgery 6–8 weeks
R1 or R2 resection Simulator Field borders 50.4 Gy/28#
2D Sup – L5/S1 over 5 12 weeks with
Patient prone Inf – anal marker/3 cm below disease chemotherapy
Anal marker Lat – 1 cm outside bony pelvis Postoperative
3 or 4 field Post – post sacrum
Ant – mid femoral head/3 cm ant to rectum
Unresectable or Simulator Field borders 30 Gy/10#
recurrent disease A + P field To cover gross disease and pelvic nodes as or 27 Gy/6#
above over 2 weeks
Consider 2 cm on gross disease if poor PS

by PET before committing patients to such useful to control bleeding in colonic and previ-
morbid surgery. If preoperative CRT is previ- ously irradiated rectal cancers.
ously not given, it should be used to decrease the
risk of further recurrence. Re-irradiation is not a Radiotherapy
standard practice but may be considered in For unresectable rectal cancer radiotherapy can
selected cases. offer symptom control, particularly for bleeding,
tenesmus and pain.
Palliation of colorectal cancer Palliative chemotherapy
Unresectable locally advanced or recurrent Chemotherapy given early, rather than after
disease and stage IV disease (excluding limited development of severe symptoms, is associated
liver and or lung metastases) is treated with with better outcomes without adverse effects on
palliative intent. quality of life.
Fluropyrimidines improve median survival by
Endoluminal procedures approximately 4 months over best supportive
Expanding metal stent can be placed endoscopi- care alone (10 vs. 6 months). The infusional
cally in upper rectal and left or right-sided colonic regimen Modified de Gramont (MdG) and oral
lesions (technically difficult to place through capecitabine have a response rate of approxi-
tumours involving the flexures). It relieves mately 30% and favourable toxicity profiles in
obstructive symptoms in 90% of patients for comparison to other 5FU/FA regimes. The addi-
more than a year (10% migration rate is 10% tion of either irinotecan or oxaliplatin to MdG
and 10% re-obstruction rate) and avoids the or capecitabine as first line treatment increases
need for a stoma. Endoscopic laser ablation is response rates to 50–60% and median survival
168
 CANCERS OF THE GASTROINTESTINAL SYSTEM 11
to 14–16 months at the cost of increased toxici- treatment are to detect recurrent disease at a
ties. The addition of second line treatment pro- potentially curable stage and surveillance for
longs median survival to more than 20 months. metachronous polyps or bowel cancers. Optimum
follow up strategy is uncertain and varies widely.
Targeted systemic therapy
Routine surveillance of the bowel
Bevacuzimab (anti-VEGF) as first line in com­
Patients who do not have their entire colon
bination with irinotecan/5FU increased median
imaged at diagnosis should have colonoscopy
survival by 4.7 months (20.3 m vs. 15.6 m), and
within 6 months of treatment to exclude syn-
with oxaliplatin/5FU increased 18 month survival
chronous polyps or cancers. For patients who
by 10% (63% vs. 53%), compared to respective
have had complete bowel imaging at staging,
chemotherapy alone. The common side effects of
initial colonoscopy 1–3 years following treat-
bevacuzimab include hypertension, proteinuria,
ment is recommended, followed by 5-yearly
gastrointestinal perforation, intra-abdominal
(more frequently in patients with ≥5 polyps)
infections, impaired wound healing, and increased
colonoscopy in polyp free patients with a life
arterial thromboembolic events. Treatment should
expectancy of ≥15 years.
not be given within 28 days of major surgery.
Cetuximab and panitumumab are anti-EGFR Routine surveillance for distant disease
antibodies. Cetuximab in combination with Studies suggest that intensive follow-up is associ-
irinotecan/5FU (CRYSTAL study) increased ated with significantly improved 5-year OS (HR
response rate (RR) (39% vs. 47%) and improved 0.81) in Dukes’ B and C patients. A significant
progression free survival (PFS) (8 m vs. 8.9 m). proportion recurs with asymptomatic liver
In combination with oxaliplatin/5FU, it increased metastasis and with active surveillance up to
RR (36% vs. 46%) but did not improve PFS. The 20% patients are candidates for curative surgery.
most common toxicities of cetuximab are skin Hence following radical treatment for Dukes’ B
reaction and diarrhoea. or C cancer, patients fit for further active treat-
The K-ras gene is emerging as both a predic- ment are followed up as follows:
tive and prognostic factor for response to tar-
geted anti-EGFR antibodies. Improved response • 6-monthly CEA for 2 years followed by yearly
rate and RR and PFS are associated with wild until 5 years.
type K-ras. Mutated K-ras appears to be associ- • CT liver (and pelvis in rectal cancer) at 12 and
ated with lack of response and worse survival 18–24 months.
compared to wild type K-ras, with some evidence • CT if rising CEA with PET if CT fails to
that anti-EGFR antibodies are actually detrimen- identify relapse.
tal compared to chemotherapy alone.
Screening
Palliation of liver metastases General population
Percutaneous radio-frequency ablation (RFA) A meta-analysis has shown that screening by
can be useful to palliate inoperable or recurrent faecal occult blood (FOB) reduces the risk of
liver metastasis in selected patients (achieves a death from CRC by 16% overall, and by 23%
median survival of up to 36 months). However, (RR 0.77) in those who are actually screened.
lesions >4–5 cm, superficial lesions and those The NHS Bowel Cancer Screening Programme
close to vessels are not effectively treated by RFA. (BCSP) for people aged 60–69 offers 2-yearly
FOB tests and colonoscopy to those with abnor-
mal results. Those >70 can request screening.
Follow-up
Eighty percent of recurrences from CRC occur High-risk populations (p. 50)
within the first 2 years and 90% within 3 years.
5- and 7-year survivals equate to cure for colon Prognosis and outcome
and rectal cancer respectively with <5% relaps- Stage is the most important prognostic factor.
ing after this. Aims of follow-up following radical Stage-wise 5-year survival rates are >90% for
169
 II SITE-SPECIFIC CANCER MANAGEMENT

stage I (Dukes’ A), 70–85% for stage II (Dukes’ Investigations and staging
B) without risk factors, 40–60% for stage II with Initial assessment includes digital rectal examina-
risk factors and stage III (Dukes’ C) and 5% for tion, examination under anaesthesia (EUA) and
stage IV disease. Median survival of inoperable biopsy. Transanal US is useful in assessing depth
metastatic disease is 6 months with best support- of invasion and perirectal nodes. CT or MRI is
ive care alone, 18–20 months with chemotherapy useful to assess pelvic nodal metastases. Up to
and over 2 years with targeted agents. 50% of palpable or radiologically suspicious
inguinal nodes are not involved and hence a fine
Anal cancer needle aspiration (FNA) of clinically suspicious
Squamous cell cancers (SCC) of the anal canal nodes, with excision biopsy if FNA is non-diag-
are uncommon. The peak incidence occurs in the nostic, is recommended. Distant metastasis is
seventh decade. There is a slight predominance seen in <5% at diagnosis and staging includes CT
of females of 2–3 : 1 for cancers of the anal chest and abdomen. Apart from routine blood
canal. Risk factors include genital infection with tests, patients with risk factors should be tested
human papillomavirus (HPV, most frequently for HIV.
type 16), chronic immunosuppression in trans- TNM staging is given in Table 11.3.
plant and HIV positive patients, and smoking
Management
(2–5 fold increase).
The treatment options for localized tumours are:
Pathogenesis and pathology • Local excision (selected stage I patients)
The anal canal is 3–4 cm long and extends to the • Concurrent chemoradiotherapy (CRT) (stage
palpable upper border of the anal sphincter. Peri- I–III)
anal cancers by definition occur within 5 cm of • Radical surgery (T3 or 4 causing sphincter
the anal verge with no extension into the canal. destruction and salvage after CRT)
Anal cancer may arise in anal intraepithelial
neoplasia (AIN), which can progress from low to
high grade and is found in areas adjacent to
squamous cell carcinoma. Table 11.3: Staging for anal cancer
Ninety percent of anal cancers are squamous Stage group TNM stage % patients
cell, histological subtypes which include large cell
I T1 (tumour ≤2 cm) N0 12
keratinizing, basaloid, and transitional (large cell
non-keratinizing). Collectively they are referred II T2 (tumour 2–5 cm) N0 55
T3 (tumour >5 cm) N0
to as cloacogenic or epidermoid cancers. All have
a similar natural history, response to treatment, IIIA T1–3 N1 (perirectal 30
nodes)
and prognosis.
T4 (tumour invading
Approximately 5–10% tumours are adenocar- adjacent organ) N0
cinoma of the anal glands and are managed as
IIIB T4N1
low rectal cancers. Other histologic types are Any T N2 (unilateral
melanoma, basal cell and small cell carcinoma. internal iliac or
inguinal nodes)
Presentation Any T N3 (perirectal
Anal carcinoma presents with discomfort, itch­ and inguinal or
ing and bleeding in 50%. Symptoms are often bilateral internal
iliac +/− inguinal
dismissed as haemorrhoids. Any patient over the
nodes)
age of 60 should be examined to exclude carci-
noma as should those with a mass, enlarged IV M1 (extra pelvic <5
metastases)
inguinal nodes, pain or persistent symptoms.
Faecal incontinence and vaginal fistula are late NB Invasion of rectum, subcutaneous tissue, skin or sphincter
symptoms of locally advanced disease. Distant muscles is not T4
metastases are rare at presentation.
170
 CANCERS OF THE GASTROINTESTINAL SYSTEM 11
Treatment options for patients with stage IV alone in terms of reduction in locoregional
disease are palliative chemotherapy, palliative failure, improvement in colostomy free and
radiotherapy and active symptom control. disease specific survival. Acute toxicities are
increased by concurrent treatment, without
Local excision
significant increase in late morbidity.
Local excision with curative intent is an option
for selected patients with stage I disease not Radiation dose and technique
invading the sphincter muscles. The 5-year The dose of radiation concurrent with che­
overall survival with local excision alone is motherapy required to treat anal cancer is
approximately 70%. However CRT gives better debatable.
chance of overall disease control and should There is evidence to suggest doses as low as
therefore be considered for all patients who are 30 Gy in combination with chemotherapy are
fit for this approach, even if local excision has sufficient for microscopic disease and 45 Gy
been performed as first line treatment. adequate to treat non bulky gross disease. This
underlies current UK practice. Since the median
Chemoradiation (CRT) potential doubling time of anal cancer is 4 days
There are no RCTs of surgery versus CRT; but (similar to that of cervix cancer), local control
CRT offers sphincter preservation for the major- rate is likely to be decreased by prolonging
ity of patients. Chemoradiation using concurrent overall treatment time.
mitomycin C (MMC) and 5 FU is the standard The failure rate in untreated clinically normal
of care for all stages of locoregional disease (Box inguinal nodes is up to 25%. This has led to the
11.12). The UKCCCR ACT I and an EORTC practice of elective nodal irradiation which reduces
study confirmed the benefit of CRT over RT the risk to <5% without significant morbidity.
The role of cisplatin
Box 11.12: CRT for anal cancer Cisplatin in combination with 5 FU is under
Radiotherapy
investigation as neoadjuvant, concurrent and
Phase I adjuvant treatment in anal cancer. The current
Patient prone with anal marker (canal tumours) and UK–ACT II is comparing two CRT schedules
palpable disease wired (margin tumours and (standard MMC/5FU versus cisplatin/5FU) and
inguinal nodes)
adjuvant chemotherapy with two cycles of
Ant and post fields
cisplatin/5FU versus no further treatment.
Borders
Superior = 2 cm above bottom of SI joints HIV positive patients
Inferior = 3 cm below anal margin or most inferior Prior to the advent of highly active antiretroviral
extent of disease
therapy (HAART), tolerance of CRT in patients
Lateral = lateral to femoral heads
with HIV and CD4 counts <200 at doses of RT
Dose 30.6 Gy in 17 fractions of 1.8 Gy
>30 Gy was poor, with excessive toxicities. The
Phase II majority of patients can now be treated with
Field borders are a 3 cm margin on GTV in all planes.
standard doses (p. 297).
N0 canal tumours = 3 field (posterior, right and left
lateral)
Radical surgery
N0 margin tumours = direct field
N+ tumours = anterior and posterior fields Patients with confirmed local relapse following
Dose 19.8 Gy in 11 fractions of 1.8 Gy CRT who are fit to consider salvage surgery
should be restaged with CT chest and abdomen
Chemotherapy
Week 1 mitomycin C 12 mg/m2 d1 and 5FU 1000 mg/ to exclude metastatic disease as well as MRI
m2/d d1–4 pelvis to stage regional disease. Approximately
Week 5 5FU 1000 mg/m2/d d1–4 50% can be cured by a salvage surgical resec-
tion, but local recurrence rates approach 50%
RT fields and doses are as per ACT II protocol. Chemotherapy
schedule is as per ACT I study even in patients undergoing complete resections.
Inguinal node dissection similarly is reserved for
171
 II SITE-SPECIFIC CANCER MANAGEMENT

patients with residual or recurrent inguinal

metastases after CRT. It carries a high risk of Table 11.4: Survival and local control with
CRT by T stage
postoperative wound complications and chronic
T stage 5-year OS % 5-year local control %
lymphoedema.
Other occasional indications for surgery T1 80 90–100
include a contraindication to primary CRT, T2 70 75
incontinence due to sphincter damage or a vaginal T3/4 45–55 55
fistula and late toxicity from CRT.
Metastatic disease
Distant metastases develop in up to 15% of
patients and the most effective chemotherapy is
survival. Overall 5-year survivals are in the
a combination of 5-FU with cisplatin. Response
region of 75%. A lesion size of 4 cm represents
rates in metastatic disease are approximately
the threshold for local control, with up to 95%
55% but rarely complete and their duration
of tumours ≤4 cm achieving complete pathologi-
usually only a few months.
cal response to CRT (Table 11.4).
Follow-up Spread to the regional nodes is an adverse
Follow-up is to diagnose local recurrence at an factor for survival, with 5-year survivals up to
early stage so that salvage surgery may be offered. 20% lower than in node-negative patients. If
Anal cancers regress slowly over several months inguinal nodes are not invading skin or deep
following CRT and therefore early random structures, control rates with CRT alone are
biopsy is not helpful. Local recurrences usually approximately 80%. Perianal lesions have a
appear within three years and distant metastases more favourable prognosis than those of the anal
within five years after CRT. Follow-up therefore canal, due to the decreased risk of nodal
commonly comprises rectal and inguinal node metastases.
examination at regular intervals – initially Median survival of patients with distant
6-weekly if there is continuing treatment response, metastases remains 9–12 months.
but possible residual disease, until resolution. Further reading
Then 2, 3 and 4-monthly for the first 3 years
followed by 6-monthly review to 5 years. The Mariette C, Piessen G, Triboulet JP. Therapeutic strategies in
oesophageal carcinoma: role of surgery and other
development of a hard-edged ulcer after previous modalities. Lancet Oncol. 2007;8:545–553.
healing, an enlarging mass, or increasing pain at Hartgrink HH, Jansen EP, van Grieken NC, van de Velde
the site of the primary tumour site are suggestive CJ. Gastric cancer. Lancet. 2009;374:477–490.
of recurrence and should be confirmed by biopsy. Rampone B, Schiavone B, Martino A, Viviano C, Confuorto
Serious late toxicity including ulceration, G. Current management strategy of hepatocellular
carcinoma. World J Gastroenterol. 2009;15:3210–3216.
radionecrosis and stenosis causing loss of anorec- Eckel F, Jelic S; ESMO Guidelines Working Group. Biliary
tal function and requiring colostomy occurs in cancer: ESMO clinical recommendation for diagnosis,
5–12% and is related to radiation dose. Perineal treatment and follow-up. Ann Oncol. 2009;20 Suppl
fibrosis, rectal urgency and diarrhoea, and 4:46–48.
dyspareunia are relatively common. Hidalgo M. Pancreatic cancer. N Engl J Med. 2010;362:
1605–1617.
Prognosis and survival Cunningham D, Atkin W, Lenz HJ et al. Colorectal cancer.
Lancet. 2010;375:1030–1047.
Size of the primary tumour, in the absence of Uronis HE, Bendell JC. Anal cancer: an overview.
metastases, is the most useful predictor of Oncologist. 2007;12:524–534.

172
Cancers of the
genitourinary system
M Beresford
12
Cancer of the kidney • Acquired cystic kidney disease – in dialysis
patients.
Introduction • Genetic factors – Von Hippel–Lindau disease
is a familial disorder characterized by the
Renal cell carcinoma (RCC) accounts for 2–3% development of multiple tumours including
of all cancers, with 6600 new diagnoses and bilateral renal cell carcinomas, retinal/central
3600 deaths per year in the UK. There has been nervous system haemangioblastomas and
an increasing incidence over the past 10–15 phaeochromocytomas. Hereditary papillary
years, at least in part due to more incidental renal cell carcinoma (HPRC) is a condition in
tumours being found with the increased use of which patients are at risk of developing mul-
cross-sectional imaging. Peak age at presentation tiple, bilateral type 1 papillary renal carcino-
is between 65–75 years, with very few cases in mas and involves mutation in the c-met
the under 40 age-group. The male to female ratio oncogene.
is 3 : 2.

Pathology
Aetiology In adults, 85% of malignant lesions arising from
Risk factors for renal carcinoma are as follows: the kidney are renal cell carcinoma, with most
of the remainder being metastases from other
• Smoking – smokers are more likely to develop
primary tumours. Other rarer cancers include
RCC than non-smokers and the effect seems
clear cell sarcoma, lymphoma, oncocytoma and
to be dose-dependent, with heavy smokers
adult form of Wilms’ tumour.
having a relative risk of 2.0.
• Occupational exposure – risk ratios of 1.3 to • Renal cell carcinomas (RCCs) – most RCCs
1.6 have been observed in individuals exposed are well-differentiated and usually arise within
to petroleum, hydrocarbon, steel, asbestos, the upper pole. The majority are of clear cell
cadmium or dry cleaning products. origin although they often contain several dif-
• Analgesic nephropathy – there is an increased ferent cell types, including granular cells and
risk of RCC in patients who develop nephro­ spindle cells (the poor prognosis sarcomatoid
pathy associated with the use of phenacetin- variant).
containing analgesics. • Transitional cell carcinomas – are relatively
• Obesity – obesity increases the risk of devel- uncommon, accounting for 5% of malignan-
oping RCC, with a linear relationship between cies in the kidney, and are sometimes a result
body weight and risk (odds ratios of up to of analgesic nephropathy. They arise in the
4.8). Excessive consumption of red meat and renal pelvis and often affect multiple sites of
dairy products might increase risk, but there the urothelial mucosa with 50% having a
appears to be no relationship with alcohol or history of bladder tumours. Transitional cell
caffeine intake. carcinomas of the renal pelvis are usually

© 2011, Elsevier Ltd 173

DOI: 10.1016/B978-0-7234-3458-0.00017-8
 II SITE-SPECIFIC CANCER MANAGEMENT

discovered late, although occasionally present

earlier with obstructive symptoms. Due to the
proximity to the renal vein, they tend to
spread early, typically with metastases to lung
and bone. 5-year survival varies from 10–
70% depending on tumour grade.
• Squamous cell carcinomas – these are rare
and usually associated with chronically
infected staghorn renal calculi. Presentation
tends to be late, with locally extensive disease.

Presentation
Figure 12.1
Renal tumours often remain asymptomatic and
CT scan showing an irregular mass lesion arising from
unnoticed until large. The classical triad (also the left kidney.
known as ‘too late’ triad) of presenting symp-
toms (loin pain, haematuria and flank mass)
occurs in less than 10% of patients. Up to 20%
Staging
of patients have a history of fever at presentation,
and a third report weight loss and cachexia. 30% Stage (Table 12.1) determines the prognosis and
have metastatic disease at presentation and a treatment of renal tumours.
further 25% have locally advanced disease.
Management
Typical sites of metastases include lungs (75%),
lymph nodes/soft tissue (36%), bone (20%) and Surgery of the primary tumour
liver (18%). Patients may also demonstrate a Curative
number of paraneoplastic manifestations such as The definitive treatment for renal cancer is surgi-
polycythaemia, hypercalcaemia etc. cal resection. Radical nephrectomy is performed
by an anterior approach and en bloc removal of
Investigations and staging the kidney, adrenal and perirenal fat. The adrenal
Initial investigations include urinalysis for gland is rarely involved in T1 or T2 tumours and
protein, blood and cytology. Blood tests should can be left behind. If tumour invades the renal
include full blood count, urea and electrolytes, vein, this can be ligated distal to the tumour
liver function, clotting and calcium levels. thrombus and even partial vena caval resection
Imaging may be undertaken if necessary.
Regional lymphadenectomy is sometimes per-
CT scan: CT scan appearance (Figure 12.1) is formed during the radical procedure, but its role
important in determining the appropriate surgi- in prolonging survival is debatable.
cal procedure – laparoscopic, partial or radical Recent improvements in surgical techniques
nephrectomy. Size is important in diagnosis – have enabled laparoscopic partial or total
benign cortical adenomas can look like malignan- nephrectomies as a less invasive technique for
cies but tend to be less than 3 cm in diameter. removing kidneys with small volume tumours.
Other investigations: for small tumours, a Nephron-sparing surgery should be considered
chest X-ray is sufficient for staging if the CT scan particularly for patients with poor renal reserve
does not include the chest. Ultrasound and colour or non-functioning contralateral kidneys.
flow Doppler are useful in assessing renal vein
and inferior vena caval invasion. A bone scan Palliative
should be considered if there are symptoms or a Nephrectomy should also be considered as a
raised alkaline phosphatase. palliative procedure in patients with metastatic
If there are concerns about renal reserve disease. Although very rarely (<1%) this may
from imaging or renal function blood tests, result in regression of metastases (‘abscopal
then more formal assessment of renal function is effect’), it is not the main reason for considering
174 appropriate. surgery. It is aimed mainly at reducing symptoms
 CANCERS OF THE GENITOURINARY SYSTEM 12

Table 12.1: Staging of tumours of the renal parenchyma

Stage
I T1 N0 M0 7 cm or less in size, confined to kidney
T1a ≤4 cm
T1b >4 cm ≤7 cm
II T2 N0 M0 >7 cm in size, confined to kidney
III T1/2 N1 M0 Confined to kidney, metastases in a single regional node
T3 N0/1 M0 T3a Invades adrenal gland or perinephric tissues but not beyond Gerota fascia
T3b Extends into renal vein(s) or vena cava below diaphragm
T3c Extends into vena cava above diaphragm
IV T4 N0–2 M0 T4 Invades beyond Gerota fascia
T1–4 N2 M0 N2 Metastases in >1 regional node
T1–4 N0–2 M1 M1 Distant metastases

such as pain, haematuria and hypercalcaemia. The optimal regimen of interferon is not yet
Removal of the tumour bulk may also improve known. Typical dose schedules are of 9–12 mega-
the efficacy of any subsequent systemic treatment units subcutaneously three times per week, often
– trials have shown that patients with metastatic starting at a lower dose to assess tolerability.
disease who are treated with interferon have Treatment is discontinued at disease progression
improved survival if they undergo palliative or after 6–9 months, whichever comes first.
nephrectomy prior to the immunotherapy. Blood counts and liver function should be moni-
tored during treatment.
Adjuvant therapy
Interferon has significant side effects (Box
Adjuvant therapy with interferon-α following 12.1) that impact on quality of life. These effects
nephrectomy has been investigated and does are dose dependent, but the majority tend to stop
not appear to confer any survival advantage. quickly on discontinuation of treatment. Common
More complicated and toxic regimes using com­ side effects include fatigue, flu-like symptoms,
binations of interferon, interleukin-2 and 5- diarrhoea, nausea and vomiting, anorexia, bone
fluorouracil (known as the Atzpodien regimen) marrow suppression and rash at injection site.
have not proved any better and in fact may be
detrimental. Interleukin 2
Interleukin works by stimulating cytotoxic
Metastatic disease
T-cells. It can be given subcutaneously, by high-
Interferon-alpha dose bolus intravenous injection or by continu-
Interferon alpha is a cytokine with anticancer and ous infusion (all give similar results). It has been
antiviral activity. Response rates in metastatic used instead of or in combination with inter-
RCC are reported as 10–15% with a 2% com- feron, and seems to result in improved response
plete response rate (although there are also occa- rates (of 15–20%), but with no improvement in
sional reports of spontaneous remissions off overall survival and significantly worse toxicity
treatment) and a stable disease rate of approxi- than interferon.
mately 25%. A Cochrane review showed a
3-month survival benefit with interferon com- Medroxyprogesterone-acetate
pared with no interferon. Interferon may be better The response rate is only 5–7%. Trials compar-
in ‘good’ prognosis metastatic disease, based on ing progestins and interferon therapy show a
the number of disease sites, performance status survival benefit of approximately 2.5 months in
and diagnosis to metastases interval. favour of the interferon. 175
 II SITE-SPECIFIC CANCER MANAGEMENT

Chemotherapy Bevacizumab is a monoclonal antibody which

Response rates with chemotherapy are less than inhibits VEGF. In conjunction with interferon it
10%. A few cases of sarcomatoid variants of has been shown to double progression-free sur-
RCC have responded to sarcoma chemotherapy vival in previously untreated metastatic RCC
regimes such as doxorubicin and ifosfamide. when compared with interferon alone.
Radiotherapy
Novel agents
Radiotherapy can be used to control bleeding
Various new targeted therapies have shown posi-
and pain from primary tumour sites and to treat
tive results in the treatment of metastatic renal
symptoms associated with bone and central
cell carcinoma and are generally better tolerated
nervous system metastases.
than interferon-α and interleukin-2. Studies are
now concentrated on the use of these agents in Surgical management of metastases
the adjuvant setting and their sequencing in met- Resection of metastases from RCC should be con-
astatic disease. sidered, particularly for pulmonary lesions, where
Sorafenib and sunitinib are oral multiple excellent results can be achieved. Consideration of
kinase inhibitors affecting VEGF, PDGF and surgical management should not be confined to
c-KIT tyrosine kinases among others (p. 370). solitary metastases, although the best survival
They have both antiproliferative and antiang- figures are seen after complete resection of solitary
iogenic activity. A phase III trial of sorafenib lesions, with 5-year survival rates of up to 50%
versus placebo in metastatic RCC patients on compared with 20% following complete resection
second-line systemic therapy showed an improve- of multiple lesions. A longer interval between
ment of progression-free survival (5.5 months primary tumour and development of metastases
versus 2.8 months respectively). correlates with a longer disease-specific survival.
In the first line setting sunitinib has shown a Resection of cerebral metastases has also shown
median progression-free survival of 11 months in favourable results, particularly when there is a
comparison with 5.1 months with interferon-α long interval from resection of the primary.
(p < 0.000001) and the median overall survival
was 26.4 months with sunitinib and 21.8 months Prognostic factors and survival
with interferon (p = 0.51). Sunitinib is the recom- Survival remains limited for patients with RCC,
mended treatment in the UK for patients with however in selected patients with metastatic
performance status 0–1. The dosage is 50 mg once disease, long-term survival is recognized. Char-
daily for 4 weeks with a 2-week rest period (6-week acteristics associated with a better prognosis
cycle). Dose may be decreased in steps of 12.5 mg include stage I disease, absence of invasion into
according to tolerance, but there is evidence that the collecting system and predominance of clear
efficacy is related to dose-intensity. Adverse events cell pattern.
include rash, diarrhoea, hand–foot skin reaction, The Memorial Sloan–Kettering prognostic
fatigue, thrombocytopaenia and hypertension. stratification is often used for metastatic disease.
These are usually easily managed and rarely result Five major prognostic factors are identified: poor
in permanent discontinuation of therapy. performance status (KPS <70), raised lactate
Temsirolimus inhibits activity of mTOR, dehydrogenase (>1.5× normal), raised serum
which features downstream in the cell signalling calcium, low haemoglobin and no nephrectomy.
pathway and is thought to be a point into which Patients are categorized into three risk groups
other critical pathways feed. It is an intravenous based on the number of these prognostic factors
agent which appears to improve progression-free present: 0 = favourable risk, 1–2 = intermediate
survival when compared with interferon in meta- risk, 3–5 = poor risk. 3-year survival rates for
static RCC and has shown particular benefit in these risk groups are reported as 31%, 7% and
poor prognosis patients. Everolimus, an oral 0% respectively.
mTOR inhibitor, has proven benefit in the Stage-wise 5-year survival for renal cell carci-
second-line setting on progression after previous noma is 66% for stage I, 64% for stage II, 42%
tyrosine kinase inhibitor treatment. for stage III and 11% for stage IV.
176
 CANCERS OF THE GENITOURINARY SYSTEM 12

Cancers of the urinary bladder carcinoma with tumours occurring in the ureters
and renal pelvis as well as the urinary bladder.
and renal pelvis Carcinoma-in-situ manifests as severely dys-
plastic cells through all layers of the epithelium.
Introduction It carries a poor prognosis and often has an inva-
Bladder cancer accounts for 4% of all malignan- sive component. At least 30% of grade III carci-
cies, with over 10,000 new diagnoses and almost noma-in-situ will become invasive.
5000 deaths each year in the UK. Worldwide it
is the 9th most common cancer, but is more Presentation
common in North America and Western Europe, The most common presentation is with painless
where it is the 4th most common cancer in males haematuria. A patient presenting with macro-
and 8th most common in females. The world- scopic haematuria has a 25% chance of having
wide male to female ratio is 10 : 3. Bladder cancer a bladder tumour (5% if microscopic haematu-
is rare in the under 50 age group, and most ria). Other symptoms include frequency, urgency,
common in over 70-year-olds. dysuria and loin pain due to ureteric obstruction.
Occasionally patients present with symptoms
Aetiology caused by metastases such as bone pain, fractures
Risk factors for bladder tumours include the or shortness of breath.
following: Lymph node involvement is strongly related to
• Smoking (2–5 fold increased risk). tumour grade. Less than 10% of grade 1 tumours
• Infections – especially schistosomiasis have nodal involvement, compared with 80% of
which increases the risk of squamous cell grade 3. Metastatic spread is predominantly to
carcinoma. the lungs and bones.
• Occupational/chemical (aniline dyes, aro-
Investigations and staging
matic amines, printing industry, rubber
industry, firelighter manufacturers, tar manu- Investigations
facturing, sewage workers, pest control, Initial investigations include urine cytology,
benzidine, cyclophosphamide, 2-naphthyline, intravenous urogram (IVU) and cystoscopy. Cys-
xenylamine, phenacetin). toscopy should include bimanual examination,
• Bladder calculi (chronic cystitis). complete inspection of the urethra and bladder,
• Chronic indwelling catheters. biopsies of all suspicious areas, transurethral
• Previous radiotherapy (risk of sarcoma). resection of visible tumour and a detailed diagram
of the findings to assist in comparison at follow-
Pathology up procedures.
In Western countries, over 90% of bladder Once a bladder tumour is confirmed further
tumours are predominantly transitional cell car- investigations should be considered, including
cinoma (TCC), often with elements of squamous, blood tests (renal function, full blood count,
adenocarcinoma or sarcomatous differentiation. liver function and calcium level), chest X-ray,
80% are papillary and 20% flat in appearance histology review and for muscle-invasive tumours,
and the most likely areas affected are the poste- CT or MRI scan of the abdomen and pelvis
rior and lateral bladder walls. Flat tumours tend (Figure 12.2). MRI is better for showing early
to be of higher grade and more aggressive. Less invasion of adjacent organs and extravesical
common histological types are squamous cell spread. A bone scan is only necessary if indicated
carcinoma, adenocarcinoma and very rarely by symptoms or a raised alkaline phosphatase.
small cell carcinoma. Chest X-ray or CT chest is useful to rule out
Tumours often present initially as low grade metastatic disease (Figure 12.3).
and superficial, but tend to be multiple and recur-
rent. With each recurrence there is a tendency to Staging
progression in cytologic atypia. The whole of the The staging of bladder tumours is shown in
uroepithelial tract is at risk of transitional cell Table 12.2.
177
 II SITE-SPECIFIC CANCER MANAGEMENT

A B

Figure 12.2
CT scan of bladder tumour: tumour shown as filling defect in the right side of base of bladder (short arrow) with
contrast filled ureter (long arrow) entering the bladder through the tumour (A). Scan shows an irregular mass arising
from base of the bladder (B).

Box 12.1: Indication for radical cystectomy

40% with chemotherapy but 90% with BCG, so
the latter is often reserved for resistant disease.
• Severe/persistent carcinoma-in-situ
• Muscle invasion Intravesical chemotherapy
• Multiple recurrences of T1 disease despite Mitomycin reduces recurrence rate following
intravesical treatment
first cystoscopy from 25% to 12%. It is admin-
• T1 G3
istered as a single dose within 6 hours of transure-
• Squamous cell carcinoma and adenocarcinoma
thral resection or weekly for 6–8 weeks. It should
• Unreliable patient (surveillance is not realistic)
be left in contact with the bladder for 1–2 hours.
Response rates are reported as 65%, with a 35%
complete response. Side effects include cystitis,
Management reduced bladder capacity, palmer desquamation
The management of bladder tumours is depend- and a rash.
ent upon the degree of invasion into the bladder
wall and the histological grade of the cancer. Intravesical immunotherapy
Superficial, non-muscle invasive tumours are Intravesical BCG results in a response rate of
generally treated by transurethral resection, with 75%, with a mean time to recurrence of 2 years.
intravesical chemotherapy or immunotherapy for It has been shown to reduce cystectomy rate in
multiple or recurrent tumours. Localized muscle CIS patients. Side effects include cystitis, fever,
invasive disease is treated by primary cystectomy haematuria and prostatitis.
or radiotherapy to the bladder and perivesical Following resection, BCG treatment should
tissues. Figure 12.4 shows the management of be withheld for a month to allow the mucosa to
bladder tumours by tumour stage. Indications for heal. A 6-week induction course (81 mg of BCG
radical cystectomy are shown in Box 12.1. in 50 ml of normal saline) of weekly treatments
is followed by cystoscopy. If there is a response
Intravesical therapy a second 6-week course is initiated. If there is
Intravesical therapy reduces short-term recur- progression, cystectomy should be considered.
rence rates following transurethral resection. The Trials of maintenance therapy have shown
options are chemotherapy with agents such as variable benefits using a schedule following the
mitomycin, or immunotherapy with BCG. The initial 6-week course with three consecutive
incidence of chemical cystitis is approximately weekly treatments every 6 months for 3 years
178
 CANCERS OF THE GENITOURINARY SYSTEM 12
Figure 12.3
Chest X-ray of a patient with
cannonball lung metastases from
metastatic transitional cell
carcinoma of the bladder.

(but less than a fifth of patients can tolerate this

Table 12.2: Staging of tumours of the bladder schedule).
Stage Muscle invasive disease
I T1 N0 Invades sub-epithelial
If disease is localized, the aim is for cure
connective tissue
T1a – deep lamina propria with bladder preservation if possible. In disease
T1b – muscularis propria confined to the bladder, radical cystectomy is
II T2 N0 Invades muscle
curative in 60–70%. Radical external beam radi-
T2a – inner half of muscle otherapy might allow preservation of bladder
(superficial) function, but reported cure rates are lower at
T2b – outer half of muscle 50% (although no direct comparisons between
(deep) surgery and radiotherapy exist). If there is spread
III T3 N0 Perivesical tissue invasion beyond bladder (T3 disease), radical treatment is
T3a – microscopic curative in <30% of patients and half of patients
T3b – macroscopic
will develop distant metastases within 1–2 years.
T4a N0 T4a – invades prostate,
uterus, vagina Radical cystectomy
Radical cystectomy involves excision of the
IV T4b N0 T4b – invades pelvic or
abdominal wall bladder, perivesical fat and the attached perito-
neum. In men the prostate and seminal vesicles
T1–4 N1–3 N1 – single regional node
≤2 cm
are removed. In women the uterus, urethra,
N2 – 2–5 cm single node adnexa, ovaries and a cuff of vagina are resected.
or multiple nodes ≤5 cm Reconstructions tend to be more difficult in
N3 – >5 cm node women. The role of lymphadenectomy has been
M1 Distant metastases controversial, but is now generally accepted as
standard. If the urethra is left in-situ, there is a
5–10% risk of urethral recurrence.
179
 II SITE-SPECIFIC CANCER MANAGEMENT

Tis Ta T1 T2 T3 T4

Grade 1/2 Grade 3 Consider neoadjuvant

chemotherapy

Single Multiple Consider Cystectomy or

lesion lesion cystectomy radical radiotherapy

Transurethral
resection

If recurrent, Transurethral If high risk Palliative

intravesical resection and or residual disease radiotherapy +/or
chemotherapy/BCG intravesical post cystectomy, chemotherapy
chemotherapy/BCG consider adjuvant
chemotherapy

If no response,
consider cystectomy

Figure 12.4
Management of transitional all bladder carcinoma by T stage.

Techniques for urinary diversion: radical cystectomy and radiotherapy should be

made at a multidisciplinary meeting and with
1. Ileal conduit (stoma)
involvement of the patient. Randomized studies
2. Continent diversions
have shown radiotherapy to have higher rates
• Mainz II (if no urethra, insert ureters into
of local recurrence, but similar overall survival
rectum – increased risk of bowel cancer
with close follow-up and salvage cystectomy on
and lifelong diarrhoea).
relapse. Approximately a third of patients treated
• Mitrofanoff diversion (ureters implanted
with radiotherapy will remain cystectomy-free.
into a small bowel reservoir and use a
There is no survival advantage from nodal
native tube (e.g. fallopian or appendix) to
irradiation and no evidence of any benefit
link reservoir to skin; self-catheterization
of adjuvant pelvic radiotherapy following
is required).
cystectomy.
• If the urethra is preserved (i.e. no CIS, high
Poor prognostic factors for radiotherapy
tumour) the ureters can be diverted into a
include ureteric obstruction, incomplete trans­
reservoir of small bowel which empties via
urethral resection, sessile (worse than papillary)
the urethra – no voiding sensation so need
tumour and persistence/recurrence at first
bladder training.
cystoscopy.
Side effects of radical cystectomy include up Radical radiotherapy is contraindicated in
to 3% mortality, impotence in men (70–100%), those who had previous pelvic radiotherapy,
dyspareunia in women, uterocutaneous fistulas, history of inflammatory bowel disease or small
infection and small bowel fistulas (30%). bowel adhesions, extensive CIS, poor bladder
function and multiple transurethral resections or
Radical radiotherapy multiple intravesical chemotherapy installations
The aim of radical radiotherapy is cure with (due to reduced bladder function which may
bladder preservation. The decision between worsen with radiotherapy).
180
 CANCERS OF THE GENITOURINARY SYSTEM 12
Radical radiotherapy is typically CT-planned Box 12.2: Chemotherapy regimes in
with a target volume including a 1.5–2 cm margin bladder cancer
around the empty bladder, prostatic urethra and Gem/Cis: Gemcitabine – 1 g/m2 Day 1, 8, 15
tumour extension. This margin is to allow for Cisplatin* 70 mg/m2 Day 1
considerable bladder movement. The rectum and Repeat every 28 days (or 21 days
femoral heads should be identified as organs at omitting day 15 gemcitabine)
risk. Treatment is usually delivered via a 3-field CMV: Cisplatin* 100 mg/m2 Day 2 only
plan (anterior and two laterals) to a dose of 55 Gy (70 mg/m2 if palliative)
Methotrexate 30 mg/m2 Day 1 and 8
in 20 fractions over 4 weeks or 64 Gy in 32 Vinblastine 4 mg/m2 Day 1 and 8
fractions over 6.5 weeks using 6–10 MV photons.
Repeat every 21 days
Complications of radiotherapy include radia-
MVAC: Methotrexate 30 mg/m2 Day 2, 15, 22
tion cystitis (<5%), radiation proctitis (<5%), Vinblastine 3 mg/m2 Day 2, 15, 22
bowel obstruction (<3%) and erectile dysfunc- Adriamycin 30 mg/m2 Day 2
tion (60%). Cisplatin* 70 mg/m2 Day 2
There is interest in partial bladder irradiation Repeat every 28 days
(or whole bladder with a second phase tumour
boost to a smaller volume) with the intention of *For patients with poor renal function (creatinine clearance of
30–60 ml/min), consider replacing cisplatin with carboplatin (AUC
reducing toxicity whilst maintaining an effective 4–5).
dose to the tumour.
Palliative radiotherapy
For node positive or locally advanced disease, outcomes, with less toxicity (Box 12.2). Single
palliative radiotherapy can be beneficial, particu- agent platinum regimes are less effective (response
larly for patients with haematuria or pelvic pain. rates of 30%).
Palliative fields are planned conventionally, Neoadjuvant chemotherapy
sometimes with use of a cystogram to localize the A meta-analysis of neoadjuvant trials in muscle
bladder at simulation. Typical dose schedules invasive bladder cancer has revealed a 5%
include 30 Gy in 10 fractions over 2 weeks, absolute benefit in overall survival for patients
21 Gy in three fractions over 1 week or, in par- treated with cisplatin-based combination chemo-
ticularly frail patients, a single fraction of therapy. This benefit was seen irrespective of the
8–10 Gy. Improved symptoms are observed in type of local treatment (surgery or radiotherapy)
approximately half of patients, but a similar pro- and applied across all patient groups. There may
portion suffers acute side effects. also be a role for neoadjuvant chemotherapy in
bladder preservation, with responding patients
Chemotherapy
being treated with radiotherapy and non-
Chemotherapy in bladder cancer has been prima-
responding patients going on to cystectomy. This
rily used in the palliative and metastatic settings,
is currently being investigated in randomized
but there is good evidence to support the use of
trials.
neoadjuvant chemotherapy prior to cystectomy.
However, the platinum-based regimes are toxic Adjuvant chemotherapy
and emetogenic, and many patients with invasive There is conflicting evidence on benefit and a
bladder cancer are frail with poor renal function Cochrane review did not recommend this as
so tolerate the chemotherapy poorly. routine treatment. Studies of immediate versus
delayed chemotherapy in high risk (node positive
Chemotherapy in metastatic disease
or T3/4) patients post-cystectomy have failed to
Response rates of 40–70% have been observed
recruit sufficient numbers.
with combinations such as CMV (cisplatin,
methotrexate, vinblastine) and MVAC (meth- Concurrent chemo-radiotherapy
otrexate, vinblastine, adriamycin, cisplatin). There is no definite evidence that concurrent cis-
Newer combinations such as gemcitabine and platin with radiotherapy is better than radio-
cisplatin have similar response rates and survival therapy alone. Concurrent 5-fluorouracil and
181
 II SITE-SPECIFIC CANCER MANAGEMENT

mitomycin-C is being investigated as a less toxic published data as to the benefits of this approach.
regime to combine with radiotherapy. The current evidence for adjuvant chemo­
therapy is stronger for node positive disease than
Management of carcinomas of for locally advanced but node negative disease.
the renal pelvis and ureter Metastatic disease is treated with similar plat-
The staging of tumours of the renal pelvis inum-based chemotherapy regimes to those used
and ureter is given in Table 12.3. Renal pelvic in metastatic bladder cancer.
and upper urothelial transitional carcinomas are
treated by radical resection of the kidney and Management of small cell carcinoma of
ureter. Nephron-sparing procedures can be the bladder
undertaken in small, localized tumours if there Small cell bladder cancer accounts for less than
are concerns about function of the remaining 1% of bladder cancers and commonly presents
kidney. Adjuvant radiotherapy confers no sur- at an advanced stage. In localized disease patients
vival advantage following complete resection, should be treated with neoadjuvant platinum-
but may be considered in patients with positive based chemotherapy prior to surgery or radio-
margins or residual local disease. Doses are therapy. Responses to chemotherapy are seen in
limited by surrounding structures, but typically metastatic disease, but median survival is less
45–50.4 Gy in 25–28 fractions can be delivered. than 12 months. Most published data relates to
There is some evidence to suggest that the addi- the use of neuroendocrine regimes such as carbo-
tion of concurrent cisplatin chemotherapy to platin/cisplatin with etoposide.
radiotherapy improves overall and disease-free
survival in T3/4 and/or node-positive disease Survival
following surgical resection. The majority of 5-year survival rates for bladder cancer are as
relapses are distant, so systemic adjuvant therapy follows:
using platinum-containing chemotherapy regimes
Stage 5-year survival
should be considered, although there is little
Ta, T1, CIS 70–95%
T2 50–80%
T3a 40–70%
T3b 20–50%
T4 10%
Table 12.3: Staging of tumours of the renal
pelvis and ureter
Stage Survival with metastatic disease is poor despite
I T1 N0 M0 Tumour invades subepithelial reasonable response rates to chemotherapy, with
connective tissue <10% 2-year survival.
II T2 N0 M0 Tumour invades muscularis
III T3 N0 M0 Tumour invades peripelvic (or Cancer of the prostate
periureteric) fat or renal
parenchyma Introduction
IV T4 T4 Invades adjacent organs or Prostate cancer accounts for 12% of all cancers
perinephric fat
(23% of cancer in men), with 32,000 new diag-
or N1–3 N1 Metastases in single node noses and 10,000 deaths each year in the UK.
≤2 cm There has been a large increase in incidence over
N2 Metastases in single node
>2 cm but ≤5 cm or multiple
the past 10–15 years due to increased detection
nodes through PSA screening and surgery for benign
N3 Metastases in single node prostatic disease. The majority of cases occur in
>5 cm the over 70 age-group and the disease is rare in
or M1 M1 Distant mets the under 50s. As yet there is no evidence that
PSA screening reduces mortality rates from pros-
tate cancer.
182
 CANCERS OF THE GENITOURINARY SYSTEM 12

Aetiology Box 12.3: Gleason grading

The exact aetiology is not known and there are 1. Well differentiated; uniform gland pattern
various suggested risk factors such as a high fat 2. Well differentiated; glands variable
diet, anabolic steroids, oestrogen exposure and 3. Moderately differentiated; papillary/cribriform
genetic. A hereditary prostate cancer gene on features or well-spaced acini
chromosome 1p has been identified. Mutation of 4. Poorly differentiated; cords, sheets, fused cells
the androgen receptor domain may be associated 5. Very poorly differentiated; minimal gland
formation and necrosis
with high grade disease, extraprostatic extension
and distant metastases. Mutation of the vitamin
D receptor gene may also play a role. There is a
link with BRCA genes as well. Box 12.4: Roach formulae

Risk of lymph node 2/3 PSA + 10 (Gleason-6)

Pathology involvement (%):
The vast majority of prostate tumours are adeno- Risk of seminal vesicle PSA + 10 (Gleason-6)
involvement (%):
carcinomas. Malignant areas are frequently Risk of extracapsular 3/2 PSA + 10 (Gleason-3)
multifocal and most often involve the posterola- extension (%):
teral part of the gland. 70% arise in the periph-
eral zone of the prostate. Rare variations include
mucinous, small cell, squamous cell, adenoid
Locally advanced cancers can be detected on
cystic and endometrioid carcinoma (the latter
rectal examination, and occasionally patients
is characterized by a normal PSA and lack of
may present with symptoms due to local exten-
hormone response). Transitional cell carcinoma
sion such as pain or bleeding. Metastases to bone
of the prostatic urethra may occur and there are
are common and bone pain or pathological frac-
rare reports of secondary spread from other
ture can be presenting features. Other areas of
tumours such as melanoma and lung cancer.
spread include obturator, perivesical and para-
The Gleason grading system, an important
aortic lymph nodes and rarely liver, lung or brain
prognostic factor, describes the degree of differ-
metastases.
entiation of the malignant cells (Box 12.3). Each
The strongest predictors of metastasis are a
tumour is graded twice, each out of five to give
high PSA, high Gleason score (8–10) and age >70
a total score out of 10 – the first grade relates to
years. The Roach formulae (based on Partin’s
the most commonly observed pattern (primary
tables) are commonly used in treatment algo-
pattern) and the second to the next most common
rithms to predict the risk of local extension and
pattern.
lymph node spread (Box 12.4).
Presentation Investigations and staging
The majority of prostate cancers are initially Initial investigations include a PSA blood test and
detected following a raised serum prostate spe- digital rectal examination (DRE). Patients with
cific antigen (PSA) level and approximately half raised PSA are offered a transrectal biopsy of the
of patients are completely asymptomatic. The prostate to obtain histological diagnosis (usually
PSA blood test may have been taken as part of 8–12 core biopsies of the prostate are obtained,
investigations into non-specific lower urinary half from each lobe).
tract symptoms of bladder outflow obstruction If cancer is confirmed, further investigations
such as hesitancy, frequency, nocturia and termi- are determined by the grade, volume of disease
nal dribbling, or increasingly as part of a well- and PSA level, but may include a pelvic MRI scan
man screening programme. In symptomatic to define extracapsular spread and seminal vesicle
patients who require a transurethral resection of or lymph node involvement (generally offered to
the prostate (TURP) for presumed benign pros- patients with Gleason 4+3 disease or above, or
tatic hypertrophy, it is not uncommon to dis- with PSA >20 ng/ml, in whom radical treatment
cover cancer cells in the prostatic chippings. is being considered) and a bone scan (if PSA
183
 II SITE-SPECIFIC CANCER MANAGEMENT

Table 12.4: Staging of prostate cancer

Stage Description
I T1a Not palpable, confined to prostate Diagnosed on TURP, <5% of chippings involved,
Gleason grade 2–4 only
II T1a Diagnosed on TURP, <5% of chippings involved,
Gleason grade ≥5
T1b Diagnosed on TURP, >5% of chippings involved
T1c Diagnosed by needle biopsy in response to a raised PSA
T2a Palpable, but confined to prostate Confined to 1 lobe, <50% involved
T2b Confined to 1 lobe, >50% involved
T2c Both lobes palpably involved
III T3a Breaches prostate capsule Extension through the prostate capsule
T3b Involvement of one or both seminal vesicles
IV T4 Local invasion Invasion of other nearby structures
Any N1 Spread to regional lymph nodes
Any M1 Distant metastases

>10–15 ng/ml). If there is doubt over lymph node time, expressed in months or years, and the
involvement, a laparoscopic retroperitoneal PSA velocity, expressed as ng/ml/year (this is
lymph node biopsy might be considered prior to commonly utilized in patients on active sur-
proposed radical treatment. veillance – see below). To get an accurate
Table 12.4 shows the staging of prostate indication of PSA velocity, at least three meas-
cancer. urements should be taken over a period of 18
As well as the absolute PSA level, various months.
other PSA parameters have been developed in an Note that very poorly differentiated cancers
attempt to improve the predictive value of the may not secrete PSA and are therefore more dif-
test for diagnosis and monitoring: ficult to diagnose, predict and monitor.
• PSA density (PSA/volume of gland) allows for
higher PSA levels in older men with large,
Management of localized disease
hypertrophied glands. A value of 0.1 ng/ml/cc The treatment options for localized disease are:
is considered normal (e.g. a PSA of 5 ng/ml • Active surveillance (for patients suitable for
with a 50 cc prostate volume). radical treatment).
• Percent-free PSA (fPSA) is the ratio of how • Watchful waiting (for patients not suitable for
much PSA circulates free compared with the radical treatment).
total PSA level, including that attached to • Radical treatment with surgery or radiother-
blood proteins. The percentage of free PSA is apy or both.
lower in men who have prostate cancer than
in men who do not and may be useful in Active surveillance and watchful waiting
determining which patients with intermediate Many patients will have slow-growing disease
PSA levels should have a prostate biopsy for which may have little or no impact on their life-
diagnosis. There is some controversy over expectancy, and they might therefore be spared
where the cut-off should lie, but fPSA levels the toxicities and inconvenience of radical treat-
of <10% are very suspicious. ment. Active surveillance implies close monitor-
• PSA kinetics give an indication of the rate of ing with early curative treatment offered to
184 tumour growth, and include the PSA doubling patients who show signs of progression. There
 CANCERS OF THE GENITOURINARY SYSTEM 12
are no absolute criteria for considering active Box 12.5: Radiotherapy for prostate
surveillance and the decision should be made (see Figure 12.5)
with the patient, but typical parameters would Localization
be T1–T2b disease, Gleason grade ≤7, PSA ≤15 CT planning with empty rectum. Target volume
(with favourable kinetics). A surveillance pro- defined on planning CT or co-registered CT/MRI
gramme might consist of 3-monthly visits for the Target volume
first 2 years, followed by 6-monthly visits there- Primary radical treatment
after, with a DRE and PSA checked at each visit. CTV = Whole prostate + tumour extension
Repeat transrectal biopsies should be performed Whole seminal vesicles included if risk of involvement
≥15%
at 18 months. Criteria for consideration of
Consider treating pelvic nodes if risk of nodal
radical treatment would be PSA progression involvement ≥15%
(doubling time <2 years), clinical progression or Phase I PTV = CTV + 1 cm margin
upgrading of the Gleason score on repeat biopsy. Phase II PTV = CTV + 0.5 cm margin
‘Watchful waiting’ is appropriate where Salvage radiotherapy
patients deemed unsuitable for radical treatment Prostate bed, any surgical clips and residual seminal
are treated with palliative endocrine therapy vesicle with 1 cm margin
when there is symptomatic progression. Dose
Prostate and seminal vesicle
Radical treatment
Phase I – 56 Gy in 28 fractions
Radical treatment options for prostate cancer Phase II – 18 Gy in 9 fractions
include radical prostatectomy, external beam Whole pelvis and prostate
radiotherapy and brachytherapy (low-dose rate Phase I (whole pelvis with prostate) – 50 Gy in 25
or high-dose rate). Each treatment has its own fractions
characteristics and may be suitable for certain Phase II (prostate alone) – 18–24 Gy in 9–12
types of patients, but reported success rates are fractions
Salvage radiotherapy
similar if patients are chosen appropriately.
66–70 Gy in 33–35 fractions
Radical prostatectomy Tolerance
Perineal, retropubic or laparoscopic approaches • Rectum: 55.5 Gy to no more than 50% of the
can be considered. There is a 5–15% risk of rectum, 70 Gy to no more than 25% and 74 Gy
to no more than 3%.
urinary dysfunction after surgery. Nerve-sparing
• Bladder: Less than 50% of the bladder should
techniques have improved morbidity, with ap- receive 67 Gy.
proximately 50% impotence rates.
External beam radiotherapy
Conformal CT planning is well established in (1.2–1.5 Gy), which implies that hypofraction-
prostate radiotherapy (Box 12.5 and Figure ated courses of radiotherapy with a high dose per
12.5). The Medical Research Council RT01 fraction might result in improved cancer control
study randomized between 64 Gy and 74 Gy and for a similar level of side effects. For this reason
found a hazard ratio for biochemical progression doses such as 57–60 Gy in 19–20 fractions over
free survival of 0.67 (CI 0.53–0.85; p = 0.0007) 4 weeks are being investigated. These shortened
in favour of the escalated group. However this schedules have the additional advantage of
was achieved at the expense of increased late sparing resources and being more convenient for
bowel and bladder toxicity. It is not yet known patients.
whether there will be any improvements in Though the survival benefit of whole pelvic
overall survival. radiotherapy in high risk of pelvic lymph node
Newer techniques such as intensity modulated involvement (≥15% on Roach criteria) remains
radiotherapy (IMRT) might enable even further to be demonstrated, it is commonly practised.
increases in the dose administered or further Acute side effects of radiotherapy include
sparing of normal tissues. dysuria, frequency, diarrhoea, lethargy and ery-
Radiobiological studies have suggested a sur- thema. Late effects include proctitis (diarrhoea,
prisingly low alpha-beta ratio for prostate cancer rectal bleeding, tenesmus: 30% mild, 5% severe), 185
 II SITE-SPECIFIC CANCER MANAGEMENT

Figure 12.5
Target volumes for radical prostate
radiotherapy. Orange line phase I
PTV including prostate and seminal
vesicle with a 10 mm margin and
purple line phase II PTV including
only prostate with a 5 mm margin.

impotence (30–40%) and urinary incontinence following a shortened course of external beam
(1–5%). radiotherapy but can also be used as mono-
therapy. Treatment is delivered through catheters
Brachytherapy implanted with ultrasound guidance into the
Low-dose rate (LDR) brachytherapy prostate under general anaesthetic. HDR boost
Permanent radioactive seeds are implanted patients are typically treated in two or three frac-
directly into the prostate via transperineal needles tions, 12 hours apart, necessitating overnight
that are inserted with ultrasound guidance under stay with the catheters and template in-situ. Box
general or spinal anaesthetic. Approximately 12.6 shows some of the HDR boost schedules
50–100 Iodine-125 or Palladium-103 seeds are currently in use.
implanted to achieve a prescribed dose of 145 Gy.
Patients eligible for this treatment are those with Role of hormones in curative treatment
a prostate volume of <50 cc, Gleason ≤6, PSA Patients undergoing radical radiotherapy are
≤15, T2 or less disease, those haven’t had a previ- commonly treated with 3 months of neoadjuvant
ous TURP and not at high risk of extracapsular luteinizing hormone releasing hormone (LHRH)
extension or lymph node involvement. Patients analogues. This approach may enable a reduc-
should have a transrectal ultrasound volume tion in the volume of tissue irradiated due to
study to assess suitability for brachytherapy. shrinkage of the prostate gland. An EORTC
Although there is good evidence to confirm the study compared radiotherapy alone versus radio-
efficacy of brachytherapy in terms of PSA control therapy with immediate androgen suppression
and biopsy findings, there is as yet no long-term started on the first day of radiotherapy and con-
survival data. The procedure has not been directly tinued for 3 years. 5-year clinical disease free
compared with external beam radiotherapy survival was 40% versus 74% and overall sur-
or radical surgery in randomized studies, but vival was 62% versus 78% in favour of the adju-
comparative and cohort studies show similar vant endocrine group.
5-year biochemical recurrence-free and overall Prolonged adjuvant treatment for 2–3 years
survival. should be offered to all patients with high risk
disease (Gleason 8–10, clinical T3/4 tumours or
High-dose rate (HDR) brachytherapy lymph node risk >30%). The role in low and
HDR brachytherapy is suitable for intermediate- intermediate risk patients is being assessed in
high risk patients. It is typically given as a boost randomized studies, but these patients are cur-
186
 CANCERS OF THE GENITOURINARY SYSTEM 12

Box 12.6: High-dose rate brachytherapy Box 12.7: Side effects of LHRH analogues
boost schedules
Hot flushes
External beam dose HDR brachytherapy boost dose Weakness/loss of muscle bulk
and fractionation and fractionation
Weight gain
35.7 Gy in 13 17 Gy in 2
Fatigue
46 Gy in 23 16.5 Gy in 3
46 Gy in 23 17 Gy in 2 Osteoporosis/fracture risk
50 Gy in 25 18 Gy in 2 Loss of libido and erectile function
45 Gy in 23 16.5 Gy in 3
Mood changes
46 Gy in 23 23 Gy in 2
Poor concentration/memory

rently treated with 3–6 months of LHRH ana- Metastatic disease, elderly and those with
logues before and during radiotherapy. significant comorbidities
It should be noted that LHRH analogues Metastatic disease (Figure 12.6) is generally
are not without side effects (see Box 12.7) and treated with endocrine therapy, usually LHRH
can add consid­erably to the morbidity of patients analogues in the first instance, with the addition
undergoing radiotherapy. of an anti-androgen to give maximal androgen
There is no established role for neoadjuvant blockade on biochemical or clinical progression.
or adjuvant hormonal manipulation in patients The typical duration of response to first line endo-
undergoing radical prostatectomy. crine therapy with LHRH analogues is 18–24
Management of locally advanced and months. There is increasing interest in intermit-
tent LHRH analogue therapy as a way of pro-
metastatic disease
longing the useful lifespan of the drug and of
Locally advanced disease allowing patients to have periods of time off
For patients with locally advanced disease radical treatment and therefore avoid some of the side
radiotherapy or surgery may add little or no effects. Typical schedules are to treat until PSA
additional benefit over hormone therapy alone, falls below 4 ng/ml (or <80% of initial value) and
although there is emerging evidence that radio- restart when PSA rises above 10 ng/ml. Studies
therapy does improve biochemical control in have shown no difference in survival when com-
patients with PSA levels up to 70 ng/ml. The pared with continuous therapy, but significant
mainstay of treatment is with LHRH analogues improvements in quality of life, with patients
or anti-androgens. Prolonged treatment with spending a median of 1 year off treatment.
LHRH analogues results in significant toxicity Third line hormonal therapy with oestrogens
due to reduction of testosterone levels (see Box can be considered but response duration tends to
12.7). Androgen receptor inhibitors, such as be short unless response to first and second line
bicalutamide, or 5-alpha reductase inhibitors treatment has been particularly good.
effectively reduce the delivery of testosterone to Elderly patients and those with significant co-
the prostate without reducing serum testosterone morbidities can be treated symptomatically with
levels and therefore tend to have a better side or without hormones.
effect profile, although they can cause significant
gynaecomastia. Prophylactic radiotherapy to the Management of relapse
breast buds or prophylactic tamoxifen 10–20 mg/ after radical treatment
day can reduce and sometimes prevent the painful Some authorities advocate postoperative radio-
gynaecomastia. Typical radiotherapy doses are therapy to the prostatic bed in cases with a posi-
8–10 Gy in a single fraction or 15 Gy in three tive margin at radical prostatectomy, whilst
fractions given on alternate days, using electron others would wait and offer radiotherapy if the
radiotherapy delivered to an 8–10 cm circle PSA fails to completely suppress or subsequently
around each nipple. rises. In these situations, salvage radiotherapy is
187
 II SITE-SPECIFIC CANCER MANAGEMENT

Figure 12.6
Bone scan in metastatic prostate
cancer. Note the absence of
uptake in the kidneys and bladder
(arrows) suggesting that uptake
is preferentially by the extensive
metastases. This picture is
called a ‘superscan’ which is a
contraindication for radioisotope
treatment (risk of lethal bone
marrow suppression)

most effective if given before the PSA reaches a weeks) when compared with the previous stand-
value of 2 ng/ml (Box 12.5). ard regimen of mitoxantrone and prednisolone.
Salvage surgery for radiotherapy failures is Doses of 75 mg/m2 are administered on a 3-weekly
rarely undertaken due to the complicated nature basis for up to 10 cycles. Although low-grade
of the procedure and questionable results. Newer neutropenia is fairly common, the rates of febrile
invasive techniques such as cryotherapy and high neutropenic sepsis are reassuringly low (<3%)
frequency ultrasound (HiFU) have shown some without colony-stimulating factor support.
success in terms of PSA control after radiother- Chemotherapy agents are now being investi-
apy failures (and perhaps as primary treatments gated in earlier stages of prostate cancer, both in
in place of radiotherapy), but long-term out- metastatic disease prior to the development of
comes are awaited. CRPC or as an adjuvant to radical prostatectomy
for localized disease. There is also interest in
Role of chemotherapy second-line chemotherapy after failure of taxanes;
in prostate cancer there is some evidence for PSA response with
Until recently, chemotherapy has been reserved satraplatin, an orally active platinum-based drug.
for advanced metastatic prostate that has become Cabazitaxel, a new taxane, has demonstrated a
refractory to endocrine treatment (known as 2.5 month survival benefit in the second-line
hormone refractory prostate cancer, HRPC, or setting.
more accurately as castration resistant prostate
cancer, CRPC). Docetaxel is now well established Palliative treatment
in this setting, with studies showing quality of life • Steroids: Low-dose steroids (0.5–2 mg of
and overall survival benefits (in the order of 10–12 dexamethasone daily) are effective in some
188
 CANCERS OF THE GENITOURINARY SYSTEM 12
patients in terms of both quality of life men, with around half in men under 35 years of
improvements and PSA control. age and 90% in men under 55 years.
• Bisphosphonates: Zoledronic acid adminis-
tered intravenously once a month has been Aetiology
shown to reduce the incidence of skeletal Apart from age and race, other risk factors
events, including fractures or the need for include a previous history of testicular cancer or
radiotherapy, in men with bone metastases. It carcinoma-in-situ. Cryptorchidism (undescended
is effective at controlling refractory metastatic testes at birth) increases the risk by 2–4 fold.
bone pain. There are some reports of increased incidence in
• Radiotherapy: External beam radiotherapy is men with subfertility and also suggested links
very effective in controlling metastatic bone with high dietary dairy product intake and a
pain and symptoms of primary tumour inva- sedentary lifestyle.
sion such as haematuria and pain. Prolonged
fractionation regimes have not been shown to Pathology
be more beneficial than a single fraction of The majority of testicular malignancies are germ
8 Gy. Radiotherapy is also commonly used in cell tumours (>90%), either seminomas or ter-
cases of spinal cord or nerve root compression atomas. Approximately 20% are of mixed cell
from vertebral metastases (p. 328). type and should be classified as non-seminoma-
• Radioisotopes: Strontium-89 and Samar- tous germ cell tumours (NSGCT). Other types
ium-153 are effective at controlling pain in up include sex cord tumours, lymphomas and
to 80% of patients with widespread bone sarcomas.
metastases. Radioisotope treatment is partic- Intratubular germ cell neoplasia has features
ularly useful in patients with diffuse bone similar to carcinoma-in-situ, seen in the contra­
pain that cannot easily be targeted with exter- lateral testes in 5% of testicular cancer patients.
nal beam radiotherapy (Figure 12.6). Care There is a risk of progression to malignancy of
must be taken if chemotherapy is to be con- 50% at 5 years. This risk can be prevented with
sidered at a later date because of a suppressive radiotherapy (20 Gy in 10 fractions), which will
effect on the bone marrow. result in infertility, but avoids the need for a
second orchidectomy. It is diagnosed by open or
Prognostic factors and survival needle biopsies and is more likely in young
Survival figures from prostate cancer vary widely, patients with an atrophic contralateral testis.
depending on histology, stage, PSA level and
therapeutic intervention. Patients with localized
Presentation
disease treated with either radiotherapy or radical The majority of testicular tumours (75%) present
surgery have 5-year biochemical control rates of with a painless, firm swelling of the testis. Occa-
75–85% and 10-year overall survival rates of sionally patients present with lower back pain
60–70%. Patients with metastatic disease can due to intra-abdominal or pelvic lymph node
survive for many years, particularly if the tumours spread, or indeed palpable lymphadenopathy,
are hormone-responsive and if the metastatic particularly in the left supraclavicular fossa.
spread is confined to the bones. Other methods of presentation include infertility,
gynaecomastia, secondary hydrocoeles or with
symptoms due to secondary spread to other
Cancer of the testes organs such as lung or liver.

Introduction Investigations and staging

Testicular cancer accounts for 0.7% of all Preoperative investigations should include tes-
cancers, with fewer than 2000 new diagnoses ticular ultrasound, chest X-ray and tumour
each year in the UK. There has been an increase markers including alpha-foetoprotein (AFP),
in incidence over recent years for reasons beta-human chorionic gonadotrophin (beta-
unknown. The majority of cases occur in younger HCG) and lactate dehydrogenase (LDH). One or
189
 II SITE-SPECIFIC CANCER MANAGEMENT

more tumour marker is raised in 75% of terato- Postoperative management of

mas and 35% of seminomas. If AFP is raised or seminoma (Figure 12.7)
beta-hCG is >200, then treat as a non-seminoma-
Stage I disease
tous germ cell tumour (NSGCT). Tumour markers
Around 80% of patients with seminoma present
should be done preoperatively and repeated a
with stage I disease and survival is >99%. There
minimum of 7 days after orchiectomy.
are two risk factors for recurrence: rete testis
Postoperative investigations should include a
invasion and tumour size of >4 cm. 5-year relapse
CT scan of the thorax, abdomen and pelvis for
rate is 12% with no risk factors, 16% with one
full systemic staging. In case of borderline lymph
factor and 32% with both factors. Current treat-
node size (normal <1 cm), a repeat CT scan after
ment is active surveillance irrespective of risk
6 weeks is indicated prior to deciding further
factors. If surveillance is not an option the active
management; CT of the brain is indicated if there
are multiple lung metastases or beta-HCG levels
>10,000 IU/L.
Postoperative tumour markers should be Table 12.5: TNM staging of testicular cancer
repeated (the half-life of the markers is up to 7 Stage 0 T1sN0M0 – intracellular germ cell
days) and are useful in measuring treatment neoplasm
response and monitoring for recurrence. A bone
Stage IA pT1N0M0 – tumour limited to testis
scan is usually only requested if indicated clini- and epididymis with no LVI or
cally. Sperm storage should be considered, par- tunica vaginalis invasion (TVI)
ticularly if chemotherapy is planned. Stage IB pT2–4N0M0 – pT2 – tumour limited to
The staging and risk classification of testicular testis and epididymis with LVI or
cancer is shown in Tables 12.5 and 12.6. TVI
pT3 – invades spermatic cord
pT4 – invades scrotum
Management of testicular cancer
Stage IIA Any T, N1 (≤2 cm regional node) M0
Primary management is a radical inguinal orchid-
ectomy and ligation of the spermatic cord at Stage IIB Any T, N2 (>2–5 cm) M0
the internal ring which should be performed Stage IIC Any T, N3 (>5 cm) M0 node
within one week after diagnosis. In patients Stage Any T, any N, M1A (non-regional
with advanced life-threatening testicular cancer, IIIA/B nodes and/or lung metastasis)
orchiectomy should not delay chemotherapy. In Stage IIIC Any T, any N, M1b (other visceral
these situations, if clinical picture and markers metastasis)
are diagnostic, treatment with chemotherapy can Mediastinal primary, any N and any M
be started. Organ sparing surgery may be an
option in cases of bilateral testicular cancer.

Table 12.6: International Germ Cell Consensus Classification prognostic criteria for non-
seminomatous tumours
Good prognosis Intermediate prognosis Poor prognosis
AFP <1000 ng/ml AFP 1000–10,000 ng/ml AFP >10,000 ng/ml
β-HCG <5000 iu/l HCG 5000–50,000 iu/l HCG >50,000 iu/l
LDH <1.5 times the upper limit of LDH 1.5–10 × ULN LDH >10 × ULN
normal (ULN)
Testis or retroperitoneal primary Testis or retroperitoneal primary Mediastinal primary site
No non-pulmonary visceral metastases No non-pulmonary visceral Non-pulmonary visceral metastases
metastases

190
 CANCERS OF THE GENITOURINARY SYSTEM 12

Seminoma

Stage I Stage IIA and IIB Stage IIB Good prognosis Intermediate prognosis
(2–2.5 cm) (2.5–5 cm) IIC/III IIC/III

Active Dog-leg field

surveillance radiotherapy

OR OR
Active treatment–options BEP x 3 BEP x 3 BEP x 3 BEP x 4
Carboplatin 1 course AUC7 or or or
Paraaortic radiotherapy EP x 4 EP x 4 EP x 4

OR

Progression Dog-leg field Complete Residual

radiotherapy response tumour

Chemotherapy Progression < 3 cm > 3 cm

as IIC/III

PET PET
(optional
If previous If previous
chemotherapy radiotherapy

Salvage Chemotherapy PET– or PET+ PET PET- PET+

chemotherapy or RT as IIC/III not done not done
for localized relapse

Follow-up Follow-up Follow-up Follow-up –Resection

or resection or resection

Progression

Bold lettering indicates standard treatment Options – salvage chemotherapy, localized RT, local re-irradiation

Figure 12.7
Postoperative management of seminoma.

treatment options are a single dose of carboplatin temic treatment. Standard treatment for stage IA
(AUC7) and para-aortic radiotherapy (20 Gy in and stage IB with 2–2.5 cm node is radiotherapy
10 fractions) (Box 12.9). to para-aortic and ipsilateral iliac nodes (‘dog leg
field’). An alternative option is three cycles of
Stage II–IV disease PEB chemotherapy (3 or 5-day schedule). Treat-
Clinical stage IIA disease should be verified ment option of stage IIB with 2.5–5 cm node is
beyond imaging (e.g. needle biopsy) before sys- three courses of PEB (Box 12.8).
191
 II SITE-SPECIFIC CANCER MANAGEMENT

Box 12.8: Testicular cancer chemotherapy regime

PEB
3-day schedule
Cisplatin 50 mg/m2 Days 1–2
Etoposide 165 mg/m2 Days 1–3
Bleomycin 30 mg on Days 1, 8, 15
5-day schedule
Cisplatin 20 mg/m2 Days 1–5
Etoposide 100 mg/m2 Days1–5
Bleomycin 30 mg Days 1, 8, 15
Chemotherapy is repeated 3-weekly independent of
leukocyte count but with platelets of >100 × 109 on
Day 22. Chemotherapy is only delayed if platelet
count is not adequate or active infection. Prophylactic
G-CSF is used if necessary.

Box 12.9: Radiotherapy in testicular seminoma

Para-aortic strip – field definition (shaded area in
Figure 12.8)
• Superior: top of T11 vertebra Figure 12.8
Radiotherapy in seminoma. Outline any enlarged lymph
• Inferior: bottom of L5 vertebra
nodes on the CT scan and modify the field to ensure
• Ipsilateral border (to primary tumour): renal hilum that nodes are covered with a 1.5 cm margin.
• Contralateral border (to primary tumour):
transverse process of vertebrae
months after initial chemotherapy are platinum
’Dog-leg field – field definition (green line in
Figure 12.8)
sensitive and the standard options are VIP, TIP
• Superior: top of T11 vertebra or VelP. There is no benefit of high dose chemo-
• Inferior: lower border of ipsilateral acetabulum therapy as second or third line chemotherapy.
• Ipsilateral border (to primary tumour): renal hilum Patients who are truly platinum-resistant
and include iliac nodes (relapse during or within 3 months post treat-
• Contralateral border (to primary tumour): ment) have a very poor prognosis (approximately
transverse process of vertebrae 10% survival) and there is no standard treatment.
Dose Gemcitabine/paclitaxel, high dose chemotherapy
Stage I – 20 Gy in 10 fractions to midplane and surgery if localized disease are the options.
Stage II (1–2.5 cm) – 30 Gy in 15 fractions
Stage II (>2.5–5 cm) – 36 Gy in 18 fractions Postoperative management of
non-seminomatous germ cell tumours
(NSCGTs) (Figure 12.9)
The treatment of stage IIC/III is three cycles of
Stage I patients are divided into low (20% relapse
PEB for good prognosis patients (3 or 5-day
rate) and high risk (40–50% relapse) based on
schedule) and four cycles for intermediate prog-
absence or presence of vascular invasion. The
nosis patients (5-day schedule). Three cycles of
management is outlined in Figure 12.9. Treat-
PEB may be substituted by four cycles of PE in
ment choice is based on toxicity, tumour burden
cases of increased bleomycin toxicity.
and patient preference. Active surveillance is
Residual disease and relapse intense follow up with frequent clinical examina-
Management of residual disease is shown in tion, tumour marker estimation and scans. Fre-
Figure 12.7. In general, patients with >3 cm quency of follow-up depends on risk of relapse.
residual mass need PET scan or frequent follow Management of stage IIA–III disease is out-
up or resection. lined in Figure 12.9. It is important that in
Patients relapsing after radiotherapy are treated patients undergoing chemotherapy, dose inten-
192 with chemotherapy. Patient who relapse >3 sity is maintained (Box 12.8, see also Box 4.3).
 CANCERS OF THE GENITOURINARY SYSTEM 12

Non-seminoma

Stage IA Stage IB Stage IIA Stage IIA Good prognosis Intermediate/poor

marker–ve marker+ or IIC/III prognosis
stage IIB IIC/III

Surveillance BEP x 2 or 6 weekly follow-up

surveillance
OR OR
BEP x 2 cycles Biopsy or BEP x 3 BEP x 3 BEP x 4
NS–RPLND or (5 day schedule)
EP x 4
Progression
on follow-up

Progression No change Restaging after 4 weeks

Marker+ Marker–
Marker normal: Marker not Marker not normal
Salvage NS-RPLND no residual normal, potentially and irresectable or
therapy tumour resectable residual multiple residual
tumour

BEP x 3 pStage I Follow-up Follow-up Follow-up

(EP x 4) 4–12 week

BEP x 3 (EP x 4) or Surveillance Marker normal:

NS-RPLND resectable
residual tumour
pStage IIA/B

Follow-up or Marker normal Marker

BEP x 2 or or plateau increase
EP x 2

Resection Salvage
chemotherapy

R0 (<10% R0 (>10% R1/R2 Progression Progression

viable cell) viable cell) >12 weeks <12 weeks

Follow-up Consider Salvage Salvage Experimental

chemotherapy chemotherapy chemotherapy chemotherapy
(VIP x 2)

NS–RPLND – nerve sparing retroperitoneal lymph node dissection

Figure 12.9
Postoperative management of non-seminoma.

193
 II SITE-SPECIFIC CANCER MANAGEMENT

Management of residual masses and recurrence Aetiology

Residual masses >1 cm in size should be resected. Risk factors for penile cancer include human
Management after resection is based on the papilloma virus (HPV) infection, smoking and
extent of resection and proportion of viable previous carcinoma-in-situ. Circumcision is
tumour cells (Figure 12.9). Chemotherapy for protective.
relapse is similar to seminoma.
Pathogenesis and pathology
Management of testicular intraepithelial
Pre-malignant conditions include condylomata
neoplasia (TIN) acuminat, leukoplakia (chronic irritation) and
3–5% of patients with testicular cancer have TIN balanitis xerotica obliterans. The following con-
in the contralateral testis with the highest risk if ditions can also progress to cancer:
testicular volume <12 ml and age <40 years
(34%) and in patients with extragonadal germ • Bowen disease (carcinoma-in-situ): solitary,
cell tumours (≥33%). If untreated, 70% of TIN grey plaque with shallow ulceration on the
progress to testicular cancer in 7 years. skin of shaft/scrotum. Approximately 10%
Patients should be offered the choice of tes- progress to invasion.
ticular biopsy or monitoring only (both strategies • Erythroplasia of Queryat: single/multiple
have excellent survival outcomes). If chemother- shiny red plaques on glans/prepuce. Approxi-
apy is given, biopsy should be delayed at least 2 mately a third progress to invasion.
years after treatment. The treatment options in • Bowenoid papulosis: multiple pigmented
proven TIN include surveillance and active treat- plaques (very similar to Bowen’s). Rarely
ment with radiotherapy (20 Gy in 10 fractions) becomes malignant.
or orchiectomy (in patients with no gonadal The vast majority (>90%) of cancers are squa-
tumour, e.g. incidental finding during biopsy for mous cell carcinomas (SCC). Verrucous carci-
infertility or extragonadal tumour). noma is an indolent variant which can present
with bulky cauliflower-like lesions. Other rare
Prognostic factors and survival malignancies of the penis include melanoma, sar-
Seminoma has >90% long-term survival with comas (particularly Kaposi’s sarcoma), basal cell
that of stage I disease at >99%. Stage I non- carcinomas and metastases from bladder, pros-
seminoma has a long-term prognosis of 98–100%. tate or bowel primary tumours.
In advanced non-seminoma, survival is 90% for
the good prognostic group, 80% for intermediate Presentation
group and 60% for poor prognostic group. Penile cancers present as erythematous patches,
exophytic growths, nodules or ulcers. There may
Follow-up be associated discharge from the prepuce and/or
Follow-up after active treatment involves fre- phimosis. Advanced cases can present with
quent clinical examination, estimation of tumour inguino-femoral lymphadenopathy.
markers, chest X-ray and CT-scan up to 5 years.
Investigations and staging
Follow-up beyond 5 years is useful in detecting
late toxicities and second cancers. Diagnosis is made by biopsy of the lesion. Inves-
tigations should include a full blood count, urea
and electrolytes and liver function. The inguinal,
Cancer of the penis pelvic and abdominal lymph nodes should be
assessed with a CT or MRI scan. Clinically
Introduction enlarged inguinal nodes can be assessed with
Penile cancers account for less than 1% of all fine needle aspiration or biopsy. A MRI of the
cancers in men, with an annual incidence of pelvis with an artificial erection may be useful
1.5/100,000 in Western Europe. Peak age of in assessing cavernal invasion (Figure 12.10).
occurrence is 60–70 years and they are extremely A chest X-ray is usually sufficient for distant
rare in men under the age of 40. staging unless there is suspicion of disease else-
194
 CANCERS OF THE GENITOURINARY SYSTEM 12
hands and to abstain from sexual intercourse
during the treatment. Alternatively, laser exci-
sion can be considered.
Invasive disease
Surgery is the treatment of choice and radio-
therapy is an alternative. Amputation with good
margins has the best long-term outcome with
90% 5-year survival. Radiotherapy has a 30%
long-term failure rate. Circumcision should be
performed in all patients, even if treated with
radiotherapy.
A
Surgery
For very small foreskin lesions, circumcision and
laser surgery can be curative. For other T1/2
lesions of the glans, a glansectomy or partial
amputation may suffice. For larger tumours, par-
ticularly if the urethra is involved, total amputa-
tion is required.
External beam radiotherapy
If disease is limited to the glans, treatment is with
electron-beam radiotherapy with a 2 cm margin
around the tumour. Perspex or bolus is placed
over the cut-out section to ensure that the skin
surface dose is 100%. For more extensive disease,
photon irradiation is appropriate. Two lateral
fields are applied with the penis placed between
two halves of a wax block. The testis and groin
are shielded with lead. The conventional dose is
60–64 Gy in 30–32 daily fractions using 4–6 MV
photons. If there is residual disease following
B radiotherapy, surgical excision should be consid-
ered as a salvage treatment. Box 12.10 lists the
Figure 12.10
Figures show a cancer of the glans penis (A) and an MRI side effects of penile radiotherapy.
(B) of the pelvis with artificial erection showing a Brachytherapy
tumour involving the meatus (T3) (red arrow) but
without involvement of tunica albuginea (yellow arrow)
Patients are circumcised and catheterized before
or corpora cavernosa (green arrow). (Courtesy of Mr. treatment. Brachytherapy is generally only
David Ralph, Institute of Urology, London, UK.) suitable for T1/2N0 tumours of less than 4 cm
in size. Two techniques are in use.
where. It is sensible to photograph the lesion • The mould technique employs two Perspex
prior to treatment for future reference. The cylinders, the outer of which is loaded with
staging of penile cancers is shown in Table 12.7. iridium 192 wires. The device is worn for
Management 8–10 hours per day for 1 week, giving a
typical dose of 60 Gy.
Management of the primary tumour • The interstitial technique involves insertion of
Carcinoma-in-situ radioactive implants to give 65 Gy to the
Carcinoma-in-situ can be treated with topical 85% isodose over 1 week using the Paris
5-fluorouracil applied twice a day. Patients system. A 2 mm lead shield is applied to the
should be warned to avoid contact with their testes and it is wise to consider stilboestrol
195
 II SITE-SPECIFIC CANCER MANAGEMENT

without clinically palpable nodes is indicated for

Table 12.7: Staging of penile cancers patients with T2/3 cancers, when the risk of
Stage lymph node involvement is >80%.
I T1 N0 Invasion of sub-epithelial tissue In patients with large or fixed nodal disease,
II T2 N0 Invasion of corpora or preoperative groin radiotherapy (45–50 Gy in
cavernosum 2 Gy daily fractions) or chemotherapy can be
T1/2 N1 Single superficial inguinal lymph
considered to downsize the nodes prior to dissec-
node involvement tion. Radiotherapy is also an option as prophy-
laxis in clinically node negative patients in place
III T3 N0/1 Invasion of urethra/prostate
T1–3 N2 Multiple or bilateral superficial of surgery. Neither surgery nor radiotherapy is
inguinal nodes curative when there is involvement of the pelvic
IV T4 N0–2 Invasion of adjacent structures
lymph nodes, and treatment becomes palliative.
T1–4 N3 Deep inguinal or pelvic nodes In these cases it is best to avoid the morbidity of
M1 involved dissecting the groin nodes, but palliative radio-
Distant metastases therapy to prevent groin ulceration and leg
oedema may be appropriate.
Chemotherapy
There may be a role for primary neoadjuvant
Box 12.10: Side effects of radiotherapy to chemotherapy in patients with fixed inguinal
the penis
metastases, approximately 50% of which can be
Early Mucositis made resectable. Possible chemotherapy regimes
Oedema of the prepuce include cisplatin and 5-fluorouracil or cisplatin,
Local infections
Dysuria methotrexate and bleomycin.
Difficulty with micturition Chemotherapy may also be used in fit patients
Late Telangiectasia with metastatic disease. There is interest in
Superficial necrosis
Urethral meatal stenosis taxane and platinum combinations.
Deep fibrosis
Loss of sexual function Prognosis
Nodal status is the major determinant of prog-
nosis. The 5-year disease-free survival rates of
treatment to prevent erections during the patients with N+ and N0 disease are approxi-
week of treatment. Local control rates of up mately 40% and 80%, respectively.
to 90% have been reported for T1 tumours.
Further reading
Patients who recur after brachytherapy are Rini BI, Campbell SC, Escudier B. Renal cell carcinoma.
salvaged with surgery. Lancet. 2009;373:1119–1132.
Rini BI. New strategies in kidney cancer: therapeutic
Palliative radiotherapy advances through understanding the molecular basis of
Palliative treatment with external beam radio- response and resistance. Clin Cancer Res. 2010;16:
therapy can be considered in unfit patients with 1348–1354.
locally advanced disease. A typical dosage sched- Kaufman DS, Shipley WU, Feldman AS. Bladder cancer.
Lancet. 2009;374:239–249.
ule is 21 Gy in three fractions over a week. Damber JE, Aus G. Prostate cancer. Lancet. 2008;371:
1710–1721.
Management of the lymph nodes Horwich A, Shipley J, Huddart R. Testicular germ-cell
Inguinal lymphadenectomy should be considered cancer. Lancet. 2006;4;367:754–765.
for patients with enlarged or involved nodes. Pliarchopoulou K, Pectasides D. Late complications of
There is controversy over the need for bilateral chemotherapy in testicular cancer. Cancer Treat Rev.
2010;36:262–267.
dissection, but prophylactic contralateral dissec- Pagliaro LC, Crook J. Multimodality therapy in penile
tion is appropriate if one side is heavily involved. cancer: when and which treatments? World J Urol.
Prophylactic lymph node dissection in patients 2009;27:221–225.
196
Cancers of the female
genital system
C Parkinson, TV Ajithkumar and HM Hatcher
13
Epithelial ovarian cancer lium lining the fallopian tube and 70–80%
respond to first line chemotherapy.
Introduction • Clear cell carcinomas (10%) resemble ‘clear
cells’ of renal cell carcinoma and they have
Epithelial ovarian cancer (EOC) is the sixth most higher rate of recurrence, with a 20–30%
common cancer in women. There are 6,800 new response to first line chemotherapy.
patients per year in the UK and 25,600 per year • Endometrioid tumours (10%) contain cells
in the USA. The median age at diagnosis is 61. resembling the endometrium and 70–80%
Aetiology respond to first line chemotherapy.
• Mucinous tumours (5%) resemble the
Age and family history are the most important
endocervical epithelium. Mucinous tumours
risk factors for ovarian cancer. Other risk factors
are less chemosensitive to carboplatin and
which have been identified are nulliparity, history
paclitaxel than other histiotypes.
of infertility, hormone replacement treatment
• Mixed carcinomas (5%) have two or more
(HRT), early menarche and late menopause, high
histologic histiotypes comprising at least 10%
body mass index (BMI), and endometriosis. Pro-
of the tumour mass.
tective factors include multiparity, oral contra-
ceptive use and tubal ligation. Within each histiotype, tumours may be
Approximately 5–10% of ovarian cancer are classed as benign, malignant, or of low malignant
familial, most of which are associated with potential (borderline). Low malignant potential
BRCA1/BRCA2 gene mutations (90%) (p. 48). tumours are composed of atypical epithelial pro-
Women with a BRCA1 mutation have a 40% liferation without stromal invasion. They present
lifetime risk of ovarian cancer, and those with early and have a low likelihood of recurrence,
BRCA2 have an 18% lifetime risk. Women with and are therefore treated with surgery alone.
HNPCC have a 10% lifetime risk of ovarian Primary peritoneal carcinoma or papillary
cancer. serous carcinoma of the peritoneum is histo­
logically indistinguishable from papillary serous
Pathogenesis and pathology ovarian cancer. Primary peritoneal carcinoma is
Most EOCs are high grade (G2/3) serous carci- treated identically to serous papillary ovarian
noma (70%) (HGS). p53 mutation is almost uni- cancer and has similar response rates to
versal (97%) in HGS. Downregulation (rather chemotherapy.
than mutation) of BRCA1 is also thought to be
important in the aetiology of non-heriditary Pattern of spread
HGS. The following are the different types of
The most common pattern of spread is perito-
EOCs:
neal. Lymphatic dissemination to the pelvic and
• Papillary serous tumors (70%) have an para-aortic nodes occurs in advanced disease.
appearance resembling the glandular epithe- Spread through the diaphragm can lead to pleural

© 2011, Elsevier Ltd 197

DOI: 10.1016/B978-0-7234-3458-0.00018-X
 II SITE-SPECIFIC CANCER MANAGEMENT

effusion, although some effusions may be reac- Box 13.1: Risk of malignancy index (RMI)
tive. Haematogenous spread to the liver or lung
Feature RMI score
is unusual (2–3%).
Ultrasound features: 0 = none
multilocular cyst 1 = one abnormality
Presentation solid areas 3 = two or more
Overall 95% of patients diagnosed with ovarian bilateral lesions abnormalities
cancer are symptomatic. The most common ascites
intra-abdominal metastases
symptoms are abdominal distension (61%), Premenopausal 1
abdominal bloating (57%) or pain (36%), indi- Postmenopausal 3
gestion (31%), pelvic pain (26%), constipation CA-125 U/ml
(24%) and urinary incontinence (24%), back
RMI score = ultrasound score × menopausal score × CA-125 level
pain (23%) and dyspareunia (17%). Half of in U/ml.
patients experience constitutional symptoms
(anorexia, weight loss or nausea). The median
duration of symptoms is 3–6 months. CA19-9 (p. 287). The immunohistochemical
Signs profile of an ovarian tumour is typically CK 7
positive and CK 20 negative. A serum CA125:CEA
Physical findings are rare in patients with early ratio >25 is strongly suggestive of an ovarian
disease. Patients with advanced disease may rather than a GI primary.
present with abdominal distension (ascites or
tumour), cachexia, bilateral swollen legs (low Tissue diagnosis
albumin, or large pelvic masses) signs of pleural Patients in whom neo-adjuvant chemotherapy is
effusion which is more often right sided, and indicated should have a tissue diagnosis prior to
pelvic or abdominal mass. surgery, usually by ultrasound or CT guided
biopsy.
Investigations and staging
All patients with suspected ovarian cancer should Preoperative investigations
have estimation of serum CA-125 and ultrasound In addition to imaging and tumour markers,
scan of the abdomen +/− transvaginal ultrasound patients should have full blood count and bio-
scan. The CA-125 is raised in 50% of patients with chemistry for renal and hepatic function. Patients
stage I disease, and in 90% of stage II–IV. Muci- who may require bowel surgery should be
nous tumours often have a normal CA-125. Raised referred to the stoma team for discussion
CA-125 is not specific to ovarian cancer. Young pre-operatively.
patients should also have estimation of germ cell
Staging
tumour markers (AFP, betaHCG, and LDH).
The risk of malignancy index (RMI) scoring The International Federation of Gynaecology
system is used to predict whether a pelvic mass is and Obstetrics (FIGO) staging is shown in Box
malignant (Box 13.1). Women with an RMI of 13.2.
>200 should be referred to a specialist centre for
Management (Figure 13.2)
further management and surgery. An RMI of >200
has a positive predictive value of 87% and a sen- Primary surgery
sitivity of 88% for diagnosing malignant disease. Surgery involves total abdominal hysterectomy
To assess operability patients should have a (TAH), bilateral salpingo-oophorectomy (BSO),
CT of the abdomen and pelvis (Figure 13.1), and infra-colic omentectomy, peritoneal washings,
a CXR. In patients with a pleural effusion, cyto- biopsy of any lesions or adhesions, blind perito-
logical diagnosis is required to determine if the neal biopsies of the bladder, cul de sac, paracolic
effusion is malignant. gutter, hemidiaphragm and pelvic sidewall and
Patients with ascites without a mass on CT, pelvic and para-aortic node sampling. Surgical
should have cytological and immunohistochemi- staging is important to guide treatment with
cal analysis, in addition to CA-125, CEA and chemotherapy and estimate prognosis.
198
 CANCERS OF THE FEMALE GENITAL SYSTEM 13

A B

Figure 13.1
A&B, CT scan in ovarian cancer. Contrast enhanced CT in a patient with advanced ovarian cancer demonstrates
bilateral solid (black arrows) and cystic (white arrows) adnexal masses and omental cake (white arrow heads).
Courtesy of Dr. E Sala, University of Cambridge.

Box 13.2: FIGO staging of ovarian cancer

Stage I – limited to one or both ovaries
IA – involves one ovary; capsule intact; no tumour on ovarian surface; no malignant cells in ascites or peritoneal
washings
IB – involves both ovaries; capsule intact; no tumour on ovarian surface; negative washings
IC – tumour limited to ovaries with any of the following: capsule ruptured, tumour on ovarian surface, positive
washings
Stage II – pelvic extension or implants
IIA – extension or implants onto uterus or fallopian tube; negative washings
IIB – extension or implants onto other pelvic structures; negative washings
IIC – pelvic extension or implants with positive peritoneal washings
Stage III – microscopic peritoneal implants outside of the pelvis; or limited to the pelvis with extension to the
small bowel or omentum
IIIA – microscopic peritoneal metastases beyond pelvis
IIIB – macroscopic peritoneal metastases beyond pelvis less than 2 cm in size
IIIC – peritoneal metastases beyond pelvis >2 cm or lymph node metastases including para-aortic nodes
Stage IV – distant metastases to the liver or outside the peritoneal cavity

Early stage disease (stage I and II) improves survival. Patients with mucinous
Surgery tumours should have an appendicectomy, as this
Initial management in early stage disease is may be the site of the primary.
maximal cytoreductive surgery and surgical
staging. Around one-third of patients with appar- Fertility preserving surgery
ent stage I–IIA disease will have a higher stage In younger patients with stage IA tumours
of disease after full staging, mostly stage III and favourable histology, unilateral salpingo-
(77%). The frequency of lymph node involve- oophorectomy and staging may be carried out,
ment for apparent stage I disease is 20%. There although data on fertility preserving surgery is
is no evidence that total lymphadenectomy limited. Endometrial biopsy should be carried
199
 II SITE-SPECIFIC CANCER MANAGEMENT

Suspected ovarian cancer based on

symptoms and clinical examination

• CA-125
• Transvaginal and/
or abdominal U/S

Pelvic mass Evidence of metastatic

spread on U/S

RMI <200 RMI >200

Advanced stage (III or IV)

Surgery at Refer to specialist CT abdomen and pelvis

local centre centre for surgery

Optimal Optimal debulking

Surgery with debulking not possible
full staging possible (technical or patient
not fit)

Early stage Advanced stage Debulking Biopsy

ovarian cancer (> stage IIa) surgery
(stage I or IIa) Neo-adjuvant
chemotherapy

Stage IAG1, 1BG1 Stage Ia Stage Ia G3, Ib G3, carbo-taxol x3

low risk early stage G2, stage 1b G2 stage Ic, IIa (or carboplatin)
fully staged (or incompletely
staged low risk)
Response No response

Interval Palliative
debulking chemotherapy
surgery or best
supportive
care or trial

No chemo Consider platinum carboplatin carboplatin carboplatin

based chemotherapy and taxol x6 and taxol x6 and taxol x3
(carboplatin x6) (or carboplatin) (or carboplatin)

Figure 13.2
Management of ovarian cancer.

out as a synchronous primary is present in 10% Chemotherapy

of patients. Wedge biopsy of the contralateral For patients with stage IA/B G1 non-clear cell
ovary should only be taken if it appears abnor- cancer (low risk) 5-year disease free survival is
mal, as the probability of involvement of a mac- >90% without chemotherapy if optimal surgery
roscopically normal ovary is low (2.5%). has been performed. For patients with high risk
200
 CANCERS OF THE FEMALE GENITAL SYSTEM 13

Box 13.3: Chemotherapy regimes in Box 13.4: Thrombosis in ovarian cancer

ovarian cancer
Patients with ovarian cancer have a relatively high
First line and platinum sensitive relapse risk of venous thromboembolism. Approximately
• Carboplatin 5% of ovarian cancer will have either a DVT or PE
AUC 5–7 IV; Cycle duration 3 weeks within in the first 2 years after diagnosis, with 30%
of these occurring within the first 3 months. Rates
• Carboplatin + paclitaxel of thrombosis are highest in those with metastatic
Carboplatin AUC 5/6 IV and paclitaxel 175 mg/ disease, medical co-morbidities and clear cell
m2 IV histology. Management is with low molecular weight
Cycle duration 3 weeks heparin. Vena-caval filters may be considered prior
to surgery to prevent pulmonary emboli if the clot
Second and subsequent lines & platinum resistant extends proximally, is non-resolving, or if the patient
relapse develops further emboli despite optimal
• Caelyx anticoagulation.
40 mg/m2 every 3–4 weeks
• Topotecan
1.5 mg/m2 D1–5 every 4 weeks Box 13.5: Stage-wise survival according to
• Weekly paclitaxel surgical cytoreduction at primary surgery
80 mg/m2 IV Median Median
5-year 5-year PFS OS
DFS OS (months) (months)
Microscopic 30% 50–60% 29 68
features (G3, clear cell, stage IIA disease), 5-year residual
recurrence rates are 25–40% and adjuvant chem- <1 cm 10% 30–35% 16 40
otherapy is recommended. In these patients, residual
>1 cm 5% 20–25% 13 33
chemotherapy improves 5-year disease free sur-
vival (DFS) by 11% (from 65% to 76%), and
5-year overall survival (OS) by 8% (75% to
82%). Chemotherapy with 6 cycles of carbo­ Meta-analyses suggest that patients with stage
platin and paclitaxel is recommended, although IV disease obtain a survival benefit after optimal
6 cycles of carboplatin is also acceptable (Box debulking surgery. Even in patients with liver
13.3). For stage I G2 tumours the role of chemo- metastases, studies indicate an improved survival
therapy is not clear but 6 cycles of carboplatin for those in whom optimal extra-hepatic cytore-
may be offered. duction is achieved (27 vs. 8 months). However,
more extensive surgery such as hepatic metasta-
Advanced stage disease (stage III and IV) tectomies does not appear to improve the sur-
Patients with advanced disease may develop vival of patients. Patients with chemotherapy
medical complications as a result of their cancer, resistant disease have a poor prognosis, even if
notably thrombosis which has consequences for optimal extra-hepatic cytoreduction is achieved.
further management (Box 13.4).
Assessment of operability
Surgery Surgery is the primary treatment of choice where
The extent of cytoreductive surgery is the most a complete debulking is considered possible.
important prognostic factor after stage. The aim Patients with bulky disease or a poor perform-
of surgery is to achieve a complete macroscopic ance status (25%) are treated with neo-adjuvant
debulking, or failing this, an ‘optimal debulking’. chemotherapy then reassessed for interval debulk-
The definition of ‘optimal debulking’ is visible ing surgery (IDS). Surgery should only be
residual tumour of <1 cm. Studies have shown attempted where optimal debulking is possible.
that patients with residual >2 cm show no In general, debulking is less likely to be successful
improvement in survival over patients without in patients with bulky upper abdominal disease
debulking, and are considered incurable. Out- or fixed tumour. Even if debulking surgery is not
comes according to cytoreductive surgery are possible, palliative bowel surgery may be appro-
shown in Box 13.5. However, even after a com- priate to relieve impending or actual bowel
plete response 25–50% will recur later. obstruction.
201
 II SITE-SPECIFIC CANCER MANAGEMENT

Neoadjuvant chemotherapy
A randomized trial (EORTC 55971) has shown Table 13.1: Prognosis of ovarian cancer
that neo-adjuvant chemotherapy has equivalent FIGO 5-year survival 5-year disease-free
efficacy with lower morbidity than primary stage (%) survival
debulking surgery in patients with stage bulky III/ I 80–90 70–85
IV disease. Neo-adjuvant chemotherapy usually II 65–80 55–65
comprises 3 cycles of carboplatin and paclitaxel IIIa 50 45
(or carboplatin alone) followed by interval
IIIb 40 25
debulking surgery for patients responding to
chemotherapy, then a further three cycles of adju- IIIc 30 20
vant carboplatin and paclitaxel. Approximately IV 15 10
10% of patients will progress on chemotherapy
(platinum refractory) and the prognosis for these
patients is poor and not improved by surgery. For
this group further treatment is with a change of
chemotherapy or best supportive care. Prognosis
Adjuvant chemotherapy Prognosis according to stage is shown in Table
Adjuvant chemotherapy is aimed at improving 13.1. The most important prognostic variables
overall survival. There are no studies comparing after stage are in order; degree of differentiation,
best supportive care with chemotherapy. Meta- cyst rupture, substage of disease and age.
analyses suggest that adjuvant treatment with
Relapse
platinum compared with non-platinum mono-
therapy achieves a 30% relative risk reduction in Despite 70% of patients with advanced disease
mortality implying some benefit from platinum having a complete clinical response at the end of
based chemotherapy. Four phase III trials have surgery and chemotherapy (no detectable disease
investigated the benefit of adding taxanes to on CT scan and/or normal CA-125), 70% of
platinum. Two trials (GOG111 and OV10) these will relapse, with a median progression free
showed a mean survival benefit of 10–14 months survival from diagnosis of 16 months. The time
whist other two (ICON3 and GOG132) did not. from first relapse to death is now around 2 years.
A meta-analysis of the four trials demonstrates a There are no studies comparing best supportive
small survival advantage with the addition of care with chemotherapy in relapsed patients,
paclitaxel to platinum. Many expert consider the but the recent studies suggest that chemotherapy
combination of carboplatin and paclitaxel as the improves survival.
standard adjuvant chemotherapy. Presentation of relapse
The choice between single agent carboplatin
55–70% of patients present with an asympto-
and carboplatin with paclitaxel as first line treat-
matic rise in CA-125. The median time from this
ment should be made after discussion of the risks
to onset of symptoms is 3 months. 30–45% of
and benefits with the patient. Since platinum
patients present with symptoms, of whom 30%
exerts the major effect, and paclitaxel increases
relapse in the abdomen, 36% in the pelvis, 14%
toxicity, single agent carboplatin will be the
in abdomen and pelvis, and the remainder have
treatment of choice for patients with poor per-
distant metastases (frequently liver metastases).
formance status or co-morbidities.
Relapse may be defined by conventional
Intraperitoneal (IP) chemotherapy RECIST criteria (p. 44) or by the gynaecological
A number of studies have investigated intra­ cancer inter-group (GCIG) CA-125 criteria.
peritoneal chemotherapy. Although some have CA-125 relapse for those who had elevated pre-
shown a small improvement in PFS and OS treatment value which normalized after first line
(GOG-172), the toxicities were high (p. 38). In treatment (60% of all new patients) is defined as
the UK, IP chemotherapy is not currently offered ≥2× upper limit of normal on two occasions not
outside a clinical trial. less than 1 week apart. Patients in whom CA-125
202
 CANCERS OF THE FEMALE GENITAL SYSTEM 13
Figure 13.3
Relapsed epithelial ovarian cancer
Treatment of relapsed ovarian
cancer.
Platinum refractory/resistant Partially platinum-sensitive Platinum-sensitive

<6 months 6–12 months >12 months

• Caelyx • Carboplatin • Carboplatin and taxol

• Paclitaxel • Caelyx • Carboplatin
(if not had first line) • Carboplatin and taxol • (Gemcitabine +
• Topotecan carboplatin – see text)
• Trial entry
• Best supportive care

was elevated but never normalized (30% of all has been suggested that the response rate to plati-
new patients): relapse is defined as a CA-125 value num can be improved by ‘artificially’ extending
≥2× nadir value on two occasions. The definition the platinum free interval by using non-platinum
of relapse in patients with normal CA-125 prior agents, but this has not been proven.
to initial treatment (10% of all new patients) is
similar to that of patients with elevated CA-125 Platinum sensitive disease
which normalized after first line treatment. Patients with a PFI of >18 months show response
rates of 60–95% to second line therapy, with a
Treatment (Figure 13.3) median time to progression of 10–12 months.
Chemotherapy for relapsed disease is palliative Those with a PFI of 12–18 months show response
and aims to prevent or treat symptoms in order rates of 50–60%, and a time to progression of
to improve quality of life and possibly extend approximately 9 months. Patients with a PFI of
survival. In selected cases with a long disease 6–12 months show response rates of 25–35% to
free interval (exceeding 12 or 18 months) and platinum chemotherapy and a median time to
localized relapse, surgery may be an option and progression of <6 months.
long term disease free survival may be possible. ICON4 showed an improvement in response
The probability of response to re-treatment rate for carboplatin and paclitaxel compared
with platinum chemotherapy depends upon the with carboplatin alone (57% vs. 50%), progres-
interval between the completion of platinum- sion free survival (12 months vs. 9 months), and
based first line therapy to the time of relapse, 2-year survival (57% vs. 50%) and median sur-
known as the platinum free interval (PFI). A vival (29 vs. 24 months). In relapsed platinum
longer PFI is associated with a higher response sensitive disease, combination treatment is there-
rate, longer PFS and improved survival. fore recommended unless there is significant
Disease relapsing >6 months after platinum residual neuropathy. Gemcitabine and carbopla-
treatment is considered ‘platinum sensitive’, tin is sometimes used as combination therapy, as
however this group is subdivided into ‘relatively’ phase III trial results show similar improvements
platinum sensitive (PFI 6–12 months) and fully in response rates and progression free survival to
platinum sensitive (PFI >12 months). carboplatin and paclitaxel.
Although most of the data about the PFI and In patients with a PFI of 6–12 months, the
its relation to response is taken from first relapse benefits of combination chemotherapy are re­
studies, this finding has been extended to second duced. Single agent carboplatin is more com-
and subsequent relapses. Standard practice is monly offered in this group. An alternative that
continue re-treating with platinum (or platinum may be considered in this group is peglyated
combination) until the patient becomes platinum doxorubicin (caelyx), since response rates from
resistant, regardless of the line of treatment. It non-comparative phase III trials are similar.
203
 II SITE-SPECIFIC CANCER MANAGEMENT

Platinum resistant disease ribose) polymerase (PARP) is an enzyme involved

Approximately 25% of patients will progress in the repair of single strand DNA breaks. The
during, or within 6 months of completion of first involvement of the PARP pathway in ovarian
line treatment. These patients have a low prob- cancer was suggested by the relationship of
ability of response to any chemotherapy and BRCA positive patients who have an increased
should be considered for clinical trials if possible. incidence of ovarian cancer and a deficiency in
The response to platinum agents is <10%. The homologous repair. In addition 50% of sporadic
overall median time-to-progression (TTP) is 2–3 serous papillary ovarian cancers also have
months from starting second line treatment. The impaired PARP expression. PARP inhibitors
median OS from time of relapse is 8–10 months, have shown some benefit in the prevention of
and 2-year survival is 17–21%. further relapse when used in a maintenance
Caelyx, paclitaxel and topotecan are useful; all setting after response to chemotherapy.
with response rates are around 6–13%. Rates of
stable disease 28–43%, PFS is 2–3 months and Palliative care
OS is 8–10 months. Caelyx is most commonly The most common palliative symptoms in
chosen as the initial treatment because of its advanced ovarian cancer are ascites, pleural effu-
favourable toxicity profile. Paclitaxel tends to be sion and small bowel obstruction. Permanent
used only when patients have not received pacli- ascitic drains can be placed for those with fre-
taxel with 1st line therapy. Recently some centres quent recurrent ascites. The most debilitating
in the UK have used a weekly carboplatin and symptom is of small bowel obstruction which is
paclitaxel regime which has shown favourable frequently recurrent. Treatment of small bowel
response rates. However this regime awaits vali- obstruction consists of minimal oral intake and
dation in a prospective RCT. Other agents with symptomatic control with anti-emetics (haloperi-
activity are oral etoposide, gemcitabine, vinorel- dol or cyclizine), antispasmodics (e.g. buscopan)
bine, ifosfamide and tamoxifen. In this group of and steroids (dexamethasone) if not responding
patients there is no evidence that combination to the initial treatment. Pain relief should be added
treatment is superior to single agent. to the syringe driver (e.g. diamorphine). If there
is colicky abdominal pain metoclopramide should
Hormonal treatment be avoided as this will exacerbate the symptoms.
A proportion of ovarian cancers express the If secretions remain high, octreotide given via a
oestrogen receptor (ER) in a percentage of the separate syringe driver can be useful. Intravenous
tumour population. After the use of tamoxifen fluids should be given but the use of parenteral
and aromatase inhibitors in breast cancers, several nutrition should be reserved for patients with a
groups have used these agents in relapsed ER meaningful chance of treatment to remission, e.g.
positive ovarian cancers. Compared with breast with bowel obstruction at presentation or at first
cancer a lower proportion of tumour cells express relapse after a long disease free interval.
ER but the response to aromatase inhibitors has
been shown to reflect the percentage of ER posi- Follow-up
tivity. In a phase II study 17% had a response and Most (approximately 95%) recurrences will
26% had stable disease by CA-125 criteria when occur in the first 3 years and relapse after 5 years
letrozole was used in patients with significant ER is rare. Follow-up is directed at detecting local-
positivity in their tumour at the time of relapse. ized relapse which is potentially curable with
By RECIST criteria 9% had a PR and 42% surgery or radiotherapy, e.g. local vaginal vault
achieved stable disease. The responses were great- relapse. Follow-up should include clinical exami-
est amongst those with the highest ER scores. nation, CA-125 (if elevated at presentation) and
intermittent imaging if CA-125 was not informa-
Future directions tive or with symptoms. A typical follow-up would
Examples of agents under investigation include be 3-monthly for 2–3 years then 6-monthly up
anti-angiogenics such as VEGF inhibition with to 5 years. Patients with an informative CA-125
bevacizumab, and PARP inhibitors. Poly (ADP- can become very focused on their blood result at
204
 CANCERS OF THE FEMALE GENITAL SYSTEM 13
each appointment so a clear plan of action with • Type I (80%) – related to oestrogen stimula-
a raised CA-125 is recommended as there is no tion and associated with obesity, nulliparity,
evidence that treatment with an asymptomatic and insulin resistance. Median age at presen-
elevated CA-125 improves outcome. tation is 59 years. The precursor lesion of
endometrioid carcinoma is atypical hyperpla-
Endometrial cancer sia. These tumours are typically low grade
(grade 1/2) endometrioid tumours presenting
Introduction in early stage and express oestrogen (ER) and
Endometrial cancer is the fifth most common progesterone receptors (PR) in 92% of cases.
female cancer in developed countries. In the UK It has an overall survival of 80%.
6800 new patients are diagnosed every year. The • Type II (20%) – unrelated to oestrogen
incidence rises steeply to a peak at 64–74, with stimulation and often occur in elderly thin
75% of cases diagnosed in post-menopausal women. Median age at presentation is 68
women. In the UK, women have a lifetime risk years. These tend to be high grade tumours
of 0.9% of developing endometrial cancer. of non-endometrioid histology (including
Endometrial cancer is responsible for 2% of all serous, clear cell and high grade endome-
cancer deaths in women in the UK. Most cases trial), usually present at a later stage and have
are diagnosed at an early stage and overall 5-year a poorer prognosis, with recurrence in 50%
survival is 75%. of patients. Endometrial intraepithelial carci-
noma is proposed as a precursor of serous
Aetiology carcinomas which express ER in 31% of
Table 13.2 shows the risk factors for endometrial cases and PR in 12%. Clear cell carcinomas
cancer. Less than 5% of endometrial cancers are do not have a proven precursor lesion and
hereditary, and most of these arise in women rarely express ER or PR.
with hereditary non-polyposis coli (HNPCC) or Histologic types of endometrial malignancies
Lynch syndrome II (p. 51). are as follows:
Pathogenesis and pathology • Endometrioid carcinomas (75%) – usually
Generally there are two types (type I and II) of low-grade and confined to uterus.
endometrial cancer and the characteristics these • Uterine serous papillary carcinoma (UPSC –
differ. 5–10%) – high-grade, high-risk of metastasis
and often presents with extra-uterine disease.
• Clear cell carcinoma (1–5%) – high-grade and
Table 13.2: Risk factors for
endometrial cancer high-risk of metastasis.
Relative
• Mixed adenocarcinomas (5%) – usually com-
Risk factor risk posed of endometrioid and serous papillary
Increased age –
carcinoma.
• Mesenchymal tumours include stromal sarco-
Unopposed oestrogen 2–10
mas, leiomyosarcoma and other types of
Late menopause (after age 55) 2 sarcoma (p. 260, uterine sarcomas). Mixed
Nulliparity 2 non-epithelial tumours include carcinosarco-
Polycystic ovary syndrome 3 mas (previously termed malignant mixed
Müllerian tumours).
Obesity 2–4
Diabetes mellitus 2 Presentation
Hereditary non-polyposis colorectal 22 to 50% Abnormal vaginal bleeding is the usual presenta-
cancer lifetime risk tion. Other presentations include vaginal dis-
Tamoxifen 2/1000 charge, pain in advanced disease and symptoms
of metastatic disease. Less than 5% are diag-
nosed incidentally (abnormal smear test).
205
 II SITE-SPECIFIC CANCER MANAGEMENT

Diagnosis and staging • CT scan of abdomen and chest is indicated

Initial investigations for patients with high risk of distant metasta-
sis such as stages II–IV and histologic types of
• Trans-vaginal ultrasound scan (TVUSS) is the clear cell, UPSC, and carcinosarcomas.
initial investigation of choice. In the UK, • PET scan – is not sufficiently sensitive to
a threshold of 5 mm has been adopted to assess lymph node involvement (60–69%)
determine if it is required. Women with an and therefore at present has no role in the
endometrial thickness >5 mm (7–8% proba- staging of endometrial cancer.
bility of endometrial cancer) need further • Examination under anaesthesia (EUA) – when
investigation by hysteroscopy. locally advanced tumour is suspected follow-
• Endometrial sampling/hysteroscopy is useful ing clinical or radiological examination, EUA
in obtaining histologic confirmation. Pre- is indicated to determine operability.
menopausal women with significant men-
strual abnormality should be investigated Staging
by endometrial biopsy with or without The FIGO postoperative surgico-pathological
hysteroscopy. staging system is given in Box 13.6.
Further investigations
Prognostic factors
Once a diagnosis of endometrial cancer is made,
The most important prognostic factors are stage,
further investigations are indicated to stage and
age, depth of myometrial invasion >50%, grade
assess fitness for definitive treatment.
3, serous or clear cell histology and lymphovas-
• Blood – full blood count, biochemistry and cular invasion (LVI). Table 13.3 shows the 5-year
serum CA-125 (raised in extrauterine spread survival rate according to stage and grade.
especially in USPC). Endometrioid cancer presents more commonly
• Chest X-ray. with stage I and II (86%) than serous papillary
• Magnetic resonance imaging (MRI) (Figure (57%) or clear cell (70%). However, serous
13.4) – is the imaging of choice to assess the papillary and clear cell carcinomas have a poorer
depth of myometrial invasion, and lymph prognosis even after their stage at presentation is
node metastasis. taken into account (see Table 13.4).

E
E

A B

Figure 13.4
MRI in endometrial cancer. Sagittal T2-weighted (A) and sagittal dynamic contrast enhanced T1-weighted (B) images
in a patient with stage 1B endometrial carcinoma demonstrate a large endometrial tumour (E) which is invading the
outer myometrium (black arrows). The tumour is extending to the endocervix, but the cervical stroma (white arrows)
is intact. Courtesy of Dr. E Sala, University of Cambridge.
206
 CANCERS OF THE FEMALE GENITAL SYSTEM 13

Box 13.6: FIGO staging of endometrial cancer

Table 13.4: 5-year relative survival rates for
Stage I* Tumour confined to the corpus uteri endometrial carcinoma according to histology
(includes endocervical gland involvement)
5-year relative survival rate (%)
IA No or less than half myometrial invasion
IB Invasion equal to or more than half of the Stage Endometrioid Serous papillary Clear cell
myometrium I 98 74 88
Stage II Tumour invades cervical stroma, but does II 86 56 67
not extend beyond the uterus
III 67 33 48
Stage III Local and/or regional spread of the tumour
IIIA Tumour invades the serosa of the corpus uteri IV 37 18 18
and/or adnexae**
IIIB Vaginal and/or parametrial involvement**
IIIC Metastases to pelvic and/or para-aortic lymph
nodes**
IIIC1 Positive pelvic nodes I cancer. For grade 3 tumours, the risk of lymph
IIIC2 Positive para-aortic lymph nodes with or without node involvement is 15%, and for those with
positive pelvic lymph nodes
more than 2 3 invasion of the myometrium, the
Stage IV Tumour invades bladder and/or bowel
mucosa, and/or distant metastases
risk is approximately 25%. With both these
IVA Tumour invasion of bladder and/or bowel mucosa factors, there is a 34% risk of pelvic node involve-
IVB Distant metastases, including intra-abdominal ment, and a 24% risk of aortic node involve-
metastases and/or inguinal lymph nodes ment. North American practice is to perform
*Grade 1–3.
routine bilateral pelvic lymph node dissection
**Positive cytology does not change stage, but reported separately. (BPLND) with or without para-aortic lymph­
adenectomy but there is no clear evidence that
lymph­adenectomy improves survival. The initial
results of the ASTEC trial comparing pelvic
lymphadenectomy with no lymphadenectomy in
Table 13.3: 5-year survival rate by stage mostly stage I disease showed similar survival
and grade and progression free survival with both approach
Stage Stage Stage and hence the UK practice is to perform lymph
1A 1B 1C II III IV
node sampling of clinically suspicious nodes
Grade 1 99 99 99 93 83 60 only. The rationale being patients with microme-
Grade 2 99 99 95 85 68 45 tastases will be identifiable as having a high risk
Grade 3 91 93 77 67 48 17 of locoregional relapse and these patients can
be stratified to receive radiotherapy. Some UK
centres perform lymphadenectomy in stage I
patients with a high risk of locoregional relapse,
and omitting External beam radiotherapy (EBRT)
Treatment (Figure 13.5) to those with uninvolved nodes.
Stage I disease Staging lymphadenectomy is useful for better
risk stratification of stage I patients with high-
Surgery
risk disease and significant co-morbidity, e.g.
Total abdominal hysterectomy with bilateral
inflammatory bowel disease which would
salpingo-oophorectomy (TAH-BSO) and perito-
increase the risk of radiation related morbidity.
neal washings for cytology is the treatment of
choice. Vaginal hysterectomy (LAVH) can be Adjuvant radiotherapy (Box 13.7)
considered in some patients. Meta-analyses show that EBRT reduces loco­
Controversy exists over the role of staging regional recurrence in stage I endometrial cancer
lymphadenectomy for stage I endometrial cancer. by 72% but does not have any benefit on sur-
Grade and myometrial invasion are important vival. Three quarters of locoregional recurrences
determinants of lymph node involvement in stage are restricted to the vagina, and most of these are
207
 II SITE-SPECIFIC CANCER MANAGEMENT

Stage II
Stage I

CXR, MRI CXR, MRI, CT

G1 or G2 G3 serous papillary Fit Less fit

stage 1A or clear cell
or 1B

Manage in unit Manage in a centre

Hysterectomy, Hysterectomy, Simple Radical Simple Radical EBRT

BSO, washings BSO, washings, hysterectomy, hysterectomy + OR hysterectomy, + BT
OR
biopsy suspicious BSO, washings, BPLND BSO
nodes BPLND

Low or High risk Nodes Nodes Nodes Nodes +ve

intermediate –ve +ve –ve or positive
risk margins

No further EBRT +/– BT BT for EBRT +/– No further EBRT +/– BT EBRT +/– BT
adjuvant higher risk cases BT treatment
treatment follow
up in unit
Stage III and IV

CXR, MRI, CT CXR, MRI, CT

Operable: Unsure if operable- Inoperable:

• Complete macroscopic laparoscopy assessment • Complete macroscopic
resection possible resection not possible
AND OR
• Fit • Unfit

Hysterectomy and BSO EBRT and BT then Stage III locally • Palliative hormones
and cytoreduction reassess advanced disease • Palliative chemotherapy
and lymphadenectomy • Palliative RT for symptom
(if involved) control
• Palliative surgery for symptom
control e.g. hysterectomy for
Optimal debulking bleeding pain

Adjuvant RT Adjuvant
chemotherapy if fit

Figure 13.5
Management of endometrial cancer.

208
 CANCERS OF THE FEMALE GENITAL SYSTEM 13

Box 13.7: Radiotherapy for endometrial cancer

associated with a diagnosis and treatment of a
relapse. A general consensus is that radiotherapy
Indications
• Primary radical radiotherapy (unfit for surgery) is considered only if the risk of relapse is >15%
• Postoperative (see Box 13.8). Role of adjuvant radiotherapy in
• Vaginal brachytherapy (BT) alone patients with intermediate risk remains contro-
– Stage IB G2 versial. In this group, PORTEC-1 identified a
• External beam radiotherapy (EBRT) and vaginal subgroup of patients (those aged more than
brachytherapy 60 years with 1C or G3 disease) who have an
– Stage I disease – IC/G3/clear cell/UPSC 18% risk of locoregional relapse. The GOG 33
– Stage II and above study identified lymphovascular invasion (LVI)
Technique as a significant poor prognostic factor for loco-
Conventional planning regional relapse (HR = 2.4, p = 0.005) Most
• Superior border: L5/S1 centres in the UK include LVI as a high risk
• Inferior border: lower edge of obturator foramen factor, and would offer patients adjuvant EBRT
• Lateral borders: 1 cm beyond pelvic brim +/− brachytherapy to patients with 1C or G3
• Anterior: mid-symphysis pubis disease if they were either >60 or had LVI, some-
• Posterior: 2.5–3 cm anterior to sacral hollow times described as high-intermediate risk. Early
CT planning results of PORTEC-2 trial suggest that vaginal
• CTV – vaginal vault and 7 mm margin around the brachytherapy (BT) alone may be sufficient for
contrast enhancing blood vessels for nodal regions
• PTV – 10–15 mm around vaginal vault, 7 mm
this group of patients.
around lymph node CTV (10–15 mm for A recent meta-analysis found a 10% statisti-
macroscopic disease) and 7 mm around cally significant difference in disease free survival
parametrium for high risk patients treated with EBRT vs. no
Dose treatment (80% vs. 69%). Hence all patients
External beam radiotherapy: 45 Gy in 25 fractions with 1CG3 disease should be offered adjuvant
Vaginal brachytherapy EBRT +/− vaginal brachytherapy.
Single modality In the UK, most patients will not have had a
HDR 21 Gy in 3 fractions to 0.5 cm from the
applicator surface staging lymphadenectomy. For those with nega-
With EBRT
tive nodes but high risk disease the role of radio-
HDR 7 Gy single fraction to 0.5 cm from the therapy is uncertain. Many would treat patients
applicator surface with 1CG3 disease and >50% myometrial inva-
LDR 15 Gy to 0.5 cm sion with BT, while some would treat with EBRT
Side effects +/− BT.
EBRT
• Bowel symptoms (22%) – abdominal cramps, Adjuvant chemotherapy
urgency and frequency of stool, and diarrhoea
The high risk of distant relapse for patients
• Bladder toxicity: reduced capacity, urgency,
recurrent infections and minor incontinence
with 1CG3 disease suggests a possible role of
• Vaginal narrowing (4%) adjuvant chemotherapy but the evidence is not
• Bone toxicity (1%) clear. The incidence of distant metastases is
reduced in women receiving chemotherapy
Brachytherapy
Temporary diarrhoea and urinary irritation (9%
compared with pelvic radiotherapy but chemo-
each), transient vaginal mucositis (17%), vaginal cuff therapy does not prevent pelvic recurrence. The
telangiectasia (14%), vaginal atrophy, stricture or ongoing PORTEC-3 study randomizes between
adhesions (16%), and dyspareunia (5%).
pelvic radiotherapy or pelvic radiotherapy with
concurrent cisplatin followed by carboplatin/
curable with vaginal radiotherapy. However, it paclitaxel chemotherapy.
is important to define the risk of loco-regional
recurrence to choose patients for adjuvant pelvic Stage II
radiotherapy is to prevent uncontrolled pelvic For patients with cervical involvement (clinically
disease and to prevent stress and morbidity or on MRI prior to surgery), a modified radical
209
 II SITE-SPECIFIC CANCER MANAGEMENT

Box 13.8: Risk of locoregional relapse

Stage 1A Stage 1B Stage 1C

Grade 1 Low Low Intermed
Age >60
Grade 2 Low Low Intermed OR LVI
Grade 3 Intermed Intermed High Intermed High

Risk of locoregional
relapse
Serous papillary or High
Low <5%
clear cell
Intermediate 5–15%
High >15%

hysterectomy with bilateral lymph node dissec- retrospective studies suggest that optimal tumour
tion is indicated. This involves resection of a cytoreduction may improve survival. The defini-
parametrial and paracervical tissue, and a cuff of tion of optimal cytoreduction varies in different
2 cm of upper vagina. Evidence show that radical studies from no macroscopic disease to <2 cm.
hysterectomy results in an improved survival in One study found a 5-year survival of 41% in
stage II patients compared to standard hyster­ patients with stage III disease had a complete
ectomy (93% vs. 89% at 5 years). For patients resection of macroscopic tumour compared with
with adequate tumour free margins and negative 16% for those without. In cases of suspicious
nodes there is no evidence that the addition of operability, a diagnostic laparoscopy should be
radiotherapy improved survival. Those with pos- carried out. In patients with borderline operabil-
itive margins or involved nodes should receive ity, primary radiotherapy may be used to improve
adjuvant EBRT and BT. chances of subsequent surgery.
For some patients, endocervical stromal Most stage IV tumours will not be considered
involvement (stage II) will have been an inciden- operable. However, in a subgroup of stage IV
tal finding following simple hysterectomy for patients where complete resection is feasible, a
presumed stage I. These patients would normally 25% long-term survival can be achieved.
receive adjuvant EBRT and BT. In practice, many Palliative hysterectomy is useful in controlling
patients are not fit enough for modified radical local symptoms such as bleeding or pain. Occa-
hysterectomy and these patients are treated with sionally bowel or urinary diversion may be
standard hysterectomy with adjuvant EBRT appropriate, although radiotherapy and/or plati-
and BT. There is no proven role for adjuvant num based chemotherapy may also offer useful
chemotherapy for stage II disease yet. palliation.
Stage III–IV Radiotherapy (Box 13.7)
The optimal management of patients with Postoperative EBRT and BT should be carried
advanced stage endometrial cancer is not well out for patients with a complete macroscopic
defined. Advanced stage endometrial cancers are resection of stage III disease. Patients with stage
a heterogeneous group and treatment needs to be IIIC disease involving the para-aortic or pelvic
individualized. nodes may have extended field radiotherapy
covering the para-aortic region. The likelihood
Surgery of local control is related to disease volume.
Primary surgery should be considered for all fit Although radiotherapy reduces the local recur-
patients with stage III disease in whom an optimal rence rates, there are no data showing improved
cytoreduction appears to be feasible. Several survival.
210
 CANCERS OF THE FEMALE GENITAL SYSTEM 13

Box 13.9: Chemotherapy regimes in

There is limited information available on quality
endometrial cancer of life or survival data.
• Carboplatin (AUC 5–7) IV d1 repeated 3-weekly The median overall survival for patients with
• Paclitaxel (Taxol) 175 mg/m2 IV repeated 3-weekly metastatic endometrial cancer following chemo-
• Doxorubicin (Adriamycin) 60 mg/m2 IV for 7 therapy is 6–12 months. The time to progression
cycles + cisplatin (CDDP) 50 mg/m2 IV repeated is generally 4–6 months. The most active single
3-weekly agents in advanced or recurrent endometrial
• Carboplatin (AUC 5–7) IV d1 + paclitaxel 175 mg/ cancer are anthracyclines, platinum and paclit-
m2 IV d1 repeated 3-weekly
axel which have similar response rates of 20–
35%. The most commonly used combination
regimes are carboplatin and paclitaxel and (60–
Patients with optimal debulking should also be 70% response from phase II studies), and cispla-
considered for adjuvant chemotherapy based on tin and Adriamycin (34% response).
the results of GOG 122 (see below) followed by
radiotherapy for those with a complete clinical Hormonal therapy
response. It is particularly useful for patients with slowly
For patients with inoperable stage III and IV progressing or asymptomatic disease, and for
disease, palliative radiotherapy is an option for those unfit for chemotherapy.
local and distant symptom control. Progestogen
Chemotherapy for Stage III–IV (Box 13.9) Oral progestogen treatment has a response rate of
Adjuvant chemotherapy 15–20%. The median duration of response is four
Adjuvant chemotherapy should be offered to months, and survival is approximately 8 to 11
patients with stage III/IV who have had a com- months. Patients with low-grade histology (37%
plete debulking, and may be considered for those response for G1 compared with 9% for G3),
with residual tumour <2 cm based on the GOG expression of oestrogen (ER) (29% response) and/
122 trial. This phase III trial randomized patients or progesterone receptors (PR) (39% response)
with stage III/IV endometrial cancer, with less and a long treatment-free interval between initial
than 2 cm of residual disease (87% with no mac- diagnosis and recurrence have the highest prob-
roscopic disease) to whole abdominal radiation ability of responding. Megestrol acetate is usually
or doxorubicin and cisplatin chemotherapy. given initially at 160 mg daily. Medroxyproges-
Chemotherapy significantly improved progres- terone acetate 200–400 mg daily is an alternative.
sion-free and overall survival compared with Side effects include weight gain and increased risk
WAI. Progression free survival at 5 – years was of thrombosis. There is no known benefit from
50% for those in the chemotherapy arm com- using progestogens for adjuvant treatment.
pared with 38% in the radiotherapy arm, and OS Tamoxifen
survival was 55% compared with 42% respec- Tamoxifen has an overall response rate of 10%
tively (p < 0.01). Other studies have reported and is not generally used as a single agent.
higher pelvic failure rate (40%) in patients with
high-risk endometrial cancer treated with adju- Gonadotrophin-releasing hormone (GnRH) analogues
vant chemotherapy alone. Hence current practice GnRH analogues may provide benefit in pro-
is to offer adjuvant pelvic radiotherapy in addi- gestogen-refractory advanced or metastatic
tion to chemotherapy. disease. The response rate is up to 28%. Complete
and partial responses to treatment are seen with
Palliative chemotherapy monthly injections of goserelin acetate 3.6 mg
Patients with unresectable disease may be treated giving a progression free-survival of several
with palliative chemotherapy or hormonal treat- months.
ment. Generally patients with rapidly progressive
or symptomatic disease are treated with chemo- Aromatase inhibitors
therapy, while those with slowly progressing or Reported response rates are approximately
asymptomatic disease are treated with hormones. 10%. One phase II study reported a disease
211
 II SITE-SPECIFIC CANCER MANAGEMENT

stabilization rate of 39% for a median of 6.7 that surgery alone is inadequate. Hence, all
months with 2.5 mg letrozole in patients with women with resected stage IB, IC, and II USPC
metastatic or recurrent endometrial cancer. or clear cell cancers may be offered platinum
based chemotherapy (usually with carboplatin
Recurrent disease
and taxol) with postoperative radiotherapy
Approximately two-thirds of relapses will either (EBRT+VBT, VBT or EBRT alone) in those with
be distant, or locoregional and distant. However a complete clinical response. Most centres would
the other third will be a pelvic recurrence, of also offer adjuvant chemotherapy and radiother-
which 75% will be the upper vagina, or ‘vaginal apy for stage IA serous papillary carcinoma in
vault’. which there was any residual disease at hysterec-
For patients with a vault recurrence who have tomy following biopsy. Some centres consider
not previously received radiotherapy, radical radi- whole abdominal radiation for UPSC because of
otherapy is the treatment of choice (Box 13.8). the high rate of abdominal relapse, though the
Those patients who had previously received only benefit has not been established.
BT can have EBRT with a boost if tumour is Surgery and chemotherapy for stage III and IV
<0.5 cm. In the PORTEC-1 study 75% of patients UPSC and clear cell carcinoma is as for ovarian
with pelvic recurrence could be treated with cura- cancer. Radiotherapy is offered to those who
tive intent and 85% achieved complete remission. have had a complete clinical response.
The survival rate after relapse was 69% at 3 years
in the control group compared with 13% in Synchronous cancers
patients who had received EBRT up-front. Synchronous primary cancers of the ovary are
In single recurrence at the vaginal vault, or found in 5% of patients with endometrial cancer.
localized pelvic disease not extending to the side- Management is the combined treatment for each
wall after previous pelvic radiotherapy, surgery separate cancer. Metastatic disease should be
may offer a chance of cure. If the bladder and considered where the disease on the ovary is
bowels are involved, then a large exenterative small volume, surface deposits, bilateral with
procedure may be required for complete resec- multinodular implants and with lymphovascular
tion. The surgical morbidity of exenteration is invasion of the ovarian cortex.
significant and is suitable only for selected
patients, after metastatic disease has been care- Follow-up
fully ruled out. Reported 5-year survival is up to There is no evidence for best follow-up. The
of 50% with a complete cytoreduction. majority of recurrences (80%) occur in the first
Patients not suitable for salvage surgery or 18 months to two years. A typical follow up
radiotherapy may be treated with systemic schedule would be outpatient appointments
therapy. three-monthly for two years, followed by six-
monthly to 5-years with full history and physical
Special situations examination (including pelvic) examination.
Serous papillary and clear cell carcinoma
Patterns of spread for uterine serous papillary Cervical cancer
carcinoma (USPC) are similar to epithelial
ovarian carcinoma and 50% of recurrences occur Introduction and aetiology
in the abdomen alone. Clear cell carcinoma Cervical cancer affects 520,000 women each year
relapses occur more commonly in the pelvis and worldwide. In the UK around 2900 women are
para-aortic nodes and less commonly in the diagnosed with cervical cancer per year which
abdomen than UPSC. represents 2% of female cancer. It is the second
The principles of surgery for both these most common cancer in women under 35 (after
tumours parallel those for ovarian cancer (p. breast cancer). In the UK, the life time risk of
198). Optimal therapy of early-stage papillary developing risk of cervical cancer is 1 in 116.
serous and clear cell carcinomas remains unde- There are a number of risk factors implicated
fined. However the high relapse rates indicate in the development of cervical cancer such as
212
 CANCERS OF THE FEMALE GENITAL SYSTEM 13
sexual activity under the age of 20, smoking, oedema, and hydronephrosis is associated with
immunosuppression, and infection with sexually extensive pelvic wall involvement. Patients with
transmitted diseases. Human papilloma virus advanced disease may present with haematuria or
(HPV) has emerged as the principal causative symptoms of a vesicovaginal fistula. Cachexia,
agent in the majority of cases of cervical cancer. cough, jaundice, and a left supraclavicular nodal
The most frequent subtypes are 16 or 18. mass may occur with distant metastases.
Pathogenesis and pathology Evaluation and staging
Most cervical carcinomas arise at the squamo- Pretreatment evaluation
columnar junction of the ectocervix and endocer- • Examination under anaesthesia (EUA).
vix. There is a progression from dysplastic lesions • FBC, and biochemistry to exclude anaemia
to invasive carcinoma. Dysplastic lesions undergo and renal impairment.
spontaneous regression in 25–38%, persist in • Biopsy for histological diagnosis.
50–60% and progress to invasive cancers in • Chest X-ray.
2–14%. • MRI pelvis (Figure 13.6) is useful in assessing
Squamous cell and adenocarcinomas account tumour extent and nodal status.
for 90–95% of the cervical cancers. Other histo- • Cystoscopy/sigmoidoscopy/barium enema/
logic types are shown in Box 13.10. IVU – if there is clinical suspicion of bladder,
Patterns of spread rectal or ureteric involvement.
• PET/CT has a role in accurate selection of
From the cervix, the tumour may extend locally patients for surgery as well as for treatment
to the lower uterine segment, vagina, or into the planning.
paracervical spaces. It may become fixed to the • CT scan chest, abdomen and pelvis are indi-
pelvic wall by direct extension or due to regional cated in patient with clinically apparent stage
adenopathy. IV disease.
Cervical cancer follows a pattern of metastatic
progression, initially to nodes in the pelvis and Staging
then para aortic nodes and distant sites. The The FIGO staging is given in Table 13.5 which
most frequent sites of distant recurrence are lung, does not take into consideration the findings on
extra pelvic nodes, liver, and bone. imaging.
Presentation Management (Figure 13.7)
Early invasive disease may be asymptomatic. The Choice of treatment is based on tumour size,
earliest symptom of invasive cervical cancer is stage, histology, evidence of lymph node involve-
usually abnormal vaginal bleeding, often post- ment, risk factors for complications of surgery or
coital. Pelvic pain may result from loco-regionally radiotherapy, and patient preference.
invasive disease. The triad of sciatic pain, leg In situ disease (CIN III) can be treated by a
number of methods (such as cone biopsy, laser
therapy etc.) depending on the extent of disease,
age of the patient, and requirement for fertility
Box 13.10: Histopathologic subtypes of preservation.
cervical cancer
• Squamous carcinoma: keratinizing, non-
Stage IA disease
keratinizing and verrucous Stage IA1
• Endometrioid adenocarcinoma IA1 without lymphovascular invasion (LVI) the
• Clear cell adenocarcinoma treatment options are:
• Adenosquamous carcinoma
• Adenoid cystic carcinoma • Cone biopsy or large loop excision of the
• Small cell carcinoma transformation zone (LLETZ) if patient
• Undifferentiated carcinoma wishes to preserve fertility.
• Simple hysterectomy.
213
 II SITE-SPECIFIC CANCER MANAGEMENT

A B

Figure 13.6
MRI scan in cervical cancer. Sagittal (A)
and axial (B&C) T2-weighed MRI in a
patient with stage 2B squamous cervical
cancer demonstrate a large cervical
tumour (C) with bilateral parametrial
invasion (black arrows) and bilateral
enlarged external iliac lymph nodes (white
arrows). Note the presence of cystic/
necrotic changes within the right external
iliac node (white arrow head) which is a
common feature of squamous cell cervical
C cancer. Courtesy of Dr. E Sala, University of
Cambridge.

IA1 with LVI is managed with: • Radiotherapy – brachytherapy alone (75–

80 Gy equivalent to point A – Box 13.11) or
• Modified radical hysterectomy with pelvic
with external beam pelvic in women who are
node dissection or
not fit for surgery.
• Radical trachelectomy with laparoscopic
pelvic node dissection if fertility is desired.
Stage IB and IIA
Stage IA2 Similar cure rates are obtained with surgery or
The treatment options are: radiotherapy for stage IB squamous carcinoma
• Radical hysterectomy (type II) with pelvic (SCC) of the cervix. The choice between treat-
node dissection (3–10% risk of node ments depends upon the age of the patient, desire
involvement). to preserve ovarian function, co-morbid condi-
• Radical trachelectomy with laparoscopic tions, and patient choice.
pelvic node dissection (if tumour <2 cm and
no LVI) if fertility preservation is intended. Stage IB1 and IIA1 (<4 cm tumour)
The 5-year cumulative pregnancy rate was The treatment options are between radical hys-
52.8% with low cancer recurrence rate with terectomy with bilateral pelvic node dissection or
this approach. radical radiotherapy.
214
 CANCERS OF THE FEMALE GENITAL SYSTEM 13
Patients with more than two involved pelvic
Table 13.5: FIGO cervical cancer staging nodes are usually offered postoperative
Stage I confined to the cervix (extension to the radiotherapy.
corpus disregarded)
Stage IB2 and IIA2 (>4 cm tumour)
IA Invasive carcinoma diagnosed only by
microscopy
The treatment options include:
IA1 Stromal invasion of ≤3.0 mm in depth and • Radical hysterectomy and bilateral pelvic
extension of ≤7.0 mm
IA2 stromal invasion of >3.0 mm and not >5.0 mm
lymphadenectomy +/− adjuvant therapy as
with an extension of not >7.0 mm indicated.
IB Clinically visible lesions limited to the cervix • Concurrent chemoradiation (weekly cispla-
uteri or pre-clinical cancers greater than tin) – deliver 85–90 Gy to point A.
stage IA • Radical radiation therapy (when cisplatin is
IB1 Clinically visible lesion ≤4.0 cm in greatest
dimension
not suitable PS >2 and GFR <50 ml/min) (Box
IB2 Clinically visible lesion >4.0 cm in greatest 13.11).
dimension
Adjuvant treatment
Stage II Cervical carcinoma invades beyond the Adjuvant chemoradiation (EBRT with concur-
uterus, but not to the pelvic wall or to the lower
third of the vagina
rent weekly cisplatin) is recommended after
radical surgery if there are any risk factors such
IIA Without parametrial invasion
as positive nodes, positive parametria, or close
IIA1 Clinically visible lesion ≤4.0 cm in greatest
dimension (≤5 mm) or positive surgical margins. Adjuvant
IIA2 Clinically visible lesion >4 cm in greatest concurrent chemoradiation (using 5FU + cispla-
dimension tin or cisplatin alone) improves survival com-
IIB Parametrial invasion pared with pelvic irradiation alone in these
Stage III patients.
IIIA Tumor involves lower third of the vagina, with Patients with any two of the three factors of
no extension to the pelvic wall deep invasion of cervical stroma, lympho-vascu-
IIIB Extension to the pelvic wall and/or lar space invasion, or tumour size >4 cm are
hydronephrosis or non-functioning kidney classified as intermediate risk. In these patients,
Stage IV extended beyond the true pelvis or has adjuvant whole pelvic irradiation reduces the
involved (biopsy proven) the mucosa of the local failure rate and improves progression-free
bladder or rectum survival.
IVA Spread of the growth to adjacent organs
IVB Spread to distant organs Concurrent chemoradiation
A recent meta-analysis of 2491 patients in 24
trials suggests that addition of concurrent chem-
otherapy to radical radiotherapy improves dis-
ease-free survival by an absolute 10% and overall
survival by 13%. Hence concurrent chemoradio-
therapy is the standard of care in patients who
Surgery involves removal of the uterus, upper have no contraindications for cisplatin.
third of vagina, bilateral parametria, uterosacral,
utero-vesical ligaments and bilateral pelvic lymph Stage IIB–IIIB
nodes. Para-aortic lymph node sampling is Concurrent chemoradiotherapy (weekly cisplatin
indicated if there is clinical suspicion of nodal during EBRT) is the treatment of choice. Using
involvement to plan radiotherapy fields. Radio- a combination of EBRT and brachytherapy a
therapy is with external beam pelvic irradiation dose of 85–90 Gy to point A and 55–60 Gy to
combined with intracavitary applications, which point B is given. Patients with common iliac
deliver a dose of equivalent to 80–85 Gy to point nodes and para-aortic nodes are treated with
A (Box 13.11). extended field radiotherapy.
215
 II SITE-SPECIFIC CANCER MANAGEMENT

Cervical cancer

Stage IA IB – IIA IIB – IVA

Cone biopsy
PA node + PA node –

Margin –, ≤3 mm Margin + or >3 mm Radical RT or radical Radical hysterectomy Extended field Chemo-RT
depth of invasion depth of invasion chemoradiotherapy and pelvic node dissection RT and
and no LVI or LVI chemotherapy

Observe or Radical hysterectomy Any two of the • Positive nodes

hysterectomy and pelvic node following: • Parametria involved
dissection or radical RT • LVI • Close margin
• Tumour >4 cm
• Stromal invasion

Consider pelvic RT Chemo-RT

Recurrence

Previous surgery Previous radiotherapy

Central recurrence Pelvic side wall or

extrapelvic recurrence

Options: Options: Palliative treatment

• Surgical salvage • Extrafacial hysterectomy including chemotherapy
• Radical chemo-RT • Exteneration
• Palliative treatment • Palliative care

Figure 13.7
Management of cervical cancer.

Stage IV 3. Palliative radiotherapy or chemotherapy.

Stage IVA 4. Best supportive care.
The management of patients with stage IVA
A radical approach with neo-adjuvant chemo-
disease (invasion of bladder and/or rectum) has to
therapy or concurrent chemoradiotherapy is suit-
be individualized. The treatment options include:
able for selected patients with good general and
1. Neo-adjuvant chemotherapy or concurrent renal status and not suitable for surgical exenter-
chemoradiotherapy. ation. Surgical exenteration is suitable for selected
2. Pelvic exenteration. stage IV patients.
216
 CANCERS OF THE FEMALE GENITAL SYSTEM 13

Box 13.11: Radiotherapy in cervical cancer

Principles of cervical cancer radiotherapy
Radical radiotherapy is aimed to delivery 80–90 Gy to point A and 50–60 Gy to point B using a combination of
external beam radiotherapy (EBRT) and brachytherapy. Point A in anatomical terms is the point of crossing of
uterine artery and ureters and for dosimetry, it is a point 2 cm from central line and 2 cm above ovoids. Point B is
3 cm lateral to point A and receives 20% dose of point A dose from intracavitary radiotherapy.
The maximum tolerated dose of pelvic EBRT is 50 Gy in 1.8–2 Gy per fraction. The rest of radiotherapy is delivered
using brachytherapy. The total dose is based on conventional radium treatment over using a dose rate of 0.5 Gy/
hour. When medium dose rate (MDR) of >1.5 Gy/hour is used, a 10% reduction of conventional dose is made to
account for the reduced treatment time. With high dose rate (1.5 Gy/minute), this reduction is 40–45% from
conventional dose.
Indications
Postoperative
• Parametrial involvement
• Positive nodes
• Close or positive margin
Radical radiotherapy
• Stage IB2–IIA
• Stage IIB–IVA
• Isolated pelvic recurrence after previous surgery
Target volume definition
Conventional
• Superior – top of L5 (to cover common iliac nodes)
• Inferior – lower border of obturator foramen/3 cm below inferior aspect of disease (IIIA disease)
• Lateral – 1 cm beyond pelvic brim
• Anterior – mid-symphysis pubis
• Posterior – 2 cm anterior to sacral hollow (1.5–2 cm behind primary disease on MRI)
CT planning (Figure 13.8 A&B)
• GTV – primary tumour and enlarged lymph nodes
• CTV – primary tumour, uterus, cervix, upper vagina, ovaries, parametria, proximal uterosacral ligament + lymph
nodes (marked as 7–10 mm margin around blood vessels)
• PTV – 10–15 mm margin around all CTV except for nodal regions and parametria where a 7 mm margin around
CTV is used
Dose
Stage EBRT Brachytherapy (Figure 13.8 C&D)
LDR HDR
Tumour <4 cm (1B1) 45 Gy in 25 30 Gy to point A 21 Gy in 3 # to point A
IB2, II, IIIB, IVA and pelvic nodal disease 50.4 Gy in 28#** 27 Gy to point A 14 Gy in 2 # to point A
IIIA 50.4 Gy in 28#** Brachytherapy using line source and dose same
as other stages
Postoperative 45 Gy in 25# 7 Gy in 1# to 0.5 cm depth
Para-aortic node 45 Gy in 25#
**Given with cisplatin 40 mg/m2 (maximum 70 mg) weekly for 5 weeks; # - fractions
When brachytherapy is not possible, additional EBRT (16–20 Gy in 8–10#) may be considered.
Parametrial boost – may be considered in patients with distal parametrial disease at the time of brachytherapy and
some centres routines consider this for bulky parametrial disease. A parallel opposed field is used to deliver
6–10 Gy in 3–5 fractions. The medial edge of the half-beam blocked parametrial boost field is placed at the
70–80% brachytherapy isodose.

217
 II SITE-SPECIFIC CANCER MANAGEMENT

Figure 13.8
A,B – Treatment volumes
for external beam
radiotherapy in cervical
cancer C,D – Brachytherapy
dose distribution and
dosimetric points (AR –
right side point A, AL – left
side point A, BR – right side
point B, BL – left side point
B, ICRU bladder – bladder
point and ICRU rectum –
rectal point).

A B

C D

The majority of stage IVA patients are of poor Recurrence after primary surgery
performance status or with many co-morbidities Relapse in the pelvis following primary surgery
and extensive local disease, and are best treated may be treated by radiotherapy or pelvic exenter-
with palliative treatment (radiotherapy or chem- ation. Radical radiotherapy (+/− concurrent
otherapy). Patients with poor general health, or chemotherapy) may cure a substantial propor-
extensive local disease can be offered best sup- tion of those with isolated pelvic failure after
portive care. primary surgery. Radiation dose and volume
Stage IVB should be tailored to the extent of disease. Where
No standard chemotherapy regimen is proven in disease is metastatic or recurrent in the pelvis
patients with stage IVB cervical cancer. Radia- after failure of primary therapy and not curable,
tion therapy can be used for palliation of central a trial of cisplatin chemotherapy with palliative
disease or symptomatic distant metastasis. The intent or symptomatic care may be considered.
role of systemic therapy is discussed later. The expected median time to progression or
death is three to seven months.
Recurrence
Treatment decisions should be based on the Recurrence after primary radiotherapy
performance status of the patient, the site and Selected patients may be considered for pelvic
extent of recurrence and/or metastases, and prior exenteration, which is the only potentially cura-
treatment. tive treatment after primary irradiation. Those
218
 CANCERS OF THE FEMALE GENITAL SYSTEM 13
with resectable central recurrences that involve Treatment toxicities
the bladder and/or rectum without evidence of Significant surgical complications are uretero-
intraperitoneal or extra pelvic spread and who vaginal fistula (<2%) and vesicovaginal fistula
have a dissectable tumour-free plane along the (<1%). The risk of complications increases with
pelvic sidewall are potentially suitable. Surgery addition of radiotherapy. Extensive pelvic fibro-
should be undertaken only in centres with appro- sis can lead to ureteric obstruction and small
priate facilities and expertise. The prognosis is bowel obstruction.
better for patients with a disease-free interval The late sequelae following radiation therapy
greater than six months, a recurrence 3 cm or commonly affect the rectum, bladder and small
less in diameter, and no sidewall fixation. The bowel. These depend on the duration of follow-
5-year survival for patients selected for treatment up, type of treatment modalities and estimated
with pelvic exenteration is between 30–60% and radiation doses to these organs. The reported
the operative mortality should be <10%. grade III/IV late sequelae range from 5–15%.
Role of chemotherapy in distant Palliative care
metastasis and recurrent
Palliative care issues include pelvic pain, bleed-
metastatic disease ing, bone pain from metastases and systemic
Chemotherapy has a palliative role after failure symptoms for advanced cancer.
of surgery or radiotherapy. There are a number
of agents with activity in metastatic or recurrent Follow-up
cervical cancer. Cisplatin is the most active agent, Optimal follow-up strategy has not been estab-
with a response rate of 20–30% and a median lished. A general guideline is for clinical evalua-
survival of 7 months. Recent studies suggest that tion three monthly for one year, four-monthly
cisplatin in combination with paclitaxel or topo- for one year, 6-monthly for three years and then
tecan is superior than cisplatin alone. annually. Patients are advised to have annual
chest X-ray. Other investigations are dictated by
Prognosis clinical indications.
Stage is the single most important prognostic
factor for local control and overall survival. Sur- Screening
vival rate after radical hysterectomy for stage IB The main goal of screening is to reduce the inci-
disease, is around 85–95% for node negative and dence and mortality. Screening has been shown
45–55% for node positive disease. Survival rates to be an effective method of identifying pre-neo-
for patients with para-aortic nodal disease treated plastic disease and reducing mortality. Cervical
with extended-field radiotherapy vary between Cytology (Pap Smear) Screening programs have
10% and 50% depending on the extent of pelvic been found to be successful in reducing cervical
disease and para-aortic lymph node involvement. cancer incidence. In the UK, women aged 25
Other factors associated with a poor prognosis years receive the first invitation for screening,
are LVSI, deep stromal invasion (10 mm or those aged 25–49 years have 3 yearly screening,
more, or more than 70% invasion) and parame- those aged 50–64 years have 5-yearly and those
trial extension. Stage-wise 5-year survival is as above 65 years have screening test only if they
follows: have not had screening since 50 years or have
• Stage I A – 95–97%. had a recent abnormal test.
• Stage I B1 – 89%.
• Stage IB2 – 76%. Prevention
• Stage IIA – 73%. HPV vaccines have been shown to reduce the
• Stage IIB – 66%. number of further pre-invasive lesions and inva-
• Stage III – 40%. sive disease in young women with pre-invasive
• Stage IVA – 22%. lesions. In the UK, there is a national programme
• Stage IVB – 9%. to vaccinate girls aged 12–13 against HPV.
219
 II SITE-SPECIFIC CANCER MANAGEMENT

Ovarian germ cell tumours • Embryonal carcinoma (3%) – is often

associated (60%) with abnormal hor-
Introduction and aetiology monal manifestations of precocious
puberty, irregular bleeding, amenor-
Ovarian germ cell tumours (GCTs) have a peak rhea, or hirsutism due to β-hCG stimu-
incidence at 15–19 years, due equally to dysger- lation. It can produce both AFP and
minoma and teratoma, and a second at age β-hCG.
65–69 mainly due to teratoma. They account • Mixed germ cell tumours (7%) are
for less than 5% of all ovarian malignancies in composed of at least two different germ
Western countries, and up to 15% of ovarian cell elements of which at least one is
cancers in Asian and black patients. primitive. The most frequent combina-
The cause is unknown. Less than 5% are asso- tion is dysgerminoma and EST fol-
ciated with dysgenetic ovaries (unlike their tes- lowed by dysgerminoma and immature
ticular counterparts). The oral contraceptive pill teratoma.
does not confer a protective effect in germ cell
tumours as it does in the epithelial ovarian cancers. Clinical features
Abdominal pain (87%) is the most frequent
Pathology symptom followed by abdominal mass (85%),
GCTs are classified as dysgerminomas or non- but 10% may present with acute abdomen due
dysgerminomas based on their origin in primor- to torsion, haemorrhage or rupture of the ovarian
dial germ cells and their ability to differentiate in tumour. Abdominal distension, fever and vaginal
vivo. Dysgerminomas are the ovarian counter- bleeding each occur in 10%. Ascites is present in
part of seminomas, whereas the non-dysgermino- 20% of cases.
matous tumours include all other germ cell
tumours and encompass a wide range of differ- Patterns of spread
entiated cell types. Spread of tumour occurs by peritoneal, lym-
phatic and haematogenous routes. Lymphatic
• Dysgerminoma – is the most common (30–
spread is predominant in dysgerminoma whereas
40%) malignant germ cell tumour. It has
other modes of spread are equally important in
the highest rate of bilaterality (10–15%)
non-dysgerminomas.
and is the commonest (20–30%) malignant
GCT associated with pregnancy. Investigations and staging
• Non-dysgerminoma – composed of imma- Initial investigations include estimation of serum
ture teratoma, endodermal sinus tumours tumour markers and imaging.
(yolk sac carcinoma), embryonal carci-
noma, non-gestational choriocarcinoma, Tumour markers
polyembryoma and mixed germ cell Estimation of the tumour markers preopera-
tumour. tively, postoperatively and during follow-up is
• Immature teratoma (20%) – is some- helpful in predicting the diagnosis, response to
times associated with miliary peritoneal the treatment and recurrence respectively.
implants composed exclusively of The two specific markers for GCTs are beta-
mature glial tissue (called gliomatosis human chorionic gonadotrophin (β-hCG) and
peritonei). alpha-feto protein (AFP). Up to five percent
• Endodermal sinus tumour or EST (also patients with dysgerminoma can have an ele-
called yolk sac tumour – YST) (20%). vated β-hCG, which gives rise to a positive preg-
It usually presents as stage I disease, but nancy test in 3% of patients. An elevated AFP or
rapidly growing with more than 50% a β-hCG level of >100 IU/L indicates the pres-
of the patients reporting symptoms of ence of nondysgerminomatous elements.
less than one-week duration. These Most endodermal sinus tumours secrete AFP.
tumours inva­riably express alpha-feto- Embryonal carcinomas can secrete both AFP and
protein (AFP). Intraperitoneal spread β-hCG whereas tumour markers are negative in
220 predominates in this tumour. pure immature teratomas.
 CANCERS OF THE FEMALE GENITAL SYSTEM 13
Other markers include lactate dehydrogenase ing, recurrent disease or poorly differentiated
(LDH) levels in dysgerminomas (88% have raised tumours.
serum LDH isoenzyme-10) and placental alka-
line phosphatase (PLAP) – raised in >95% of Management (Figure 13.10)
dysgerminomas. More than 50% of GCTs Germ cell tumours are potentially curable malig-
express CA-125 but its role in clinical manage- nancies with platinum-based chemotherapy.
ment not known.
Surgery
Imaging
Primary surgery
Dysgerminomas and non-dysgerminomas exhibit Principles of surgery follow that of the epithelial
different radiological features. On CT (Figure ovarian cancer. However, since this disease
13.9) and MRI dysgerminoma shows multilocu- predominantly affects the young females,
lated solid mass divided by fibrovascular septa. conservative surgery to preserve fertility is pre-
There can be associated abdominal lymphaden- ferred and the minimal surgery is unilateral
opathy. Calcification is rare in dysgerminoma oophorectomy. Even in advanced stage (20–
but when present it appears as a speckled pattern. 30%), the contralateral ovary, fallopian tube and
Non-dysgerminomas are usually unilateral uterus may be left in situ to preserve fertility, and
mixed solid and cystic mass. On CT and MRI, postoperative chemotherapy is given. Although
there may be a heterogeneous enhancement due the role of maximal cytoreduction is less defined
to haemorrhage or necrosis. Calcification occurs than for epithelial ovarian cancer, all obvious
in up to 40% of the cases. metastases should be debulked or removed if
There are so far no studies examining the role possible. Even if BSO is necessary, the uterus can
of PET scans in ovarian GCTs, however, in be left behind for future assisted reproduction.
future, it may have the similar clinical applica- Routine biopsy of a normal looking contralateral
tion as that of testicular germ cell tumours. ovary is not advised due to the risk of infertility
Staging from peritoneal adhesion or ovarian failure. The
role of routine lymphadenectomy is yet to be
The GCTs are staged according to the FIGO
established.
staging (Box 13.2). 60–70% of GCTs are
stage I, 25–30% in stage III and stage II and IV Secondary cytoreduction and
are rare. Distant metastases occur in long stand- second look laparotomy
A small study suggests that there may be a pos-
sible role for secondary debulking in chemo-
refractory patients with immature teratoma.
Routine second-look surgery is not recommended
because of the low incidence of positivity after
combination chemotherapy. However, a second-
look procedure may be recommended for the
subset of patients with a teratoma component in
the primary tumour and persistent radiologic
abnormalities along with normal serum tumour
markers at the end of chemotherapy.

Postoperative management
Dysgerminoma
Adequately staged FIGO IA dysgerminoma has
long-term survival of more than 90%, and these
Figure 13.9 patients are observed without any postoperative
Dysgerminoma of the ovary. Contrast-enhanced CT scan
shows a large, multilobulated solid mass with highly
treatment. The recurrences (rate of 15–25%) in
enhancing fibrovascular septa (arrows) and cystic change these patients can be effectively salvaged with
(arrowheads). chemotherapy. All other patients need adjuvant 221
 II SITE-SPECIFIC CANCER MANAGEMENT

Staging laparotomy and

optimal debulking surgery

Non-dysgerminoma Dysgerminoma

Incompletely Completely Completely Incompletely Completely Stage IA

resected stage resected stage stage IA resected stage resected stage completely
IB-III and IB-III grade I IB-III and IB-III resected
stage IV immature stage IV
teratoma

BEP x 4* BEP x 3 Follow-up BEP x 4 BEP x 3 Follow-up

Marker Marker Complete Follow-up Recurrence Follow-up Follow-up Recurrence

negative positive marker and
and radiologic radiologic
residual response
disease Recurrence BEP x 3-4 Recurrence Recurrence BEP x 3-4

Consider VeIP or TIP Follow-up VeIP or TIP VeIP or TIP VeIP or TIP
resection

Active No active Recurrence

tumour tumour

Chemotherapy Follow-up VeIP or TIP

Figure 13.10
* If adequate marker response may continue up to 5–6 courses Management of malignant ovarian germ cell tumours.

treatment after maximal debulking with or Non-dysgerminoma

without fertility preservation. Surgery alone is adequate for properly staged
Completely resected stage IB–III and those FIGO Stage IA grade I immature teratoma, which
without staging laparotomy are treated with has 80–85% long-term disease-free-survival. All
three courses of standard chemotherapy with other groups of patients with non-dysgerminoma
BEP regime (Box 13.12). Disease-free survival of should receive postoperative chemotherapy.
completely resected dysgerminoma is very high, The optimal number of courses of chemother-
approaching 100% and that of advanced disease apy for GCT is unclear, unlike testicular tumours.
is in the range of 60–80%. Incompletely resected One GOG study had shown that three courses
stage II–IV are treated with 3–4 courses of BEP. of BEP will nearly always prevent recurrence in
Rarely, radiotherapy may be an option for well-staged patients with completely resected
women with other co-morbid conditions prevent- ovarian germ cell tumours. However, those with
ing che­motherapy administration or those who a raised tumour marker but with no measurable
decline chemotherapy. Whole abdominal radio- disease should receive two more courses of chem-
therapy is used which leads to loss of fertility. otherapy after normalization of serum markers
222
 CANCERS OF THE FEMALE GENITAL SYSTEM 13

Box 13.12: Chemotherapy GCTs

include advanced stage, bulky residual disease
after surgery, age >22 years, endodermal sinus
BEP
• Bleomycin 30U IM Days 2, 8 & 16 tumour and AFP of >1000 ng/ml at diagnosis.
• Etoposide 100 mg/m2 IV Day 1–5 In stage I dysgerminoma the long term survival
• Cisplatin 20 mg/m2 IV Day 1–5 approaches 100%. The stage-wise overall sur-
Cycle repeated in every 3 weeks vival long-term survival is stage I 100%, stage II
85%, stage III 79% and stage IV 71%.
VeIP
• Vinblastine 0.11 mg/kg/day intravenously Day 1 & 2
• Ifosfamide 1.2 g/m2/day Day 1–5 with mesna
Follow-up and survivorship
120 mg/m2 as initial IV bolus and then 1200 mg/ The majority of case relapses occur within the
m2/day by continuous IV infusion Day 1–5 first two years after completion of treatment,
• Cisplatin 20 mg/m2/day intravenously Day 1–5 although dysgerminoma can relapse late. Initial
Cycle repeated in every 3 weeks follow up should be every 2–3 months for 1–2
TIP years then 3–4 months up to 3 years after which
• Paclitaxel 175 mg/m2 Day 1 6-monthly to 5 years. Dysgerminomas should be
• Ifosfamide 1 g/m2 Day 1–5 followed up to 10 years. For those who had
• Cisplatin 20 mg/m2 Day 1–5 raised markers at the time of presentation, these
Cycle repeated every 3 weeks should be followed every 2 months for the first
year and 3-monthly for the second year, pref­
erably alongside clinical follow-up. Regular
and those with bulky residual tumour may need imaging depends upon the nature of the previous
5–6 courses. tumour. With the risk of radiation from regular
The role of carboplatin in place of cisplatin is CT scanning, USS or MRI is advocated in most
undergoing clinical trials. cases. Patients without raised markers should be
scanned alongside their clinical follow-up.
Recurrence Limited experience suggests that future fertility
The role of surgery in the management of re­ is not significantly affected by previous treatment
currence has yet to be established. One study for GCTs and there are no reports of adverse
reported better survival for patients with imma- outcome or increased malformations in the fetus.
ture teratoma who underwent salvage surgery
than of those with other tumour cell types. Future directions
There is no clear standard for treatment Due to the success of treating most cases,
of relapsed ovarian germ cell tumour. Based on current developments are in optimizing treat-
experience of testicular tumours, ovarian GCTs ment for relapsed disease. This includes high
can also be divided into those which are platinum dose chemotherapy.
resistant and those which are platinum sensitive.
Platinum resistant tumours are defined as pro- Sex cord stromal tumours
gressive disease during treatment or during 6–8
weeks of stopping treatment. Prognosis in these Ovarian sex cord stromal tumours comprise 5–8%
cases is dismal and high dose chemotherapy or of all primary ovarian tumours. These tumours
experimental drugs are advocated. Platinum sen- are generally low grade with no associated
sitive tumours are defined as relapses occurring BRCA mutations. Many tumours produce steroid
after 6–8 weeks of discontinuation of treatment. hormones and present with features of oestrogen
Prognosis in these cases is good. They are treated or androgen hypersecretion. These are classified
with platinum containing salvage chemotherapy as granulosa cell tumours, thecoma-fibroma,
regimens such as VeIP or TIP (Box 13.12). Sertoli–Leydig cell tumours and gynandroblast-
oma. Inhibin, a protein secreted by these tumours,
Prognosis and survival can be used as a diagnostic marker, particularly
In spite of high cure rates, 12–20% of patients for granulosa cell tumour. These tumours are
still die of this disease. Poor prognostic factors staged similar to epithelial ovarian cancers.
223
 II SITE-SPECIFIC CANCER MANAGEMENT

Granulosa cell tumour treated with platinum based chemotherapy (usual

There are two subtypes: regime is BEP).

• Adult type – 95% of tumours occur in 5th Gynandroblastomas

decade of life. These are very rare benign mixed tumours with
• Juvenile type – 5% of tumours occur in elements of Sertoli–Leydig or granulosa cell ele-
children and young women. ments. Presentation can be either with features
These tumours usually present with large of virilization or increased oestrogen production.
masses with features of increased oestrogen pro- Unilateral oophorectomy is the treatment of
duction. These can be associated with endome- choice.
trial hyperplasia and adenocarcinoma. TAH-BSO
is the treatment of choice in those who have Gestational trophoblastic
completed their family. Unilateral salpingo- disease
oophorectomy is an option for young women
with stage I disease. Role of adjuvant chemo-
Introduction
therapy after surgery is unknown. The approaches
vary from routine chemotherapy for stage II–IV Gestational trophoblastic disease (GTD) is a
to no treatment until recurrence. Retrospective rare complication of pregnancy. The gestational
data suggests that adults with stage III–IV disease trophoblastic tumours include invasive mole,
have a better progression free survival with choriocarcinoma and placental site trophoblastic
adjuvant chemotherapy. The most commonly tumour (PSTT). 15% of complete moles develop
used chemotherapy is BEP (p. 223). Alternative into an invasive mole and around 3% of com-
options include combinations of carboplatin plete moles may develop into choriocarcinomas.
with paclitaxel and cisplatin with etoposide. Risk factors include age (<16 and >40 years),
Patients with recurrent localized disease may previous molar pregnancy and Asian origin.
undergo salvage surgery if feasible; otherwise
Pathology
treated with chemotherapy. Radiotherapy may
have a role in patients with isolated inoperable Persistent GTD can occur after any pregnancy.
pelvic recurrence. Invasive mole is composed of diffuse trophoblas-
5-year survival of completely resected stage I tic hyperplasia invading underlying tissues.
disease is >90% and advanced stage is 30%. Late Choriocarcinoma is characterized by absence of
relapses are not unusual. chorionic villi with sheets of anaplastic cyto- and
syncytiotrophoblasts. PSTT is composed mainly
Fibroma/thecoma of intermediate trophoblasts.
Fibromas are treated with oophorectomy, while
thecomas are treated with either conservative Clinical features
surgery or TAH-BSO. Up to 20% of patients present with persistent
trophoblastic disease after surgical evacuation.
Sertoli–Leydig cell tumours The usual presentation is irregular vaginal bleed-
The majority of these tumours (75%) occur in ing and/or persistently elevated serum beta-hCG.
women aged less than 40 years. These can be Metastatic disease can occur in 4% of patients.
either benign or malignant (<20%) and only The commonest site of metastasis is lung fol-
2–3% have extra-ovarian disease at presentation. lowed by vagina, CNS, liver and pelvis and
The presentation is with abdominal pain or dis- presentation depends on the site of disease.
tension or with features of virilization. TAH-BSO All women are followed up with serum beta-
is the treatment of choice and conservative hCG estimation after evacuation of a molar
surgery is attempted when fertility preservation pregnancy to identify persistent disease. 5–10%
is intended. The benefit of adjuvant chemother- women may need chemotherapy for persistent
apy is not known. 5-year survival is 70–90%. GTD. The indications for chemotherapy are
Patients with recurrent and metastatic disease are shown in Box 13.13.
224
 CANCERS OF THE FEMALE GENITAL SYSTEM 13

Table 13.6: FIGO-WHO prognostic scoring

Score 0 1 2 4
Age (years) <40 >40 – –
Antecedent pregnancy Mole Abortion Term –
Interval months from index pregnancy <4 4 –<7 7 –<13 ≥13
Pre-treatment serum hCG (IU/L) <103 103–<104 104–<105 ≥105
Largest tumour size (including uterus) (cm) <3 3–<5 ≥5 –
Site of metastasis Lung Spleen, kidney Gastrointestinal Liver, brain
Number of metastasis NA 1–4 5–8 >8
Previous failed chemotherapy NA NA Single drug ≥2 drugs

Box 13.13: Indications for chemotherapy in Box 13.14: FIGO staging of GTD
persistent trophoblastic disease
• Stage I – Disease confined to uterus
• Serum hCG >20,000 iu/l after one or two uterine • Stage II – disease beyond uterus but confined to
evacuations genital structures
• Static or rising hCG levels after one or two uterine • Stage III – lung metastasis with or without genital
evacuations tract involvement
• Persistent hCG elevation six months post-uterine • Stage IV – distant metastasis other than lung
evacuation
• Persistent vaginal bleeding with raised hCG levels
• Pulmonary metastasis with static or rising hCG
levels
• Metastasis in liver, brain, or GI tract Box 13.15: Chemotherapy in GTD
• Histological diagnosis of choriocarcinoma Low risk
• Methotrexate with folinic acid
• D-actinomycin
Salvage chemotherapy for low risk and first line
Assessment prior to chemotherapy chemotherapy in high risk
• MEA (methotrexate, etoposide and dactinomycin)
Investigations • EMA/CO (methotrexate, etoposide, dactinomycin/
Patients need further investigations with FBC, cyclophosphamide and vincristine)
biochemistry, serum beta hCG, chest X-ray and Salvage chemotherapy for high risk
CT scan of thorax and CNS staging in high risk • EMA/EP (methotrexate, etoposide, dactinomycin/
etoposide, cisplatin)
patients (WHO score of ≥7, high risk score, mul-
tiple lung metastases and hCG >50,000 iu/l).
CNS staging consists of imaging the cranio­
spinal axis and CSF examination (ratio of Treatment
CSF: serum hCG > greater than 1 in 60 suggests
Low-risk disease (score ≤6)
involvement).
Single agent chemotherapy is the treatment
Staging and prognostic scoring of choice and the commonly used agents are
FIGO staging (Box 13.14) is mainly used to methotrexate and dactinomycin (Box 13.15).
compare outcome data and the scoring system Methotrexate does not cause alopecia. Around
(Table 13.6) guides treatment. Low risk disease 10–20% patients do not respond to methotrex-
is defined by a total score of ≤6 and high risk ate, and salvage treatment options are single
score ≥7. agent D-actinomycin (if hCG level is low) or
225
 II SITE-SPECIFIC CANCER MANAGEMENT

combination chemotherapy (if hCG level is high) given. There is no consensus on when to stop
(Box 13.15). Selected patients are salvaged with chemotherapy after biochemical remission. Many
hysterectomy. patients receive 1–3 cycles of chemotherapy after
biochemical remission, depending on the risk
High risk disease (score ≥7)
category and the rate of reduction of hCG.
Patients with high risk disease are treated with
combination chemotherapy with or without Follow-up and survivorship
surgery. The commonly used combination chem-
otherapy regimes are shown in Box 13.15. Most Patients need regular follow-up after completion
of the chemotherapy regimes give an 80–85% of treatment. Women are advised not to conceive
complete remission. for at least 12 months after completion of their
treatment. Women are advised not to take the
Relapse or resistant disease oral contraceptive pill until hCG is normal.
20–30% of patients will be resistant to treatment There is no evidence that treatment for a
or relapse after initial treatment. The commonly pre­vious GTD affects future pregnancy and its
used regime is EMA/EP (Box 13.15). There is a outcome. Chemotherapy generally results in an
role for surgical salvage in selected patients. early menopause such that patients are advised
to complete their families before the age of 35.
Central nervous system disease
There is also a risk of second tumours such as
Patients with CNS disease are treated with chem- AML.
otherapy with or without surgery or radiother-
apy. Modifying EMA/CO chemotherapy with an
increased dose of systemic methotrexate and Vulval cancer
with the addition of intrathecal methotrexate
may improve the dose of methotrexate in CNS. Introduction
Vulval cancer is rare, with 1022 new cases being
Placental site trophoblastic diagnosed in the UK each year. It predominantly
tumour (PSTT) affects older women, with 80% of cases occurring
PSTT is less chemosensitive than other GTDs in those over 60. HPV (mainly 16, 18 and 31) has
and hence hysterectomy is the treatment of choice been found to be responsible for approximately
for disease limited to uterus. Metastatic PSTT is 30–50% of vulval cancers and up to 80% of
treated like high risk GTD. vulval intraepithelial neoplasias (VIN). There is
also an increased risk in those with HIV as well
Assessing response to treatment and as those on immunosuppressions. Other risk
number of courses of chemotherapy factors include smoking and chronic skin condi-
In patients receiving chemotherapy for low-risk tions such as lichen sclerosus (a 4–7% risk of
disease, patients are closely monitored after one malignancy), lichen planus and Paget’s disease.
course of chemotherapy with weekly hCG.
Further treatment is withheld as long as serum Pathology
hCG is falling. A second course of treatment is There are two varieties of intraepithelial neopla-
indicated if the hCG levels are stationary for sia: squamous cell carcinoma-in-situ (Bowen’s
three consecutive weeks, re-elevates or does not disease) or vulvar intraepithelial neoplasia III and
decline by one logarithmic fall within 18 days of Paget’s disease.
completion of the first treatment. If a second The majority (90%) of vulval cancers are
course of chemotherapy is necessary, the same squamous cell (SCC) in origin, however, melano-
treatment is given if there was an adequate mas (4%), basal cell carcinomas, adenocarci­
response to previous treatment. An adequate nomas (1–2%), undifferentiated carcinomas,
response is defined as at least a logarithmic fall sarcomas (<2%) and metastatic tumours from a
in hCG after a course of chemotherapy. If the variety of primary sites also occur. Verrucous
response is not adequate, another single agent SCC carcinomas are a slow growing type of
chemotherapy or combination chemotherapy is squamous cell carcinoma.
226
 CANCERS OF THE FEMALE GENITAL SYSTEM 13

Patterns of spread Box 13.16: FIGO staging of vulval cancer

Vulval cancer spreads by direct extension to Stage I – Tumour confined to the vulva
involve adjacent structures such as the vagina, • IA – Lesions ≤2 cm in size, confined to the vulva
urethra and anus, by lymphatic channels to the or perineum and with stromal invasion
≤1.0 mm, no nodal metastasis
inguinal and femoral groin nodes, and haematog-
• IB Lesions >2 cm in size or with stromal
enously to distant sites including the lungs, liver invasion >1.0 mm
and bone. The overall incidence of lymph node Stage II – Tumour of any size with extension to
metastases is approximately 30%. Haematoge- adjacent perineal structures ( 13 lower urethra,
nous spread tends to occur late, and is rare in the 1
3 lower vagina, anus) with negative nodes.

absence of nodal metastases. Stage III – Tumour of any size with or without
extension to adjacent perineal structures ( 13 lower
urethra, 13 lower vagina, anus) with positive
Clinical features inguino-femoral lymph nodes.
• IIIA
The most common symptoms include itch or irri-
(i) With 1 lymph node metastasis (≥5 mm), or
tation, pain and soreness, a thickened, raised
(ii) 1–2 lymph node metastasis(es) (<5 mm)
area of discolouration, ulcer, vaginal discharge
• IIIB
or bleeding, or lump.
(i) With 2 or more lymph node metastases
(≥5 mm), or
Diagnosis and staging (ii) 3 or more lymph node metastases (>5 mm)
The size and location of the lesion should be • IIIC With positive nodes with extracapsular
spread
documented, and any involvement of adjacent
Stage IV – Tumour invades other regional ( 2 3 upper
structures such as vagina, urethra, base of bladder urethra, 2 3 upper vagina), or distant structures.
or anus, should be noted. The diagnosis of vulval • IVA Tumour invades any of the following:
cancer is made after biopsy. Vulval cancer is (i) upper urethral and/or vaginal mucosa,
staged using the FIGO classification (Box 13.16). bladder mucosa, rectal mucosa, or fixed to
pelvic bone, or
(ii) fixed or ulcerated inguino-femoral lymph
Management (Figure 13.11) nodes
Early-stage disease (Stages I and II) • IVB – Any distant metastasis including pelvic
lymph nodes
Surgery is the treatment of choice which involves
a wide and deep resection (radical local excision)
to obtain surgical margins of at least 1 cm. All
patients except stage Ia (depth of penetration
<1 mm when the risk of node metastasis is <1%) Advanced disease
need an ipsilateral inguinofemoral lymphadenec- If it is possible to resect the primary lesion with
tomy to reduce the risk of recurrence. Bilateral clear margins and without the need for a bowel
lymphadenectomy is indicated if the tumour is or urinary stoma, primary surgery is desirable.
within 1 cm of midline or involving labia minor. Surgery involves radical vulvectomy, bilateral
Postoperative bilateral pelvic and groin irradia- groin node dissection and pelvic exenteration, or
tion is indicated in the following setting: ano-vulvectomy with formation of end colos-
tomy. The overall 5-year survival rate in women
• One macrometastases (>5 mm in diameter).
with locally advanced disease treated by radical
• Two or more micrometastases (≤5 mm).
ano-vulvectomy has been reported to be 62%.
• Extracapsular spread.
Postoperative radiotherapy is indicated if the
Radiotherapy field should include inguino- margin is <5 mm and re-excision is not feasible.
femoral nodes and at least pelvic nodes below Primary radiotherapy is the treatment of
the SI joints. Microscopic disease needs 50 Gy in choice in those women with larger, more
1.8–2 Gy per fraction, 60 Gy for extracapsular advanced lesions involving bladder or rectum, or
spread or multiple nodes and 60–70 Gy for who are considered unsuitable for surgery. Nodal
macroscopic disease. disease may be dissected prior to management of
227
 II SITE-SPECIFIC CANCER MANAGEMENT

Histologically
confirmed vulval cancer

Refer to gynae oncology centre

CXR, bloods & staging

Early stage Lateral vulval Advanced

disease tumour disease

Lesion <2 cm Lesion >2 cm WLE Radical vulvectomy RT ?Chemotherapy,

SI < = 1 mm SI >1 mm Ipsilateral groin nodes, Bilateral LN chemoRT,
contralateral dissection ?surgery
lymphadenectomy
if positive

WLE WLE and RT

separate groin
node dissections Figure 13.11
Management of vulval cancer.

primary tumour. Initial treatment involves 50 Gy frequency, and the formation of fistulae (recto-
at 1.7–1.8 Gy per fraction to include pelvis, vaginal, vesico-vaginal and entero-vaginal). The
inguinal nodes and primary tumour. The second incidence of developing lower limb lymphoedema
phase of treatment is to the gross disease to is also greater in those women who have been
deliver a total dose of 60–70 Gy. The exact role treated by surgery including lymphadenectomy,
of the combination of chemotherapy (cisplatin and adjuvant radiotherapy (groin and pelvis).
alone or in combination with 5-FU) with radio-
therapy is not fully explored. Recurrence and management
15 and 33% of vulval cancers recur and the
Prognosis most common sites of recurrence are the vulva
Prognosis depends on nodal status and the size (69.5%), groin nodes (24.3%), the pelvis in
of the primary lesion. In the absence of lymph 15.6% and distant metastases in 18.5%.
node involvement, the 5-year survival is >80%. Local vulval recurrences are treated by surgery
This decreases to approximately 50% with when possible. Groin recurrences are more dif-
inguinal node involvement, and to 10–15% with ficult to manage. Radiotherapy is the preferred
pelvic node metastases. treatment, but surgery should be considered in
patients who have already received groin
Post-treatment issues irradiation.
Lymphoedema is a late complication, with an
incidence of 62–69% following groin node Cancer of the vagina
dissection. When it occurs, the onset of lym-
phoedema is apparent within three months in Introduction
50% of women, and within 12 months in 85% Primary vaginal cancer constitutes 2% of female
of women. genital tract cancers, and 240 new cases are diag-
Complications following radiotherapy include nosed annually in the UK. It causes approxi-
vulval soreness, skin blistering, diarrhoea, urinary mately 100 deaths in the UK each year.
228
 CANCERS OF THE FEMALE GENITAL SYSTEM 13

Aetiology Box 13.17: FIGO staging of vaginal cancer

The incidence of vaginal cancer is greatest in
Stage I Tumour limited to vaginal wall
women between the ages of 60–70 years, with Stage II Tumour involving the subvaginal tissue
more than 70% of cases occurring in this group. but not extending to pelvic side wall
Risk factors include fetal exposure of diethyl­ Stage III Tumour extending up to pelvic side wall
Stage IVa Spread to adjacent organs and/or direct
stilboestrol (vaginal clear cell carcinoma), per- extension beyond true pelvis
sistent HPV infection especially 16, a history (in Stage IVb Distant
up to 30%) of in-situ or invasive cervical cancer
treated in the preceding 5-years, and a previous
history of chronic vaginal irritation, use of ring
pessaries, and previous treatment with radiother- may also complain of pelvic pain, constipation,
apy. Vaginal cancer is also common in less well difficulty in micturition and lower limb oedema.
educated women, those with lower income, with
five or more lifetime sexual partners, an early age Diagnosis and staging
at first intercourse, and smokers. The diagnosis of primary vaginal cancer is made
by histology and clinical examination. Tumours
Pathology extending to the external cervical os are classified
The common histologic types are: as cervical cancers, while tumours involving the
vulva as vulval cancers. MRI scan is useful in
• Squamous cell carcinoma – 80% of vaginal
assessing local extension of tumour. FIGO
cancers are due to direct extension of adjacent
staging for vagina is given in Box 13.17.
tumours (e.g. cervical) or metastases (e.g.
endometrial) and 20% originate in the vagina, Principles of management
the most common histological type is squa- Factors to be considered when planning treat-
mous cell (over 90% of cases). ment for vaginal cancer are the stage, size and
• Adenocarcinoma – tends to occur in women location of the lesion, previous pelvic irradiation
over the age of 50, with the exception of clear and performance status.
cell carcinoma. Clear cell adenocarcinoma is
rare, almost always associated with an expo- Surgery
sure to diethylstilboestrol in utero, and most Surgery can be curative in selected women with
commonly presents between 17 and 22 years early stage (I, small stage II) disease, and in
of age. women with stage IV disease in whom exentera-
• Papillary adenocarcinoma tends to arise tion is planned. Surgery is the treatment of choice
from the connective tissue surrounding the if clear excision margins (at least 1 cm) are
vagina, and is less likely to spread via the achievable.
lymphatics. Superficial lesions may be treated by wide
• Adenosquamous carcinomas (2%) tend to be local excision. Stage I lesions at the apex, particu-
more aggressive. larly on the posterior vaginal wall may be treated
• Malignant melanomas of the vagina (2%) – with a partial vaginectomy or extension of a
develop in women in the 5th decade of life, radical hysterectomy. Lesions that lie in the
and in the lower third of the vagina. upper part of the vagina can be treated by radical
hysterovaginectomy with removal of the parame-
Presentation tria and paracolpos. In women who have had a
Patients generally remain asymptomatic (20%) previous hysterectomy, an upper vaginectomy
in both the pre-invasive and early stages of and parametrectomy can be performed. Both
vaginal cancer, and early lesions are most com- procedures should also include bilateral pelvic
monly detected during routine cervical screening. node dissection.
80–90% of women will present with bleeding, In stage II disease with lesions in sites
discharge, dyspareunia, vaginal irritation, or a that would allow a less aggressive procedure
vaginal mass. In more advanced disease, women than a radical vaginectomy and with minimal
229
 II SITE-SPECIFIC CANCER MANAGEMENT

extension outside the vaginal wall, surgery may vagina, and poorly differentiated tumours, are
be considered. poor prognostic factors.
Pelvic exenteration is useful in stage IVa disease
without extension of the lesion to the pelvic side Recurrence and management
walls, and distant sites of metastases. The main site of relapse is the pelvis. In central
In young patients requiring radiotherapy, recurrence, there may be a role for pelvic exen­
laparotomy is done to transpose ovaries. teration or further radiotherapy. The 5-year
survival rate following recurrence is approxi-
Radiotherapy mately 12%. There is no proven benefit for
Radiotherapy is the treatment of choice unless chemotherapy.
clear resection margins (at least 1 cm) can be Follow-up
obtained. The proximity of the vagina to the
bladder and rectum can potentially limit treat- Follow-up is important in addressing the issues
ment options and increase the risk of complica- of treatment-induced morbidities. Vaginal scar-
tions to these organs. ring and stenosis are the main problems leading
In early stage disease (stage I and II), intra­ to depression and sexual dysfunction. Late
cavitary radiation may be used, while both intra­ bladder and bowel toxicities and early meno-
cavitary and external irradiation are required for pause due to radiation also need attention.
larger and more advanced lesions. The use Further reading
of both external irradiation and brachytherapy
in treating vaginal cancer has been shown to Colombo N, Peiretti M, Castiglione M. Non-epithelial
ovarian cancer: ESMO clinical recommendations for
achieve excellent results, and allows vaginal diagnosis, treatment and follow-up. Ann Oncol. 2009;20
preservation. If the lower one-third of the vagina Suppl 4:24–26.
is involved groin nodes should be irradiated or Han LY, Kipps E, Kaye SB. Current treatment and clinical
dissected. trials in ovarian cancer. Expert Opin Investig Drugs.
Women with advanced disease tend to be 2010;19:521–534.
Amant F, Moerman P, Neven P et al. Endometrial cancer.
treated with chemoradiation rather than radio- Lancet. 2005;366:491–505.
therapy alone. Gehrig PA, Bae-Jump VL. Promising novel therapies for the
treatment of endometrial cancer. Gynecol Oncol.
Chemoradiotherapy 2010;116:187–194.
Goonatillake S, Khong R, Hoskin P. Chemoradiation in
Most of the evidence for chemoradiotherapy in gynaecological cancer. Clin Oncol. 2009;21:566–572.
vaginal cancer originates from studies in cervical Taylor A, Powell ME. Conformal and intensity-modulated
cancer using cisplatin or cisplatin with 5-FU. radiotherapy for cervical cancer. Clin Oncol. 2008;20:
Chemotherapy alone appears to offer little benefit 417–425.
in the management of advanced (stage III and IV) del Campo JM, Prat A, Gil-Moreno A et al. Update on novel
therapeutic agents for cervical cancer. Gynecol Oncol.
disease. 2008;110:S72–S76.
Koulouris CR, Penson RT. Ovarian stromal and germ cell
Prognosis tumors. Semin Oncol. 2009;36:126–136.
The overall 5-year survival rate for vaginal cancer Crosbie EJ, Slade RJ, Ahmed AS. The management of vulval
cancer. Cancer Treat Rev. 2009;35:533–539.
is 44%, which is poorer than that for both cervi- Gray HJ. Advances in vulvar and vaginal cancer treatment.
cal and vulval cancer. Women over 60 years of Gynecol Oncol. 2010 May 13. [Epub ahead of print]
age, lesions in the middle and lower third of the PMID: 20471671

230
Cancers of the skin
HM Hatcher and TV Ajithkumar
14
Cutaneous melanoma • Naevi – Multiple benign naevi (>100) as well
as multiple aypical naevi increases the risk of
Epidemiology melanoma (RR 11)
Melanoma is the most aggressive form of skin • Immunosuppression – Transplant recipients
cancer which is increasing in incidence. In Europe, (RR 3) and patients with AIDS (RR 1.5) have
its incidence has risen by 3–8% per year since the increased risk of melanoma
1960s. The lifetime risk of melanoma in the UK • Previous melanoma – those with a previous
is 1 in 147 for men and 1 in 117 for women. In melanoma have a 2–10% risk of a further
Australia the risks are significantly higher with melanoma which increases further with two
lifetime risks of 1 in 25 for men and 1 in 35 for previous melanomas.
women. Overall survival rates have improved
due to early detection but survival of higher Pathology
stage disease has improved very little in the past There are four histological variants of cutaneous
10 years. melanoma:
The peak incidence of melanoma occurs in
middle age (40s) with less than 10% occurring • Superficial spreading is the most common
in childhood, although the rates in those under type. This often arises within a pre-existing
20 have increased by over 3% in the past naevus and is surrounded by a zone of atypi-
10 years. cal melanocytes that may extend beyond the
visible border of the lesion.
Aetiology • Nodular melanoma (10–15%) presents as
symmetrical, uniform dark blue-black lesions.
Ultraviolent sun radiation (especially UVB) is
Amelanotic nodular melanomas are often
the main risk factor for the development of
misdiagnosed.
cutaneous melanoma. People with a history of
• Lentigo maligna melanoma (10–15%) usually
blistering sunburns have a 2.5 times higher risk
occurs on the sun-exposed areas of head and
of melanoma. Other surrogate makers of sun
neck and hands. Clinically these are large
sensitivity such as freckling (RR 2.5), burn
(often >3 cm) flat lesions with areas of dark
without tanning (RR 1.7), red hair (RR 2.4) and
brown or black discolouration. These lesions
blue eyes (RR 1.6) also have an increased risk.
arise from the premalignant lesion called
Other risk factors are:
Hutchinson’s freckle.
• Genetic – people with a strong family history • Acral-lentigenous melanomas, as the name
and multiple atypical moles are at the suggests (acral – distal), occur on the palms,
greatest risk of melanoma. Those with an soles and subungual regions. These lesions
inherited mutation in the CDKN2A and occur with the same frequency in whites and
CDK4 genes have 60–90% lifetime risk of non-whites (2–8% of melanoma in whites
melanoma. and 40–60% melanoma of non-whites). These

© 2011, Elsevier Ltd 231

DOI: 10.1016/B978-0-7234-3458-0.00019-1
 II SITE-SPECIFIC CANCER MANAGEMENT

Box 14.1: Prognostic factors in

cutaneous melanoma
• Breslow thickness
• Ulceration
• Presence of satellite lesions
• LDH
• Vascular invasion
• Surgical margin
• Clark’s level
• Nodal disease
• Extranodal metastases
• Mitotic count A

lesions can be easily misdiagnosed as sub­

ungual haematoma.
Other forms of melanoma include ocular,
mucosal and vulval (p. 236).
The histology of melanomas is very variable
depending on the specific subtype and primary
site. Many of the features assessed by histology
have prognostic value (Box 14.1). In addition to
these the pathologist should report the type of
melanoma, greatest thickness, radial or vertical B
growth phase, excision margins and immuno­
histochemical stains. Immunohistochemical stains Figure 14.1
used in melanoma include S100 (the most fre- Early melanoma showing ABCD signs (A) and advanced
quently used but also stains benign melanocytes), plaque like melanoma (B) with nodule which also
exhibits ABCD signs. From Darrell Rigel: Cancer of the
HMB-45, Mitf, MART-1 and tyrosinase. Skin (Saunders) with permission.
Presentation
Patients usually present with new skin lesions or
change in existing skin lesion. It is important to include itching, bleeding, ulceration or changes
get a detailed history of: in a pre-existing mole. ABCDE features (Figure
14.1) help to distinguish early melanoma from a
• How long lesion has been present?
benign mole:
• When did it start changing?
• Whether it arose from a pre-existing lesion? • A – Asymmetry.
• Previous history of sun exposure, sun • B – Border irregularity.
burns, skin cancers and immunosuppressive • C – Colour variation.
treatment. • D – Diameter of >6 mm.
• Family history of melanoma. • E – Evolution (change in lesion).

Initial assessment Investigations

Initial assessment of patients with suspected In the absence of clinical evidence of meta-
melanoma includes detailed examination and a static disease in regional lymph nodes at presen-
clinical photograph of the lesion, full skin exami- tation, there is no indication for any staging
nation and examination for lymphadenopathy investigations. In patients with thick primary
and hepatomegaly. Clinical signs of melanoma tumours (>4 mm), CT scan may be useful prior
232
 CANCERS OF THE SKIN 14
to rule out metastatic disease. Studies show that Management of regional lymph node
a routine chest X-ray revealed metastasis in only The role of elective lymph node excision for node
0.1% whereas 15% showed false positivity. Sim- negative patients has being debated for several
ilarly CT scan showed metastasis in 1.3% while years. Although initial retrospective studies
false positivity was 16%. showed a survival benefit with this approach,
Patients with >4 mm thick lesion and evidence four randomized studies failed to show any sur-
of nodal metastasis (including micrometastasis) vival advantage. Debate on the role of elective
need staging investigations with full blood count, node dissection has been subsumed by emergence
liver function tests, serum lactate dehydrogenase of the sentinel node concept.
(LDH), chest X-ray and CT scan of chest, The sentinel node (SN) is the node to which
abdomen and pelvis. the lymph initially drains from a tumour before
passing to the other regional nodes. In theory the
Tissue diagnosis sentinel node is most likely to contain the tumour
Excision biopsy to include 2–5 mm of clinical cells and if none are present in this node, it is
margin of normal skin with a cuff of subdermal unlikely that other lymph nodes are involved.
fat is the standard procedure. This helps to The risk of sentinel node metastasis depends
confirm diagnosis and provide guidance for on the thickness of lesion. A tumour less than
subsequent management based on Breslow thick- 0.8 mm thick has 1% SN positivity, 0.8 to
ness. Full thickness incisional biopsy from the 1.5 mm has 8%, 1.5–4 mm thickness has 23%
thickest part of the lesion is acceptable as a mode and more than 4 mm thickness has 36% risk.
of diagnosis in certain anatomical areas (e.g. Although, sentinel node positivity is proven to
face, ear, palm/sole) and for large lesions. Shave have strong correlation with survival (90% 5-year
and punch biopsies are not recommended. survival for SN negative vs. 56% for SN positive),
the role of lymph node dissection for SN positive
Staging
disease is still evolving. Many agree that there is
Breslow thickness, ulceration and mitotic count no proven overall survival benefit from the routine
are most important prognostic factors of local- application of SN to patients with cutaneous
ized disease whereas Clark level is an independent melanoma. However, there is some suggestion
prognostic factor for melanoma of <1 mm that it may increase the disease free survival.
thickness (Box 14.1). Staging is by TNM AJCC Patients with >4 mm thick lesions have a pre-
system and is related to prognosis (Table 14.1). dicted incidence of SN positivity of 30–40%.
M1a includes distant skin, subcutaneous or nodal Hence it is reasonable to offer SN in this group
metastases with a normal LDH. M1b is lung of patients to provide prognostic information
metastases with a normal LDH and M1c is with and selection into clinical trials.
any other metastases or with a raised LDH level. The ongoing MSLT-II trial aims to examine
Management the benefit of complete dissection on survival by
randomizing patients with SN positive melanoma
Non-metastatic disease to undergo either complete nodal dissection or
Primary surgery observation.
Surgical excision with an adequate margin is
primary treatment of choice for patients with no Adjuvant treatment
distant metastasis. The margin is the clinically No trial has shown a survival benefit for adjuvant
measured margin during surgery rather than his- chemotherapy in localized malignant melanoma.
topathological margin. The extent of the margin Due to the activity of immune treatment in
depends on the depth of the melanoma and may advanced melanoma several trials have examined
need to be adjusted for cosmetic or functional the role of interferon and vaccines in the adjuvant
reasons. The recommended margins are: 1 cm treatment of melanoma. A pooled analysis of
for lesions less than 1 mm in depth, 1–2 cm for three ECOG studies showed that adjuvant high
lesions 1–2 mm in depth, and 2 cm for lesions dose interferon improves relapse-free – survival
>2 mm in depth. (about 10% at 5- years) but not overall survival
233
 II SITE-SPECIFIC CANCER MANAGEMENT

Table 14.1: TNM staging & 5-year survival of cutaneous melanoma

Staging 5-year survival (%)
Stage IA 95
T1aN0M0 ≤1 mm thickness without ulceration and mitosis <1/mm 2

Stage IB 91
T1bN0M0 ≤1 mm thickness with ulceration or mitosis ≥1/mm2
T2aN0M0 1.01–2 mm thickness without ulceration
Stage IIA 77–79
T2bN0M0 1.01–2 mm thickness with ulceration
T3aN0M0 2.01–4 mm thickness without ulceration
Stage IIB 63–67
T3bN0M0 2.01–4 mm thickness with ulceration
T4aN0M0 >4 mm thickness without ulceration
Stage IIC 45
T4bN0M0 >4 mm thickness with ulceration
Stage IIIA
T1-4aN1aM0 Micrometastasis* in 1 node 70
T1-4aN2aM0 Micrometastasis in 2–3 nodes 63
Stage IIIB
T1-4bN1a/2aM0 50–53
T1-4aN1bM0 Macrometastasis** in 1 node 46–59
T1-4aN2bM0 Macrometastasis in 2–3 nodes 46–59
T1-4aN2cM0 in-transit metastases/satellites without nodes
Stage IIIC 24–29
T1-4bN1b/2b/2cM0
Any T N3M0 metastasis in >3 nodes or matted nodes or in-transit or satellites with
metastatic nodes
Stage IV
Any T, any N, M1 distant metastasis 7–19%

*micrometastases after sentinel node biopsy; **macrometastases are clinically detectable pathologically confirmed nodes.

in patients with a high-risk resected melanoma. A trial examining the role of a ganglioside
This group included patients with ≥4 mm thick vaccine in the adjuvant treatment of high risk
with no nodal involvement and melanoma involv- melanoma showed no benefit and there were
ing regional nodes or in-transit metastasis. concerns that patients may have done worse than
However, high dose interferon is associated with with no treatment.
a number of side effects such as acute constitu-
tional symptoms, chronic fatigue, headache, Management of positive nodes
weight loss, nausea, myelosuppression and Patients with metastatic lymph node disease are
depression and most patients will require dose treated with regional node dissection if feasible
modifications during treatment. and up to 13–59% of these patients do not
234
 CANCERS OF THE SKIN 14
develop metastatic disease. There is a significant been used to exclude further distant disease,
risk of lymphoedema (especially with groin dis- especially if complex surgery is planned, e.g.
sections) and patients should wear compression resection of cerebral metastases.
stockings for many months. Some trials are Patients with up to three visceral metastases are
examining the role of adjuvant treatment, such candidates for surgical resection and the 5-year
as bevacizumab, after groin dissection. A rand- survival can be more than 20% after complete
omized study has evaluated the role of postop- resection of lung metastases and 28–41% after
erative radiotherapy (48 Gy in 20 fractions) in complete resection of gastrointestinal metastases.
patients with a high risk (>25%) of regional Similarly patients with solitary brain metastases
recurrence after lymphadenectomy. The two- can also be candidates for resection. Adjuvant
year lymph node field relapse-free rate was sig- radiotherapy is often used in some of these patients,
nificantly improved with adjuvant radiotherapy especially after resection of cerebral metastasis.
compared with observation (82 vs. 65% HR
Role of radiotherapy
0.47, 95% CI 0.28–0.67); but without no
Radiotherapy can also be given after surgical
improvement in 2-year overall survival. The long
resection of a solitary metastasis and this is
term toxicity of radiotherapy yet to be reported.
particularly the case after resection of a solitary
brain metastasis. The treatment options include
Management of metastatic disease
whole brain radiotherapy (20 Gy in five fractions
Metastatic melanoma has a poor prognosis. Most or 30 Gy in 10 fractions), stereotactic radio­
patients with non-visceral metastases survive up surgery or a combination of both. The optimal
to 18 months whereas the median survival of radiotherapy in this situation is yet to be defined.
those with visceral involvement or an elevated Palliative radiotherapy is useful in bone metas-
serum LDH is 4–6 months. Lymph node and skin tasis and spinal cord compression not amenable to
metastases in the absence of other metastases surgical decompression (p. 328). Skin metastases
have the best prognosis (up to 18 months). Those which are rapidly enlarging and about to ulcerate
with lung metastases in the absence of other vis- can also be treated with palliative radiotherapy.
ceral disease have an intermediate prognosis (up
to 12 months median survival). Those with other Chemotherapy and other systemic treatments
visceral disease have a median survival of less in metastatic disease
than 6 months which is limited further in the Dacarbazine is the standard intravenous chemo-
presence of a high and rapidly increasing LDH. therapy drug for metastatic melanoma with a
Patients with liver metastases from a primary response rate of 10–20% and a median duration
uveal melanoma have a particularly poor prog- of response of 3–6 months. It is given 3–4 weekly
nosis usually limited to less than 3 months. at doses of 850–1000 mg/m2 with nausea as the
Treatment of melanoma metastases depends main side effect. Temozolamide is an oral ana-
on the site of disease, whether or not it is local- logue of dacarbazine and crosses the blood–brain
ized and the overall fitness of the patient. Treat- barrier but is more expensive and has no improve-
ment can be with surgery, radiotherapy, systemic ment in response rates compared with dacar-
therapies or best supportive care. bazine (Table 14.2). There is no evidence that
combination chemotherapy regime is superior to
Role of surgery single agent drugs in terms of response rates or
In the presence of an isolated metastasis, espe- survival.
cially if the patient has a long disease free inter- Immunotherapy with high dose interleukin-2
val, e.g. 1 year, surgery may be the best option. (IL-2) or interferon alpha has shown response
The most common sites for surgical resection are rates of 10–21%. Toxicities include hypotension,
skin, brain and lung. Resection of liver metas- capillary leak syndrome, sepsis and renal failure.
tases is not usually performed as liver metastases A recent study of ipilimumab, a monoclonal
are associated with such a poor prognosis. antibody against cytotoxic T-lymphocyte antigen
Appropriate staging is important in these patients 4 (CTLA-4), showed improved overall survival
who undergo surgical resection. PET scans have in previously treated patients with unresectable
235
 II SITE-SPECIFIC CANCER MANAGEMENT

Newer agents
Table 14.2: Response rates (%) for single Given the risk of recurrence and poor outcomes
agents in metastatic melanoma
with systemic treatment in metastatic disease,
% Response rate new agents are being developed to target specific
Agent (CR + PR)
pathways involved in melanoma. Examples
Dacarbazine 20
include VEGF, BRAF and bcl-2. Studies are
Temozolamide 21 ongoing to assess the potential benefit of bevaci-
Carmustine (BCNU) 18 zumab in resected stage III and stage IV disease
Lomustine (CCNU) 13
and the role of other anti angiogenics. Sorafenib
which is a TKI which has activity against BRAF
Cisplatin 23
has been shown to improve response rates when
Carboplatin 16 combined with chemotherapy, although no sur-
Vinblastine 13 vival benefit was observed. Agents with a more
Paclitaxel 18
specific BRAF activity are being developed.
Docetaxel 15
Prognostic factors and survival
Prognostic factors are highlighted in Box 14.1.
Survival according to stage is included in
stage III/IV melanoma who were positive for Table 14.1.
HLA-A*0201. Side effects of this treatment
included rash, colitis, diarrhoea and hepatitis. Follow-up
Combining chemotherapy with an immune
modulator has been assessed in several clinical After surgery all patients should be followed up
trials. A meta-analysis showed that this improved due to the risk of further melanomas as well as
response rates, but did not translate into a nodal or systemic recurrence. Full skin and nodal
survival benefit. examination should be carried out and abdomi-
In summary no drug or combination of drugs nal examination to exclude hepatomegaly. For
has shown a significant response rate and high-risk patients (>IA) blood tests to examine
survival benefit over single agent dacarbazine. It LDH, liver function tests and FBC may be carried
remains the standard drug in metastatic melanoma out. At the point of nodal recurrence reassess-
but patients should be entered into clinical trials ment with CT is suggested prior to surgery and
where possible. 6–12 months later. For those who have had met-
astatic disease resected a CT several months later
Isolated limb perfusion is recommended along with close follow-up. All
In some cases widespread metastases do not occur patients, especially who have had nodal disease
but there may be disseminated skin metastases in or metastases, should be warned about the symp-
a limb which cover an area too large for radio- toms of spinal cord compression.
therapy. In these patients, if systemic treatment is
not feasible, isolated limb perfusion with TNF-
alpha and melphalan can establish good local Non-cutaneous melanoma
control. This is only performed in a limited number Ocular melanoma
of centres but can provide good clinical benefit.
Ocular melanoma is a rare subtype of melanoma
Radiofrequency ablation which can occur in many areas of the eye. Most
For some patients with limited systemic disease commonly it occurs in the choroid but less than
but in whom surgery is not possible, radiofre- 5% occur in the iris. The aetiology is uncertain;
quency ablation (RFA) has been used for liver some studies suggest a link with UV radiation.
and lung metastases. In general they should be The risks are higher in those who have had cuta-
less than 5 cm in size and accessible to the RFA neous melanoma, pale iris colour or who have a
catheter used. Complications include bleeding family history of ocular melanoma. The staging
236 and pneumothorax. system differs to that of cutaneous melanoma.
 CANCERS OF THE SKIN 14
Poor prognostic factors include age over 60, practice. A study using carbon ions to minimise
size and involvement of the ciliary body. Although local morbidity showed good local control but
often localized at presentation they have a 5-year survival was still less than 30%. Chemo-
high risk (10–80% depending on number of therapy with standard drugs for cutaneous
prognostic factors) to spread to the liver, often melanoma has been tried with similar success.
several years after successful treatment of the Nodal disease occurs to a greater extent than in
primary. Long-term survival is less than 35% ocular melanoma so regional lymph nodes should
even with successful treatment of the primary. always be examined at follow-up.
Surgery used to be the standard treatment but
radiotherapy has replaced this in most cases. Basal cell carcinoma
Radiotherapy can be administered as external
beam, as a radio-active plaque (e.g. iridium-192) Introduction
or with protons or other charged particles. Local Basal cell carcinoma (BCC) is a slow growing,
control rates are similar with each technique. The locally invasive (hence called rodent ulcer) malig-
vision is often lost in the irradiated eye with the nant epidermal skin tumour. The exact incidence
list of complications including cataracts, glau- is difficult to obtain; though there is a worldwide
coma, retinopathy and vitreous haemorrhage. trend in increasing incidence.
Treatment of metastases in ocular melanoma The most significant aetiological factors appear
has shown that they tend to have a reduced to UV exposure and genetic predisposition. BCC
response rate to chemotherapy and immuno- is common in the sun-exposed area of head and
therapy than cutaneous melanoma and are more neck. Multiple BCC is a feature of Gorlin’s syn-
rapidly progressive. drome. Other risk factors include increasing age,
Due to their propensity for metastases (espe- male, fair skin, immunosuppression, vaccination
cially liver and lung) which can be delayed, fol- scars and arsenic exposure. Sunscreen use and
low-up includes imaging of the liver and lungs in low fat diet are thought to be protective.
addition to LDH and liver function tests. Com-
bined follow-up with ophthalmology is required. Pathology
The common histologic subtypes are superficial,
Mucosal melanoma
nodular and morphoeic (sclerosing). Other vari-
Mucosal melanomas constitute less than 2% of ants include micronodular, infiltrative and baso­
all melanomas. The most common sites of pres- squamous BCC which are aggressive with high
entation are head and neck (up to 50%), female local recurrence. Perivascular and perineural
genital tract (25%) and anorectal (20%). The invasion is associated with aggressive tumours.
remainder occur in very rare sites such as other BCC infiltrate tissues in a three dimensional
areas of the gastrointestinal tract, Eustachian fashion. Lymph node metastasis is extremely rare
tube and salivary glands. They occur later in life except in those with multiple recurrences or
(50–70s) than cutaneous melanoma, are more uncontrolled primary tumour.
common in non-Caucasians and slightly more
common in men than women. They tend to Clinical features
present late as they are essentially hidden from
The common growth patterns are superficial,
sight and have a very poor prognosis. For head
multifocal, nodular and morphoeic (Figure 14.2).
and neck tumours 5-year survival is less than
The sites affected are head and neck (52%), trunk
30% which reduces to <20% with involved
(27%), upper limb (13%) and lower limb (8%).
lymph nodes. The most common presentation is
with bleeding, anaemia or local symptoms such • Superficial BCC occurs on the trunk or limbs
as pain. There is no specific staging system. The of young people. It presents as a well-defined,
treatment of choice is surgical resection with clear erythematous, scaling or slightly shiny
margins but this is often difficult due to location macular lesion. Stretching the lesion causes an
of the tumour. Radiotherapy has been used to try increase in the degree of erythema, highlights
to improve local control but has not shown an the shiny surface and reveals a peripheral
improvement in survival and is not a standard thread-like pearly rim or island of pearliness 237
 II SITE-SPECIFIC CANCER MANAGEMENT

Box 14.2: Treatment modalities in BCC

Surgical excision
• Wide excision
• Mohs’ micrographic surgery
Surgical destruction
• Curettage and cautery
• Cryosurgery
• Carbon dioxide laser
Non-surgical destruction
• Topical immunotherapy with imiquimod
A • Photodynamic therapy
• Radiotherapy

which extends more widely and deeply than

is evident on inspection. It slowly enlarges to
reach a large size. Biopsy is necessary.
Other histolological subtypes are uncommon
and do not have any characteristic clinical
presentation.
Examination
Clinical examination should be done in a well-lit
B
area with the aid of a magnifier. Whole skin
Figure 14.2 examination and regional nodal examination is
Nodular BCC with rolled borders with telangiectasia (A) necessary.
and a morphoeic BCC characterized by a white plaque
with telangiectasia and ill-defined borders (B). From Diagnosis
Darrell Rigel: Cancer of the Skin (Saunders) with
permission.
Diagnosis is often clinical. Biopsy is indicated
when there is clinical suspicion of an alternative
diagnosis or histologic subtype may influence
treatment decision. Punch or shave biopsy may
distributed throughout the lesion. These be appropriate. Imaging of the local area, e.g. by
lesions will progressively enlarge and may CT, may be indicated when there is suspicion of
reach 5–10 cm in diameter. Biopsy is needed bone involvement and deep infiltration (particu-
prior to definitive treatment. larly for a lesion close to the embryonic fusion
• Nodular BCC occurs on the head and neck lines such as the nasal vestibular region, or pre-
region of elderly patients. It presents as a and post-auricular regions).
shiny, pearly, telangiectatic papule or nodule.
The pearly appearance becomes more obvious Treatment
during skin stretching. Radially arranged Treatment is aimed at eradication of tumour
dilated capillaries are often seen across the with acceptable cosmetic and functional outcome.
surface of lesion. With ongoing growth, A number of treatment options are available
tumour ulceration can occur which leads to (Box 14.2) and the choice of treatment in small
central umbilication of lesion with a raised BCC depends on various factors (Box 14.3).
rolled border. Islands of pigments can also Radiotherapy is indicated when cosmetic and/or
be seen. functional outcome is better with radiotherapy
• Morphoeic SCC typically presents as a pale compared with surgery and when there is a need
scar and palpation reveals firm induration to avoid complex plastic surgery.
238
 CANCERS OF THE SKIN 14

Box 14.3: Treatment of choice in BCC

tumour free. This is more appropriate for tumours
with poorly defined borders, recurrent tumour
Surgery and radiotherapy (RT) are effective treatment
for small and less invasive tumours. Large and deeply and extensive disease.
invasive lesions are treated with surgery with or
without postoperative radiotherapy. Radiotherapy
RT favoured in: Radiotherapy results in 93–95% 10-year control
• Mid-face, nasal , inner canthus, lower eye lid, lip rate for BCC of ≤2 cm. Radiotherapy details are
commissures (better function) given in Box 14.4.
• Multiple superficial lesions difficult to excise
(better cosmesis) Recurrence
• Patients >70 years (long-term toxicity is less of an
issue)
Recurrence is common with mid face and pre-
• Patients who wish to avoid surgery
auricular lesions, tumours >2 cm and aggressive
• Patients prone to keloid formation
subtypes. Two-thirds of recurrences occur within
Surgery is the choice in: 2 years of primary treatment and 20% occur in
• Readily excisable lesions in those <70 years 2–5 years. Recurrences after non-surgical treat-
• Lesions in hair-bearing areas or overlying lacrimal ment are generally treated with surgical resection
gland followed by plastic surgical repair. Recurrence
• Recurrence after radiotherapy after surgical treatment can be treated with
• Multifocal disease especially with dysplastic skin surgery or radiotherapy.
• Upper eyelid tumours (better function)
• Dorsum of the hand (better function)
Prognosis
• Below knee and other sites of poor vascularity Overall 10-year control rate is >90%. A number
(problem with healing and function) of factors influence prognosis. The important
• Invasion to bones and joints* prognostic factors are size, depth of invasion,
*Cartilage invasion is not an absolute contraindication to
histological subtype (morphoeic, infiltrative and
radiotherapy. Radiotherapy is, however, avoided in large pinna basosquamous have higher recurrence), comple-
lesions with extensive, inflamed or painful cartilage invasion. tion of excision (incomplete excisions have a
30% recurrence rate), site of disease (disease
around nose, eyes and ears have higher recur-
Surgery rence rates) and presence of perineural spread.
Wide excision (WE)
WE of simple lesions need a 2–3 mm margin Squamous cell carcinoma
whereas complex lesions or clinically poorly
Introduction
defined lesions need a margin of 3–5 mm. An
adequate microscopic margin is 0.5 mm. The Squamous cell carcinoma (SCC) is the second
most appropriate management after incomplete most common skin cancer constituting 20% of
excision is debatable. The treatment options skin malignancies. The incidence appears to be
include re-excision, radiotherapy or observation. increasing and males are more commonly affected.
Adjuvant radiotherapy improves 5-year survival Risk factors include exposure to ionizing or
from 61 to 91%. Observation is an option for ultraviolet radiation, immunosuppression, scars,
elderly patients where further surgery and radio- chronic wounds, smoking and arsenic exposure.
therapy may not be appropriate. Congenital conditions such as oculocutaneous
albinism and xeroderma pigmentosum are also
Mohs’ micrographic surgery associated with increased risk of SCC. It is
During this procedure, the tumour is excised common in sun-exposed areas and hence sun
and the entire peripheral and deep margins are screen is protective.
examined by frozen section for residual tumour.
Mapping and staining of excised tissue and a Pathology
specialized tissue sectioning procedure enables In situ (Bowen’s disease) SCC is limited to
precise localization of residual tumour and the epidermis which presents as a flat scaling pink
process of excision continues until the margin is lesion with irregular borders. There is no risk of
239
 II SITE-SPECIFIC CANCER MANAGEMENT

Box 14.4: Radiotherapy for skin cancer

Consent
• Acute reactions involve dermatitis and mucositis which resolve by 6 weeks following treatment.
• Late effects involve thinning of skin, alopecia, loss of sweating, change in colour, telangiectasis and fibrosis.
Position and immobilization
Depends on the site.
Type of radiation
Depends on depth of penetration needed and type of underlying tissue.
Depth of penetration
• ≤5 mm deep lesion – superficial X-ray.
• >5 mm–2 cm deep lesion – deep X-ray or low energy electrons (6 MeV).
• >2 cm tumour – high energy electrons or photons.
Underlying tissue
• Bone – electrons are preferable to avoid increased absorbed dose from deep X-rays.
• Air cavities (e.g. near sinuses) – X-rays or photons preferred as dosimetry is difficult with electrons.
Treatment volume
• Well-defined BCC – 5 mm margin around macroscopic tumour.
• Ill-defined BCC and SCC – 10 mm margin.
Beam shaping – custom made lead cut out for X-rays and end frame cut-out for electron. Crenallation of the
margin of a round cut out gives a better cosmesis by blurring the edge of radiation reaction.
Radiotherapy dose
BCC is thought to be more radiosensitive than SCC. Equivalent doses for BCC and SCC and rough guide for
selection of fractionation regime are as follows:
BCC SCC
60 Gy/30 fractions/6 weeks* 60–66 Gy/30–32 fractions
50 Gy/20 fractions/4 weeks* 55 Gy/20 fractions
40 Gy/15 fractions/3 weeks 40 Gy/10 fractions
40.5 Gy/9 fractions/3 weeks 45 Gy/9 fractions
32.5 Gy/5 fractions/1 week 32.5 Gy/5 fractions
32 Gy/4 fractions/4 weeks** 32 Gy/4 fractions/4weeks
12–15 Gy/1 fraction** 12–15 Gy/1 fraction
*fractionation used in patient aged <70 years and/or tumour of >3–4 cm; **used in frail patients.

Special considerations
Electron planning
• Electron beam field is defined by 50% isodose and the 90% isodose is 3–5 mm inside the field. Hence, in order
to enclose the PTV within 90% isodose, a 5 mm larger electron applicator than defined by PTV is needed.
• At higher energies, isodoses close to the surface bows inwards which necessitates 1 cm larger applicator
diameter than the defined PTV to ensure homogenous dose to the tumour (p. 18, Figure 3.2B).
• Surface dose increases with electron energy; a bolus is needed for lower energies to bring up 90% isodose to
the skin surface (p. 18, Figure 3.2A).
• Bolus is also used to bring up high dose to surface to avoid radiation to underlying critical structures.
• Stand off effect – fill the area with bolus/calculate correction
Normal tissue shielding
• Lower eyelid and canthi tumours need corneal shielding.
• Lip tumours need buccal shields. Shields should be coated with wax to absorb scattered radiation.
• Tumours in the pinna and nasal regions when treated with electrons need wax coated lead plugs in the
external auditory canal and nose respectively to avoid normal tissue damage.

240
 CANCERS OF THE SKIN 14
metastasis, although progression to invasive SCC masses and bleeding. Metastasis is primarily to
occurs in 3–11% of cases. the regional nodes (2–6%). The head and neck
In situ SCC of the glans penis (erythroplasia region is the commonest site in men whereas the
of Queyrat) has 20% risk of metastasis and 30% upper limb followed by head and neck are the
can progress to invasive disease. commonest sites in females. Only 8% of SCC
Invasive SCC is composed of a collection of arise on the trunk.
atypical keratocytes which invade the dermis and
deeper structures. Other histologic variants are: Examination
Examination should be of the whole skin and
• Adenoid SCC – can metastasize in 3–19% regional lymph nodes.
and associated with rapid local growth.
• Adenosquamous SCC – shows squamous Diagnosis
appearance superficially and glandular appear- Tissue biopsy is essential for diagnosis. CT scan
ance deeply. These are aggressive tumours. helps to detect regional lymph nodes. FNA of the
• Spindle cell SCC – appears as ulcerated nodules enlarged lymph node under radiological guid-
or exophytic tumours and may be difficult to ance is advised. Open surgical biopsy should be
distinguish from sarcoma histologically. These avoided. The role of sentinel node biopsy is
tumours are aggressive with a tendency to evolving.
perineural invasion and metastasis (25%).
• Verrucous SCC – appears like a large wart. Staging
These are slow growing, locally invasive and T1 – ≤2 cm in greatest dimension.
do not metastasize. T2 – >2 to 5 cm in greatest dimension.
• Keratoacanthoma – appears as a rapidly T3 – >5 cm in greatest dimension.
growing nodule with a central keratin plug. T4 – tumour invades deep extradermal
True lesions can undergo spontaneous regres- structures.
sion but most are now viewed as SCC. N1 – regional nodal metastasis.
Clinical presentation M1 – distant metastasis.
Typical presentation is a raised pink papule or Treatment
plaque with erosion or ulceration (Figure 14.3). Three factors that influence treatment of SCC
In advanced cases it presents as large ulcerated are: the need for removal of tumour locally, the
possibility of ‘in-transit’ metastasis and regional
nodal metastasis. Treatment options include:
• Cryotherapy (for small tumours with well
defined borders).
• Curettage and electrodessication (for well
differentiated tumours of <1 cm size).
• Radiotherapy (see Box 14.3) – used as a
primary treatment and adjuvant after surgery.
• Surgical excision (see Box 14.3) and Mohs’
micrographic surgery.
Surgery
Surgery is aimed at complete removal of the
tumour and of any metastasis. Low-risk tumours
of <2 cm are excised with a minimal margin of
4 mm whereas tumours of >2 cm size, high risk
Figure 14.3
tumours (grade 2–4, in high risk locations such as
Digital squamous cell carcinoma. From Darrell Rigel: ear, lip, scalp, eyelids and nose) and those extend-
Cancer of the Skin (Saunders) with permission. ing into subcutaneous tissue need a minimum
241
 II SITE-SPECIFIC CANCER MANAGEMENT

margin of 6 mm or more. Depth of excision should Chemotherapy

be through normal underlying fat. The accepted In patients with distant metastasis from SCC,
minimal microscopic margin is >1 mm. cisplatin based chemotherapy is the most effective
Mohs’ micrographic surgery is indicated in regime. A commonly used combination is cisplatin
high risk tumours and recurrences. with adriamycin, which has an overall response
rate of >80% with complete response rate of
Management of lymph nodes 30%. However, survival is generally less than
The treatment of metastatic lymph nodes is 2 years.
primary surgery. Elective lymph node dissection
is not routinely advised. There is some evidence Recurrence
that it may have a role in tumours of >8 mm in Most recurrences occur within 2–3 years. Treat-
depth. Patients with recurrent thick (>4 mm) ment is individualized based on the extent of
lesions in the vicinity of the parotid (temple, fore- recurrence and previous treatment.
head and preauricular area) may also be consid-
ered for elective nodal treatment. Prognostic factors
• Grade of differentiation – grade 3–4 lesions
Radiotherapy are twice as likely to recur and three times as
Principles of primary radiotherapy and treatment likely to metastasize than grade 1–2 lesions.
guidelines are same as that of BCC (Boxes 14.3 • Histologic type – spindle cell carcinoma and
and 14.4). 5-year control rate with radiotherapy adenosquamous carcinoma have high risk of
is comparable with surgery with >93% for T1 recurrence and metastasis.
lesions, 65–85% with T2 and 50–60% with • Location of tumour – scalp, lips, pinna, nose
T3–4 lesions. Radiotherapy is indicated after and genital lesions have a high risk of
incomplete excision when further surgery is not metastasis.
contemplated, as incomplete excision leads to • Tumour size – risk of recurrence and metas-
50% local recurrence. tasis increases with size of the tumour. Risk
Postoperative radiotherapy to the primary of recurrence is twice (15% vs. 7%) and risk
tumour site is considered for patients with high of metastasis is three-fold (30% vs. 9%) in
risk disease after complete excision. High risk tumours >2 cm compared with tumours of
disease includes: tumour invasion beyond sub­ <2 cm.
cutaneous tissue (T4), recurrent disease, margin • Depth of invasion – tumours with depth
<5 mm, perineural invasion (major or minor <2 mm seldom metastasize whereas those
nerve), lymphovascular invasion, in-transit with >4 mm have high risk of recurrence and
metastases and nodal metastasis. Indications for metastasis.
postoperative radiotherapy after primary surgi- • Perineural invasion – occurs in 2.5% of
cal management of metastatic lymph nodes are: tumours and its presence indicates a high risk
of local recurrence (up to 50%) and distant
• ≥3 cm node.
metastasis (up to 35%).
• ≥2 positive nodes in neck and ≥3 nodes in
• After lymphadenectomy, prognosis depends
axilla and groin.
on number of positive nodes and presence of
• Extranodal extension.
extranodal spread.
• Close or positive margin.
• Recurrence – local recurrence increases rate
• Skin involvement.
for further recurrence (25%) and lymph node
• Major nerve involvement.
metastasis (30%).
• Parotid node metastases.
• Tumours in immunosuppressant patients
• After salvage surgery for recurrent nodal
and those arising from scars have a poor
metastases.
prognosis.
The role of postoperative chemo-radiotherapy
for high risk SCC is being evaluated. Palliative Outcome
radiotherapy is used in metastatic disease to Local control rate for SCC is 10–15% lower than
242 obtain symptom relief. a similarly sized BCC.
 CANCERS OF THE SKIN 14

Bowen’s disease (in situ SCC)

Presents as a slow-growing erythematous plaque.
Surgery, topical treatment and radiotherapy are
the options of treatment. Radiotherapy involves
40–50 Gy in 10–20 fractions using 100–150 kV
superficial X-rays resulting in 95–100% local
control.

Keratoacanthoma
Presents as a rapidly enlarging lesion with central Figure 14.4
keratin plug. Histologically, it is difficult to Merkel cell carcinoma. From Darrell Rigel: Cancer of the
distinguish this from SCC. In up to 20% of Skin (Saunders) with permission.
patients spontaneous regression can occur over
6–12 weeks. Treatment options include early develop distant metastasis. Liver, lung, bone and
excision and radiotherapy (similar to SCC). brain are the sites of distant metastases.
Squamous cell carcinoma of lip Diagnosis and staging
Lesions involving <30% of lip can be treated Initial evaluation includes clinical examination
with wedge excision and repair. When >30% of of the whole skin surface and regional nodes.
the lip is involved, surgery results in functional Imaging includes CT scan of the relevant nodal
disability and hence radiotherapy is a treatment region as well as chest and liver. Blood tests
option. Treatment is with orthovoltage X-rays or include full blood count and biochemistry.
electrons with an intraoral lead shield to protect 70–80% patients present with local disease
the mandible or teeth or by implantation. Typical (stage IA ≤2 cm and IB >2 cm), 10–30% with
radiation dose is 50–55 Gy in 20–25 fractions. regional nodal disease (stage II) and 1–4% with
distant metastasis (stage III).
Merkel cell carcinoma
Treatment
Introduction
Stage I disease is usually treated with wide excision
Merkel cell carcinoma (MCC) is a rare aggressive of the primary tumour (2.5–3 cm margin) and
neuroendocrine tumour of the skin. The exact sentinel node biopsy. All patients receive postop-
aetiology is not known. The reported risk factors erative radiotherapy to the primary site with a
include ultraviolet exposure, previous skin generous margin of 3–5 cm (to ensure dermal
cancers and haematological malignancies, immu- lymphatics are treated). Regional lymph nodes are
nosuppression and HIV infection. The average generally treated electively due to the high risk of
age at presentation is 69 years. Males are more recurrence (46–76%) when nodes are not treated.
commonly affected. Radiotherapy dose ranges from 45–60 Gy using
Pathology 1.8–2 Gy per fraction. The role of adjuvant chem-
Histologically these are small blue cell neoplasms otherapy is unknown. Recent studies indicate that
which express neuroendocrine and cytokeratin primary radiotherapy (60 Gy) is an appropriate
markers. alternative which yields a better cosmesis.
Stage II disease is treated with surgery of the
Clinical features primary lesion and nodal dissection. All patients
MCC present as red or violaceous nodules with receive postoperative radiotherapy (50–60 Gy).
a shiny surface, often with overlying telangi­ Adjuvant chemotherapy may be considered.
ectasia (Figure 14.4). Spread through dermal Chemotherapy regime mirrors those used for
lymphatics can result in the development of satel- small cell lung cancer.
lite lesions. The most common site of disease is Stage III disease has a median survival of 9
the head and neck region, followed by extremi- months. Platinum based chemotherapy yields a
ties and trunk. One-third of patients have regional short lived complete response of 44% and partial
nodal metastases at presentation and 50% response of 11%. 243
 II SITE-SPECIFIC CANCER MANAGEMENT

Prognosis Cutaneous lymphoma

Stage is an important prognostic factor. The The role of radiotherapy is essentially palliative
median survival of node negative patients is 40 in cutaneous lymphoma, the exceptions being
months whereas that of node positive patients is primary cutaneous B cell lymphoma (CBCL) and
11 months. Other poor prognostic factors include selected patients with cutaneous T-cell lymphoma
tumour >2 cm, age >60 years and lack of adju- especially mycosis fungoides. In CBCL, radio-
vant radiotherapy. therapy of 36–40 Gy results in an 85–100%
control rate. Selected patients with mycosis fun-
Skin adnexal carcinoma goides can be treated with total skin electron
Skin adnexal carcinomas are eccrine and apocrine radiotherapy to a dose of 36 Gy over 9 weeks.
sweat gland carcinomas, sebaceous gland carci- This is a complex treatment and is only possible
noma and microcystic adnexal carcinoma. These in specialist centres.
represent 0.2% of skin cancers and usually exhibit
aggressive behaviour and local recurrence. There Kaposi’s sarcoma
are a number of histological subtypes.
See p. 295.
Eccrine sweat gland carcinoma is common in
the head and neck region, trunk and extremities
and apocrine carcinoma is common in the axilla. Further reading
These tumours exhibit an initial indolent growth Garbe C, Peris K, Hauschild A et al. Diagnosis and
followed by rapid progression including distant treatment of melanoma: European consensus-based
interdisciplinary guideline. Eur J Cancer.
metastasis. Surgery is the treatment of choice
2010;46:270–283.
which involves wide excision and elective lymph Mouawad R, Sebert M, Michels J et al. Treatment for
node dissection. Postoperative radiotherapy is metastatic malignant melanoma: old drugs and new
advisable in the presence of tumour of >5 cm, deep strategies. Crit Rev Oncol Hematol. 2010;74:27–39.
infiltration, close (<1 mm) or positive margin, Thompson JF, Scolyer RA, Kefford RF. Cutaneous
melanoma in the era of molecular profiling. Lancet.
high-grade tumours, perineural infiltration,
2009;374:362–365.
dermal lymphatic invasion, ≥4 positive nodes and Miller AJ, Mihm MC Jr. Melanoma. N Engl J Med.
extranodal invasion. Radiotherapy management 2006;355:51–65.
is same as that of SCC. Telfer NR, Colver GB, Morton CA. Guidelines for the
Sebaceous carcinoma commonly occurs in the management of basal cell carcinoma. Br J Dermatol.
2008;159:35–48.
upper lid, scalp or face and is common in women.
Veness MJ. The important role of radiotherapy in patients
Surgery is the treatment of choice; either wide with non-melanoma skin cancer and other cutaneous
excision or Mohs’ micrographic surgery. Radio- entities. J Med Imaging Radiat Oncol. 2008;52:278–
therapy may be indicated for high risk patients 286.
such as those with a positive margin and exten- Neville JA, Welch E, Leffell DJ. Management of
nonmelanoma skin cancer in 2007. Nat Clin Pract Oncol.
sive nodal involvement. However, the risk of
2007;4:462–469.
potential damage to ocular structures needs to be Rockville Merkel Cell Carcinoma Group. Merkel cell
considered. Elderly patients may be treated with carcinoma: recent progress and current priorities on
primary radiotherapy delivering >55 Gy. 36% etiology, pathogenesis, and clinical management. J Clin
patients develop local recurrence and 20–25% Oncol. 2009;27:4021–4026.
Eng TY, Boersma MG, Fuller CD et al. A comprehensive
patients die of this cancer.
review of the treatment of Merkel cell carcinoma. Am J
Microcystic adnexal carcinoma is a locally Clin Oncol. 2007;30:624–636.
destructive carcinoma often present as a sclerotic Senff NJ, Noordijk EM, Kim YH et al. European
or indurated plaque with an intact dermis. The Organization for Research and Treatment of Cancer and
usual sites of involvement are mid face and lip. International Society for Cutaneous Lymphoma consensus
recommendations for the management of cutaneous B-cell
Wide local excision or Mohs’ surgery is the treat-
lymphomas. Blood. 2008;112:1600–1609.
ment of choice. Surgery is associated with a local Willemze R, Dreyling M. Primary cutaneous lymphoma:
recurrence of 50–60%. These are thought to be ESMO clinical recommendations for diagnosis, treatment
radioresistant tumours. and follow-up. Ann Oncol. 2009;20 Suppl 4:115–118.
244
Cancers of the
musculoskeletal system
HM Hatcher and TV Ajithkumar
15
Overview Aetiology
Cancers of the musculoskeletal system or sarco­ Most primary bone tumours arise spontaneously
mas can be divided into primary tumours of bone without a predisposing risk factor. However
and soft tissue sarcomas. Each of these can be for each subgroup there are recognized risk
subdivided into specific subgroups. This results factors.
in a large number of tumours which are often For osteosarcoma the most important risk
grouped together, but which have different factor is prior radiotherapy which accounts
responses to treatment. Due to their rarity, for only 3% of cases, with a time interval of
sarcomas should be treated in a centre with 14 years (range 4–40 years). It is the most
appropriate expertise. common secondary malignancy following treat­
ment for childhood cancer. Other factors include
chemotherapy with alkylating agents, Paget’s
Primary bone tumours disease, chronic osteomyelitis, and hereditary
Epidemiology and incidence conditions such as hereditary retinoblastoma and
Primary malignant tumours of bone are rare. The Li–Fraumeni syndrome (p. 53, 55). In hereditary
most common subtypes are osteosarcoma, the retinoblastoma, the relative risk (RR) of osteo­
Ewing’s family of tumours and chondrosarcoma. sarcoma is 500 for limb osteosarcomas and
In the UK, osteosarcoma accounts for up to 2000 for skull osteosarcomas following irradia­
35% of all primary bone tumours. There are two tion for retinoblastoma. Li–Fraumeni syndrome
peaks of incidence: in those aged 15–19 and a patients have a RR of 15 for osteosarcoma at
smaller second peak occurs over the age of 65 all sites.
associated with Paget’s disease. There are few risk factors for Ewing’s sarcoma
Ewing’s sarcomas and their soft tissue but treatment for a primary cancer in childhood
counterpart, primitive neuroectodermal tumour is a known association.
(PNET), are the second most common bone For chondrosarcoma, there is an increased risk
malignancy. The median age at diagnosis is 14 is those with hereditary multiple exostosis or
although they can occur at any age. There is a enchondromatosis syndromes, in whom it tends
male predominance with a 1.5 : 1 male:female to present at an earlier age.
ratio.
Chondrosarcomas comprise less than 12% Pathogenesis
bone tumours and are the third most common Ewing’s tumours consistently have reciprocal
malignant bone tumour. It is common over the chromosomal translocations, usually between
age of 40 with the peak incidence in those over the EWS gene on chromosome 22 and FLI-1 on
the age of 70. chromosome 11. In 85% of cases this is t(11;22)

© 2011, Elsevier Ltd 245

DOI: 10.1016/B978-0-7234-3458-0.00020-8
 II SITE-SPECIFIC CANCER MANAGEMENT

Box 15.1: Clinical features seen in many types

often marked by clips to ensure it is removed at
of bone tumour the time of definitive surgery.
• Localized bone pain, usually present for several Due to the consistency of chromosomal trans­
months locations in Ewing’s tumours these are used in
• Pain at night or at rest diagnosis, either with cytogenetics, FISH or PCR.
• In some cases localized swelling and overlying
erythema Staging
• Often a previous injury to the region has been Adequate staging includes optimal imaging of the
noted and can result in delay in diagnosis
In advanced disease systemic symptoms may be
primary site (MRI) and the entire bone to exclude
present. These include intra-medullary skip metastases, which occur in
• fever osteosarcomas and Ewing’s tumours. A CT scan
• weight loss and of the chest should be done to assess for possible
• lethargy pulmonary metastases. For PNETs arising in the
lower half of the body a CT of the pelvis and
abdomen can be considered as there may be
(q24;q12). Other variants place EWS with other lymph node involvement. A bone scintigram, or
genes such as t(21;22)(q22;q12) EWS-ERG in some centres a CT-PET, will assess for bone
translocation which occurs in up to 10%. metastases. A whole body MRI on STIR sequence
Unlike Ewing’s sarcomas there are no char­ has shown to be effective in detection of bone
acteristic chromosomal translocations in osteo­ metastases which may not be visible with other
sarcomas, although loss of heterozygosity in the forms of imaging, particularly in Ewing’s
regions of both the retinoblastoma gene and p53 tumours. A bone marrow aspirate should be
have been described. A significant number of performed in patients with a Ewing’s tumour
osteosarcomas express insulin-like growth factor to exclude bone marrow involvement. Staging is
receptor-1 (IGFR-1) which is being explored as according to the AJCC bone tumour staging
a therapeutic target. (Table 15.1).
Patients should also undergo investigations
Clinical features which will be relevant to the further manage­
There are some features which are common to ment of their individual sarcoma. LDH has
many types of bone tumour (Box 15.1). prognostic value in Ewing’s tumours and ALP in
Systemic symptoms occur more often in osteosarcomas.
Ewing’s sarcoma than any other bone sarcoma.
Ewing’s sarcomas which can have a significant
Principles of surgical management
soft tissue component may be mistaken for infec­ in bone tumours
tion and can also occur in areas of long standing Complete surgical resection of the tumour by
infection. These factors can also lead to signifi­ specialist sarcoma orthopaedic surgeons is
cant delays which can impact on the prognosis required for the best outcome. Surgery is the
and psychological impact for the patient. major component of management in chondro­
sarcomas but is also essential for local control in
Diagnosis Ewing’s and osteosarcomas. Limb sparing surgery
An X-ray of the affected area may be suggestive has evolved significantly in the past 30 years such
of a diagnosis but a diagnostic biopsy is required that amputation is used less often and should be
to make an accurate diagnosis and direct further avoided if possible. Extending endoprostheses
treatment. A biopsy should only be performed by have also been developed to minimize the number
a specialist sarcoma surgeon who will take into of surgeries a growing child or young adult may
account possible future surgery and will mini­ require.
mize the risks of tumour spread to the skin or
adjacent structures. Fine needle biopsies are not Osteosarcoma
suitable for primary diagnosis but can be used to Several subtypes of osteosarcoma exist. Over
confirm metastatic disease. The biopsy tract is 90% are high-grade intramedullary tumours,
246
 CANCERS OF THE MUSCULOSKELETAL SYSTEM 15

Table 15.1: AJCC 2002 TNM staging for

primary bone tumours
Primary tumour (T)
TX Primary tumour cannot be assessed
T0 No evidence of primary tumour
T1 Tumour 8 cm or less in greatest
dimension
T2 Tumour more than 8 cm in greatest
dimension
T3 Discontinuous tumours (skip lesions)
in the primary bone site
Regional lymph nodes (N)
NX Regional lymph nodes cannot be
assessed
Figure 15.1
N0 No regional lymph node metastasis
Coronal MRI of pelvis and thighs showing osteosarcoma
N1 Regional lymph node metastasis of the left acetabulum (arrow). Note the change in bone
texture compared with the normal side.
Distant metastasis (M)
MX Distant metastasis cannot be assessed
M0 No distant metastasis half of which are osteoblastic and the other half
M1 Distant metastasis are split equally between fibroblastic and chondro­
M1a Lung
blastic osteosarcomas. The remaining 10% are
made up of small subgroups including telangiec­
M1b Other distant sites
tatic osteosarcoma, extraosseous osteosarcoma,
Histological grade (G) juxtacortical osteosarcoma and malignant fibrous
GX Grade cannot be assessed histiocytoma of bone which is treated in the same
G1 Well-differentiated – low-grade way as intramedullary osteosarcoma.
Figures 15.1 and 15.2 show imaging features
G2 Moderately differentiated – low-
grade of osteosarcoma. Box 15.2 shows prognostic
factors in osteosarcoma. An overview of manage­
G3 Poorly differentiated – high-grade
ment is shown in Figure 15.3.
G4 Undifferentiated – high-grade
Note: Ewing’s sarcoma is classified as G4 Localized osteosarcoma
Stage grouping Localized osteosarcoma is treated with neoadju­
vant chemotherapy followed by surgery (Figure
Stage IA T1 N0 M0 G1, 2
Low-grade
15.4) and adjuvant chemotherapy.
Stage IB T2 N0 M0 G1, 2 Chemotherapy
Low-grade Prior to the 1980s all patients with apparently
Stage IIA T1 N0 M0 G3, 4 localized disease had surgery (usually amputa­
High-grade tion) but only 20–30% survived over 5 years.
Stage IIB T2 N0 M0 G3, 4 Most died of disseminated disease suggesting the
High-grade presence of micrometastases in apparently early
Stage III T3 N0 M0 Any G disease. A pivotal study showed that giving adju­
Stage IVA Any T N0 M1a Any G vant chemotherapy improved survival from 17%
to 66%, and neoadjuvant chemotherapy was
Stage IVB Any T N1 Any M Any G
subsequently implemented. The most frequently
Any T Any N M1b Any G used drugs are cisplatin and doxorubicin.
Methotrexate at doses up to 12 g/m2 is used in
247
 II SITE-SPECIFIC CANCER MANAGEMENT

Box 15.3: Chemotherapy for metastatic

osteosarcoma
• In younger patients: cisplatin, doxorubicin and
methotrexate (PAM)
• In older patients the methotrexate is often
omitted due to increased toxicity
• If the patient has relapsed with metastases within
1–2 years of original treatment, ifosfamide with or
without etoposide can be effective
• High-dose methotrexate with folinic acid rescue
can be effective if previously treatment was with
cisplatin and doxorubicin alone

Recently a study with the bacterial cell wall

mimic muramyl tripeptide (MTP) when added to
combination chemotherapy showed an improve­
ment in 6-year survival to 78% in primary
osteosarcomas.
Figure 15.2
X-ray of left knee showing characteristic features of an Radiotherapy
osteosarcoma of the medial proximal tibia with bone Radiotherapy is markedly inferior to surgical
destruction due to an expansile lesion (arrows) and resection of the primary tumour for osteosarco­
periosteal elevation (arrow head). (Courtesy of Mr mas in terms of overall survival but has been used
Rob Grimer, Royal National Orthopaedic Hospital,
Birmingham.)
in patients who decline or who are unable to
have surgery.
Metastatic osteosarcoma
Box 15.2: Factors predicting a poor prognosis In one study 11.4% osteosarcoma patients had
• Age <14 years or >40 years metastases at the time of presentation. Metas­
• Poor response (<90% necrosis) to neoadjuvant tases can occur in the lungs, bone and bone
chemotherapy marrow. Lymph node and brain metastases are
• Pathological fracture exceptionally rare. Isolated pulmonary metas­
• Large tumour volume, which is also associated tases have the best prognosis and bone metas­
with lung metastases
• Metastases at presentation with bone metastases
tases the worst prognosis. Overall survival at
having a worse prognosis than lung metastases 5 years ranges from 10–50%. Up to 30% of
• Primary tumours which are axial or extraosseous. patients with lung metastases survive over 10
Secondary osteosarcoma years with a combination of surgery, combina­
• Raised ALP or LDH tion chemotherapy and occasionally radiother­
• Increased cadherin 11 expression apy. Although the chance of cure is small, patients
particularly with limited and potentially resect­
able lung metastases should be treated aggres­
sively with chemotherapy and surgery.
addition to cisplatin and doxorubicin in younger
patients and has been found to increase tumour Chemotherapy
necrosis. The degree of tumour necrosis after As in the adjuvant setting, the most effective
neoadjuvant chemotherapy is of prognostic agents are cisplatin, doxorubicin, methotrexate
value. Less than 90% necrosis is associated with and ifosfamide (Box 15.3). Response rates are
a poorer prognosis. Whether prognosis can be between 20–40% although some tumours and
improved by changing chemotherapy after metastases may not reduce in size. Apparent cal­
surgery is one of the roles of the international cification of lung metastases can occur (Figure
EURAMOS trial. 15.5). If the presentation is with metastases,
248
 CANCERS OF THE MUSCULOSKELETAL SYSTEM 15
Figure 15.3
Biopsy
Management of osteosarcoma.

Staging
CT chest
Bone scan
Work up for treatment:
bloods, MUGA/ECHO, GFR

Localized Metastatic

Neoadjuvant Small number of Extensive

chemotherapy* operable lung inoperable lung
(?eligible for clinical trials) metastases metastases or bone
metastases

Surgery Chemotherapy Chemotherapy +/–

Assess pathological then assess radiotherapy for
response response painful metastases

>90% <90% Good Poor

Continue same Consider changing Surgery for Change

chemotherapy chemotherapy or primary and chemotherapy
follow trial protocol lung metastases and reassess

Postoperative
chemotherapy

* Neoadjuvant chemotherapy PAM (cisplatin, doxorubicin and methotrexate) for young fit patients
and cisplatin/doxorubicin for older patients

combination chemotherapy should be the volume lung metastases, or with the intention of
primary treatment. cure, e.g. resection of lung metastases.
High-dose treatment with stem cell rescue has
Radiotherapy
shown no improvement in survival. Trials are
Although osteosarcomas are relatively radio
underway to evaluate biological agents such
resistant tumours, radiotherapy has been success­
as insulin like growth factor 1 receptor (IGF1-R)
fully used in a number of clinical situations
antagonists. Immunotherapy may have a role
such as to control bone pain. It has also been
and the use of liposomal muramyl tripeptide-
used in addition to chemotherapy and surgery,
phosphatidyl-ethanolamine has been shown to
e.g. following resection of lung metastases some
produce a survival benefit in the adjuvant setting.
groups advocate whole lung radiotherapy in
Surgery addition to chemotherapy. It may provide local
Surgery in the metastatic setting should either be control for some patients with advanced meta­
aimed at palliation of symptoms, e.g. resection static disease for whom resection of the primary
of a large primary extremity tumour with low is inappropriate.
249
 II SITE-SPECIFIC CANCER MANAGEMENT

Box 15.4: Poor prognostic factors in Ewing’s

sarcoma
• Age over 14 years
• Metastases at presentation (especially non-
pulmonary metastases)
• Pelvic or axial primary site
• Size greater than 8 cm
• Raised LDH

radiotherapy. Chemotherapy drugs are the same

as those used for metastatic disease. Surgery may
be possible but limb sparing surgery is less likely
for local recurrence of extremity tumours. Radio­
therapy may be useful for local control but is less
Figure 15.4
effective than surgery.
X-ray of knee showing endoprosthetic replacement for
osteosarcoma of the right tibia.
Ewing’s sarcoma
Presentation
Unlike osteosarcomas which present most often
in the epiphyses of long bones, Ewing’s sarcomas
occur within the diaphysis and are often associ­
ated with a soft tissue mass. The soft tissue reac­
tion may be confused for infection and contribute
to delay in diagnosis. The median delay from
symptoms (Box 15.1) to diagnosis is 6–9 months.
The most common sites are long bones (53%) or
the axial skeleton (47%). 25% have a soft tissue
primary. Systemic symptoms (fever, anorexia,
weight loss, and lethargy) may be present and are
associated with advanced disease. 25% patients
have metastases at presentation. Subclinical
metastases are present in 80–90% with appar­
ently localized disease, necessitating multimodal­
ity treatment even in apparently small volume
localized disease. Prognostic factors are listed in
Figure 15.5 Box 15.4.
Axial CT of chest showing pleurally based and calcified X-ray may show a characteristic destructive
metastases characteristic of osteosarcoma (arrow). These
lesion within the bone with surrounding peri­
lung metastases can bleed giving rise to bloody pleural
effusions. osteal reaction known as an onion skin appear­
ance (Figure 15.6). A soft tissue reaction
may also be seen on X-ray and a pathological
Recurrent osteosarcoma fracture is seen in 15%. Ewing’s sarcomas, like
Approximately 40% of patients treated with a osteosarcomas, show intense tracer uptake in
primary osteosarcoma will recur either locally or bone scan (Figure 15.7). Staging is given in Table
with metastatic disease. Management of local 15.1 and Figure 15.8 shows an overview of
recurrence can involve chemotherapy, surgery or management.
250
 CANCERS OF THE MUSCULOSKELETAL SYSTEM 15

Biopsy

Staging
MRI of primary site
CT chest
Bone scan
Bone marrow
Work up for treatment:
bloods, MUGA/ECHO, GFR

Neoadjuvant
chemotherapy
e.g. 6 cycles of VIDE

Surgery and/or radiotherapy

Assess response and consider

volume of disease

Further chemotherapy
Figure 15.6 e.g. VAI, VAC
X-ray of Ewing’s sarcoma of right proximal femur with
destructive lesion and onion skin appearance of Figure 15.8
periosteal reaction. Courtesy of Mr Rob Grimer. Management of Ewing’s sarcomas (VIDE – vincristine,
ifosfamide, doxorubicin & etoposide; VAI – vincristine,
actinomycin-D & ifosfamide; VAC – vincristine,
actinomycin-D & cyclophosphamide).

etoposide. Trials such as IESS-III showed that

alternating ifosfamide and etoposide with
vincristine, doxorubicin and cyclophosphamide
(VAC) improved survival from 54 to 69% in
localized disease. High-dose treatment in local­
ized low-risk disease has not been shown to
improve survival. Response to chemotherapy at
the time of surgery reflects prognosis.
Stratifying treatment according to risk is under
investigation in the EUROEWING99 trial (Figure
15.9). Low-risk patients are randomized between
Figure 15.7 standard treatment and less intense treatment.
Bone scintigram of Ewing’s sarcoma of left proximal
High-risk/metastatic patients are randomized
radius showing localized uptake at the site of the
tumour. between standard treatment and high-dose with
stem cell rescue.
Management of localized disease Surgery
Chemotherapy Surgery is performed if possible after neoadjuvant
Combination chemotherapy is usually given pre- chemotherapy to assess response and reduce risk
and postoperatively. Alkylating agents have the of relapse. Pelvic tumours are the most difficult
highest response rate and have been combined to resect, especially if they involve the sacrum,
with doxorubicin, vincristine, actinomycin D and due to the risk of sacral nerve involvement.
251
 II SITE-SPECIFIC CANCER MANAGEMENT

Biopsy Surgery
Surgery of the primary lesion may still be appro­
priate with limited pulmonary metastases if these
Staging respond to initial chemotherapy. Surgery may
MRI of primary site
also be necessary for local control, especially if
CT chest
Bone scan highly symptomatic.
Bone marrow
Work up for treatment: Radiotherapy
bloods, MUGA/ECHO, GFR Radiotherapy can be used to treat either the
primary tumour or metastatic lesions in advanced
disease. The dose (radical or palliative) used for
Neoadjuvant the primary will depend on the extent of other
chemotherapy
6 cycles of VIDE disease. Bilateral low-dose lung radiotherapy can
be used as an adjunct to chemotherapy for
patients with lung metastases who have had a
Surgery and/or radiotherapy good response to treatment. Unilateral lung irra­
diation is used for symptomatic bulky chest wall
lesions. Palliative radiotherapy is used for painful
Assess response and consider
volume of disease bony metastases.
Prognosis of Ewing’s sarcoma
Good Poor Extensive disease Prognosis in localized disease has improved sig­
nificantly since the introduction of chemother­
apy. Poor prognostic features are listed in Box
VAI x 1 then VAI x 1 the High dose or
15.4. With combination chemotherapy and
VAC vs VAI x 7 VAI x 7 vs phase II trial
high dose surgery or radiotherapy 5-year survival is 70%.
With limited lung metastases and treatment with
Figure 15.9 chemotherapy plus surgery or radiotherapy
Management of Ewing’s sarcoma Euro Ewing 99 5-year survival of 20–40% can be expected. With
Protocol.
more extensive disease 5-year survival falls to less
than 25%.
Recurrent Ewing’s sarcoma
Radiotherapy Recurrence usually occurs within the first 2–5
Unlike osteosarcomas, Ewing’s tumours are radio­ years and the prognosis for these patients is poor.
sensitive and, radiotherapy used to be the prin­ Relapse after 5–10 years is associated with a
ciple method of achieving disease control. Studies survival similar to that of advanced disease at
have shown radiotherapy without surgery has a presentation.
worse outcome than surgery for local control but After 10 years very few patients relapse but it
there may be some selection bias. However, does occur. Treatment depends on the nature of
radiotherapy still remains a primary method of relapse (local/systemic), nature of initial chemo­
local control in unresectable tumours when doses therapy and time from the end of primary treat­
of 45–55 Gy have been used (Box 15.5). ment. Isolated lung metastases after a long
Management of metastatic disease treatment interval may be suitable for surgical
resection and further chemotherapy. To date
Some patients with limited pulmonary metas­
high-dose regimens remain experimental in this
tases at presentation may still be cured with
group. The type of chemotherapy depends on the
combination treatment.
initial regimen but high-dose ifosfamide with
Chemotherapy etoposide has shown some activity. Trials of new
The same combination chemotherapy agents are agents such as insulin growth factor 1 receptor
used in advanced disease as in localized disease. antagonists are underway.
252
 CANCERS OF THE MUSCULOSKELETAL SYSTEM 15

Box 15.5: Radiotherapy in sarcomas

Indications
• Radical radiotherapy – inoperable Ewing’s sarcoma
• Postoperative adjuvant – deep, >5 cm or high-grade soft tissue sarcoma. Positive margins and further surgery is
not contemplated. Local recurrence after a repeated resection
• Preoperative – soft tissue sarcoma and Ewing’s sarcoma progress during chemotherapy
• Palliative radiotherapy
• Whole lung radiotherapy – Ewing’s sarcoma with lung metastases and good response to chemotherapy
Position & immobilization – depends on site of tumour
Tumour localization – with CT scan or co-registered CT/MRI
Clinical target volume
• Ewing’s sarcoma:
• Long bones – pre-treatment tumour with 5 cm margin superoinferior and 2 cm axial for phase 1 and 2 cm
margin for phase II. Whole bone if extensive intramedullary involvement with sparing of epiphyseal plate
• Flat bones and soft tissue – pre-treatment tumour with 2 cm circumferential
• Pelvis and chest wall – post-chemotherapy residual volume in areas of non-infiltrative tumour near critical
organs with 2 cm margin
• Soft tissue sarcoma
• CTV – surgical bed and possible areas of spread with 5 cm margin supero-interiorly and 2 cm
circumferentially for phase I and 2 cm margin for phase II. Include scars and biopsy sites
Planning target volume – 5–10 mm to CTV depending on immobilization
Dose
• Ewing’s tumour – 54.4 Gy in 30 fractions in two phases
• Soft tissue sarcoma – Phase I and preoperative 50 Gy in 25 fractions; phase II: 10–14 Gy in 5–7 fractions
• Whole lung radiotherapy for Ewing’s sarcoma – 15–18 Gy as 1.5 Gy per fraction per day
Special notes
• Keep radiation dose to the critical organs near an area being treated within the tolerance.
• Always leave a strip of skin unirradiated over the limbs to avoid fibrosis.
• If joints are in the treatment volume keep dose below <45 Gy.

Chondrosarcoma
The most common sites are pelvis (Figures 15.10
and 15.11), axial skeleton and proximal limbs.
As with other bone tumours axial tumours have
a worse prognosis than extremity tumours. It
presents with a mass which may be painful or
painless or with symptoms due to local disease.
Systemic symptoms are rare. Diagnosis may be
suggested from plain X-rays but MRI should be
undertaken for suspected sarcomas.
Chondrosarcomas frequently exhibit calci­
fication. MRI can also assess soft tissue exten­
sion. The lesion often has a cauliflower
appearance. 5-year survival is over 90% for a
localized grade 1 (well-differentiated) tumour Figure 15.10
but reduces to 25% for a grade 3 (poorly dif­ X-ray of pelvis showing destructive lesion around right
ferentiated) tumour. pubic ramus (arrow).
253
 II SITE-SPECIFIC CANCER MANAGEMENT

Figure 15.11
T1 weighted MRI of same patient showing extensive
chondrosarcoma (arrows) with some calcification and
soft tissue extension either side of the pubic ramus.

The primary modality of treatment is surgery. Figure 15.12

Chemotherapy and radiotherapy have limited Coronal MRI showing MPNST of right brachial plexus
role except for palliation. (arrows) in a patient with NF1.

Giant cell tumours of bone

These represent less than 5% of primary bone
tumours and only around 10% are malignant Soft tissue sarcomas
and 5% develop lung metastases. Malignant Soft tissue sarcomas (STS) represent a collection
tumours are usually secondary to radiotherapy. of heterogeneous tumours characterized by the
The most frequently affected sites are distal malignant growth of mesenchymal tissue. The
femur, proximal tibia and distal radius. Presenta­ different subgroups can be divided by genetics,
tion is usually due to pain which increases pathology, anatomical location and clinical
with activity. Typical radiological feature is an behaviour.
expansile lytic lesion (soap bubble appearance) STS comprise less than 1% of malignant
near the epiphysis. MRI is used to assess soft tumours and the median age at presentation
tissue and intramedullary extension. Staging depends on histological subtype.
should include chest CT due to possibility of lung
metastases. A bone scintigram will show increased Aetiology
tracer uptake in the region of the tumour. Giant The majority of cases arise de novo. Known pre­
cell tumours have a different staging system. disposing factors include familial cancer syn­
Surgery is the most effective treatment but dromes, prior radiotherapy and/or chemotherapy,
complete resection without leaving a residual chronic lymphoedema or infection. Familial
deficit in the bone is often difficult. Adding bone cancer syndromes include Li–Fraumeni, heredi­
cement to the bone graft may reduce the risk of tary retinoblastoma and familial GIST tumours.
recurrence from 45% to less than 30%. Addi­ Malignant peripheral nerve sheath tumours
tional local treatments include cryotherapy. (MPNST) are more common in neurofibromato­
Embolization is often used prior to surgery, espe­ sis due to inherited mutations in NF1 associated
cially for sacral tumours, to prevent excessive with a 10% lifetime risk of MPNST (Figure
blood loss at the time of surgery. Radiotherapy 15.12). Desmoid tumours and aggressive fibroma­
can be used for these tumours but there is a risk tosis occur in those with APC gene mutations
of secondary malignancy. associated with familial adenomatous polyposis.
254
 CANCERS OF THE MUSCULOSKELETAL SYSTEM 15

Pathology size >5 cm, deep to the deep fascia, rapid growth
There are over 80 subtypes of soft tissue sarcoma. and pain. Systemic symptoms (fever, weight
The most common are leiomyosarcoma, lipo­ loss, anorexia, breathlessness) may be present in
sarcoma, synovial sarcoma, rhabdomyosarcoma, advanced disease, particularly if associated with
fibrosarcomas (several subtypes), and malignant extensive chest disease.
peripheral nerve sheath tumour. Many soft tissue
Diagnosis
sarcomas are characterized and classified accord­
ing to specific translocations and gene rearrange­ Correct diagnosis requires an adequate biopsy
ments (Box 15.6). which, like bone tumours, should not compro­
mise later surgery. Samples should be sent to
Presenting features microbiology if infection is suspected. Pathology
Presentation depends on the stage and site of should be reviewed by an experienced sarcoma
disease as well as the histological subtype of pathologist. Due to the difficulty of diagnosis
sarcoma. The majority of soft tissue masses will even with immunohistochemistry, specialist tech­
be benign but risk factors for malignancy include niques such as cytogenetics and polymerase chain
reaction (PCR) may also be necessary to identify
Box 15.6: Examples of soft tissue sarcomas translocation specific sarcomas.
which have characteristic chromosomal
translocations Staging
Translocations associated with sarcomas Staging should include evaluation of the primary
Type of fusion tumour and a CT of the chest to exclude lung
Translocation Genes gene
metastases. In certain rare subgroups (rhabdo­
Ewing’s family of tumours
myosarcoma, synovial sarcoma, clear cell and
t(11;22)(q24;q12) EWSR1-FLI1 Transcription
factor epithelioid sarcomas) nodal disease may occur so
t(21;22)(q22;q12) EWSR1-ERG Transcription regional CT scanning may be appropriate. The
factor role of bone scintigraphy is less established in soft
t(7;22)(p22;q12) EWSR1-ETV1 Transcription
factor tissue sarcomas than bone sarcomas. PET has not
t(17;22)(q21;q12) EWSR1-ETV4 Transcription been fully evaluated (except for GIST) in soft
factor tissue sarcomas. Several staging systems exist,
t(2;22)(q33;q12) EWSR1-FEV Transcription
factor one of the most frequently used is AJCC (Table
Clear-cell sarcoma 15.2) which does not include histology and
t(12;22)(q13;q12) EWS-ATF1 Transcription site, and should not be used for non-extremity
factor sarcomas.
Desmoplastic small round-cell tumour
t(11;22)(p13;q12) EWSR1-WT1 Transcription General management principles of soft
factor
Myxoid chondrosarcoma tissue sarcoma
t(9;22) EWSR1-NR4A3 Transcription The overall management is shown in Figure
(q22-31;q11-12) factor
15.13.
Myxoid liposarcoma
t(12;16)(q13;p11) FUS-CHOP Transcription Localized disease
factor Surgery
t(12;22)(q13;q12) EWSR1-CHOP Transcription
factor Resection has to extend beyond the tumour to a
Alveolar rhabdomyosarcoma wide margin as an involved resection margin is
t(2;13)(q35;q14) PAX3-FKHR Transcription the most important factor which predicts risk of
factor recurrence. Margins have to be defined in terms
t(1;13)(p36;q14) PAX7-FKHR Transcription
factor of compartments and fascial or skin borders as
Synovial sarcoma well as distance. Surgery should be discussed
t(X;18)(p11;q11) SYT-SSX Transcription within a sarcoma multidisciplinary team to ensure
factor morbidity is minimized with the use of radio­
therapy if required.
255
 II SITE-SPECIFIC CANCER MANAGEMENT

Table 15.2: AJCC staging system for soft tissue sarcomas. This uses four criteria of tumour size,
nodal status, grade, and metastasis (TNGM)
Grade and TNM definitions Grade and TNM definitions
Tumour grade (G) AJCC Stage Groupings
GX Grade cannot be assessed Stage I
G1 Well differentiated Stage I tumour is defined as low-grade, superficial,
and deep
G2 Moderately differentiated
G1, T1a, N0, M0
G3 Poorly differentiated
G1, T1b, N0, M0
G4 Poorly differentiated or undifferentiated
G1, T2a, N0, M0
Primary tumour (T)
G1, T2b, N0, M0
TX Primary tumour cannot be assessed
G2, T1a, N0, M0
T0 No evidence of primary tumour
G2, T1b, N0, M0
T1 Tumour 5 cm or less in greatest
dimension: G2, T2a, N0, M0
• T1a: Superficial tumour G2, T2b, N0, M0
• T1b: Deep tumour
Stage II
T2 Tumour 5 cm or larger in greatest
Stage II tumour is defined as high-grade,
dimension:
superficial, and deep
• T2a: Superficial tumour
G3, T1a, N0, M0
• T2b: Deep tumour
G3, T1b, N0, M0
[Note: Superficial tumour is located exclusively
above the superficial fascia without invasion of the G3, T2a, N0, M0
fascia; deep tumour is located either exclusively
G4, T1a, N0, M0
beneath the superficial fascia, or superficial to the
fascia with invasion of or through the fascia, or G4, T1b, N0, M0
both superficial yet beneath the fascia.
G4, T2a, N0, M0
Retroperitoneal, mediastinal, and pelvic sarcomas
are classified as deep tumours.] Stage III
Regional lymph nodes (N) Stage III tumour is defined as high-grade, large,
and deep.
NX Regional lymph nodes cannot be assessed
G3, T2b, N0, M0
N0 No regional lymph node metastasis
G4, T2b, N0, M0
N1 Regional lymph node metastasis [Note:
Presence of positive nodes (N1) is Stage IV
considered stage IV.]
Stage IV is defined as any metastasis to lymph
Distant metastasis (M) nodes or distant sites.
MX Distant metastasis cannot be assessed Any G, any T, N1, M0
M0 No distant metastasis Any G, any T, N0, M1
M1 Distant metastasis

256
 CANCERS OF THE MUSCULOSKELETAL SYSTEM 15
Figure 15.13
Biopsy proven
Management of limb soft tissue
sarcomas (LG-low grade; HG-high
grade).
Staging
MRI of primary if not done
CT chest
Other imaging according to specific
subtype e.g. bone scan, regional CT/
Assess for surgery

Metastatic Localized

Painful metastases

Palliative RT Extensive inoperable Small number Surgery or

lung metastases or of operable lung radiotherapy if
visceral bone metastases not operable
metastases

Yes Yes LG HG / + margin

Chemotherapy if chemo- Consider RT not needed Radical RT

sensitive tumour then surgery to if clear 60 Gy
reassess both margins
Consider trial if chemo-
resistant tumour

Radiotherapy tumour bed but must not cross the fascial com­
Surgery is the primary curative modality for soft partment to avoid lymphoedema and delayed
tissue sarcomas; radiotherapy has a significant fibrosis which significantly affects mobility.
role in the prevention and treatment of local Chest wall sarcomas may be close to the heart
recurrence although there is no evidence that or spinal cord making planning complex and
radiotherapy improves overall survival. Many potentially limiting doses delivered. They may
soft tissue sarcomas are radiosensitive. A dose of follow the pleural contour of the chest wall
>60 Gy is needed and the radiotherapy details making it difficult to avoid significant lung
are shown in Box 15.5. volumes within the treatment field.
For some patients who are unfit for surgery Preoperative and postoperative radiotherapy
or in whom resection is technically not feasible, Radiotherapy is usually planned postoperatively
radiotherapy may be considered as a primary in two phases to take into account possible
treatment modality. However, unless the tumour tumour spillage at the edge of the surgical pro­
is very small and superficial, local control will cedure then to focus on the central tumour bed.
not be as good as with surgery. Planning must take into account preoperative
Limb sarcoma radiotherapy presents several scans to estimate tumour location, but should
challenges including positioning and immobiliz­ also encompass the surgical edges. Preoperative
ing the limb to ensure consistent placement and radiotherapy allows a single phase approach.
accurate dose to the tumour bed with a margin. An ongoing trial, VORTEX, is examining the
An adequate dose must be delivered to the possibility of reducing the volume of the post­
257
 II SITE-SPECIFIC CANCER MANAGEMENT

operative treatment comparing a single phase surgeons. Radiotherapy is recommended for the
treatment with a standard 2-phase approach. majority of cases except low-grade tumours
Radiotherapy has traditionally been given which have been excised with a wide margin.
postoperatively but the potential benefits of Radiotherapy is indicated for low grade tumours
giving preoperative radiotherapy include a with involved resection margin when further
smaller treatment volume, tumour visible on surgery is not contemplated. The role of adjuvant
planning scan, reduction of tumour prior to chemotherapy for most subgroups remains con­
surgery allowing a less morbid and complete troversial but could be considered within the
operation and reduction in significant late toxic­ context of a clinical trial (Box 15.8).
ity such as limb oedema, joint restriction and
Advanced and metastatic soft tissue sarcomas
fibrosis. Concerns about using preoperative radi­
otherapy are effect it may have on interpretation Many sarcomas present with locally advanced or
of histology and its associations with wound metastatic disease. In the majority of cases this
complications postoperatively. presentation carries a very poor prognosis. Prog­
nostic factors are listed in Box 15.9. The median
Adjuvant chemotherapy survival with metastatic disease is 12–14 months.
The use of adjuvant chemotherapy in soft tissue In other cases, presentation with limited
sarcomas remains controversial and is com­ metastatic disease occurs several years after their
pounded by different histological subtypes of initial treatment for localized sarcoma and the
sarcoma with varied chemo-sensitivities being prognosis may be slightly better in this situation,
included as a group in the majority of studies. if the disease is operable. In all these situations
There are some sarcomas, which tend to pre­ treatment options depend on performance
dominate in the paediatric setting, in which adju­ status, co-morbidities and histological subtype of
vant treatment has been shown to be useful, sarcoma.
e.g. rhabdomyosarcomas and the extraskeletal
Ewing’s sarcoma. However, for the majority Chemotherapy
there is no consensus concerning the use of adju­ Systemic treatment with chemotherapy can be
vant chemotherapy (Box 15.7). A meta-analysis useful but its role is more complex than in other
showed a statistically significant improvement in malignancies. There is little evidence that chemo­
local and distant recurrence if adjuvant chemo­ therapy prolongs survival but it can provide sig­
therapy was given. There was a trend towards an nificant benefits in symptom control. Response
improved overall survival of 4% at 10 years, but rates as determined by RECIST criteria often do
this was not statistically significant. A multi-cen­ not reflect symptomatic benefit or disease control,
tre international EORTC study randomized 351 especially in response to certain agents such as
patients to standard treatment versus ifosfamide trabectedin. Different tumour types show differ­
with doxorubicin. A preliminary analysis has ent responses to chemotherapy in general and to
shown no statistically significant difference specific drugs (Box 15.10).
between the two groups in either local recurrence Doxorubicin is a standard first agent with
rates or overall survival. response rates of 20–25%. Doses below 60 mg/m2

Treatment recommendations
Surgical resection with wide margins remains the
mainstay of treatment for soft tissue sarcoma. Box 15.8: Sensitivity to chemotherapy of soft
This should be performed by specialist sarcoma tissue sarcomas
The most chemosensitive tumours are synovial
sarcoma, myxoid liposarcoma and childhood
rhabdomyosarcoma. Extraskeletal Ewing’s tumours,
Box 15.7: Adjuvant chemotherapy
discussed under bone tumours, are also chemo-
The use of adjuvant chemotherapy is not routinely sensitive. The most chemoresistant tumours are
recommended outside a clinical trial, but the studies dedifferentiated liposarcoma, alveolar soft part
should be discussed with patients along with their sarcoma, GIST, low-grade liposarcoma and clear cell
particular situation. sarcoma.

258
 CANCERS OF THE MUSCULOSKELETAL SYSTEM 15

Box 15.9: Prognostic factors in soft tissue Box 15.11: When to use the combination of
sarcomas ifosfamide and doxorubicin
Different prognostic factors predict for local and There are a few special circumstances in which
systemic recurrence: combined chemotherapy may be used first line:
• Size and grade best predict distant recurrence and • Life-threatening progressive disease
overall survival. • Preoperatively to downstage and aim for
• Other factors which predict survival include age, resection
anatomical site and histological subtype. • Unassessable advanced disease (e.g. diffuse
• Retroperitoneal and visceral tumours carry a worse peritoneal metastasis)
prognosis than extremity tumours as, like pelvic
Ewing’s, they can grow to a very large size before
they are detected.
• Specific tumour subtypes such as MPNST and Box 15.12: Criteria for resection of lung or
leiomyosarcoma have a poorer overall survival. intra-abdominal metastases in metastatic soft
• Increased proliferative activity as assessed by tissue sarcoma
immunocytochemical stains has shown a • No other sites of disease, including primary site
correlation with poorer survival in at least three
studies. • A long disease-free interval of at least a year
• In synovial sarcomas, several studies have shown a • The disease should be slowly progressing or stable
poorer prognosis with the SYT-SSX1 combination • Complete resection must appear possible
rather than SYT-SSX, but this has not been • Low numbers of metastases although some centres
confirmed in other studies. have removed multiple metastases
• Involved resection margins and age >50 are worst
for local recurrence.
• Specific histological tumour types with a higher
rate of local recurrence include MPNST and with no improvement in PFS or overall survival
fibrosarcomas. and with increased toxicity. Combination chemo­
• Nomograms have been developed, and validated, therapy does have a role in the childhood and
which help to predict survival based on these
features. The best known is the MSK nomogram adolescent tumours such as rhabdomyosarcoma
which can be found at http://www.mskcc.org/ and extraskeletal Ewing’s sarcoma (Box 15.11).
mskcc/html/443.cfm
Surgery
Despite the poor median overall survival with
metastatic disease a small group of patients have
Box 15.10: Specific chemotherapy and histology a prolonged survival most of whom have disease
Recent studies have shown that some chemotherapy which is amenable to surgery, e.g. lung metas­
agents are more effective in some tumours: tases or isolated intra-abdominal recurrence. No
• Taxanes and liposomal doxorubicin have been randomized trial has evaluated the benefit of sur­
shown to be effective in angiosarcomas.
gical resection of lung metastases but the 5-year
• Gemcitabine and docetaxel initially showed
activity in uterine leiomyosarcomas but also have survival of patients selected using strict criteria
a response rate up to 30% in other (Box 15.12) is up to 40%.
leiomyosarcomas. Resection of liver metastases, other than for
• Trabectedin has been shown to be effective in the GIST, is performed rarely and there is little
treatment of liposarcomas, especially myxoid
liposarcomas. It also has over a 30% response rate evidence that it is of benefit either in terms of
in previously treated leiomyosarcomas and some survival or symptom control.
activity in other sarcomas.
Radiotherapy
The majority of soft tissue sarcomas are radio­
sensitive and radiotherapy can be an effective
have been shown to be ineffective and above tool in symptom control. Doses used are in the
75 mg/m2 to have increased toxicity without clini­ range of 35–54 Gy.
cal benefit. Ifosfamide is often used as a second
line agent and has a response rate of 25% overall. Isolated limb perfusion
In general combination chemotherapy has been Some patients present with a massive inoperable
shown to improve response rates up to 46% but limb sarcoma, often accompanied by significant
259
 II SITE-SPECIFIC CANCER MANAGEMENT

symptoms, and too large to be encompassed

within a radiotherapy field. For some there may
be an option of isolated limb perfusion therapy
(ILP) with melphalan and recombinant TNF-
alpha within specialist centres.
Treatment recommendations
Metastatic soft tissue sarcomas should be
managed by a multidisciplinary team of sarcoma
specialists who can discuss all available options.
Where appropriate, surgery should be performed
for isolated recurrence or metastasis. Chemo­
therapy can provide effective symptom control
in many sarcomas but an understanding of
the specific differences in histological subtypes
is required. There is no evidence that combina­
tion chemotherapy improves survival but it is
useful in special situations and in adolescent
sarcomas. Figure 15.14
Axial CT showing a large retroperitoneal dedifferentiated
Specific soft tissue sarcoma subtypes liposarcoma (arrows) displacing the left kidney.
Leiomyosarcoma
These are smooth muscle tumours and can occur Dedifferentiated liposarcomas usually occur in
at any site in the body and can be any grade of the retroperitoneum or abdomen (Figure 15.14).
tumour. The most common sites of metastases They are high-grade, chemoresistant tumours.
are in the lung, except in uterine leiomyosarco­ They have characteristic genetics with abnor­
mas in which they frequently occur within the malities in CDK4/MDM2.
liver. Soft tissue and bone metastases also occur.
The response to chemotherapy is variable but Synovial sarcoma
they have a high response rate to gemcitabine Synovial sarcomas predominate in children and
and docetaxel, especially the uterine tumours. younger adults and prognosis is related to age.
Those aged 1–10 years have the best prognosis.
Liposarcoma The common sites are limbs and trunk. The lungs
Liposarcomas represent a range of tumours with are the major site of metastasis. They are one of
different subtypes having considerable differences the most chemo-sensitive sarcomas with rela­
in behaviour and management. tively high response rates, particularly to ifosfa­
Myxoid or round cell liposarcomas arise in the mide. They have a balanced translocation t(X;18)
limbs and spread to soft tissues (retroperitoneum, between SYT and SSX1 or SSX2.
mediastinum) but can occur as a primary retro­
peritoneal tumour. They have a propensity for Uterine sarcomas
bone metastases (especially spine) in up to 17% The most common histologies are leiomyosar­
which may only be visualized on MRI. They are coma (LMS) and endometrial stromal sarcoma
chemo-sensitive, especially to trabectedin. They (ESS). Many are found unexpectedly at the
have a characteristic balanced translocation time of hysterectomy. A significant proportion
t(12;16) which gives rise to the TLS-CHOP of uterine sarcomas express oestrogen (ER) or
fusion gene. progesterone (PgR) receptors. Staging is cur­
Well-differentiated liposarcomas are often rently according to the FIGO staging system.
abdominal. They tend to recur locally rather than In ESS pelvic recurrence is more common
systemically. They are resistant to chemotherapy although distant relapses to the lungs can occur.
and radiotherapy. In LMS pelvic and extra pelvic recurrences
260
 CANCERS OF THE MUSCULOSKELETAL SYSTEM 15
can occur. Extra pelvic metastases in LMS study was associated with worse outcome. In
can occur in the liver, lung, lymph nodes and advanced disease chemotherapy has been used to
bone. Extra pelvic relapse has been shown to be aim for operability but there is no evidence it
more frequent in those who have had adjuvant improves overall survival.
radiotherapy. In metastatic disease or inoperable recurrence
The prognosis in uterine sarcomas is signifi­ chemotherapy may have a role but is dependent
cantly worse than epithelial endometrial cancer upon histology.
of comparable stage. In one study 5-year surviv­ In those cases where postoperative resection
als of 75.8% for stage I, 60.1% for stage II, margins are involved radiotherapy may be con­
44.9% stage III and 28.7% for stage IV were sidered although the presence of vital structures
described. Low-grade ESS have a 5-year survival (kidney, small bowel) may limit the ability to
of 80% but an increased risk of long-term relapse deliver a sufficient dose. The presence of a large
even 20 years after diagnosis. Undifferentiated tumour provides some protection to these critical
uterine sarcoma (previously termed high-grade surrounding tissues (kidney, small bowel) if
ESS) have a very aggressive course with a 5-year radiotherapy is given preoperatively. This allows
survival around 30%. higher doses to be administered to the tumour
In the advanced setting chemotherapy has an and is technically easier to plan with the tumour
established role in the treatment of most uterine in situ. In general, retroperitoneal tumours have
sarcomas. Agents used include ifosfamide and a worse prognosis than other soft tissue sarcomas
doxorubicin. The combination of germcitabine/ of the same histology.
docetaxel has shown response rate up to 53% in
Gastrointestinal stromal tumour (GIST)
pre-treated LMS with improvement in overall
survival up to 18 months. In low-grade ESS GISTs are a rare subgroup of soft tissue sarcomas
chemotherapy is rarely effective with response which can occur anywhere in the gastrointestinal
rates less than 10%. Many of these respond to tract. A small number are associated with a
hormonal manipulation. In undifferentiated familial GIST syndrome in which there are germ­
(high-grade ESS) sarcomas ifosfamide has the line mutations in the KIT gene. Rare paediatric
highest response rate (33% in a phase II GOG cases are usually wild type with no KIT mutation
study) although the duration of response is and tend to have a more indolent course.
limited to a few months. There are reports of
activity with aromatase inhibitors.

Retroperitoneal sarcoma
Retroperitoneal sarcomas represent 13% soft
tissue sarcomas. The most common histologies
at this site are liposarcoma (Figure 15.14) and
leiomyosarcoma. Many are found incidentally.
When they occur symptoms are due to a large
mass (abdominal swelling, leg swelling distal to
the mass, pain).
If operable a biopsy may not be performed and
the tumour resected en masse to prevent tumour
seeding the biopsy tract. If not operable a biopsy
must be obtained to ensure correct management
of an unsuspected alternative diagnosis. Suffi­
cient material must be obtained to perform
immunohistochemistry to exclude lymphoma,
carcinoma and germ cell tumours. Figure 15.15
Adjuvant chemotherapy is not standard treat­ Large gastric GIST (shown by arrows) arising from the
ment in these tumours and in one retrospective greater curvature of the stomach.
261
 II SITE-SPECIFIC CANCER MANAGEMENT

The most common sites are stomach (50%)

(Figure 15.15) and small bowel (25%) but they Table 15.3: Risk of aggressive behaviour in
GISTs according to NIH consensus criteria
can occur in the colon (10%), and other sites.
Risk Size of tumour Mitotic count
Presentation is commonly with anaemia or
abdominal mass but abdominal pain can occur Very low risk <2 cm <5 per 50 hpf*
with larger tumours. Patterns of spread include Low risk 2–5 cm <5 per 50 hpf
liver metastases (most common) and peritoneal <5 cm 6–10 per 50 hpf
metastases. Bone metastases occur rarely and
Intermediate 5–10 cm <5 per 50 hpf
late, often after years of treatment. Lung metas­ risk
tases are exceptionally rare. Nodal metastases >5 cm >5 per 50 hpf
are also uncommon. High risk >10 cm Any mitotic rate
Any size >10 per 50 hpf
Pathology and genetics
The morphology can be spindle cell (70%), epi­ *hpf – high power field
thelioid (20%) or mixed type (10%). 95% of
GISTs express c-KIT or the CD117 antigen.
Mutations in the KIT gene occur in over 90%
cases involving exon 11 (in 66%), 9 (in 13%), Box 15.13: Other features which predict
13 (in 1.2%), and 17 (0.6%). GIST with muta­ aggressive behaviour of GISTs
tions within the PDGFRA gene (7% cases) are • Primary site. Duodenal and small bowel GISTs
are more aggressive than those arising in the
more frequently associated with an epithelioid stomach.
morphology, usually occurs in the stomach and • Location of the c-KIT mutation has been evaluated
tends to be indolent. in several studies. Some have shown mutations in
The malignant potential of GISTs has been Exon 9 to have a more aggressive course than
Exon 11. Mutations within codons 562–579 in one
shown to be related to size of the tumour, mitotic study and 557–558 in another were associated
rate and location of the primary as described in with a higher risk of metastases.
the NIH consensus criteria (Table 15.3 and Box
15.13).

Management Box 15.14: Location of mutations and response

to TKIs
Definitive curative treatment is only possible
There is a correlation between location of c-KIT or
with resection of the primary tumour in the PDGFR mutation and response to imatinib or
absence of metastases. High risk (and intermedi­ sunitinib.
ate risk) tumours are at risk of relapse after a • Patients with an exon 11 mutation have a greater
clear resection. Several trials are examining the chance of response to imatinib (67–84%) than
those with an exon 9 (40–48%) or no (0–39%)
use of the drug imatinib in the adjuvant setting. mutation at a dose of 400 mg per day.
Imatinib is an oral tyrosine kinase inhibitor (TKI) • Exon 11 responses were also of a longer duration
which blocks signalling via KIT by binding to the (576 days) than exon 9 (308 days) or those without
ATP-binding pocket which is essential for phos­ a mutation (251 days).
phorylation and activation of the c-KIT receptor • Higher dose imatinib (800 mg per day) has been
shown to be of greater benefit in progression free
(p. 370 and Box 15.14). Patients with inoperable survival in patients with exon 9 mutations.
primary tumours who do not have metastases • Of the 7% patients with PDGFRA mutations, the
may be rendered operable by the use of imatinib. commonest is resistant to imatinib (D842V) but
Patients with metastatic disease should be treated others may respond.
initially with imatinib 400 mg per day. • Sunitinib has been shown to be more effective
against exon 9 mutant GIST than standard dose
The median time to progression for metastatic imatinib and also appears to be effective against
disease on imatinib is 2 years. Imatinib should be wild-type disease. Secondary mutations that confer
continued without a break (except for toxicity) resistance to imatinib occur more commonly after
prolonged exposure (hence in exon 11 mutant
until progression. It has been shown that inter­ tumours) and may respond to sunitinib.
rupting treatment is associated with progression.
262
 CANCERS OF THE MUSCULOSKELETAL SYSTEM 15
At progression dose escalation to 800 mg per been shown to correlate better with survival than
day may enable temporary control of disease in RECIST.
30–35% cases with a median time to progression
of 4 months. For patients with an isolated liver Further reading
metastasis who have responded to imatinib, local Federman N, Bernthal N, Eilber FC, Tap WD.
hepatic resection or radiofrequency ablation may The multidisciplinary management of osteosarcoma.
be considered. Curr Treat Options Oncol. 2009;10:82–93.
Sunitinib malate is a multi targeted TKI which Ferrari S, Palmerini E. Adjuvant and neoadjuvant
combination chemotherapy for osteogenic sarcoma.
has shown activity in GISTs which have pro­ Curr Opin Oncol. 2007;19:341–346.
gressed on imatinib. The median progression free Balamuth NJ, Womer RB. Ewing’s sarcoma. Lancet Oncol.
survival in this clinical situation is 6 months. 2010;11:184–192.
68% patients achieved a partial response or Riedel RF, Larrier N, Dodd L et al. The clinical management
stable disease on sunitinib. of chondrosarcoma. Curr Treat Options Oncol.
2009;10:94–106.
Assessment of response Reynoso D, Subbiah V, Trent JC et al. Neoadjuvant
treatment of soft-tissue sarcoma: a multimodality
Assessment of response in GIST may be with CT
approach. J Surg Oncol. 2010;101:327–333.
scan but it has been shown that RECIST criteria Katz SC, Brennan MF. Randomized clinical trials in soft
may not be the only measure of response in these tissue sarcoma. Surg Oncol Clin N Am. 2010;19:1–
tumours. FDG-PET can detect reduction in 11.
tumour activity within days of commencing Verweij J. Soft tissue sarcoma trials: one size no longer fits
all. J Clin Oncol. 2009;27:3085–3087.
imatinib or can visualize small liver metastases
Judson I. State-of-the-art approach in selective curable
which may not be visible on CT. Similarly it can tumours: soft tissue sarcoma. Ann Oncol. 2008;19 Suppl
detect increased activity should the tumour 7:vii166–169.
develop resistance (new mutations) once on Nam JH, Park JY. Update on treatment of uterine sarcoma.
imatinib. Choi described alternative criteria to Curr Opin Obstet Gynecol. 2010;22:36–42.
Katz MH, Choi EA, Pollock RE. Current concepts in
evaluate GIST response. A 15% reduction in
multimodality therapy for retroperitoneal sarcoma.
tumour density or 10% unidimensional reduc­ Expert Rev Anticancer Ther. 2007;7:159–168.
tion in tumour size was a better predictor of Rubin BP, Heinrich MC, Corless CL. Gastrointestinal
response than RECIST and these criteria have stromal tumour. Lancet. 2007;369:1731–1741.

263
 Central nervous
system tumours
TV Ajithkumar
16
Introduction 2. Prior radiotherapy increases the risk of a second
intracranial tumour, particularly meningiomas
Primary central nervous system (CNS) tumours and gliomas with a typical latent period of 10
can arise from any structures in the cranial vault. years. Immunosuppression increases the risk of
Around 4000 new patients with malignant brain primary CNS lymphoma.
tumours are diagnosed per year in the UK and 3. Brain tumours are not associated with
22,000 new patients in USA. There is a bimodal smoking, alcohol intake or mobile phone use.
distribution with small peak in children (p. 323)
and a steady increase starting at the age of
20 years. Males are more commonly affected, Pathology
particularly with malignant tumours, whereas Box 16.1 shows WHO classification of brain
women have a higher rate of non-malignant tumours. WHO grading system (Box 16.2) is
tumours, particularly meningiomas. important in deciding management and progno-
sis. Molecular features can be incorporated in
Aetiology this grading system to yield important prognostic
information. Clinico-pathological features of
The majority of brain tumours are sporadic with individual tumours are discussed later.
an unknown cause. A small proportion of
tumours are associated with genetic syndromes
and other factors. Presentation
1. Genetic syndromes – fewer than 5% patients Brain tumour can present with non-specific as
with glioma have a family history of brain well as specific features. Non-specific features
tumours: are headache (50%) and vomiting due to raised
• Neurofibromatosis type I – neurofibro- intracranial pressure. Specific features are due
mas, optic nerve glioma and pilocytic to location of the tumour. Lateralizing signs
astrocytoma. (50%) include hemiparesis, aphasia and visual
• Neurofibromatosis type II – meningioma, field defects. Seizure, generalized, partial or
gliomas and bilateral acoustic neuroma. focal, can be the presenting symptom in 50% of
• Tuberous sclerosis – subependymal giant high-grade and 25% of low-grade gliomas.
cell astrocytoma, hamartomas. Stroke-like presentations occur mainly due to
• Turcot syndrome – glioblastoma and bleeding associated with the tumour. It can occur
medulloblastoma. in 5–8% of high-grade and 7–14% of low-grade
• Li–Fraumeni syndrome – astrocytoma and tumours. Altered mental status can be a present-
PNET. ing feature of primary brain tumour, but is
• Basal naevus syndrome – medulloblast- more commonly a presentation of multiple brain
oma. metastases.
264 © 2011, Elsevier Ltd
DOI: 10.1016/B978-0-7234-3458-0.00021-X
 CENTRAL NERVOUS SYSTEM TUMOURS 16

Box 16.1: WHO classification of brain tumours Box 16.2: WHO grading of primary CNS tumours
Tumours of neuroepithelial tissue Grade 1 – tumours with low proliferative potential
1. Astrocytic tumours and tumour growth by expansion. Generally
curable by surgery alone.
• Pilocytic astrocytoma (grade 1)
Grade 2 – tumours with low proliferative potential
• Diffuse astrocytoma (grade 2) but exhibit infiltration. Surgery alone is rarely
• Anaplastic astrocytoma (grade 3) curative and these tumours can progress to grade
• Glioblastoma (grade 4) 3–4 tumours.
2. Oligodendroglial tumours Grade 3 – tumours with cytological evidence of
malignancy such as nuclear atypia, endothelial
• Oligodendroglioma (grade 2) proliferation and mitotic activity. These are rarely
• Anaplastic oligodendroglioma (grade 3) curable.
3. Ependymal tumours Grade 4 – highly malignant tumours often with
• Ependymoma (grade 2) necrosis. These are aggressive.
• Anaplastic ependymoma (grade 2)
4. Mixed glioma
• Oligoastrocytoma (grade 2)
• Anaplastic oligoastrocytoma (grade 3)
Choroid plexus tumours oedema, hydrocephalus, haemorrhage and calci-
• Papilloma and carcinoma fication depending on the histological variant of
Embryonal tumours brain tumour. Table 16.1 shows radiological
• Medulloblastoma and its variants (grade 4) appearance of common tumours.
• Supratentorial primitive neuroectodermal
tumour (PNET) (grade 4) MRI scan
Pineal tumours MRI scan with gadolinium and FLAIR (fluid-
Neuronal tumours attenuated inversion recovery) sequence is the
• Ganglioglioma standard investigation for brain tumours. T1W
• Anaplastic ganglioglioma imaging demonstrates anatomy and areas of con-
• Neurocytoma trast enhancement and T2W and FLAIR images
Tumours of cranial/spinal nerves are useful in demonstrating oedema. Appearance
Tumours of the meninges of tumour on T1W image is similar to that on
• Meningioma (grade 1–3) CT, but better delineated on MRI. Tumour and
Tumours of uncertain histogenesis oedema demonstrate increased signal on T2 and
Haematopoietic neoplasms the area of increased T2 signal on MRI usually
Germ cell tumours includes the hypodense area on CT (Figure 16.1).
Tumours of sellar region Various MR imaging techniques are being
• Pituitary adenoma and carcinoma evolved to improve the diagnostic ability in the
• Craniopharyngioma imaging of brain tumours.
Metastatic tumours
Magnetic resonance spectroscopy (MRS)
MRS is clinically useful in distinguishing high-
grade glioma and metastases from abscess,
assessing tumour recurrence and radiation necro-
Investigations sis, and identification of atypical meningioma as
a true meningioma.
Imaging
Diffusion tensor imaging (DTI)
CT scan In radiotherapy planning for high-grade gliomas,
Contrast enhanced CT scan is usually the initial conventional methods of imaging cannot distin-
investigation in patients suspected to have a guish oedema from peritumoural white matter
brain lesion. CT scan is not an ideal investigation infiltration, resulting in large target volumes. DTI
for low-grade tumours or tumours in the poste- shows white matter abnormalities resulting from
rior fossa. CT scan may also show features of tumour infiltrating, and thereby reducing the
265
 II SITE-SPECIFIC CANCER MANAGEMENT

Table 16.1: Radiological appearance of common brain tumours

Type of tumour Imaging characteristic
Pilocystic astrocytoma Well-circumscribed, contrast enhancing tumour with a cystic or enhancing mural
nodule.
Grade II astrocytoma Isodense or hypodense on CT. Hypointense on T1W image and hyperintense on
T2W and FLAIR images. No contrast enhancement and if present suggest
malignant transformation. No associated cerebral oedema.
Oligodendroglioma Same CT/MRI as grade II astrocytoma; but can be associated with areas of contrast
enhancement, calcification and haemorrhage.
Anaplastic astrocytoma CT – irregular hypodense lesions with varying degree of contrast enhancement
and GBM and associated oedema and pressure effect. Ring-like enhancement surrounding
an irregular shaped necrosis suggests GBM. Some of the high-grade tumours
can be non-enhancing particularly in the elderly.
MRI – irregular hypointense on T1W and irregular contrast enhancement and
hyperintense on T2W and FLAIR, representing tumour and oedema.
Anaplastic Contrast enhancing heterogeneous mass with frequent cystic components,
oligodendroglioma calcifications and necrosis.
Medulloblastoma CT – hyperdense midline mass with associated hydrocephalus. Marked contrast
enhancement. Sometimes show calcification cysts, haemorrhage and nodular
seedling.
MRI – heterogeneous hypo or isointense on T1W with slightly heterogeneous
contrast enhancement. Iso-hyperintense on T2W.
Ependymoma Heterogeneously enhancing lesion with cystic component. There may be
associated calcification and haemorrhage.
Primary CNS lymphoma Solitary or multiple periventricular homogenously enhancing diffuse lesions
(‘cotton wool’ appearance). Ring enhancement common in
immunocompromised patients.
Meningioma Homogenously contrast enhancing lesion arising from the dura. There is little
associated brain oedema. There will be enhancement of dura (’dural tail’ sign).
Craniopharyngioma Solid and cystic lesion on CT scan. MRI appearance depends on the composition
of tumour. T1W can be hypo, iso or hyperintense with variable contrast
enhancement. T2W can also be hypo, iso or hyperintense.
Pituitary Contrast enhancing seller/suprasellar lesion on CT. T1W iso-hypointense and T2W
hyperintense.
Metastasis Solitary or multiple irregularly contrast enhancing lesion which may be solid or
cystic at the junction of grey and white matter. Location and characteristic
depends on type of tumour.

target volume, which would allow significant moma (Figure 16.2). CSF evaluation includes
dose escalation to the tumour with acceptable CSF biochemistry (typically elevated protein
damage to the normal tissue. >40 mg/dL and reduced glucose <50 mg/mL),
cytology and in cases of suspected germ cell
Evaluation of the craniospinal axis tumours, the estimation of tumour markers (AFP
MRI of the craniospinal axis and CSF evaluation and beta hCG) in CSF and serum. Evaluation of
is needed for tumours with a high risk of CSF the craniospinal axis is best done prior to surgery
dissemination such as medulloblastoma, germ or >3 weeks after surgery to avoid false positive
cell tumours, CNS lymphoma, PNET and ependy­ results.
266
 CENTRAL NERVOUS SYSTEM TUMOURS 16

A B C

Figure 16.1
MRI scan of diffuse astrocytoma. Scan shows hypointense lesion on left parieto-occipital region (A) without contrast
enhancement (B) on T1W image. T2W image (C) shows a hyperintense lesion. Since low-grade tumours are not
associated with oedema, this hyperintense lesion represents just the tumour.

may cause neurologic damage and hence may be

avoided. Biopsy is avoided in patients with mul-
tiple brain metastases from a known primary,
optic meningioma and CNS lymphoma in HIV
positive patients showing typical radiological
findings.

Prognostic factors
The outcome of brain tumours depends on the
following factors:
1. Pathology – outcome depends on pathologic
type and grade. High-grade tumours have
poor prognosis. Recently molecular factors
are shown to be important in certain tumour
types.
2. Age – increased age is associated with poorer
outcome.
3. Performance status – is an important factor
in outcome and guiding treatment.
4. Extent of surgical resection – based on
observational studies, patients with less
residual disease after surgery have a better
Figure 16.2 prognosis.
Multiple contrast-enhancing tumour nodules in
ependymoma suggesting leptomeningeal disease.
Principles of management
Tissue diagnosis General medical management
Histologic confirmation is necessary in all patients Steroids
prior to definite treatment. Biopsy is obtained Steroids may improve symptoms by reducing
by either stereotactic guided techniques or open intracranial pressure. The most commonly used
biopsy. In intrinsic brainstem tumours, biopsy agent is dexamethasone which is started at a dose
267
 II SITE-SPECIFIC CANCER MANAGEMENT

of 2–16 mg daily (low doses given once daily and guide resection based on real time shift of
higher doses as 2–4 equally divided doses) and structures during operation.
titrated against the patient’s symptoms. The 3. Cortical mapping awake craniotomy – is
optimal dose is just above that at which sympto- useful in resection of tumours inside or adja-
matic deterioration occurs. If there is no symp- cent to functional brain areas. Intraoperative
tomatic improvement, steroids should be stopped. cortical or subcortical stimulation helps to
map functional areas. Initial craniotomy and
Anti-epileptics preliminary stimulation are done with the
All patients who have had a seizure should patient asleep. After arousal, under sedative/
be treated with an anti-epileptic drug (AED); hypnotic anaesthesia, the patient responds to
prophylactic use of anti-epileptics is not recom- motor or language commands but with sub-
mended. Many anti-epileptics are enzyme- sequent amnesia.
inducers, and hence should be carefully monitored 4. Fluorescent guided surgery – an evolving tech-
when they need to be used concurrently with nique for malignant gliomas.
drugs metabolized by cytochrome p450 enzyme
system. Radiotherapy in brain tumours
Analgesics Radiotherapy has a major role in the manage-
ment of CNS tumours. Radiotherapy is proven
Patients requiring pain control are managed
to improve local control and/or survival in grade
according to the WHO analgesic ladder (p. 66).
3–4 tumours whereas its role in grade 2 tumours
Surgical management is doubtful and has limited role for grade 1
Surgery in brain tumours helps in pathological tumours. Radiotherapy is delivered by the fol-
diagnosis, symptom control and definite lowing methods:
treatment. 1. External beam radiotherapy is commonest
Biopsy can be either stereotactic guided or mode of delivery of radiotherapy to the brain.
an open biopsy. Surgery is useful in relieving Immobilization and proper localization is
pressure symptoms as well as decreasing the important in the delivery of EBRT. Target
frequency and intensity of seizures. Surgical volume depends on the type of tumour and
resection is constantly evolving in brain tumours. intention of treatment.
It is common practice to confirm the diagnosis 2. Stereotactic technique – this technique involves
with an intraoperative frozen section or smear improved localization of tumour and preci-
prior to attempting a full resection. Complete or sion. Treatment is delivered either as multiple
maximal resection with minimal injury to neigh- fractions using linear accelerator (called
bouring critical structures is the aim of surgery. stereotactic radiotherapy) or as single fraction
The importance of surgical resection in specific (called radiosurgery) using gamma knife, a
tumours is discussed later. The various resection special machine for cranial radiosurgery.
techniques are: 3. Charged particle radiotherapy – mainly
1. Image guided stereotactic resection – is useful protons, which deposit the energy only at a
in technically challenging locations such as depth and hence useful in skull base tumours.
the peri-thalamic region, to minimize critical A summary of radiotherapy details for
structure injury. common tumours are given in Table 16.2.
2. Neuronavigation guided resection – distor-
tion of brain anatomy by tumour and oedema Radiation tolerance and reactions
makes surgical resection according to conven- Radiation to the brain can cause structural
tional landmarks difficult. Neuronavigation damage to critical structures if attention is not
systems allow registration of stored imaging paid not to exceed the tolerance dose of indi-
data which can be incorporated with real time vidual structures.
intra-operative imaging using intra-operative Acute radiation reactions may manifest up to
ultrasound or MRI. This helps surgeons to 6 weeks following completion of irradiation.
268
 Table 16.2: Radiotherapy for common brain tumours
Tumour Intent of treatment GTV* CTV+ (margin added to GTV) Dose
Low-grade glioma Radical Abnormality on T2W image on fused image 1.5 cm 54 Gy in 30#
Grade III glioma Radical Contrast enhancing abnormality on co-registered Phase I – 2.5 cm 45 Gy in 25#
image Phase II – 1.5 cm 9 Gy in 5#
Grade IV glioma Radical Contrast enhancing abnormality on co-registered Phase I – 2.5 cm 50 Gy in 25#
image Phase II – 1.5 cm 10 Gy in 5#
Palliative Contrast enhancing tumour 2.5 cm 30 Gy/6# or
35 Gy/10#
Brainstem glioma Radical Abnormality on T2W/FLAIR on co-registered image 1–1.5 cm 54 Gy/33#
Medulloblastoma Adjuvant CT planning for craniospinal RT Phase I – whole craniospinal axis 35 Gy/21#
Abnormality on fused image for phase II Phase II – posterior fossa or visible 20 Gy/12#
tumour + 1.5 cm
Phase II – spinal metastasis boost 15 Gy/9#
Ependymoma Adjuvant/radical Contrast enhancing lesion or surgical cavity in case 1.5–2.5 cm 55 Gy/33# or
of complete resection on fused image 54 Gy/30#
Germinoma Radical Phase 1 – CT planning Phase I – whole craniospinal axis 25 Gy/15#
Phase 2 – primary and other metastatic sites on Phase 2 – plan before start of 15 Gy/9#
fused image treatment. Contrast enhancing
tumour + 1–2 cm
Non-germinoma After chemotherapy CT planning Phase 1 – craniospinal RT 30 Gy in 20#
– meningeal disease
Abnormality on co-registered image Phase 2 primary tumour + 2 cm 24 Gy/12#
Residual disease Contrast enhancing mass on co-registered image Primary + 2 cm 54 Gy/33#
Acoustic neuroma Progressive disease Residual tumour on fused image No margin needed 50 Gy/30#
Craniopharyngioma Postoperative/ Residual tumour on fused image Preoperative GTV + margin for 50 Gy/30#
progressive doubtful margin
Pituitary adenoma Postoperative or Visible tumour on co-registered image No margin 45 Gy/25#
progressive
Meningioma Radical/postoperative Contrast enhancing tumour on co-registered 0–0.5 cm 50 Gy/30# or
image. The practice of including dural tail in 55 Gy/33#
GTV is variable; many studies fail to show any
meningioma in dural tail

*GTV is outlined on MRI co-registered with planning CT scan. T2W MRI is used for co-registration in low grade glioma, whereas contrast enhanced T1W is used for high-grade glioma,
meningioma, craniopharyngioma and pituitary adenoma.
+CTV needs to be edited to confine to skull or skull base. PTV depends on immobilization device: for Perspex shell add 5 mm to CTV and for relocatable stereotactic frames add 2–3 mm to
CENTRAL NERVOUS SYSTEM TUMOURS

CTV.
Normal tissue tolerance doses (at ≤2 Gy per fraction): brain 60 Gy; brainstem 54 Gy; optic nerve and chiasm 50–54 Gy; pituitary gland <40 Gy; middle and inner ear <40 Gy; lacrimal gland
<20 Gy; lens <10–15 Gy as fractions; permanent alopecia 43 Gy.
16

269
 II SITE-SPECIFIC CANCER MANAGEMENT

These reactions are generally those of raised Box 16.3: Chemotherapy regimes in
intracranial pressure, fatigue and worsening of brain tumour
neurology. Vomiting is particularly common in PCV (glioma)
patients receiving radiotherapy to the brainstem • Procarbazine 100 mg/m2 (max 200 mg) oral Day
region. 1–10
Early delayed (intermediate) side effects usually • CCNU 100 mg/m2 (max 200 mg) oral Day 1
appear from 6 weeks to 6 months following • Vincristine 1.5 mg/m2 (max 2 mg) IV Day 1
radiotherapy and are due to changes in capillary Cycles repeated every 6 weeks for 6 cycles
permeability and transient demyelination. Symp- Temozolomide (glioma)
toms include headache, somnolence syndrome, • Concomitant – 75 mg/m2 D1–D42 oral, 1 hour prior
to radiotherapy & morning dose on weekends
lethargy and frequently recurrence of the original
• Adjuvant and palliative – 150 mg/m2 D1–5 oral for
presenting features. Recovery is spontaneous but first cycle, then 200 mg/m2 D1–D5 total 6 cycles
can be accelerated by steroids. (adjuvant starting 4 weeks after radiotherapy)
Delayed radiation reaction develops 6 months Packer regime (medulloblastoma and PNET)
after radiotherapy. This is thought to be due to • Concurrent with radiotherapy – vincristine 1.5 mg/
white matter injury secondary to vascular injury, m2 (max 2 mg) weekly with radiotherapy, then 6
weeks of rest followed by:
demyelination and necrosis. The most serious
• A combination of:
form of this is radiation necrosis which peaks at
• CCNU 75 mg/m2 every 6 weeks and cisplatin
3 years. Conventional imaging fails to distinguish 68 mg/m2 every 6 weeks and vincristine 1.5 mg/
this from recurrent tumour and special imaging m2 (max 2 mg) for 3 consecutive weeks. Cycle
is therefore needed (p. 265). Treatment is with repeated every 6 weeks for total of 8 cycles
steroids and debulking. Other late effects include,
depending on the area irradiated, memory prob-
lems, pituitary failure, hearing loss, visual changes
and second malignancies.
antagonists (e.g. imatinib) and farnesyltrans-
Chemotherapy in brain tumours ferase inhibitors (e.g. tipifarnib).
Chemotherapy has an established role in paedi-
atric brain tumours mainly as a substitute for Follow-up
radiotherapy. The role of chemotherapy in adult
Follow-up consists of clinical evaluation with
brain tumours is increasing. The active agents are
attention to neurological examination and assess-
nitrosoureas (carmustine and lomustine), procar-
ment of seizure control. MRI is the image of
bazine, temozolomide, platinum and vincristine.
choice whenever imaging follow-up is indicated.
The role of chemotherapy in specific brain
Visual field and hormonal function assessments
tumours is discussed later in this chapter and the
are important in sellar tumours.
commonly used chemotherapy regimens are
given in Box 16.3.
Clinico-pathological features
New agents in brain tumours and management of
A number of biological agents have been tried specific tumours
recently in the management of brain tumours,
particularly in gliomas. Since gliomas exhibit Glioma
marked neovascularization, anti-angiogenesis Astrocytomas diffusely infiltrate surrounding
inhibitors are an attractive option. Bevacizumab brain. Pilocytic astrocytoma (grade 1) occurs in
has been studied alone and in combination with children and young adults and are located in the
chemotherapy in recurrent GBM. optic tract, hypothalamus, basal ganglia and pos-
Since EGFR are frequently amplified and over- terior fossa. These tumours grow slowly and sta-
expressed in GBM, agents such as cetuximab and bilize spontaneously. Diffuse astrocytoma (grade
tarceva seem to be attractive agents. Other target 2) is a low-grade tumour. Anaplastic astrocy-
molecules under investigation include PDGF toma (grade 3) and glioblastoma multiforme
270
 CENTRAL NERVOUS SYSTEM TUMOURS 16

A B

Figure 16.3
MRI scan of oligodendroglioma in right temporal area. MRI scan of oligodendroglioma will exhibit the same features
of astrocytoma (A); however oligodendroglioma can have subtle contrast enhancement (arrows on B) and calcification.

(grade 4-GBM) are high grade tumours. Ana­ tumours with progressive neurological deficit
plastic astrocytoma is distinguished from low- are treated with radiotherapy and carboplatin-
grade tumours by greater cellular differentiation based chemotherapy.
and hyperchromasia, more frequent mitoses and
prominent small vessels lined by epithelioid Treatment of low grade glioma
endothelial cells. Glioblastoma is distinguished (WHO grade 2)
by increased cellularity, pleomorphism, giant Diffuse astrocytoma, oligodendroglioma (Figure
cells, abnormal mitotic figures and endothelial 16.3) and mixed oligoastrocytoma are grouped
cell proliferation. Necrosis surrounded by nuclei together as low-grade glioma. These tumours
aligned in pseudopalisading pattern is character- mainly affect the young adults (mean age of 35
istic. Astrocytomas stain for glial fibrillary acidic years for astrocytoma and 45 years for oligoden-
protein (GAFP). droglioma). Patients generally present with sei-
Oligodendroglial tumours have typical histo- zures and in the majority adequate seizure control
logical appearance of evenly distributed cells with with serial MRI monitoring will be sufficient.
uniform and rounded nuclei with perinuclear Many of these patients have slow growing
halo. Mixed tumours are composed usually of tumours. There are two main patterns of
an oligodendroglial component and an astro- progression – secondary gliomatosis cerebri
cytic component. Their overall prognosis and and malignant transformation. Secondary
treatment is dictated by the most aggressive gliomatosis cerebri is characterized by diffuse
component. extension of the tumour sometimes to the oppo-
site hemisphere and it often remains low-grade.
Treatment of pilocytic astrocytoma
Malignant transformation involves progression
Complete surgical resection alone is adequate to a high-grade tumour with characteristics of
which results in a 20-year survival of 80%. In anaplastic astrocytoma, anaplastic oligodendro-
patients for whom a complete resection is not glioma or glioblastoma. Imaging shows new
possible, maximal safe resection should be areas of irregular contrast enhancement in a pre-
attempted followed by observation. In the viously non-contrast enhancing tumour.
majority of these patients the tumour does not
progress. A second surgery may be attempted Surgery
during progression, if feasible, followed by non- The role of surgery in grade 2 tumours is unclear.
surgical management. Patients with unresectable When safe complete or near complete resection
271
 II SITE-SPECIFIC CANCER MANAGEMENT

is feasible, it may be attempted. A recent retro- Management of recurrence or progression

spective study showed that gross total resection after first definitive treatment
(complete resection of preoperative FLAIR Management of recurrence or progression
abnormality) improved survival (10-year OS depends on previous treatment. Radiotherapy
76%) compared with near total resection (<3 mm can be considered for those who have not previ-
thin residual FLAIR abnormality around resec- ously received radiation treatment. Chemother-
tion cavity) (10-year OS 57%) and subtotal apy is the option in patients who progress after
resection (residual nodular FLAIR abnormality) previous radiotherapy.
(10-year OS 49%; p = 0.017). Incomplete resec-
tion is only indicated to control specific symp- Gliomatosis cerebri
toms such as seizures or intracranial pressure Gliomatosis is characterized by diffuse infiltra-
which may be relieved with removal of the tion of the brain with malignant glial cells. It
appropriate region of tumour. The majority of usually presents with headaches, personality
patients are followed up or treated with non- changes or seizure. MRI with FLAIR is more
surgical treatment after biopsy. sensitive in detecting the lesion which shows
diffuse isointense to hypointense lesions on T1W
Radiotherapy and hyperintense lesions involving at least two
Immediate radiotherapy is as effective as delayed lobes of the brain on T2W & FLAIR. Surgery is
radiotherapy (i.e. delayed until progressive symp- of little benefit but radiotherapy (principles same
toms). In a symptomatic patient, radiotherapy as low grade glioma) can stabilize or improve the
reduces the tumour size and leads to symptomatic disease. Chemotherapy can be attempted when
improvement in 50–75%. However, in patients radiotherapy is technically difficult. Median sur-
with well-controlled seizures early radiotherapy vival is around 12 months.
does not improve overall survival compared
with radiotherapy deferred until clinical progres- Treatment of high-grade (malignant) glioma
sion, but improves the progression-free interval. (WHO grade 3 and 4)
A randomized study of early vs. delayed radio- High-grade gliomas account for around 50% of
therapy showed a 5-year overall survival of brain tumours. These can be either anaplastic
63% with early radiotherapy compared with 66% glioma (grade 3) or GBM. These tumours are
with delayed radiotherapy. The 5-year disease free highly aggressive and the aim of treatment is to
survival was better (44% vs. 37% p = 0.02) with improve neurological deficit, quality of life and
early radiotherapy. There is no clinical benefit to increase survival. Optimal medical manage-
beyond a radiotherapy dose of 45–50 Gy, and ment includes steroids to improve oedema, anti-
higher doses cause significant side effects of fatigue convulsants in patients who have had seizures
and poor emotional functioning. and rehabilitation.
Chemotherapy GBM
Chemotherapy can improve symptoms and lead GBM accounts for 75% of malignant gliomas.
to a radiologic response. The role of chemo­ The median survival is around 1 year. There is
therapy in newly diagnosed disease is however no randomized data showing superior survival
undefined. Chemotherapy is used in malignant with surgical resection compared with biopsy
transformation. Oligodendroglioma with allelic alone. Maximal resection will improve time to
loss of chromosome 1p/19q usually responds to progression as well as tolerability to subsequent
chemotherapy with alkylating agents (Box 16.3). radiotherapy and hence, maximal safe resection
is recommended.
Outcome Adjuvant radiotherapy improves median sur-
The median survival of low-grade glioma is 5–8 vival of GBM from 14 weeks to 40 weeks and is
years. Oligodendroglioma has a better prognosis given as a dose of 58–60 Gy in 1.8 to 2 Gy per
of 12–16 years. fraction. Hence patients aged <70 years with
272
 CENTRAL NERVOUS SYSTEM TUMOURS 16

Box 16.4: Treatment of glioma

median survival of 3 years and those with ana-
plastic oligodendroglioma have a better progno-
• Surgical resection alone is the treatment option
for pilocytic astrocytoma sis, particularly those with loss of heterozygosity
• Low-grade glioma is treated with active of 1p and 19q (median survival 5–7 years).
surveillance, complete resection or biopsy followed Current standard treatment of AG is maximal
by delayed radiotherapy cytoreduction with postoperative radiotherapy.
• High-grade glioma is treated with: The value of temozolomide in grade 3 astro-
• Radical radiotherapy (with concomitant and cytoma and oligodendroglioma is not proven.
adjuvant temozolomide for GBM) for <70 years,
PS0–1 and no significant neurological deficit Patients with anaplastic oligodendroglioma
• Palliative radiotherapy for >70 years and PS0–2, demonstrating LOH on 1p/19q have 60–80%
or <70 years with significant neurological response rates with alkylating chemotherapy.
deficit or midline tumours
Despite that, early administration of adjuvant
• Supportive care for PS>2 or severe residual
deficit (e.g. hemiplegia, confusion)
chemotherapy before or after radiotherapy does
not impact on overall survival and there is no
difference in efficacy between PCV and temo-
zolomide chemotherapy.
good performance status (0–1) are considered for Management of recurrence and progression
radical radiotherapy, whereas patients aged >70 In the majority of patients (>80%) with high-
years and performance status of 0–2 may be con- grade glioma, tumours recur within a 2–3 margin
sidered for short course radiotherapy. Patients of the original tumour (Figure 16.4). Repeat
with poor PS and significant neurological deficit surgery is an option for those with favourable
are treated with supportive measures (Box 16.4). prognostic features such as age <50 years, good
A meta-analysis of adjuvant chemotherapy performance status, progression free survival of
trials showed a slight improvement in median >6 months and well circumscribed tumour, which
survival of 2 months. Recently a randomized offers a median survival of 6–8 months with 20%
study reported a significant survival benefit with 1-year survival. In this group of patients polymer-
concurrent and adjuvant temozolomide. In this based carmustine chemotherapy in a wafer
study of newly diagnosed GBM patients, temo- (Gliadel) is proven to be useful. A randomized
zolomide (75 mg/m2) given concurrently with study showed an increased 6-month survival
radiation followed by adjuvant monthly treat- from 44% to 64% (p = 0.02) and median survival
ment (200 mg/m2 days 1–5) up to 6 months pro- from 23 to 31 weeks with Gliadel wafers.
duced a survival advantage at 2 years of 16% An alternative treatment option is radiosurgery
which was sustained at 4 years compared to if the recurrent tumour is small. In patients who
radiation alone (10–26%). Hence this is the are not suitable for the above options palliative
treatment of choice for GBM. However, the chemotherapy should be considered. PCV results
benefit of temozolomide is only seen in patients in 20–50% response with 4–8 months survival.
with methylation of the O6-methylguanine-
Brainstem glioma
DNA methyltransferase (MGMT) gene pro-
Brainstem gliomas are rare in adults. Diffuse
moter. The overall survival was increased in
intrinsic pontine gliomas are generally high grade
patients with methylated MGMT promoter
whereas exophytic tumours are low grade. These
regions compared to those with unmethylated
tumours usually present as multiple cranial nerve
MGMT promoter regions (18.2 months and 12.2
paralysis, ataxia and hemiparesis. MRI shows
months, p < 0.001). However test for methyla-
diffuse enlargement of the pons on T1W images
tion of the MGMT gene promoter is not rou-
and enhancement is seen in high-grade glioma.
tinely used, to select patients for concurrent
Surgery is an appropriate treatment for exophytic
chemoradiotherapy.
low-grade lesions whereas inoperable low-grade
Anaplastic glioma (AG) lesions and intrinsic lesions are treated with
AG constitutes 25% of high-grade glioma. involved field radiotherapy. The median survival
Patients with anaplastic astrocytoma have a of non-enhancing lesions is in the region of 7
273
 II SITE-SPECIFIC CANCER MANAGEMENT

A B

Figure 16.4
GBM recurrence. GBM can spread along the white matter track and manifest with recurrence away from the original
lesion. This patient, who had left temporal lobectomy (B-long arrow) for GBM (A), presents with a non-homogenous
contrast enhancing recurrent lesion (B-arrow head), which indicates spread along the white matter track.

years and of enhancing lesions is approximately These are cured with excision. Choroid plexus
11 months. carcinomas (grade 3) are also common in chil-
dren and behave aggressively with extensive ven-
Ependymoma tricular and subarachnoid space spread. Choroid
Ependymomas (grade 2) are slow growing plexus carcinoma is treated with a combination
tumours arising from the ependymal or sub- of surgery and radiotherapy, with or without
ependymal cells surrounding the ventricles, spinal chemotherapy.
canal or filum terminale. These are typically low-
grade but exhibit a high risk of recurrence and Medulloblastoma and PNET
can spread through the CSF. They are rarely
Medulloblastoma (grade 4) commonly occurs in
infiltrative and seldom metastasize outside CNS.
children, but can also occur in adolescents and
Subependymoma, which occur in the cerebral
adults. It usually affects the cerebellum and can
ventricles and myxopapillary ependymoma,
spread locally, through CSF and outside the
which occurs in the filum terminale are grade 1
CNS. Histologically the tumour consists of small
variants of ependymoma. Histologically these
primitive round or spindle cells which might
tumours consist of uniform round cells with
express neuron specific enolase, synaptophysin,
widespread pseudorosette formation. Maximal
Leu-7 and protein gene product 9.5.
surgical resection followed by postoperative
PNET (grade 4) are aggressive supratentorial
radiotherapy is the treatment of choice in adults
tumours in children and young adults. Histology
(Table 16.2). Local radiotherapy is recommended
shows highly cellular diffuse sheets of cell with
if spinal MRI and CSF cytology are clear.
extensive necrosis. The prognosis is worse than
Craniospinal RT is recommended only in cases
medulloblastoma.
of neuraxis spread. There is no recommended
role for chemotherapy, except in recurrence
after radiotherapy. Postoperative radiotherapy Treatment of medulloblastoma and PNET
increases 5-year survival from 18% to 68%. In medulloblastoma, the extent of surgical resec-
tion correlates with survival and hence, maximal
Choroid plexus tumour surgical resection is attempted in localized
Choroid plexus papilloma (grade 1) usually disease. All patients are treated with postop­
presents as an intraventricular mass in children. erative craniospinal radiotherapy followed by
274
 CENTRAL NERVOUS SYSTEM TUMOURS 16
additional radiotherapy to the posterior cranial Germ cell tumours
fossa. Radiotherapy with concurrent vincristine Germ cell tumours occur in the midline struc-
followed by adjuvant chemotherapy with cispla- tures, pineal, sellar, hypothalamic and third
tin, CCNU and vincristine (Packer regime) is an ventricular regions. The majority of patients are
effective regime (Box 16.3); but it is very toxic diagnosed between 11–20 years. Histological
in adults (especially neurotoxicity) and hence appearance is similar to their gonadal counter-
sometimes radiotherapy alone may be used. part. Immunohistochemically germinomas may
stain for placental alkaline phosphatase (PLAP)
Acoustic neuroma and hCG and non-germinoma may stain for hCG
(vestibular schwannoma) and AFP.
Acoustic neuromas are tumours arising from the Presentation depends on the tumour type and
Schwann cell of the myelin sheath of the eight location. These tumours usually arise from the
cranial nerves. These can occur sporadically (4– pineal region and present with features of CSF
5th decade of life) or as part of NF2 (2nd–3rd obstruction and Parinaud’s syndrome (dorsal
decade of life). These are expansile slow growing midbrain compression leading to failure of up
tumours. Clinical presentation is usually with gaze, nystagmus and light-near dissociation of
progressive sensorineural hearing loss (up to pupil). Suprasellar tumours present with neuro­
95%). Large cerebello-pontine angle tumours endocrine deficits.
can lead to trigeminal involvement and pressure On imaging germinomas appear as a homog-
effect on the cerebellum and brainstem can give enously enhancing mass and non-germinomas as
rise to ataxia and lower cranial nerve (IX–XII) a heterogeneous mass with cysts, calcification
involvement. and/or haemorrhage. Spinal imaging with MRI
Imaging shows a homogenously enhancing may show leptomeningeal disease in 10–15% of
lesion close to internal auditory canal. Follow-up cases.
with regular imaging may be adequate for some The role of surgery is mainly to obtain a
patients. When treatment is indicated, for pro- tissue biopsy. In tumour marker positive disease
gressive tumours or large tumours with pressure (AFP above 25 IU/L or serum or CSF hCG
symptoms, the treatment options are surgery and of >50 IU/L in Europe and >100 IU/L in
radiotherapy (either radiosurgery or fractionated USA), imaging alone is sufficient prior to non-
radiotherapy). Surgery achieves a complete exci- surgical treatment. Surgery may have a role in
sion of 97% at the expense of complete hearing symptomatic residual masses after non-surgical
loss and transient facial palsy. Radiosurgery is management.
appropriate for lesions of <3 cm size. Fraction- Germinoma is treated with craniospinal radio-
ated radiotherapy may preserve hearing in therapy, which results in a 5-year survival of
patients with good control rates; but long-term 90–95% and 10-year survival of 91%. Chemo-
follow-up is needed. therapy is being evaluated to avoid the need
for craniospinal radiotherapy and to reduce the
dose of radiotherapy in paediatric germinoma.
Pineal tumours
Non-germinoma is treated with platinum based
Pineal tumours are common in children. Pineocy- chemotherapy followed by radiotherapy. In non-
toma (grade 2) are slow growing tumours which germinoma, with radiotherapy alone the overall
are treated with surgery and radiotherapy. survival is only 10–30%, whereas combined
Pineoblastomas (grade 4) are aggressive tumours modality treatment results in a 5-year survival
treated with surgery, radiotherapy and chemo- of 45%.
therapy. Pineal parenchymal tumours of inter­
mediate differentiation have an unpredictable
clinical behaviour. Treatment recommendation Meningeal tumours
varies from surgery alone to surgery followed by Meningiomas (Figure 16.5) account for 30% of
craniospinal radiotherapy. Management of pineal primary intracranial neoplasms and occur pre-
germ cell tumours is discussed below. dominantly in women. Grade 1 meningiomas
275
 II SITE-SPECIFIC CANCER MANAGEMENT

A B

Figure 16.5
CT scan of meningioma. A, A homogenously contrast enhancing lesion arising from the dura. B, Bone window showing
increase in thickness of skull bone (hyperostosis) at the site of the tumour (arrows), a feature of meningioma.

(90% of meningiomas) are benign with a low apy is indicated (e.g. tumour near optic
risk of recurrence, atypical (grade 2) meningi- chiasma).
omas (5–7%) have a high risk of local recurrence 2. Grade of tumour – grade 2 and 3 tumours
after complete excision and grade 3 meningiomas have a 5-year recurrence rate of 40–100%
(3–5%) are aggressive. Papillary meningioma even after complete resection whereas that of
(grade 3) is seen in young patients, shows aggres- grade I tumour is 7–12%. Hence all patients
sive behaviour with frequent recurrences, brain with grade 2/3 tumours are treated with
invasion and metastasis. Anaplastic (malignant) immediate postoperative radiotherapy.
meningioma is also aggressive.
Data suggest that postoperative radiotherapy
An incidental finding on CT/MRI is one of
improves local control compared with no radio-
the common modes of diagnosis. Presentation
therapy after subtotal resection (15-year local
depends on the location of tumour. Base of skull
control 81% vs. 49%; p = 0.0001).
tumours usually present with cranial nerve
involvement whereas tumours over the convexity Primary CNS lymphoma (PCNSL)
of the cerebrum present with headache or seizure. PCNSL has a higher incidence in immunocompro-
Treatment of meningioma mised individuals than in the normal population.
It commonly presents in the third and fourth
Meningiomas can be observed if they are small
decades in immunocompromised individuals
and asymptomatic. Treatments of choice for pro-
whereas it occurs three decades later in those who
gressive or symptomatic meningioma are either
have a competent immune system. The usual pres-
complete surgical resection if in an operable
entations include focal symptoms, raised intra­
location or radical radiotherapy or radiosurgery,
cranial pressure, behaviour and personality
if in an inoperable site. Complete resection is
changes and confusion. Biopsy shows diffuse
usually difficult for skull base (Figure 16.6A),
large cell B cell lymphoma in 80–90%. Up to
cavernous sinus and cerebellopontine angle men-
20–40% patients have CSF involvement. Less
ingiomas. After incomplete resection, either a
than 5% people have systemic involvement.
policy of imaging surveillance with delayed
Tissue diagnosis is made from an open or stere-
radio­therapy on progression or immediate post-
otactic biopsy. Staging investigations include HIV
operative radiotherapy is adopted. The policy of
testing, chest X-ray, CSF examination and slit
image surveillance with delayed radiotherapy
lamp examination (10–20% have uveitis). Sys-
depends on:
temic staging is only indicated if B symptoms are
1. Location of tumour – tumour near critical present (see p. 306).
structures may cause neurological damage The role of surgery is limited to biopsy.
when it progresses and hence early radiother- Steroids may cause complete disappearance of
276
 CENTRAL NERVOUS SYSTEM TUMOURS 16

A B

Figure 16.6
Tumours of the base of the brain.
A, Homogeneously enhancing
meningioma. B, Heterogeneously
enhancing craniopharyngioma. C, Cystic
enhancing pituitary adenoma.

tumour (ghost tumours) and hence should be optic pathway (visual field defects) and neuro-
avoided until tissue diagnosis. Current standard logical symptoms.
treatment is high-dose intravenous methotrexate Surgical resection is the recommended treat-
with whole brain radiotherapy (40–50 Gy) which ment if feasible. Following incomplete resection
results in a 2-year survival of 43–73%. However or cyst decompression and biopsy, postoperative
this treatment is extremely toxic particularly in radiotherapy is indicated which results in a
the elderly when 60–80% patients older than 5-year survival of 89% and 10-year survival of
60 years develop progressive leucoencephalopa- 77%.
thy and cognitive dysfunction. Hence in the
elderly chemotherapy alone with delayed radio- Pituitary adenoma and carcinoma
therapy is an alternative. In immunocompro-
mised patients reduction of radiotherapy dose Pituitary adenoma
may be necessary to reduce toxicity. Pituitary adenoma (Figure 16.6C) usually
presents between the ages of 30–50 years. These
Craniopharyngioma are slow growing tumours with an insidious
Craniopharyngioma (Figure 16.6B) arises from onset of symptoms. The usual presentation
the epithelial remnants of Rathke’s pouch. These is hormonal dysfunction or symptoms result-
are slow growing tumours often with a solid and ing from pressure effects such as visual field
cystic component, the latter filled with a fluid defects.
having a ‘motor oil’ appearance. Medical management is important in secre-
The clinical presentation is with pituitary hor- tory tumours. Transphenoidal surgery is the
monal abnormalities, pressure symptoms on the standard surgery for secretory tumours other
277
 II SITE-SPECIFIC CANCER MANAGEMENT

than prolactinoma and macroadenoma pro­ Diagnosis

ducing pressure symptoms. The indication for Contrast enhanced CT scan is usually diagnostic
radiotherapy is relative and usually indicated in with more than half of the patients showing mul-
tumour progression after surgery, uncontrolled tiple metastases (Figure 16.7). The lesions are
hormone production, extensive residual tumour typically contrast enhancing and located in the
and invasion of the cavernous sinus. Radiother- junction between grey and white matter. MRI
apy is usually given as stereotactic fractionated scan is useful in lesions in the posterior fossa,
radiotherapy or radiosurgery. Radiotherapy con- those with negative CT scans, those with sus-
trols hypersecretion in 80% patients with pected leptomeningeal disease and to confirm a
acromegaly, 50–80% with Cushing’s disease and solitary lesion if planning for surgical resection.
33% with hyperprolactinaemia. In non-secretory
tumours, surgery followed by radiotherapy Prognosis
results in a 20-year progression free interval of Untreated symptomatic patients have a median
>90%. The long-term side effects of radiotherapy survival of 4–8 weeks. With steroids the survival
are hypopituitarism, increased risk of a second is 8–12 weeks. A prognostic classification is
cancer (20-year risk of 2.4%), and increased risk shown in Table 16.3.
of cerebrovascular death (relative risk 4.1).
Treatment
Pituitary carcinoma Initial management includes high-dose steroids
Pituitary carcinomas are rare (0.2% of pituitary which reduce the symptoms of cerebral oedema,
tumours). They often present with secretory fea- pain management and anti-epileptics for
tures (Cushing’s or hyperprolactinaemia). There seizures.
is limited literature, but the prognosis is poor Multiple brain metastases
with multiple local recurrences and metastatic Whole brain radiotherapy (WBRT) is the treat-
spread. ment of choice for the majority of class 1 patients.
Most of the Class 2 patients are not suitable for
Metastatic tumours of brain WBRT. Class 3 patients are treated with sup-
portive care only. The standard radiotherapy
Metastatic brain tumours are four times com- regime is either 20 Gy in five fractions or 30 Gy
moner than primary brain tumours and one in 10 fractions. Around 10% of patients are alive
quarter of all cancer patients develop brain after 12 months.
metastases during their illness. The incidence of
brain metastases is increasing because of the
improved systemic control of many cancers. The
commonest primaries are lung in whom 30–80%
Table 16.3: Prognostic groups in brain
develop brain metastases, breast (20–30%) and metastases
gastrointestinal cancer. Other cancers include Prognostic Median survival
renal cell carcinoma (5–10%) and malignant group* Definition (months)
melanoma (10–20%). Class 1 Age less than 65 7.1
years, KPS ≥70,
Presentation controlled primary
disease and no
Eighty percent of brain metastases are diagnosed
extracranial
after development of the primary cancer and metastases.
20% present with brain metastases prior to and
Class 2 Neither class 1 nor 2 4.2
simultaneously with the diagnosis of primary.
Headache is the commonest symptom. Up to Class 3 KPS <70 2.3
20% can have seizures and lateralizing signs.
*Based on RTOG RPA prognostic group. This is not applicable
5–10% can present with an acute neurological to chemosensitive tumours such as germ cell tumours,
deficit due to bleeding into the tumour or choriocarcinoma etc.
cerebral infarction.
278
 CENTRAL NERVOUS SYSTEM TUMOURS 16

A B

C D

Figure 16.7
Various appearances of brain metastases. A, Bleeding metastasis (melanoma). B, Single cystic metastasis (mucinous
carcinoma, breast). C, Multiple metastasis (lung cancer). D, Predominant posterior fossa metastases (HER2+ breast
cancer).

There is no role for surgery in multiple metas- Box 16.5: Single or solitary metastasis
tases, except to relieve hydrocephalus. Patients
• Single metastasis – one lesion within the brain
with highly chemosensitive tumours (e.g. germ irrespective of status of systemic disease
cell tumours, choriocarcinoma) are treated with • Solitary metastasis – the one lesion in the brain is
initial chemotherapy followed by consolidation the only metastatic disease in the body
whole brain radiotherapy in some cases. • Oligometastases – solitary or small number (<4)
metastases which can be treated aggressively
Single or solitary metastasis (on MRI) (Box 16.5)
In a group of patients with operable single or
solitary metastasis, surgical excision followed by previous 3 months. Complete excision followed
WBRT improve survival compared with WBRT by close imaging follow-up may be appropriate
alone (40 weeks vs. 15 weeks; p < 0.01). Most for some patients with good prognosis.
benefit is seen in patients <65 years with KPS Patients with inoperable tumours due to
of ≥70 and no extracranial progression in the inaccessible locations may be considered for
279
 II SITE-SPECIFIC CANCER MANAGEMENT

stereotactic radiosurgery followed by WBRT if weeks, with prompt treatment median survival is
they have a PS of 0–1, >1year disease-free inter- around 6–8 months.
val and controlled systemic disease.
Spinal cord tumours
Brain metastasis after prophylactic cranial Spinal cord tumours can be either primary or
secondary. Primary spinal cord tumours consist
radiotherapy and previous treatment
of 2–4% of all primary CNS tumours. Common
Patients with isolated metastasis can be con­ spinal cord tumours are shown in Box 16.6.
sidered for radiosurgery in a selected group of Pain is the commonest presenting symptom.
patients. If a patient had previously benefited There will be varying degrees of spinal cord com-
from WBRT for at least 4 months and the general pression depending on the location of tumour.
condition is good (PS 0–1), re-irradiation, either Evaluation includes a full neurological examina-
partial brain or whole brain may be considered. tion to assess the extent and level of neurological
Leptomeningeal carcinomatosis deficit. MRI is the imaging of choice. Intramedul-
lary tumours may expand the cord and other
Infiltration of the leptomeninges by cancer com-
imaging features are similar to that of corre-
monly occurs with breast and lung cancer,
sponding tumours in the brain (Table 16.1).
melanoma, lymphoma and leukaemias. Clinical
presentation can be with features of increased Management
intracranial pressure, cranial nerve palsies or General management includes pain control, ster-
impaired higher function. Diagnosis is based on oids which reduce both pain and the neurological
MRI scan (CT has a reduced sensitivity of 30% deficit and rehabilitative measures.
compared with 70% for MRI) and CSF examina- The definitive treatment is surgery. Early
tion. Typical findings on MRI are subarachnoid surgery is advocated to avoid further neurologi-
or parenchymal nodule (Figure 16.8) and sulcal/ cal damage. Maximal safe removal with the help
dural enhancement. Patients with good prognosis of operative microscope and tools such as intra-
(limited disease, PS0–1, chemo-sensitive tumour operative ultrasound and cavitating ultrasonic
and minimal neurologic deficit) are treated with aspirator is the norm. Indication for and dose of
intrathecal chemotherapy with radiotherapy to radiotherapy is as in Box 16.7. Radiotherapy is
symptomatic sites and systemic chemotherapy. indicated for all intramedullary tumours except
Median survival in untreated patients is 4–6 the following situations:
1. Pilocytic tumours (grade 1) after complete and
incomplete resection (5-year survival 90%).
2. Myxopapillary ependymoma (grade 1) after
complete (10-year survival 98%) or incom-
plete resection (10-year survival 70%).

Box 16.6: Spinal cord tumours

Intramedullary (within spinal cord)

• Glioma – ependymoma or astrocytoma
• Metastasis (rare)
Extramedullary – intradural (outside the cord but
within the dura)
• Meningioma – usually grade 1
• Nerve sheath tumours – usually grade 1
Figure 16.8 Extradural
Ommaya reservoir (arrows) in situ for intrathecal • Metastasis – lung, breast, prostate etc.
chemotherapy, and there is an enhancing parenchymal • Primary tumours of spine
lesion (arrow head).
280
 CENTRAL NERVOUS SYSTEM TUMOURS 16

Box 16.7: Radiotherapy for intramedullary

Management of recurrence
tumours A second surgery if feasible is the treatment
Position – depends on the site of tumour option in low-grade tumour recurrences. Radio-
• Cervical – prone therapy may be considered if surgery is not pos-
• Thoracic – supine sible and radiotherapy has not previously been
• Lumbar – supine or prone given. Chemotherapy is an option for high-grade
Target volume recurrences (Box 16.3).
• CTV – spinal canal in axial direction and 2–3 cm
superioinferior margin Further reading
• PTV – 1 cm
Nieder C, Mehta MP, Jalali R. Combined radio- and
Dose 50 Gy in 30 fractions chemotherapy of brain tumours in adult patients.
Clin Oncol. 2009;21:515–524.
van den Bent MJ, Hegi ME, Stupp R. Recent developments
3. Grade 2 astrocytoma after complete in the use of chemotherapy in brain tumours. Eur J
resection. Cancer. 2006;42:582–588.
Noda SE, El-Jawahri A, Patel D, Lautenschlaeger T, Siedow
Extramedullary tumours are treated with M, Chakravarti A. Molecular advances of brain tumors
surgical excision followed by imaging follow-up. in radiation oncology. Semin Radiat Oncol. 2009;19:
171–178.
Incompletely excised grade 2–3 meningiomas are Van Meir EG, Hadjipanayis CG, Norden AD, Shu HK, Wen
considered for postoperative radiotherapy. PY, Olson JJ. Exciting new advances in neuro-oncology:
Extradural tumours treated according to the the avenue to a cure for malignant glioma. CA Cancer J
histologic type of the tumour. Clin. 2010;60:166–193.
Chemotherapy has a limited role in spinal cord Soffietti R, Rudà R, Trevisan E. Brain metastases: current
management and new developments. Curr Opin Oncol.
tumours except in high-grade glioma. When nec- 2008;20:676–684.
essary, agents used in brain tumours can be used. Khuntia D, Brown P, Li J, Mehta MP. Whole-brain
radiotherapy in the management of brain metastasis.
Prognosis J Clin Oncol. 2006;24:1295–1304.
Traul DE, Shaffrey ME, Schiff D. Part I: spinal-cord
Prognosis depends on histologic type and grade, neoplasms-intradural neoplasms. Lancet Oncol. 2007;
age (younger the better), functional status at 8:35–45.
presentation, size of the tumour (dictates opera-
bility) and extent of resection.

281
 Endocrine tumours
TV Ajithkumar
17
Thyroid cancer noma and hemithyroidectomy is indicated for all
follicular lesions. MRI is the preferred imaging
Thyroid malignancies are the commonest endo- to assess local invasion (Figure 17.1) as the use
crine malignancy. Common types of thyroid of iodine containing contrast can cause thyroid
cancers are papillary and follicular carcinomas stunning which may prevent effective use of radi-
(well-differentiated cancers) arising from epithe- oiodine for at least three months subsequently.
lial cell, medullary carcinomas from the para­
follicular C cells, anaplastic carcinoma and Staging
NHL. Well-differentiated cancers typically affect Box 17.1 shows the TNM staging system. The
women in their 40s. The median age of presenta- TNM and MACIS (Box 17.2) have been shown
tion of medullary carcinoma is 50–60 years and to be the best predictors of outcome in differenti-
older for anaplastic carcinoma. ated thyroid cancer.
Aetiology Management
The majority of thyroid cancers are sporadic. Well-differentiated cancer
Other risk factors include radiation exposure Surgery is the definitive treatment of all malig-
(papillary carcinoma), genetic (e.g. MEN2 nancies except lymphoma. The majority of
with medullary carcinoma, FAP with papillary patients need total or near total thyroidectomy.
carcinoma) and endemic goitre (follicular In low-risk patients (<1 cm papillary cancer with
carcinoma). no nodes, <2 cm follicular cancer in women aged
less than 45 years and <1 cm follicular cancer
Presentation with minimal capsular invasion) lobectomy is
Common presentation is with an enlarging adequate. Patients with high-risk disease (male
solitary nodule. Cervical lymphadenopathy is >45 years, tumour >4 cm and extracapsular
common with medullary, papillary and anaplas- spread) are at risk of level VI nodal involvement
tic carcinoma. Local invasion can lead to symp- and hence elective central node dissection is indi-
toms of hoarseness of the voice and dysphagia. cated. Patients with proven neck node metastases
Anaplastic carcinoma has an aggressive growth are treated with modified radical neck dissection.
with local invasion and rapid growth which can All patients should have serum calcium postop-
lead to stridor. eratively to rule out transient hypocalcaemia.
Serum thyroglobulin (TG), the tumour marker,
Evaluation is estimated 6 weeks postoperatively which
Evaluation includes clinical examination and should be undetectable in patients who had total
assessment for thyrotoxicosis which is rare in thyroidectomy and have no residual disease.
cancer. Initial investigations include thyroid Patients after total thyroidectomy are started on
function tests and FNA of the lesion. Biopsy may triiodothyronine (T3) 20 mg thrice daily which
be indicated for lymphoma and anaplastic carci- is subsequently changed to T4. T4 is started
282 © 2011, Elsevier Ltd
DOI: 10.1016/B978-0-7234-3458-0.00022-1
 ENDOCRINE TUMOURS 17

A B

Figure 17.1
Axial (A) and coronal (B) view of MRI scan in anaplastic carcinoma of thyroid.

Box 17.1: TNM staging in thyroid cancer Box 17.2: MACIS (Metastasis, Age, Completeness
of resection, Invasion, Size). Scoring system to
T stage
assess 20-year survival probability of papillary
pT1 Tumour ≤2 cm in greatest dimension
pT2 Intrathyroidal tumour >2–4 cm in greatest Scores
dimension Metastasis – Present: score 3
pT3 Intrathyroidal tumour >4 cm in greatest Age – <40 years: score 3.1
dimension >40 years: score = 0.08 × age
pT4 Tumour beyond the thyroid capsule
Completeness of resection – incomplete: score 1
N stage (cervical and upper mediastinal)
Invasion – present: score 1
N0 No nodes involved Tumour size: score = 0.3 × size in cm
N1 Regional nodal involvement
N1a Ipsilateral cervical nodes Total score and 20-year survival
N1b Bilateral, midline or contralateral cervical
<6 99%
nodes, or mediastinal nodes 6–6.99 89%
Distant metastases 7–7.99 56%
>8 24%
M0 No distant metastases
M1 Distant metastases
MX Distant metastases cannot be assessed
Staging of epithelial thyroid carcinomas with a dose of 100 mcg daily and increased by
Stage I 25 mcg every 6 weeks until TSH levels are below
Aged 45 or younger with any pT, any N M0 0.1 MiU/L.
Aged 45 or older with pT1N0M0
Radioablation
Stage II
Aged 45 or younger with any pT any N M1
Postoperative radioiodine ablation is recom-
Aged 45 or older with pT2N0M0 or pT3N0M0
mended for all patients except for those who had
total thyroidectomy for a well-differentiated uni-
Stage III
Aged 45 or older with pT4N0M0 or any pT, N1M0
focal tumour of <1 cm with no vascular or extra­
capsular invasion. Informed consent should be
Stage IV
Aged 45 or older with any pT, any N, M1 obtained and instruct female patients not to get
Anaplastic thyroid carcinoma any age or stage pregnant prior to and up to 12 months after
treatment (Box 17.3). T4 is substituted with T3
4–6 weeks before radioablation and T3 is with-
drawn 2 weeks before ablation. 3–3.7 GBq of
radio­iodine is administered orally. In patients
with a history of myxoedema psychosis, severe
283
 II SITE-SPECIFIC CANCER MANAGEMENT

Box 17.3: Side effects of radioablation Total/near total thyroidectomy

Early effects
• Sialoadenitis and taste changes • Start T3 20 mg TDS initially and then change to T4
• Nausea • Serum thyroglobulin at 6 weeks
• Neck pain and swelling
• Radiation cystitis, gastritis • Change T4 to T3 4–6 weeks prior to radioblation
• Stop T3 2 weeks prior to radioblation
• Symptoms of hypothyroidism for 4–6 weeks
Late effects
• Dry mouth and taste changes Oral radioiodine 3–3.7 GBq
• Dry eyes due to lachrymal gland dysfunction
• Increase in miscarriage rate in first year after Uptake scan 3–10 days later and serum thyroglobulin
treatment
• Pulmonary fibrosis
• Male infertility If uptake or raised thyroglobulin
No uptake or
• Risk of 2nd malignancy raised TG
Surgery or 5.5 MBq radioiodine

cardiac disease and high volume disease, T3 Stimulated TG estimation and radioiodine uptake scan at 6 months
withdrawal can be dangerous and hence recom-
binant human TSH (0.9 mg IM daily for 48 Increased TG and Increased uptake
hours before radioablation) is used. Patients are no uptake on scan on scan
admitted to and remain in a specialist facility
with appropriate shielding and sanitation. Isola- Repeat stimulated TG Surgery if feasible or
tion is continued until safe levels of radiation are at 6 months radioiodine 5.5 MBq
measured by a medical physicist. Patients are
advised to keep well-hydrated, empty the bladder Decreasing Increasing Uptake scan at 3-20 days
frequently and to take prescribed laxatives to after radioiodine
avoid constipation and these measures are aimed
Follow-up PET scan
at minimizing the absorbed dose of radiation. An 6 monthly radioiodine
uptake scan is done 3–10 days after radioiodine 5.5 MBq until no more
uptake or bone marrow
to assess residual thyroid tissue. In patients with suppression or lung
elevated TG and positive uptake scans, either No disease Disease present toxicity
further surgery or repeat dose of radioiodine
(5.5 MBq) is indicated. Further management Observation or
afterwards is shown in Figure 17.2. empirical radioiodine
Some patients do not have a take-up of radio- Figure 17.2
iodine when external beam radiotherapy to the Management of well-differentiated thyroid cancer.
entire thyroid bed has been carried out, and level
III–VI nodes (60 Gy in 30 fractions) is indicated
if there is gross residual disease, extranodal
disease and in patients >60 years with T4 disease. if metastatic disease is present. In metastatic
disease this helps with optimal local symptom
Medullary carcinoma control and control of calcium levels. In patients
All patients with medullary carcinoma should with level II–V nodal involvement modified
have screening for phaeochromocytoma with radical neck dissection is done. All patients need
24-hour urinary catecholamines and serum a suppressive dose of thyroxine.
calcium to exclude hyperparathyroidism (MEN2 There is no role for radioiodine ablation. In
syndrome). patients with incomplete resection, postoperative
Total thyroidectomy with elective central radiotherapy to the thyroid bed, bilateral cervical
nodal dissection is the treatment of choice even and upper mediastinal nodes (50–60 Gy in 2 Gy
284
 ENDOCRINE TUMOURS 17
per fraction) may be given to improve relapse- virilization is the most common presentation.
free survival. Other presenting symptoms include virilization in
Follow-up is life-long with clinical examina- women and gynaecomastia and testicular atrophy
tion, serum calcitonin estimation and ensuring in men, hypertension and hypokalaemia.
adequate thyroid suppression. Non-secreting tumours present with abdomi-
Patients presenting with recurrence may be nal discomfort or back pain due to mass effect.
treated with surgical excision if feasible. Radio- Rarely patients can present with fever, weight
therapy is useful in inoperable local recurrence. loss and anorexia.
Patients with symptomatic metastatic disease
may be considered for 131I-MIBG or radiolabelled Diagnosis
somatostatin analogues if there is uptake with Initial investigations include hormonal workup
the corresponding scans. and imaging with CT chest and abdomen (Figure
All patients with medullary carcinoma thyroid 17.3). MRI is also useful in identifying invasion
require genetic screening for mutations in the of adjacent organs and the inferior vena cava,
RET gene at exon 10, 11, 13 and 16. Prophylac- and hence in planning surgery. Biopsy of an
tic surgery is indicated in gene carrier mutated adrenal tumour is controversial because of the
relatives (before 1 year in MEN 2B and 5–10 theoretical risk of needle tract metastases.
years in MEN 2A). However, it may be acceptable if primary surgical
management is not feasible and diagnosis cannot
Anaplastic carcinoma thyroid be established with non-invasive measures.
Surgery is an option only in a small proportion
of patients and the majority of patients present Staging
with locally advanced and metastatic disease. WHO (2004) staging for adrenocortical carci-
Radiotherapy is the principal treatment which is noma is as follows:
essentially to improve local control. It is given
Stage I: localized tumour of ≤5 cm.
either as 50–60 Gy in 2 Gy per fraction or in
Stage II: localized tumour of >5 cm.
combination with chemotherapy (adriamycin).

Prognosis
The long-term survival of well-differentiated
thyroid cancer is >90%. 10-year survival of med-
ullary carcinoma thyroid is 50–70% and median
survival of anaplastic carcinoma is less than 6
months (5-year survival <10%).

Adrenocortical carcinoma
Introduction
Adrenocortical carcinoma (ACC) is a rare malig-
nancy with heterogeneous manifestations and a
poor prognosis. In adults it peaks at 57 years of
age. There are no proven aetiological factors.
ACC is rarely reported in multiple endocrine
neoplasia I (MEN I), Li–Fraumeni and Wiede-
mann–Beckwith syndromes.
Figure 17.3
Presentation CT scan in adrenocortical carcinoma. On CT scan
adrenocortical carcinoma is typically more than 4 cm
Approximately 60% patients present with fea- with central necrosis with heterogeneous enhancement
tures of adrenal steroid hypersecretion. Rapidly and may show calcification (30%) and invasion into
progressing Cushing’s syndrome with or without adjacent structures.
285
 II SITE-SPECIFIC CANCER MANAGEMENT

Stage III: locally invasive or tumours with Outcome

regional lymph node metastases. The reported 5-year survival is 60% for stage I,
Stage IV: tumour invading adjacent organs or 58% for stage II, 24% for stage III and 0% for
distant metastases. stage IV. Median survival of stage IV patients is
Management less than 12 months. Cortisol secreting tumours
are associated with worse prognosis, partially
Complete removal of tumour offers best chance
attributable to morbidity associated with Cush-
for cure in patients with stage I–III tumours.
ing’s syndrome.
Radiotherapy has an established role in the pal-
liation of bone and brain metastases. Mitotane Further reading
(o,p’-DDD) is a specific drug for the treatment of
British Thyroid Association – Guidelines from the
adrenocortical cancer which leads to an objective management of thyroid cancer 2nd Edition. 2007.
response of 25% of cases. The main side effects Available from: http://www.british-thyroid-association.
are vomiting, diarrhoea, lethargy, somnolence, org/
depression, and adrenal insufficiency. All patients Ganti AK, Cohen EE. Iodine-refractory thyroid carcinoma.
need high-dose gluococorticoid replacement (e.g. Rev Recent Clin Trials. 2006;1:133–141.
Tuttle RM, Ball DW, Byrd D et al. Medullary carcinoma. J
50 mg hydrocortisone daily) which helps to Natl Compr Canc Netw. 2010;8:512–530.
minimize mitotane-induced side effects. Sherman SI. Molecularly targeted therapies for thyroid
Combination chemotherapy with mitotane cancers. Endocr Pract. 2009;15:605–611.
with streptozocin has yielded a response rate Neff RL, Farrar WB, Kloos RT, Burman KD. Anaplastic
(partial and complete) of 36%. thyroid cancer. Endocrinol Metab Clin North Am.
2008;37:525–538.
The commonly used combination regimes Wandoloski M, Bussey KJ, Demeure MJ. Adrenocortical
used are cisplatin, etoposide and doxorubicin cancer. Surg Clin North Am. 2009;89(5):1255–1267.
(EDP) with mitotane (Berruti Regime) and EDP Fassnacht M, Allolio B. Clinical management of
with streptozocin (Khan Regime). The ongoing adrenocortical carcinoma. Best Pract Res Clin Endocrinol
FIRM-ACT trial is comparing efficacy of these Metab. 2009;23:273–289.
two combination regimes in patients with inoper-
able stage III–IV disease.

286
Cancers of
unknown primary
TV Ajithkumar and HM Hatcher
18
Introduction entity which may be a favourable (15% patients)
or unfavourable (85% patients) (Box 18.1).
Cancers of unknown primary (CUP) constitute All patients should have an assessment of
3–5% of all cancers. The criteria for diagnosis of performance status and co-morbidities, which
CUP includes patients who have a biopsy proven will guide treatment decisions.
metastatic cancer in whom a detailed history,
physical examination, blood tests, immunohisto- Management
chemistry of biopsy, chest X-ray, CT scan of the
abdomen and pelvis and in certain cases, mam- The decision to treat depends on the clinico-
mography or FDG-PET fail to detect a primary pathological entity and performance status.
tumour. Patients with poor performance status (>2) are
generally treated symptomatically. Treatment of
Evaluation various subsets is as described below.
Clinicopathological evaluation aims to identify a Women with isolated axillary
primary site, a clinicopathological subset and to lymphadenopathy
rule out non-epithelial tumours. The first step Women presenting like this are treated like stage
includes clinical history to establish risk factors, II breast cancer. Previous studies showed an
clinical examination, investigations and patho- occult primary in 50–60% of cases after mastec-
logical evaluation. Initial investigations include tomy. However, if MRI of the breast failed to
blood tests, urinalysis, faecal occult blood test and show any primary, breast surgery or radiother-
CT scan of the chest, abdomen and thorax. Endo- apy may not be warranted. Axillary lymphaden-
scopic evaluation is guided by symptoms and/or opathy is treated with lymph-node dissection
signs. In patients suspected to have extragonadal followed by regional radiotherapy based on
germ cell tumours a serum beta-hCG and AFP breast cancer radiotherapy principles (p. 124).
should be estimated. Other tumour markers Adjuvant systemic treatment is similar to stage II
depending on the clinical context include PSA, breast cancer. The reported 5-year survival for
CEA, CA-125 and CA19-9. Pathological evalua- patients with 1–3 nodes are 87% and those with
tion includes light microscopy and expedient use >3 nodes are 42%.
of immunohistochemical techniques. Immunohis-
tochemistry is useful in differentiating epithelial Women with peritoneal carcinomatosis
from non-epithelial tumours, such as sarcoma and Women with peritoneal carcinomatosis are
lymphoma (Table 18.1). The majority of epithe- treated like stage III ovarian cancer with initial
lial tumours are adenocarcinoma (65–80%) fol- cytoreduction followed by combination chemo-
lowed by squamous cell carcinoma (10–15%) and therapy or vice versa depending on performance
undifferentiated carcinoma (5–10%). status and co-morbidities (p. 201). CA-125 may
The outcome of first step evaluation is be used as a tumour marker if elevated and the
identification of a specific clinicopathological reported long-term survival is 15%.

© 2011, Elsevier Ltd 287

DOI: 10.1016/B978-0-7234-3458-0.00023-3
 II SITE-SPECIFIC CANCER MANAGEMENT

Table 18.1: Immunohistochemistry in cancers of unknown primary

CK7 CK20 TTF-1 Other markers
Colorectal – + – CDX-2
Pancreas + +
Stomach Variable Variable CDX-2 (intestinal-type cancers)
Lung + – +*
Ovary + +
Breast + – ER/PR/HER2
Prostate – – PSA/PSAP
Melanoma – – – S100+ (except signet ring)
HMB-45 and Melan-A
Lymphoma – – – CD45
CD79a/CD20 (B cell)
Small cell dot + dot + +/– CD56/chromogranin/synaptophysin

*Adenocarcinoma in lung – TTF-1 is highly specific for lung and thyroid adenocarcinoma, lung small cell, and may stain extra-pulmonary
small cell carcinoma.

Box 18.1: Clinicopathological subsets of cancer Single metastatic disease

of unknown primary Patients with single metastatic disease are treated
Subset with surgical excision or radical radiotherapy or
Favourable subset combination. Role of systemic treatment is not
Adenocarcinoma
• Women with isolated axillary lymph node known.
• Women with peritoneal papillary serous Cervical lymphadenopathy
adenocarcinoma
• Men with sclerotic metastases Upper or mid-cervical lymphadenopathy can be
• Single metastatic lesion due to a head and neck primary whereas lower
cervical lymphadenopathy or supraclavicular
Squamous cell cancer
• Patients with cervical lymphadenopathy lymphadenopathy can be due to either a head and
• Patients with inguinal lymphadenopathy neck cancer or lung tumour. Investigations using
Poorly differentiated or undifferentiated
panendoscopy with CT/MR imaging will help to
• Undifferentiated neuroendocrine carcinoma identify the primary site of the tumour in 85–90%
• Poorly differentiated carcinoma of the midline in of cases. If a lesion is not identified, unilateral
the young tonsillectomy is done to rule out a tonsillar
Unfavourable subset primary. PET scan may also be useful in identify-
• Metastasis to liver or multiple sites ing the primary. If a primary is detected it is treated
• Malignant ascites with non-papillary serous accordingly with combined modality treatment
carcinoma
with surgery and radiotherapy or chemo-radio-
• Multiple brain metastases
therapy. If no primary is detected, lymphadeno­
• Multiple bone metastases
pathy is treated with neck dissection followed by
radiotherapy or radical radiotherapy. The reported
5-year survival ranges between 20–70%.
Men with sclerotic metastasis
Men with sclerotic metastasis and with either Patients presenting with inguinal
raised serum PSA or immunohistochemical stain lymphadenopathy
for PSA are treated with hormonal treatment for In this group of patients investigations are to
288 prostate cancer. rule out a primary site in the perineal area. If
 CANCERS OF UNKNOWN PRIMARY 18
no primary tumour is detected, treatment is regime like that used for germ cell tumours. In a
node dissection with or without postoperative study of 220 patients with median age of 39
radiotherapy. years, the overall response rate was 64% with
27% complete response and median survival of
Poorly differentiated carcinoma with 20 months.
midline distribution in young
These patients are usually male under 50 years Patients with unfavourable disease
of age, with mediastinal and/or retroperitoneal
Patients in the unfavourable subset are treated
tumours. Serum beta-hCG and AFP estimation
with symptomatic and palliative care. Those with
(raised in 20%), CT scan of chest, abdomen and
good performance status are treated with chemo-
pelvis and ultrasound of testis are needed. These
therapy with cisplatin-based or taxane/platinum
patients are treated as poor prognostic germ cell
combination which yields a response rate between
tumours with four courses of BEP chemotherapy
10–40% and median survival of 5–9 months.
followed by surgical resection of any residual
disease.
Further reading
Poorly differentiated neuroendocrine
Pavlidis N, Fizazi K. Carcinoma of unknown primary (CUP).
carcinomas Crit Rev Oncol Hematol. 2009;69:271–278.
These are treated with a combination of chemo- Greco FA, Erlander MG. Molecular classification of cancers
therapy with cisplatin and etoposide which yields of unknown primary site. Mol Diagn Ther.
a response rate of over 70% with 16% durable 2009;13:367–373.
Morris GJ, Greco FA, Hainsworth JD et al. Cancer of
remission based on a small series of 51 patients. unknown primary site. Semin Oncol. 2010;37:71–79.
Varadhachary GR, Abbruzzese JL, Lenzi R. Diagnostic
Poorly differentiated carcinoma strategies for unknown primary cancer. Cancer.
without features of neuroendocrine or 2004;100:1776–1785.
germ cell tumour Pavlidis N, Briasoulis E and Pentheroudakis. Cancer of
unknown primary site: ESMO clinical practice guidelines
Patients with these tumours are in the good prog- for diagnosis, treatment and follow-up. Ann Oncol.
nosis group and hence treated with a cisplatin 2010;21(suppl 5):v228–v231.

289
 Cancer in pregnancy
TV Ajithkumar and HM Hatcher
19
Cancer during pregnancy poses a very challeng- been suggested due to the risk of foetal heating/
ing situation. Cancer complicates 0.02–0.1% of cavitation. Abdominal X-rays, CT scans and
pregnancies. The oncologist faces the difficult isotope scans should be avoided during preg-
situation of optimizing the care of the mother nancy. However, a final decision to perform
without causing harm to the foetus. The common these investigations is based on the risk benefit
tumours diagnosed during pregnancy are malig- for the mother (your patient), their expected
nant melanoma, breast cancer and cervical cancer. survival and the gestation of the foetus.

Diagnostic work-up Principles of management

All patients require a complete physical examina- Termination of pregnancy
tion. Although histological diagnosis with fine Termination of pregnancy is an option when preg-
needle aspiration cytology and core biopsies are nancy itself is an obstacle to aggressive manage-
safe, general anaesthesia during the first trimester ment of cancer and is associated with unacceptable
carries a 1–2% risk of spontaneous abortion. risks for the health of mother and foetus. Termi-
Endoscopic biopsies as well as lumbar puncture nation of pregnancy in the first trimester is indi-
and bone marrow examinations are safe. Radio- cated only when treatment cannot be delayed and
logical investigations should be restricted to min- should take into consideration the curability of
imize the foetal exposure to ionizing radiation. cancer, drugs to be used and wishes of the patient.
A foetal exposure dose of 1 mGy is considered The indications for termination generally are:
safe. Box 19.1 shows various imaging procedures • Abdominal/pelvic tumour necessitating imme-
and uterine/foetal exposure dose. A dose of less diate treatment, especially if radiotherapy is
than 100 mGy (10 cGy) is associated with less needed.
than 1% risk of foetal malformation and car- • Aggressive disease course.
cinogenesis and hence, in the event of inadvertent • Poor general condition of the patient.
exposure of pregnant women to radiation, termi- • Inadvertent foetal exposure to more than
nation of pregnancy is not recommended if the 100 mGy during the first trimester.
foetal dose does not exceed this limit.
During the first trimester of pregnancy, radio-
logical investigations are indicated only if abso-
Surgery
lutely necessary. Chest X-ray with lead apron is Surgery can be performed without major risk to
considered safe and hence can be used with ultra- the patient during the first two trimesters, but
sound sonogram for initial evaluation. MRI with a 1–2% risk of foetal loss, small risk of low
without gadolinium (which crosses the placenta) birth weight (RR 1.5–2.0) and premature deliv-
can be used to rule out metastatic disease in the ery. Foetal harm during surgery is due to various
brain, liver and bone when indicated. Avoidance factors including placental transfer of drugs,
of MRI in the first trimester of pregnancy has intraoperative complications such as hypoxia,
290 © 2011, Elsevier Ltd
DOI: 10.1016/B978-0-7234-3458-0.00024-5
 CANCER IN PREGNANCY 19

Box 19.1: Uterine/foetal radiation dose during Box 19.2: Foetal radiation dose
various radiological investigations during radiotherapy
Investigation Uterine/foetal dose Radiotherapy Foetal dose
Chest X-ray 0.000005 Gy Cervical cancer 45–50 Gy
Abdominal X-ray 0.022 Gy Mantle field 0.014–0.13 Gy
Mammogram 0.04 Gy Breast cancer 0.14–0.18 Gy
Chest CT scan 0.002 Gy Brain tumour and head and neck 0.0015–0.08 Gy
Abdominal CT scan 0.02 Gy cancer
Pelvic CT 0.07 Gy
Barium enema 0.036 Gy
IVU 0.045 Gy
Bone scan 0.018–0.045 Gy than 100 mGy (Box 19.2). During radiotherapy
1 Gy = 100 cGy = 1000 mGy to the breast and chest wall, the dose to the
foetus increases with gestational age. The foetal
dose depends on the radiation field, dose, the
hypotension, and long-term supine positioning distance between the edge of radiation field
of mother during surgery causing placental and foetus, and the machine and its shielding
underperfusion. measures.
In the third trimester surgery after foetal matu- Radiotherapy should be delayed until postpar-
ration and delayed surgery until post-partum if tum if possible. If radiotherapy cannot be post-
appropriate are the options. poned the second trimester is the preferable time
Intra-abdominal surgery is more likely to inter- to deliver with appropriate precautions to keep
fere with pregnancy. During major abdominal foetal dose below 5–10 cGy.
and pelvic surgery, continuous monitoring of the
foetus is necessary. Measures to suppress prema- Systemic treatment
ture labour and prophylactic treatment to improve Most cytotoxic drugs have a low molecular
foetal lung maturity should be undertaken if the weight of less than 600 kDa and can cross the
surgery carries a risk of premature labour. placenta. The concern is that these agents can
cause various mutagenic, teratogenic and carci-
Timing of delivery and nogenic effects in the foetus. Physiological
breast feeding changes due to pregnancy such as change in
haemodynamics and renal clearance will also
Delivery is generally planned after weeks 32–35
alter the metabolism, distribution and elimina-
(earlier in modern neonatal units with better
tion of cytotoxic agents leading to unpredictable
outcome for the baby) and 3 weeks after the last
effects. Chemotherapy interferes with organo-
chemotherapy. Breast feeding is not recom-
genesis in the first trimester, leading to a high risk
mended during chemotherapy, up to 2–4 weeks
of teratogenesis (10% with single agent and 20%
after completion of chemotherapy and during
with combination) and hence is not advised.
hormonal treatment.
After the first trimester organogenesis is complete
except for the brain and gonads. Chemotherapy
Radiotherapy during this period can cause foetal growth retar-
The developing embryo or foetus is extremely dation (2-fold risk), stillbirths (5%), premature
sensitive to ionizing radiation, which can cause delivery (5%), low birth weight (7%) and myelo-
foetal loss, malformations, growth retardation suppression (4%). However, the risk of tera-
and defects in intelligence. Radiotherapy is there- togenesis is almost similar to the general
fore contraindicated for abdominal and pelvic population (2–3%); but there is concern about
malignancies during pregnancy. Several studies risk of sterility, defects in intellectual function
support the use of radiotherapy for head and and other organ dysfunction due to in utero
neck cancer, breast cancer and brain tumours. exposure of chemotherapy.
Radical radiotherapy to the head and neck and Alkylators and anti-metabolites are the most
brain can be achieved with a foetal dose of less teratogenic and have high abortive potential.
291
 II SITE-SPECIFIC CANCER MANAGEMENT

Vinca alkaloids, anthracyclines, 5-fluorouracil, or invasive disease. When indicated conization is

cytarabine, taxanes and platinums appear to be done at 14–20 weeks of pregnancy. The majority
relatively safe. of cervical cancer in pregnancy is squamous cell
Chemotherapy during pregnancy needs to be carcinoma (80–90%) and 80% present with
modified according to the toxicity data of indi- stage IA–IIA disease. Staging includes physical
vidual drugs. Chemotherapy is not given after 35 examination, chest X-ray and MRI of abdomen
weeks and stopped 3 weeks prior to a planned and pelvis.
delivery of the baby to allow for recovery of bone Cervical carcinoma-in-situ (CIN) can be
marrow function of the mother and foetus and managed with close follow-up with cytology and
for placental drug excretion from the foetus. colposcopy. When invasive cancer is diagnosed
the choice is between termination of pregnancy
Postpartum care followed by treatment or postponing treatment
until delivery. Cervical cancer with less than
The placenta should be send for histopathologic 3 mm invasion can be followed and delivered
examination as there is risk of placental metas- vaginally, whereas those with 3–5 mm invasion
tasis. Metastases can also occur in the foetus. and/or lymphovascular invasion are delivered by
In the absence of placental metastasis, optimal caesarean section at 32–36 weeks.
follow-up of a healthy baby is not known. Management of stage IA disease during the
first trimester is debatable. Some advise radical
Future pregnancies hysterectomy for margin positive IA1 disease and
Most oncologists would recommend women not IA2 disease. Patients with IA disease diagnosed
to become pregnant during follow-up for a period during the second or third trimester can be fol-
of 2–3 years depending on the type of cancer, lowed up and treated only after delivery.
risk of recurrence and patient’s age and wishes. Patients with stage IB–IVA disease during the
There is no evidence to suggest that future preg- first and second trimesters of pregnancy are
nancies compromise survival. managed by termination of pregnancy and imme-
diate treatment, whereas those diagnosed during
the third trimester may be followed up until deliv-
Care of the baby ery after 32–38 weeks. Some patients diagnosed
Anthracycline exposure in utero may affect with cervical cancer in later second trimester and
heart development so this should be assessed as early third trimester can be treated with neoadju-
the child grows. With platinum-based chemo- vant chemotherapy until delivery of the baby.
therapy during pregnancy, there is a concern that Radical treatment involves radical hysterectomy
any non-renally excreted dose will be retained with lymphadenectomy or chemoradiotherapy.
within the tissue which may affect later develop- There is no evidence to suggest that cervical
ment, e.g. neural, although there is little evidence cancer diagnosed during pregnancy has a worse
of this. outcome than those diagnosed when not preg-
nant, stage for stage.
Management of specific cancers
Breast cancer
Cervical cancer Breast cancer in pregnancy can occur at any time
The majority of cervical cancers in pregnancy are during pregnancy and within 12 months postpar-
asymptomatic, diagnosed by abnormal cytology. tum. The median age at diagnosis is 33 years and
Though atypical cytology is not uncommon in the commonest presentation is a painless palpa-
pregnancy, dysplastic changes are suspicious. ble lump (80–95%). Presentation is similar to
Colposcopic biopsy is needed for suspected non-pregnant breast cancer. Diagnosis may be
malignancy. Cone biopsy is associated with delayed accounting for a 2.5-fold increased risk
increased risk of vaginal bleeding, abortion, of advanced cancers (40%) at presentation.
infection and premature delivery and hence used Diagnosis is by mammogram, ultrasonography
only for patients with suspicion of microinvasion and non-enhanced MRI. Cytology may be
292
 CANCER IN PREGNANCY 19
difficult to interpret due to pregnancy associated be given after the first trimester if the patient
changes and hence needle biopsy or open biopsy decides to continue with the pregnancy.
is diagnostic. The most common histological type Studies suggest that the survival following a
is invasive ductal carcinoma (80–90%) followed diagnosis of melanoma in pregnancy is the same
by lobular carcinoma. The majority of tumours as an equivalent stage of melanoma diagnosed in
are high grade with axillary involvement (60– a non-pregnant woman.
90%). Hormone receptors are negative in 40–
70% and HER2 positive in 28–58%. Lymphomas
Staging investigations include chest X-ray, Lymphomas present with lymphadenopathy (70–
USS of abdomen and axilla and MRI if indicated. 80%) and B symptoms (20%). A small series
Serum alkaline phosphatase is doubled during suggested that in NHL there is a higher chance
pregnancy, but serum transaminases and CA of presentation with extranodal manifestation
15-3 are unaffected. (breast, GI, cervix and ovary). 70% of Hodgkin’s
In patients with non-metastatic disease, mas- disease (HD) presents with stage I–II disease,
tectomy and breast conserving surgery followed whilst 70–80% of NHL present with stage III–IV
by radiotherapy (post partum) are accepted surgi- disease.
cal treatments. Sentinel node biopsy using blue Investigations include full blood count includ-
dye (risk of allergic reaction) and radioisotope are ing ESR (raised in pregnancy), biochemistry,
not advised (though the exposure is <5–15 mGy). lymph node excision biopsy, bone marrow exam-
Patients who need adjuvant chemotherapy can be ination, USS of abdomen and pelvis. ENT exami-
safely treated after 12 weeks of gestation (1.3% nation, endoscopy and nervous system staging
risk of malformation) using anthracycline con- are done whenever indicated.
taining regime. Hormonal treatment and transtu- The most common type of HD is nodular
zumab are not advised during pregnancy. sclerosis and 90% of pregnancy associated NHL
Patients with metastasis can be treated with are high grade.
chemotherapy after the first trimester. However, When the diagnosis is made in the first trimes-
the issue of termination of pregnancy should be ter, termination of pregnancy is considered par-
discussed in the appropriate context. ticularly in those with B-symptoms, bulky stage
Most series suggest that pregnancy does not I–II, stage III–IV and high-grade lymphoma. If
affect the natural course of illness or prognosis. the patient refuses termination, single agent vin-
blastine may be given until the second trimester.
Melanoma The preferred regime for HD is ABVD and for
Common presenting symptoms are change in size NHL is CHOP (p. 298). Treatment may be
and colour and bleeding or ulceration of pre- delayed until delivery in low volume low-grade
existing melanotic lesion as with melanomas NHL. If treatment is needed for low-grade NHL,
diagnosed outside pregnancy (p. 234). Patients single agent chemotherapy or limited field radio-
can present with lymphadenopathy and features therapy is used.
of metastatic disease. Evaluation includes full When the diagnosis is made in the third tri-
clinical examination and skin examination fol- mester, treatment may be delayed until delivery
lowed by excisional biopsy, in limited disease. at 32–35 weeks. Radiotherapy whenever indi-
The commonest type is superficial spreading cated is generally delayed until delivery.
(74%) followed by nodular melanoma (16%). In Prognosis of pregnancy associated lymphomas
the absence of clinical features of metastases, is similar to that of non-pregnant patients. The
chest X-ray and USS abdomen are sufficient for long term remission is 88% for HD and 45% for
staging. NHL.
The surgical excision margin is based on thick-
ness of primary (p. 234). Treatment of metastatic Ovarian cancer
melanoma is essentially palliative. Pregnancy ter- Ovarian cancer is diagnosed rarely in pregnancy
mination should be discussed with the patient. with 35% adenocarcinoma, 30% borderline
Chemotherapy using dacarbazine or cisplatin can ovarian tumour and 35% germ-cell/sex cord
293
 II SITE-SPECIFIC CANCER MANAGEMENT

ciated ascites). Surgical principles follow that of

ovarian cancer in non-pregnant women (p. 197).
Maximum feasible cytoreduction is attempted
and bilateral salpingo-oophorectomy after week
7 is feasible as the hormonal function will be
taken up by placenta. Other option is neoadju-
vant chemotherapy depending on the stage of
gestation. In high-grade bulky tumours hysterec-
tomy is also advisable. Chemotherapy may be
administered after the first trimester.

Psychosocial support
A diagnosis of cancer during pregnancy is an
extremely distressing situation for the patient and
family, as they may have to decide about future
plans which may not include both of them. This
necessitates provision of adequate psychosocial
support for both the parents (and probably grand-
parents!). Needless to say that there will be anxiety
about the baby, though evidence shows little harm
to date (but is minimal). The risks of a genetically
associated cancer in the child should be evaluated
Figure 19.1
Pregnancy associated ovarian cancer – MRI shows uterus by clinical genetics criteria (p. 45) but are not
with foetus (white arrow heads) and omental thickening affected by being diagnosed in pregnancy.
(arrow). Biopsy of the omental thickening confirmed
serous papillary adenocarcinoma consistent with a
primary peritoneal cancer. Further reading
Azim HA Jr, Peccatori FA, Pavlidis N. Treatment of the
pregnant mother with cancer: a systematic review on the
use of cytotoxic, endocrine, targeted agents and
stromal tumour (most common dysgerminoma). immunotherapy during pregnancy. Part I: Solid tumors.
Cancer Treat Rev. 2010;36:101–109.
Most of the borderline and germ cell tumours are
Azim HA Jr, Pavlidis N, Peccatori FA. Treatment of the
diagnosed at an early stage. pregnant mother with cancer: a systematic review on the
Staging includes chest X-ray, abdominal and use of cytotoxic, endocrine, targeted agents and
pelvic ultrasound and MRI if indicated (Figure immunotherapy during pregnancy. Part II: Hematological
19.1). CA-125, beta-hCG and AFP are raised in tumors. Cancer Treat Rev. 2010;36:110–121.
Kal HB, Struikmans H. Radiotherapy during pregnancy: fact
pregnancy.
and fiction. Lancet Oncol. 2005;6:328–333.
Laparotomy or laparoscopy is indicated when Pentheroudakis G, Pavlidis N. Cancer and pregnancy:
there is suspicion of an ovarian lesion (persistent poena magna, not anymore. Eur J Cancer. 2006;42:
solid or complex mass lesion of >6 cm with asso- 126–140.

294
 20
Human
immunodeficiency
virus (HIV) related
malignancies
TV Ajithkumar

Introduction • Immunosuppression – organ transplant recip-

ients have an almost 100-fold increased risk
Malignancies have a significant impact on the compared with the general population.
morbidity and mortality of people with human • Though HIV is not generally considered as
immunodeficiency virus (HIV) infection. 30–40% oncogenic, a possible direct role has been
of HIV-infected patients develop malignancies suggested recently.
during the course of their illness. Some of the • Increased risk of other viral infections – such
malignancies are AIDS-defining conditions as Epstein–Barr virus (Hodgkin’s disease),
whereas others appear to be more common in human papilloma virus (cervical cancer,
HIV patients (Box 20.1). Although AIDS-defining anal cancer), human herpes virus (Kaposi’s
malignancies may be caused mainly by progres- sarcoma) and hepatitis virus (hepatocellular
sive immunosuppression, the exact relationship carcinoma).
between immunosuppression and non-AIDS-
defining malignancies is yet to be established. The
most common cancers in the general population AIDS-defining malignancies
such as breast, prostate and colon do not appear Kaposi’s sarcoma
to increase in HIV infection.
KS is one of the most common neoplasms in
Introduction of highly active antiretroviral
HIV-infected patients, associated with human
therapy (HAART) has brought significant changes
herpes virus-8 (HHV-8). With the introduction
to the natural history of HIV-infection. The inci-
of highly active anti-retroviral therapy (HAART),
dence of Kaposi’s sarcoma and NHL has generally
the risk of both visceral and cutaneous KS has
declined whilst the incidence of Hodgkin’s lym-
decreased dramatically.
phoma and non-AIDS-defining cancers has not
The clinical manifestation of KS varies from a
changed. With the introduction of antiretroviral
mild to a fulminant course. Skin lesions appear
therapy, 28% of deaths in HIV infection are due
mainly on the lower extremities, face and geni-
to cancer compared with 10% before HAART.
talia. Skin lesions are typically multifocal and
papular (Figure 20.1), but can appear plaque-like
Pathogenesis or as a fungating mass. Extracutaneous lesions
Development of cancers in HIV-infected indi- appear in the oral cavity (most commonly palate
viduals may be similar to that occurring in followed by gingiva), larynx, gastrointestinal
patients with immunosuppression and immune- tract and lung. Gastrointestinal lesions can be
deficiency disorders. The possible mechanisms asymptomatic or can cause weight loss, abdo­
for increased incidence of various malignancies minal pain, nausea, vomiting and bleeding. Pul-
in HIV-infected people include: monary KS may be symptomatic with cough,

© 2011, Elsevier Ltd 295

DOI: 10.1016/B978-0-7234-3458-0.00025-7
 II SITE-SPECIFIC CANCER MANAGEMENT

Box 20.1: Cancers in HIV patients Box 20.2: Staging of Kaposi’s sarcoma
AIDS-defining cancers Good risk (all of Poor risk (any of the
• Kaposi’s sarcoma the following) following)
• Invasive cervical cancer Tumour (T) Confined to skin • Associated oedema
and/or lymph or ulceration
• Non-Hodgkin’s lymphoma
nodes and/or • Oral disease other
• Burkitt’s non-nodular than non-nodular
• Immunoblastic disease in disease in palate
• Primary cerebral palate
• Gastrointestinal KS
Non-AIDS-defining cancers • Non-nodal visceral
• Anal cancer KS
Systemic No history of History of
• Liver cancer illness opportunistic opportunistic
• Hodgkin’s disease infection or infection or thrush
• Penile cancer thrush B symptoms present
• Vulva and vagina cancer No B symptoms* <70 KPS
• Oral cavity and pharynx ≥70 KPS Other HIV-related
illness
• Larynx
*B symptoms – unexplained fever, night sweats, >10% involuntary
• Lung
weight loss or diarrhoea persisting more than 2 weeks
• Myeloma
• Acute myeloid and monocytic leukaemia

viraemia, effective combination HAART is the

initial management. Local therapy is indicated for
bulky lesions and for cosmetic reasons. Local
treatment options include external beam radio-
therapy, laser therapy, cryosurgery, photody-
namic therapy and intralesional vinblastine.
Indications for systemic chemotherapy (Box
20.3) include:
• widespread skin involvement (>25 lesions)
• extensive oral KS
• symptomatic oedema
• rapid progression
• symptomatic visceral KS
• KS flare.
Figure 20.1
Kaposi’s sarcoma. From Clutterbuck: Specialist Training
Cervical cancer
in Sexually Transmitted Infections and HIV, with Cervical cancer in HIV-infected women is associ-
permission. ated with advanced disease at diagnosis, high
recurrence rate and frequent cytotoxicity. Onco-
dyspnoea, haemoptysis etc. or present with logical management is similar to seronegative
asymptomatic radiological features of infiltrates, patients with cervical cancer; however special
isolated nodules, pleural effusion and hilar or consideration should be given for interaction
mediastinal lymphadenopathy. between cytotoxics and antiretroviral agents
In the post HAART era, tumour burden and
systemic illness are useful to categorize patients Non-Hodgkin’s lymphoma
into two prognostic groups (Box 20.2). Diagno- Almost all of the HIV associated lymphomas are
sis of KS is confirmed by biopsy. diffuse B cell (immunoblastic) or Burkitt’s like.
Treatment is aimed at symptom relief, prevent- Approximately two-thirds of the patients present
ing progression, cosmetic improvement, relief of with extranodal disease and up to 20% will have
oedema and avoiding organ compromise. For meningeal disease, necessitating CSF examina-
296 patients with limited cutaneous lesions and HIV tion in all.
 HUMAN IMMUNODEFICIENCY VIRUS (HIV) RELATED MALIGNANCIES 20

Box 20.3: Systemic treatment in KS

epithelial neoplasia (AIN), invasive anal margin
2 cancer and those with severe drug reactions
• Liposomal doxorubicin 20 mg/m three-weekly
require surgical management. Although the
• Liposomal daunorubicin 40 mg/m2 two-weekly
response to treatment is equivalent to seronega-
• Paclitaxel 100 mg/m2 two to three-weekly
• Others: vinorelbine, alpha-interferon, thalidomide
tive patients with anal cancer, there is a high risk
and imatinib of severe radiation toxicity.

Liver cancer
Hepatocellular cancer is increased by 8-fold in
Optimal treatment of HIV-related lymphoma
the HIV population. Tumours tend to be more
is not known. Patients are generally treated simi-
symptomatic, advanced at presentation and have
larly to those who are seronegative (p. 302). The
an aggressive course. Resection or transplanta-
overall prognosis is poor with a less than 1 year
tion is an option for early stage whereas systemic
median survival.
chemotherapy is used in advanced cancer (p.
Primary CNS lymphoma is 15 times more
147). Survival is not influenced by CD4 count.
common than in the general population. The
histology is large cell or immunoblastic type of B
Hodgkin’s disease
cell origin. Treatment involves radiotherapy com-
bined with steroids, which extend the median Patients present early in HIV infection with
survival from 2–3 months to 6–8 months (p. 306). unfavourable histologic subtypes (mixed cellu­
larity, lymphocyte depleted). There is a 5–15 fold
Non-AIDS-defining malignancies increase in risk with a high rate of EBV co-
infection (75–100%). Clinical presentation with
These account for the increased mortality in the B symptoms and extranodal disease are common.
HAART era. HIV-infected people have an They are treated as seronegative patients (p. 298)
increased risk of these cancers (RR 1.9), and and the median survival is 12–18 months.
these tumours occur at a relatively younger age.
Apart from duration of immunosuppression, Other cancers
other contributing risk factors include HAART Other cancers are treated similarly to seronega-
interruption, smoking, sun exposure, oncogenic tive patients.
viruses and family history. The diagnosis needs
to be confirmed by biopsy and staging will be
affected by the presence of reactive lymphaden- Interactions between
opathy as well as unrelated imaging abnormali- chemotherapy and HAART
ties. Treatment is based on performance status,
There are interactions between some cytotoxic
co-morbidity and potential for surgery. Non-
agents and antivirals due to cytochrome p450
medical management is also challenging due to
enzymes and p-glycoprotein. These interactions
chemotherapy-enhanced immunosuppression,
may account for the better response rate and
added cytotoxicity, drug interaction with
higher rates of survival seen with combinations
HAART and severe radiation reactions. Patients
of cytotoxics and antivirals compared with cyto-
need regular monitoring of their CD4 count.
toxics alone in patients with HIV associated
Continuation of HAART, prophylaxis of oppor-
malignancies. These interactions can also result
tunistic infections and supportive medications
in higher toxicities with treatment.
such as G-CSF are important.
Anal cancer Further reading
The high-risk group includes patients who prac- Spano JP, Costagliola D, Katlama C et al. AIDS-related
tice receptive anal intercourse, men who have sex malignancies: state of the art and therapeutic challenges.
J Clin Oncol. 2008;26:4834–4842.
with men and anal co-infection with HPV or
Deeken JF, Pantanowitz L, Dezube BJ. Targeted therapies to
syphilis. The clinical presentation and treatment treat non-AIDS-defining cancers in patients with HIV on
is similar to that of the seronegative population HAART therapy: treatment considerations and research
(p. 170). Patients with high-grade anal intra- outlook. Curr Opin Oncol. 2009;21:445–454.
297
 Cancers of the
haematopoietic system
TV Ajithkumar and HM Hatcher
21
Hodgkin’s disease cells in a background of non-neoplastic cells such
as lymphocytes, histiocytes, neutrophils, eosi-
Epidemiology nophils and monocytes. Classical HD is charac-
terized by CD30 positive H-RS cells and the
Around 1500 cases of Hodgkin’s disease are nodular lymphocyte predominant form of HL
diagnosed every year in the UK and approxi- (LPHL) with CD20 positive lymphocytic and his-
mately 350 people die of this disease every year. tiocytic (L and H) cells. In classical HD, RS cells
Males are predominantly affected (male : female stain positive for CD15 (80%) and CD30 (90%).
1.8 : 1). There is bimodal peak of incidence with
the first peak in those between 15 and 30 and the Clinical features
second peak between 50 and 60 years. The most common presentation is lymphaden-
opathy in the cervical or supraclavicular region
Aetiology (60–70%). Almost two-thirds of patients with
• EBV increases the risk of HD by two- to classical HL have mediastinal nodal disease pro-
threefold. In up to 50–90% of classical HD, ducing symptoms: tight chest, cough, venous
RS cells stain for EBV DNA. congestion, or dyspnoea. About 40% of patients
• Family members of patients affected by HL present with ‘B-symptoms’ of fever >38°C,
are at a three to nine fold increased risk of drenching night sweats, or weight loss >10%
developing the same disease. Same sex sib- within the previous 6 months (not from other
lings have 10 times higher risk of HD. causes). Bone marrow involvement at presenta-
tion occurs in less than 10% of cases. Extranodal
Pathology involvement commonly occurs in the lung.
The WHO classification of HD is shown in Table Investigations and staging
21.1. Nodular sclerosis is the common subtype • Blood – full blood count and ESR, biochem-
in young adults (more common in females), istry including LDH.
which presents with early stage supradiaphragm­ • Tissue diagnosis – An excision biopsy of a
atic disease whereas mixed cellularity presents lymph node is required for accurate diagnosis
with generalized lymphadenopathy or extra­ and subtyping. All patients need bone marrow
nodal disease with B symptoms. Lymphocyte examination.
depletion type presents with advanced stage
disease with extranodal involvement and aggres- Imaging
sive clinical course. • Chest X-ray may show mediastinal widening
LRCHL usually presents in young males with (Figure 21.1), pleural effusion or pericardial
localized cervical node involvement with no B effusion.
symptoms. • CT of the neck, thorax, abdomen and pelvis
Histologically HD is characterized by the will delineate lymphadenopathy as well as
presence of Hodgkin and Reed–Sternberg (H-RS) visceral involvement.
298 © 2011, Elsevier Ltd
DOI: 10.1016/B978-0-7234-3458-0.00026-9
 CANCERS OF THE HAEMATOPOIETIC SYSTEM 21

Table 21.1: WHO classification of Hodgkin’s Table 21.2: The Cotswolds modification of
lymphoma Ann Arbor staging for lymphoma
Classical Hodgkin’s lymphoma Frequency Stage I Involvement of a single lymph node
region or lymphoid structure or
Nodular sclerosis Hodgkin’s 60–70%
involvement of a single
lymphoma (grades 1 and 2)
extralymphatic site (IE)
Mixed cellularity Hodgkin’s lymphoma 20–30%
Stage II Involvement of two or more lymph
Lymphocyte-rich classical Hodgkin’s 3–5% node regions on the same side of the
lymphoma (LRCHL) diaphragm; localized contiguous
involvement of only one extranodal
Lymphocyte-depleted Hodgkin’s 0.8–1%
organ or site and lymph node
lymphoma (LDHL)
region(s) on the same side of the
Nodular lymphocyte-predominant 3–5% diaphragm (IIE)
Hodgkin’s lymphoma (LPHL)
Stage III Involvement of lymph node regions
on both sides of the diaphragm
(III),which may also be accompanied
by involvement of the spleen (IIIS) or
by localized contiguous involvement
of only one extranodal organ site
(IIIE) or both (IIISE)
Stage IV Diffuse or disseminated involvement
of one or more extranodal organs or
tissues, with or without associated
lymph node involvement
Designations applicable to any disease stage
A: No B symptoms
B: Presence of B symptoms
X: Bulky disease (a widening of the
mediastinum by more than one third
of the chest or presence of a nodal
mass with a maximal dimension
greater than 10 cm)

Figure 21.1
Mediastinal widening in Hodgkin’s disease.

• Lung function tests, especially for those who

Management
may receive bleomycin as part of their HD is a highly curable disease with long-term
treatment. disease-free survival (DFS) exceeding 80%.
• PET scan – the role of FDG-PET is increasing. Current efforts are to improve the chances of
It is useful to define the extent of lymphaden- cure with the least long-term toxicity. Measures
opathy at diagnosis, as well in assessing post- to preserve fertility should be discussed with all
treatment residual disease. young patients prior to starting chemotherapy.
• MRI is useful to delineate disease in bone and Patients with early stage disease (clinical stage
the nervous system. I/II) are categorized as favourable and unfavour-
able group based on risk factors (Table 21.3).
Staging Prognosis of patients with advanced-stage (stage
Cotswolds modification of the Ann Arbor Clas- III and IV) disease is defined using the Interna-
sification is used for staging (Table 21.2). tional Prognostic Score (IPS) (Box 21.1).
299
 II SITE-SPECIFIC CANCER MANAGEMENT

Box 21.2: Radiotherapy techniques in lymphoma

Table 21.3: EORTC risk grouping of early
stage HD Definitions (see Figure 21.2 showing nodal regions)
Treatment group Definition • Involved field radiotherapy – involved lymph
nodes with or without first echelon nodes.
Favourable CS I–II without risk factors • Extended field radiotherapy – involved lymph
Unfavourable CS I–II with ≥ 1 risk factors nodes with 1st and 2nd echelon nodes.
• Total nodal radiotherapy – all nodal regions.
Risk factors A large mediastinal mass Localization – based on CT scan or conventional
(>10 cm/> 13 thorax) definition of nodal regions.
B age ≥50 years Target volume definition – CTV depends on possible
C B symptoms or elevated microscopic disease and PTV depends on site of
ESR* treatment.
D ≥4 involved regions Dose
Hodgkin’s lymphoma
* Erythrocyte sedimentation rate (≥50 mm/h without or • Macroscopic disease: 30–36 Gy in 20 fractions.
≥30 mm/h with B-symptoms). • Prophylactic nodal areas: 30 Gy in 15–20 fractions.
• Postchemotherapy: 30–35 Gy in 15–20 fractions.
NHL
• RT alone: 40 Gy in 20 fractions.
• Postchemotherapy: 30–35 Gy in 15–20 fractions.
Box 21.1: International prognostic score of
Hasenclever Total body electrons
• Serum albumin <4 g/dl • Whole skin to a depth of 3–5 mm (6 MeV).
• Haemoglobin <10.5 g/dl • Dose 24 Gy in 8 fractions, 3 fractions per week.
• Male sex
• Age >45 years
• Stage IV disease
• White cell count >15,000/mm3
• Lymphocyte count <600/mm3 and/or <8% of Box 21.3: ABVD regime
white-cells
• Doxorubicin 25 mg/m2 IV D1 and D15
Presence of each prognostic factor reduces the 5-year
rates of freedom from progression of disease by 8%. • Bleomycin 10 units/m2 IV D1 and D15
i.e. those without any risk factors have a 5-year rate • Vinblastine 6 mg/m2 (max 10 mg) IV D1 and D15
of 80% which is reduced to 45% by the presence of • Dacarbazine 375 mg/m2 IV D1 and D15
all 7 factors.
Cycles repeated every 4 weeks

Nodular lymphocyte predominant (NLP)

Patients with localized NLP HD are treated with cycles of ABVD chemotherapy (Boxes 21.2 and
involved field radiotherapy (30–35 Gy in 15–20 21.3), followed by 30–35 Gy in 15–20 fractions
fractions) which results in a 96% response rate of involved field radiotherapy (IF-RT).
and >90% 8-year survival (99% for stage I and
94% for stage II). Advanced stage and relapsed Early-stage unfavourable
NLP disease is treated similar to classical HD. These patients are also treated with combined
Since this subtype usually expresses CD20, modality treatment; however, the optimal chem-
the anti-CD20 antibody, rituximab may have a otherapy regime and radiotherapy fractionation
future role in the management of these patients. are yet be determined. The current treatment is
four courses of ABVD followed by involved field
Classical HD radiotherapy of 30–35 Gy in 15–20 fractions
Early-stage favourable (Boxes 21.2 and 21.3). With this treatment 5%
The current standard treatment is combined patients progress during or immediately after
modality treatment, consisting of two to four treatment and 15% relapse within 5 years.
300
 CANCERS OF THE HAEMATOPOIETIC SYSTEM 21
previous radiotherapy alone. Treatment options
for relapse after prior chemotherapy include
salvage radiotherapy for localized relapse in pre-
viously non irradiated areas, salvage chemo­
therapy, or high-dose chemotherapy followed by
a b autologous stem cell transplantation (SCT).
Patients who relapse after autologous stem cell
transplantation may be candidates for allogeneic
transplantation. Patients who cannot have inten-
d e sive chemotherapy may be treated with palliative
c intent with drugs such as gemcitabine, vinca
f alkaloids, idarubicin etc.

g
Survival
h i
With combined modality treatment patients in
the early-favourable group achieve a disease free
survival (DFS) of more than 90% and an overall
survival of about 95% at five years. Patients in
j k the early unfavourable group have a DFS of
about 84% and an OS of 91%. In advanced stage
combination chemotherapy results in 5-year
failure free survival of 78% and overall survival
Figure 21.2
Nodal regions: cervical (a-b), mediastinal (c), axillary
of 90%. High-dose therapy and autologous stem
(d-e), mesenteric (f), paraaortic (g), iliac (h-i) and cell transplantation results in DFS of 55% and
inguinal (j-k). the overall survival 71% at 5 years.

Advanced stage
Follow-up
Combination chemotherapy with 6–8 cycles of Two-thirds of relapses occur within 3 years of
ABVD is the current treatment of choice; although initial treatment and more than 90% occur
this regime is not as successful as in earlier stage within 5 years. Since a significant proportion of
disease. Various attempts are being made to patients who relapse can be successfully salvaged,
modify the ABVD regime by adding newer drugs all patients need regular follow-up (Box 21.4).
and increasing dose intensity. Follow-up is also helpful in identifying and man-
The role of consolidation radiotherapy in aging long term side effects such as endocrine
advanced stage HD is also not clear. A meta- dysfunction.
analysis of combined modality treatment showed
equal tumour control but inferior overall survival
Survivorship issues
compared with chemotherapy alone. An EORTC The major causes of excess death in survivors of
study suggested that involved field radiotherapy HD are second malignancies and ischaemic heart
did not result in better outcomes in patients who disease (p. 58).
achieve complete response after chemotherapy, One of the most common second malignancies
but may be beneficial in patients with a partial is lung cancer which is attributed to mediastinal
response. Hence consolidation radiotherapy is radiotherapy, chemotherapy and smoking.
considered in those with initial bulky disease and Patients who had thoracic radiotherapy are
those who fail to achieve a complete response to encouraged not to smoke. There is 20–50% risk
chemotherapy. of second breast cancer after mediastinal/axillary
radiotherapy in young females and these patients
Recurrence should be screened for breast cancer. Common
Combination chemotherapy is usually the treat- haematological neoplasms include acute myeloid
ment of choice for patients who relapse after leukaemia, myelodysplastic syndrome (develops
301
 II SITE-SPECIFIC CANCER MANAGEMENT

Box 21.4: Follow-up and screening after

European and American lymphoma) classifica-
treatment for HD tion system which is broadly divided into B-cell,
• History and physical examination, FBC, ESR, LDH, T-cell/natural killer cell and Hodgkin’s disease
electrolytes, liver function tests and chest X-ray at (Table 21.4). Table 21.5 shows cytogenetic and
each visit if chest CT is not done: 3–4-monthly for molecular characteristics of NHL.
first 2 years, 6-monthly for years 3–5 and then
annually.
• CT scan chest: 6–8 monthly for first 2 years, yearly
Clinical features
for years 3–5 and then only if any abnormality on The most common presenting symptom is pain-
CXR. less lymphadenopathy. B symptoms (weight loss
• CT abdomen and pelvis: in stage I–II annually for 5 >10% within the previous 6 months, fever, night
years; in stage III–IV, 6-monthly for first 2 years,
annually for years 3–5. sweats) occur in up to half of the patients, pre-
• Others: dominantly in those with high-grade disease.
• Serum TSH estimation 6-monthly if Symptoms can be due to involvement of specific
radiotherapy to neck. organs such as dyspnoea due to mediastinal
• Mammogram: annually beginning at age 40; nodes or effusion, abdominal symptoms and neu-
if received radiotherapy above the diaphragm
start at age ≥30 years.
rological symptoms such as cord compression.
• MRI breast: consider for those who received
radiation above the diaphragm before age 30
Evaluation and staging
years. Initial evaluation includes detailed history, full
clinical examination and assessment of perform-
ance status. Blood tests include FBC with periph-
within 3–5 years) and non-Hodgkin’s lymphoma eral smear, serum biochemistry, serum LDH and
(develops after 5–15 years). serological tests for HIV and hepatitis.
Biopsy – Excisional biopsy of an enlarged
Future perspectives lymph node or generous incision biopsy is
Future studies will address the issues of improv- required to make an accurate diagnosis. Immuno­
ing survival whilst minimizing the risk of long- histochemistry and genetic analyses are impor-
term side effects. Newer imaging modalities such tant in making an accurate diagnosis. All patients
as functional imaging are already being incorpo- need bone marrow biopsy with aspiration.
rated into risk stratification to determine future
treatments. Imaging
CT scans of the neck, chest, abdomen and pelvis
Non-Hodgkin’s lymphoma are carried out to assess lymphadenopathy and
organ involvement (Figure 21.3).
Introduction Other investigations
Non-Hodgkin’s lymphomas are a group of lym- • Lumbar puncture-CSF studies are needed
phoid malignancies of varying subtypes with a for patients with neurological symptoms or
range of clinical behaviours and treatment strate- those with paranasal sinus or testicular
gies. Around 8450 new cases are diagnosed per involvement.
year in the UK and 65,980 cases in the USA. • Endoscopy depends on the clinical situation
The median age is 65, although aggressive B- and type of lymphoma.
cell lymphomas are the predominant NHL in
younger adults. Male : female ratio is 1.5 : 1.
Staging
Almost 2 3 of cases are due to two specific sub-
types: diffuse large B-cell lymphoma and follicu- Staging is similar to Hodgkin’s disease (p. 299).
lar lymphoma.
Prognostic factors
Pathology Stage, age, LDH and performance status have
The cell of origin is different for each subtype prognostic value. The Follicular Lymphoma Inter-
of lymphoma. Classification is by the updated national Prognostic Index (FLIP) score is used for
302 WHO modification of the REAL (revised indolent lymphomas (Box 21.5). The interna-
 CANCERS OF THE HAEMATOPOIETIC SYSTEM 21

Table 21.4: Abridged WHO/REAL classification of NHL

B-cell neoplasms
• Precursor B-cell neoplasm
• Peripheral B-cell neoplasms
 B-cell chronic lymphocytic leukaemia/small lymphocytic lymphoma

 Mantle cell lymphoma

 Follicular lymphoma

 Extranodal marginal zone B-cell lymphoma of mucosa-associated lymphatic tissue (MALT) type

 Hairy cell leukaemia

 Plasmacytoma/plasma cell myeloma

 Diffuse large B-cell lymphoma

 Burkitt lymphoma

T-cell and putative NK-cell neoplasms

• Precursor T-cell neoplasm
• Peripheral T-cell and NK-cell neoplasms
1. T-cell chronic lymphocytic leukaemia/prolymphocytic leukaemia
2. T-cell granular lymphocytic leukaemia
3. Mycosis fungoides/Sézary syndrome
4. Peripheral T-cell lymphoma, not otherwise characterized
5. Enteropathy-type intestinal T-cell lymphoma
6. Adult T-cell lymphoma/leukaemia (human T-lymphotrophic virus [HTLV] 1+)
7. Anaplastic large cell lymphoma

Table 21.5: Cytogenetic and molecular characteristics of NHL

Lymphoma Cytogenetics Genes
Burkitt’s t(8;14)(q24q32) c-MYC (8q24)
Or t(2;8) or t(8;22) Immunoglobulins (other chromosome)
Follicular lymphoma t(14:18)(q32;q21) BCL-2 (18q)
Ig heavy chain (14q)
Diffuse large B-cell lymphoma t(14:18)(q32;q21)+others such
as p53, p16, p15
Mantle cell lymphoma t(11;14)(q13;q32) BCL-1 or PRAD1 (11q) Ig heavy chain (14q)
Anaplastic lymphoma t(2;5)(p23:q35) TCR-ALK
T cell receptor

tional prognostic index (IPI) is used for patients disease and median survival is 10–15 years from
with diffuse large B-cell lymphoma (Box 21.6). diagnosis. Spontaneous regression can occur
and 40% of patients transform to an aggressive
Treatment histologic type. Over 90% have rearrangement
Follicular lymphoma of the bcl-2 gene which inhibits apoptosis.
Follicular lymphoma accounts for approximately Early stage
20% of all lymphomas and has a variable clinical Only about one-third of patients with follicular
course. The median age at presentation is 50 lymphoma present with stages I and II or limited
years. Most patients present with advanced stage III (with up to five involved lymph nodes 303
 II SITE-SPECIFIC CANCER MANAGEMENT

A B

Figure 21.3
CT scan in NHL. Figure shows massive para-aortic lymphadenopathy (A) and iliac and inguinal lymphadenopathy (B).

Box 21.5: Follicular Lymphoma International

wait policy is appropriate for these patients.
Prognostic Index Alternatives include the anti CD20 antibody
1. Age (≤60 years vs. >60 years). (rituximab), alkylating agents or experimental
2. Serum LDH (normal vs. elevated). therapies. Indications for systemic treatment are:
3. Stage (stage I or stage II vs. stage III or stage IV). • Symptomatic bulky disease
4. Haemoglobin level (≥12 g/dL vs. <12 g/dL). • Massive hepato-splenomegaly
5. Number of nodal areas (≤4 vs. >4). • Bone marrow suppression
Patients with 0 to 1 risk factors have an 85% 10-year survival rate. • B symptoms
Those with three or more risk factors have a 40% 10-year survival • Transformed lymphoma
rate.
The commonly used regime is either single
agent chlorambucil or fludarabine. Chlorambucil
results in 50–75% response rate with no com-
Box 21.6: The International Prognostic
Index (IPI) for aggressive NHL (diffuse large plete response, whereas fludarabine can result in
cell lymphoma) a complete response (15%). Combination chem-
1. Age (≤60 years of age vs. >60 years of age). otherapy (e.g. CVP and CHOP) (Table 21.6)
2. Serum LDH (normal vs. elevated). have no overall survival benefit. The role of
3. Performance status (0 or 1 vs. 2–4). chemotherapy with rituximab is being investi-
4. Stage (stage I or stage II vs. stage III or stage IV). gated. Elderly patients may be treated with
5. Extranodal site involvement (0 or 1 vs. 2–4). rituximab or single agent chemotherapy.
Patients with two or more risk factors have a less than 50% Relapse
chance of relapse-free survival and overall survival at 5 years. Two trials report prolonged event-free survival
and overall survival with a combination of
rituximab with chemotherapy (CHOP).
areas) disease. Treatment options include watch-
ful waiting, or radiotherapy (Box 21.2). High-grade lymphoma
High-grade lymphomas include a number of
Advanced stage
lymphoma subtypes including:
The optimal treatment for patients with bulky
stage II, III and stage IV disease is yet to be • Diffuse large B cell (DLBCL)
defined. There is no proven role for early chemo- • Burkitt’s
therapy in asymptomatic patients. A watch and • Mantle cell
304
 CANCERS OF THE HAEMATOPOIETIC SYSTEM 21
Burkitt’s lymphoma
Table 21.6: Chemotherapy regimes in NHL Burkitt’s lymphoma is a rare (2–3%) aggressive
• CHOP – cyclophosphamide, adriamycin, B cell NHL There are two main forms: the
vincristine and prednisolone endemic form observed in Africa and associated
• CVP – cyclophosphamide, vincristine and with EBV and the sporadic form which accounts
prednisolone
for up to 30% childhood lymphomas (p. 323,
• ESHAP – etoposide, methylprednisolone,
cytarabine and cisplatin children’s cancers). The endemic form classically
• BEAM – BCNU, etoposide, cytarabine, presents with enlargement of the jaw. The spo-
melphalan radic form presents rapidly increasing disease
• CODOX-M – cyclophosphamide, vincristine, with intra-abdominal masses often involving the
doxorubicin, araC, methotrexate
gastrointestinal tract (especially ileocaecal),
ovaries or kidneys. Bone marrow and CNS
involvement is frequent. These patients are at a
high risk of developing tumour lysis syndrome
due to an almost 100% cell turnover (p. 342).
• Lymphoblastic lymphoma/leukaemia (pre­ Survival rates vary from 30% to 70% and have
cursor T/B lymphoma/leukaemia) (p. 310, improved with intensive regimes and risk group.
leukaemias). Low-risk patients include those with a low LDH
• HIV associated (p. 296). and those with a completely resected abdominal/
single lesion. All others should be considered
DLBCL high risk.
Diffuse-large cell lymphoma (DLBCL) comprises Treatment with intensive multiagent chemo-
30% of NHL and is characterized by an aggres- therapy (e.g. CODOX-M) is started rapidly with
sive clinical behaviour with rapidly enlarging tumour lysis prophylaxis. There is no evidence to
lymphadenopathy frequently associated with support high-dose treatment with transplanta-
extra-nodal disease. tion as first line treatment. CNS involvement is
In early-stage disease without adverse factors extremely common and hence CNS prophylaxis
(see Box 21.6), treatment is with 3–4 cycles is essential for all cases.
of CHOP in combination with rituximab Relapse should be treated with further inten-
(R-CHOP) followed by involved-field radiation sive chemotherapy and young fit patients should
therapy (30–35 Gy in 1.75–3 Gy per fraction) or then be considered for autologous or allogeneic
6–8 cycles of R-CHOP. stem cell transplantation.
Patients with early stage disease with adverse
factors and advanced disease are treated simi- Mantle cell lymphoma
larly. CHOP chemotherapy with rituximab Mantle cell lymphoma (MCL) comprises less
shows a significant improvement in response than 4% of NHL. The median age at presenta-
rate, event-free and overall survival in younger tion is 62 years. It usually presents with advanced
and older patients. Patients with bulky disease disease involving the bone marrow and/or spleen.
seemed to benefit the most from rituximab. The Overall long term survival is poor at less than
role of additional locoregional radiotherapy in 20% but with recent improvement in median
patients with bulky sites or extra-nodal disease survival from 2.7 to 4.8 years.
is of no proven benefit. With this approach, the Optimal initial treatment in MCL is yet to be
5-year survival of early stage disease is 80–90% established. The commonly used first line chemo-
and that of advanced disease is around 50%. therapy regime is CHOP. Other first line options
In diffuse-large cell lymphoma, risk factors include fludarabine-containing regimens, single
for CNS relapse are involvement of the skull, agent cladribine and a combination of high-dose
more than one extra-nodal manifestation (espe- methotrexate with cytarabine. Consolidating
cially testis), IPI >1 and bone marrow infiltration autologous stem cell transplantation in first
and hence need to be considered for CNS remission improves progression free survival in
prophylaxis. eligible younger patients. Rituximab mainte-
305
 II SITE-SPECIFIC CANCER MANAGEMENT

nance therapy seems to be a therapeutic alterna- The prognosis of HIV-associated primary

tive particularly in elderly patients. In relapsed CNS lymphoma is generally worse and depends
patients, fludarabin-containing regimens, benda- on the CD4+ cell count. Whereas patients with
mustine and bortezomib seem to be effective. In a CD4+ cell count >200/µl can achieve a long-
the absence of allogenic stem cell transplanta- term remission, those with a CD4+ cell count less
tion, a potentially curative but investigative treat- than 200/µl do not respond to chemotherapy.
ment option, the median survival is 4–6 years. These patients may respond to highly active
antiretroviral therapy.
Primary extra-nodal NHL
Primary extra-nodal NHLs are defined as lym- Bone lymphoma
phomas which present with a predominantly In most cases, involvement of the bone is second-
extra-nodal tumour mass which represent ary in patients with advanced-stage lymphoma
approximately 25 to 30% of NHL. whereas primary bone lymphoma is rare. The
Histologically, nearly 50% of all extra-nodal presenting symptom is mainly localized bone
lymphomas are diffuse, large B-cell lymphomas. pain. DLBCL is the most common histological
It is the most common histological subtype in the diagnosis.
testis, brain, bone, thyroid and sinus. The median age is 63 years. 10-year overall
The vast majority of the remaining group arise survival is approximately 41%. Three different
from the mucosa-associated lymphoid tissue prognostic groups (patients <60 years with IPI
(MALT) and represents 5–10% of all NHL. The 1–3, patients ≥60 years with IPI 0–3, and patients
most common involved sites are the stomach, ≥60 with IPI 4–5) with significantly different
small intestine, orbit, salivary glands and the lung. overall survival at 5 years of 90%, 61% and
25%, respectively, have been identified. The
Primary CNS lymphoma treatment involves combination of rituximab and
Primary CNS lymphoma occurs are a median age CHOP with or without radiotherapy. Radical
of 60 years in immunocompetent patients and 30 surgery does not improve outcome.
years in HIV patients. Primary CNS lymphoma
often has a rapidly progressive course. Systemic Testicular lymphoma
dissemination is rare. The finding of characteristic Primary testicular lymphoma represents 1–2% of
features on CT (Figure 21.4) and MRI imaging all NHL. It is the most common malignancy of
should prompt a stereotactic biopsy. Management the testis in men older than 60 years and the most
of primary CNS lymphoma is discussed on p. 276. common presentation is unilateral painless

A B

Figure 21.4
CT scan in primary CNS lymphoma. Non-contrast enhancing CT scan shows a periventricular hyperdense lesion (A)
which uniformly enhances on contrast administration (B).
306
 CANCERS OF THE HAEMATOPOIETIC SYSTEM 21
scrotal swelling. DLBCL is the most common
histology and diagnosis is usually established
by initial orchidectomy. Approximately 80% of
cases are stage I or II at presentation. A low IPI,
no B-symptoms, the use of anthracyclines, and
prophylactic contralateral scrotal radiotherapy
are significantly associated with longer survival.
Systemic chemotherapy alone seems not to be
effective in preventing relapses in the contralat-
eral testis because the testis is a sanctuary site
(p. 35). Treatment consists of 6–8 courses of
R-CHOP followed by prophylactic irradiation
of the contralateral testis. Although data are Figure 21.5
not convincing, prophylactic intrathecal therapy Cutaneous lymphoma. From Darell Rigel: Cancer of the
Skin (Saunders), with permission.
should be considered. This approach results in a
3-year overall survival of 86% and 3-year pro-
gression-free survival 77%.
logic evidence of leukaemic involvement and can
Cutaneous NHL be preceded by mycosis fungoides. The clinical
Primary cutaneous lymphomas differ considera- behaviour of the disease is aggressive.
bly in their clinical course and outcome from Primary cutaneous marginal zone B-cell lym-
systemic lymphomas. Primary cutaneous lym- phoma and primary cutaneous follicle centre
phomas are generally divided into lymphomas B-cell lymphoma usually show an indolent
with an indolent or an aggressive clinical course. clinical behaviour.
Approximately 75% of primary cutaneous lym- Spontaneous resolution may occur. Primary
phomas are T-cell lymphomas which include cutaneous follicle centre B-cell lymphoma prefer-
mycosis fungoides (MF) and Sezary syndrome entially involves the head and trunk with solitary
(SS) and 25% are primary cutaneous B-cell or grouped plaques and tumours. The 5-year sur-
lymphomas. vival is excellent with more than 95% in both
entities.
Clinical features
In contrast, primary cutaneous diffuse-large
Mycosis fungoides typically presents with ery-
B-cell lymphoma, leg-type, behaves aggressively
thematous patches, plaques and tumours usually
and affects predominantly elderly patients. This
in areas not often exposed to sunlight (Figure
entity typically presents as red solitary or multi-
21.5). Most patients have multiple lesions and
ple nodule on the leg but can also rarely be found
ulcerations can occur. The course of the disease
at other sites. Both cutaneous relapses and extra-
is indolent.
cutaneous dissemination are frequent. With a
The lesions of mycosis fungoides can be clas-
5-year survival of only 50%, prognosis is signifi-
sified into four groups: Patches, papules and/or
cantly worse than in the other two entities.
plaques affecting less (T1) or more (T2) than
10% of body surface, T3 with tumours >1 cm Management of cutaneous T-cell lymphoma
and T4 with erythroderma affecting more than In patients with early stages of MF topical
80% of body surface. In T1 disease outcome is therapy with mechlorethamine or bexarotene,
excellent and also patients with T2 disease have superficial radiotherapy and phototherapy
a median overall survival of more than 10 years. (PUVA) are appropriate treatment options.
Patients with erythrodermic mycosis fungoides Patients with more advanced disease will
have a median survival of 5 years and those with require systemic treatment. Total skin electron
visceral involvement have an even worse survival beam therapy (TSEBT) is appropriate in patients
with only one or two years. with generalized thickened plaques due to its
Sezary syndrome is defined as an erythroder- depth of penetration. The rate of complete
mic cutaneous T-cell lymphoma with haemato- responses is greater than 80% but the long-term
307
 II SITE-SPECIFIC CANCER MANAGEMENT

outcome is not affected. TSEBT should be previously metabolically active area becomes
followed by an adjuvant therapy such as inactive after treatment.
mechlorethamine or PUVA. Several new monoclonal antibodies are under
Systemic therapy with the orally administered investigation including atumumab (a human
retinoid bexarotene can achieve response rates of monoclonal IgG1 antibody against a small loop
50%. MF and SS are relatively chemoresistant epitope on the CD20 molecule) and epratuzumab
diseases. The most frequently used combination (anti-CD22). Radioimmunotherapy (RIT) is an
chemotherapy regimens include cyclophospha- innovative treatment modality that combines the
mide, vincristine and prednisone (CVP) with or tumour cell targeting ability of monoclonal anti-
without doxorubicin. High-dose chemotherapy bodies with the cytotoxic effect of radiation by
followed by autologous stem cell transplantation linking a radioisotope to the antibody. This is
in patients with advanced disease has been shown under investigation for NHL with 90Y-ibritu-
to induce high response rates in most patients momab tiuxetan and 131I-tositumumab. Other
but the responses were predominantly of short agents under investigation include bortezomib
duration. In contrast, allogeneic transplantation (30–40% response) and lenalidomide.
seems to induce long-term durable remissions of
more than 3 years. Follow-up in NHL
The purpose of follow-up is to detect early
Management of cutaneous B-cell lymphoma
relapse and to educate about possible long-term
Due to their indolent course and excellent
complications. A typical schedule is 3-monthly
outcome in primary cutaneous marginal zone
follow up for 1 year, 4-monthly during the 2nd
and follicle centre B-cell lymphoma a watch-and-
year, 6 monthly for the 3rd year, annually up to
wait strategy is the adequate management in
10 years and then on alternate years. At each visit
most cases. In patients with limited symptomatic
detailed history is taken and clinical examination
skin lesions, local excision or radiotherapy (20–
is done with routine bloods including LDH and
36 Gy) are the first treatments of choice. Cutane-
ESR. Chest X-ray is done in patients with chest
ous relapses can be treated in the same way as
disease at presentation. Further investigations are
the initial lesion and do not worsen prognosis.
needed depending on any new symptoms or signs
In patients with extensive skin lesions rituxi-
or other abnormal tests.
mab is the treatment of choice. Oral chloram-
bucil is a treatment option often used in Europe.
A multiagent chemotherapy is rarely indicated in Acute leukaemias
these types of cutaneous lymphomas with the
exception of patients developing extracutaneous Introduction
disease. Acute lymphoblastic leukaemia (ALL) occurs
most frequently either between the ages of 15–25
The role of stem cell transplantation
(p. 321) or over the age of 75. In the UK there
in aggressive lymphoma are 200 new adult cases per year and the
Autologous stem cell transplantation has become male : female ratio is roughly equal. Acute myeloid
the standard treatment in younger patients with leukaemia (AML) occurs more frequently and the
a first chemosensitive relapse of aggressive lym- median age at presentation is 65. In the UK,
phoma. The role of autologous stem cell trans- around 2000 new cases are diagnosed per annum.
plantation in relapse after rituximab-containing
front-line treatment has not been determined. Aetiology
The role of allogeneic transplantation in the The majority of acute leukaemias are sporadic,
management of patients with aggressive lym- although some genetic syndromes and other
phoma remains controversial. factors can predispose to acute leukaemia.
Recent advances • Genetic syndromes
The use of FDG-PET imaging in lymphomas is • Down’s syndrome
evolving. It is useful to define the extent of disease • Fanconi anaemia
308 as well as allow cessation of treatment when a • Neurofibromatosis
 CANCERS OF THE HAEMATOPOIETIC SYSTEM 21
• Chemicals:
• benzene
• pesticides
• Previous chemotherapy (AML):
• alkylating agents
• topoisomerase II inhibitors

Pathology
AML and ALL are characterized by circulating
blasts cells which may be seen in the peripheral
blood. Bone marrow examination with immuno­
phenotypic analysis is needed for establishing a
diagnosis. Both myeloblasts and lymphoblasts A
are characterized by a high nuclear : cytoplasmic
ratio and prominent nuclei. Azurophilic Auer
rods are pathognomonic of AML (Figure 21.6).
The French–American–British (FAB) classifica-
tion recognizes three subtypes of ALL: L1 (30%),
L2 (60%) and L3 (10%), whereas the current
WHO classification incorporates immunopheno-
typing and cytogenetics. By immunophenotyp-
ing, 75% ALL arise from B-cell progenitors and
25% from T-cells.
The FAB classification recognizes eight sub-
types of AML: M0 minimal myeloid differentia-
tion (3%), M1 poorly differentiated myeloblasts
(15–20%), M2 myeloblastic with differentiation
(25–30%), M3 promyelocytic (5–10%), M4 B
myelo-monoblastic (20%), M5 monoblastic (2–
Figure 21.6
9%), M6 erythroblastic (3–5%), and M7
AML M3 shows promyelocytes with multiple/stacked
megakaryoblastic (3–12%). The recent WHO Auer rods (A) and AML with a blast in the centre
classification incorporates cytogenetics and showing an Auer rod (B). Courtesy of Dr. Priyanka
classifies AML as: Mehta, Bristol Oncology Centre.

• AML with recurrent cytogenetic abnormalities.

• AML with multilineage dysplasia.
• AML and MDS, therapy related.
• AML not otherwise categorized.
of acute leukaemia can present with features of
hyperleucocytosis (WBC >100 × 109/L) such as
Clinical features dyspnoea and CNS symptoms.
The majority of patients present with features of Clinical examination may show lymphaden-
bone marrow failure, which include anaemia, opathy, bruising, patechiae, gum hypertrophy,
neutropenia and thrombocytopenia, clinically hepato-splenomegaly, chest signs of effusion, and
manifesting as fatigue, and pallor, fever and pate- mediastinal mass.
chiae, easy bruising or bleeding. ALL can produce
weight loss, bone pain, symptoms of CNS disease Diagnosis
and features of extramedullary infiltration (in Blood tests include FBC and peripheral smear
50%) such as lymphadenopathy, splenomegaly with cytogenetics and immunohistochemistry
or a mediastinal mass. AML can present with and biochemistry, including uric acid. Bone
gum infiltrates (M4/M5) and disseminated intra- marrow examination is essential for definitive
vascular coagulation (M3). A small proportion diagnosis of acute leukaemia and subtyping. 309
 II SITE-SPECIFIC CANCER MANAGEMENT

Prognostic factors and as consolidation chemotherapy. CNS directed

risk classification treatment and maintenance treatment (up to 2
years) are part of the ALL treatment. It is being
The most important predictor of outcome in
increasingly recognized that an early allogeneic
both AML and ALL are presentation, karyotype,
transplantation is beneficial in high-risk ALL
age and response to initial treatment.
patients.
ALL
ALL
Clinical features (age >50 years, WBC count),
immunophenotyping (pro-B, early-T, mature-T), Current treatment of adult ALL leads to long-
cytogenetics and molecular biology [t (9;22), t term survival of 30–40%. Initial chemotherapy
(4;11)], and response to treatment (late achieve- utilizes vincristine, corticosteroids and daunoru-
ment of response, minimal residual disease bicin (induction). Such intensive combination
[MRD] positivity) have prognostic importance chemotherapy results in a complete remission
and are used to define standard risk (those (CR defined as <5% blast cells with return of
without any risk factors) and high risk (those marrow cellularity and function and disappear-
with one or more risk factors) ALL. Philadelphia ance of extramedullary manifestations) in 80–
chromosome positive (Ph+) ALL (t (9; 22)/BCR- 90% cases. Once CR is achieved consolidation
ABL) predicts a high relapse rate and <10% therapy is started with a combination of chemo-
chance of overall survival with chemotherapy therapy. In patients with Ph+ disease, concurrent
alone. This group of patients is eligible for tyrosine inhibitor imatinib (a tyrosine kinase
treatment with tyrosine kinase inhibitors such as inhibitor [p. 312]) may improve survival. CNS
imatinib. directed treatment with intrathecal methotrexate
and high-dose methotrexate and/or cranial radia-
AML tion to treat the central nervous system is required
Based on cytogenetics there are three prognostic for patients who are not planned to have undergo
groups in AML: bone marrow transplantation.
After consolidation, maintenance therapy
• Favourable group with core binding factor given over 1.5 to 2 years is still standard in ALL.
(CBF) leukaemias [inv (16), t (16; 16), or t Omission of maintenance therapy has been asso-
(8;21)], and t (15;17). This group represents ciated with shorter DFS rates. Daily doses of
10% of patients and involves mainly patients mercaptopurine and weekly doses of methotrex-
<60 years of age. With intensive treatment ate are the backbone of maintenance, and are
survival rates are around 60%. combined with monthly pulses of vincristine
• Unfavourable group with monosomies or and corticosteroids. Intrathecal treatment is
partial deletions of chromosome 5 and/or 7, also continued but the frequency decreases in
or with abnormalities involving chromosome the maintenance phase. Patients with mature
3. This group constitutes about 30–40% of B-ALL do not require maintenance. In T-ALL,
all patients, on average older (>50–60 years) the benefit of maintenance chemotherapy has
often with an antecedent haematological been questioned.
disorder or AML related to therapy. The
survival rates are around 20%. Transplantation
• Intermediate group – the remaining 50–60% Unrelated donor transplant is generally advised
of patients with normal cytogenetics falls into in Ph+ ALL and high-risk ALL, which gives a
this group whose outcome is intermediate. survival of 50%. For patients under the age of
45 years with an available HLA identical sibling,
Treatment allogenic transplant may be considered.
The principle of management of acute leukaemia
is to achieve a morphological complete remission Salvage therapy
(<5% blast cells in bone marrow) with induction The outcome of salvage therapy remains unsat-
chemotherapy followed by further chemotherapy isfactory. CR rates range from 10–50% and
310
 CANCERS OF THE HAEMATOPOIETIC SYSTEM 21
long-term DFS is poor. Various combinations of as consolidation. ATRA syndrome is the major
chemotherapy are used. Although stem cell trans- toxicity of this treatment characterized by fever
plantation (SCT) is superior to chemotherapy and leakage of fluid into the extravascular space
with long-term DFS rates of 20–40% in salvage producing fluid retention, dyspnoea, effusions,
therapy, only 30–40% of patients who achieved and hypotension. It is treated with high doses of
a second complete remission are eligible for SCT methylprednisolone or dexamethasone.
and fewer than 50% have enough time before In patients relapsing after initial CR, arsenic
disease recurrence to undergo SCT. trioxide achieves a CR of 80%. Some studies
show that in patients with APML and t (8;21)
AML and inversion (10), a second CR autologous
transplantation can result in high rates of DFS.
Induction
70–90% patients achieve a CR with two courses New agents
of induction chemotherapy with cytarabine and Monoclonal antibodies are an attractive treat-
an anthracycline (usually idarubicin). Complete ment option in ALL, especially in the setting of
remission is defined as <5% blasts cells in the MRD. The agents studied include rituximab
bone narrow, absence of cells with Auer rods and (anti-CD20 antibody) and alemtuzumab
resolution of peripheral blood cytopenia. (anti-CD52).
New drugs being studied for AML include
Post-induction drugs that specifically bind to the surface of the
Patients with favourable cytogenetics receive two AML blasts such as Mylotarg (gemtuzumab ozo-
further courses of consolidation chemotherapy gamicin), agents that inhibit the multidrug-resist-
with cytarabine, an anthracycline and etoposide. ant (MDR) protein (PSC-833, Zosuquidar) etc.
Patients with intermediate and unfavourable
cytogenetics, those under 40 years with a HLA
identical sibling are considered for allogeneic Chronic myeloid leukaemia
transplantation. The role of post-consolidation Chronic myeloid leukaemia (CML) accounts for
maintenance therapy is not clearly defined and 20% of leukaemia. The median age at diagnosis
hence not recommended. is 55 years. Males are affected more frequently
There is some suggestion that in younger than females (male : female ratio of 1.3 : 1). There
patients with primary refractory AML, allogeneic are 750 new cases per year in the UK. Only rec-
transplant may improve survival and hence may ognized risk factor is prior radiation.
be considered for those who fail to achieve CR
after two courses of induction chemotherapy. Cytogenetics
Allogeneic stem cell transplantation is also About 90–95% patients with CML exhibit a
indicated after a second CR with salvage chemo- chromosomal translocation that results in one
therapy in relapsed patients. shortened chromosome 22 (22q– called the Phil-
adelphia [Ph] chromosome) and one elongated
Acute promyelocytic leukaemia (APML) chromosome 9 (9q+). The resulting fusion onco-
APML has a high risk of disseminated intra­ protein from the BCR-ABL1 fusion gene has
vascular coagulation (DIC). Patients with DIC deregulated tyrosine kinase activity which prob-
should be treated with supportive measures ably is thought to be the initiating event in the
(frozen plasma, fibrinogen and platelet support) chronic phase of CML.
and all-trans retinoic acid (ATRA) to reverse the Patients with CML but without Ph chromo-
coagulopathy. ATRA acts by stimulating differ- some may still have BCR-ABL rearrangement
entiation of the leukaemic blasts. In addition to which will behave similar to Ph+ disease. Patients
treating DIC, when administered with idarubicin without Ph chromosome and BCR-ABL molecu-
it reduces the risk of disease relapse (DFS >80%). lar abnormalities are classed as atypical CML
In patients achieving a CR, two further courses and they often need a different approach to treat-
of anthracycline based chemotherapy are given ment approach.
311
 II SITE-SPECIFIC CANCER MANAGEMENT

Natural history Management

The three phases of disease are: Chronic phase
• Chronic phase (CP) – 90% of patients present Initial treatment is with the tyrosine kinase inhib-
at this stage. Without treatment median sur- itor (TKI), imatinib (400 mg daily). This results
vival is 3–4 years. in 5-year event free survival of 83%, overall sur-
• Accelerated phase (AP) – characterized by vival of 89% and a cumulative complete cyto­
increasing blast count and organomegaly. genetic response (CCyR) of 87%. Indefinite
Median survival is 1–2 years and most treatment is recommended. RQ–PCR for the
progress to blastic phase in 4–6 months. BCR-ABL transcript is the cornerstone for moni-
• Blast phase (BP) – resembles acute leukaemia toring patients for response to treatment. Patients
with >20% blasts in peripheral blood or with a suboptimal response or failure to respond
marrow. 20–30% of BP is lymphoid, 50% to an initial dose are treated either with an
myeloid and 25% undifferentiated. Median increased dose of imatinib (600–800 mg daily)
survival is 3–6 months. or a second generation TKI such as dasatinib
(70 mg twice daily).
AP and BP are combined as advanced phase Patients who fail treatment with a TKI may be
disease. considered for allogenic stem cell transplant. The
suitable candidates are aged <60 years and have
Clinical features an HLA-identical sibling or an HLA-matched
50% patients are asymptomatic and are diag- unrelated donor.
nosed following an abnormal blood count. The
remainder presents with non-specific symptoms Advanced phase
of weight loss, excessive sweating, spontaneous Newly diagnosed patients with advanced phase
bleeding and pain due to splenic enlargement disease are treated with imatinib 660–800 mg
and hyperviscosity. Some patients with hyperu- daily. The median survival of these patients is 7.5
ricaemia present with a gout-like arthritis. months and hence fit patients who respond to
Symptoms of advanced stage include general treatment should proceed to allogenic SCT if
cachexia, fever, bone marrow failure and bone there is an appropriate donor. Those who have
pain. had previous imatinib are treated with dasatinib
or allogenic SCT.
Investigations
Full blood count and peripheral smear Chronic lymphocytic leukaemia
• Chronic phase – WBC count is usually around Chronic lymphocytic leukaemia (CLL) is the most
20–30 × 109/L. Peripheral smear shows mye- frequent (30%) leukaemia in the Western world.
locytes and myeloblasts. The median age at diagnosis is 70 years. There is a
• Accelerated phase – raised WBC count, 2 : 1 male : female ratio. The aetiology is unknown.
anaemia, thrombocytosis or thrombocyto­ No specific risk factors have been identified.
penia.
• Blastic phase – shows blasts or blasts and Clinical features
promyelocytes in the blood. About 50–70% patients are asymptomatic. The
most frequent presentation is painless symmetri-
Bone marrow cal lymphadenopathy. Other presenting features
Bone marrow shows hypercellular marrow with include systemic symptoms of weight loss, night
complete loss of fat spaces. Metaphase cytoge- sweats, tiredness and features of bone marrow
netics or FISH is useful to identify Ph chromo- failure. Autoimmune complications especially
some. The presence of the BCR-ABL1 fusion haemolytic anaemia and immune thrombocyto-
gene may be identified by real time quantitative penia can occur. Infections are common due to
polymerase chain reaction (RQ-PCR). hypogammaglobulinaemia.
312
 CANCERS OF THE HAEMATOPOIETIC SYSTEM 21
10% patients can undergo transformation to • Rapidly rising lymphocyte count in peripheral
a more aggressive tumour, most commonly blood (doubling time <6 months or >50% rise
diffuse large B-cell lymphoma, called Richter’s in lymphocyte count within 2 months).
syndrome. • Systemic symptoms:
• weight loss >10% in six months
Diagnosis • fever >38°C for >2 weeks
CLL is a proliferative disorder of monoclonal • extreme fatigue or night sweats
CD5+ B lymphocytes. The diagnostic criteria for • Autoimmune cytopenias (this may only
CLL are: require treatment of the autoimmune compo-
nent not necessarily the leukaemia).
• Lymphocytosis >5 × 109/l.
• Typical morphology – small to medium sized The treatment options are chlorambucil,
lymphocytes with clumped chromatin, absent fludarabine with cyclophosphamide and alemtu-
nucleoli and scanty cytoplasm. zumab (if no response or relapse following
• Typical immunophenotype – SmIg (weak), fludarabine). Most patients are actively moni-
CD5+, CD19+, CD20 (weak) and CD23+. tored after initial treatment. Recently the role of
consolidation treatment with monoclonal anti-
A direct Coombs test and serum immunoglob-
bodies and stem cell transplantation are being
ulin estimation is needed. Bone marrow exami-
evaluated.
nation helps to establish the extent and pattern
The choice of salvage treatment depends on
of marrow involvement and to evaluate response
the first line treatment and clinical situation at
to treatment.
relapse. Patients with previous prolonged remis-
Staging sion (>12 months) will respond to the same treat-
ment but with a shorter duration of remission.
Two staging systems exist based on the extent of
Patients who are refractory to chlorambucil can
disease and bone marrow failure and correlate
be treated with fludarabine or its combination.
with median survival (Table 21.7).
Treatment options after fludarabine treatment
Treatment are alemtuzumab, CHOP chemotherapy, and
Most patients need only active monitoring. allogeneic transplantation.
Treatment is indicated only when one of the fol- Richter’s transformation is treated with CHOP
lowing features is present: chemotherapy which yields 40% response and a
poor survival of <6 months.
• Progressive marrow failure.
• Massive (>10 cm) or progressive lymphaden- Supportive treatment
opathy. Patients with hypogammaglobulinaemia with
• Massive (>6 cm) or progressive splenomegaly. recurrent infection need regular intravenous

Table 21.7: Staging systems and survival in CLL

Risk group Binet staging Rai staging Median survival (years)
Low A 0–2 areas involved* 0 Lymphocytosis >10
Intermediate B ≥3 areas involved I Lymphadenopathy 5–7
II Splenomegaly and/or hepatomegaly
High C Hb <10 g/dL or platelet III Hb <11 g/dL <3–4
<100 × 109/L
IV Platelet <100 × 10 /L 9

* Areas are liver, spleen or lymph nodes (either unilateral or bilateral) in inguinal, axillary and cervical region

313
 II SITE-SPECIFIC CANCER MANAGEMENT

immunoglobulin (400 mg/kg 3–4 weekly).

Patients on intensive treatment with purine ana-
logues and alemtuxumab (Campath) need Pneu-
mocystis jiroveci prophylaxis. All patients need
influenza vaccine annually.
Splenectomy may be useful for patients with
features of hypersplenism and symptomatic
splenic enlargement.

New agents
Oblimersen sodium, an antisense molecule to
Bcl-2 (Bcl-2 is an anti-apoptotic protein, is highly
expressed in CLL cells), in combination with Figure 21.7 Peripheral-blood smear showing
fludarabine and cyclophosphamide has shown to characteristic hairy-cell features. From Mey U, Strehl J
improve CR. Lenolidomide, an anti-angiogeneic et al. Advances in the treatment of hairy cell leukaemia,
agent, and flavopiridol, a cyclin dependent kinases Lancet Oncology 2003;4:86–94.
inhibitor, are shown to have activity in CLL.
two months followed by nucleoside analogue
Hairy cell leukaemia treatment.
Patients with a large spleen and with little
Hairy cell leukaemia (HCL) constitutes 2% of
or moderate bone marrow can be treated with
lymphoid leukaemias. The median age at presen-
splenectomy with delayed purine analogues until
tation is 55 years and males are commonly
progression.
affected. There is no known aetiological factor.
The majority (70%) of relapsed patients
One-quarter of patients are asymptomatic and
respond to retreatment with pentostatin or
diagnosis is made after an incidental finding
cladribine. In patients who fail to respond to
of splenomegaly or cytopenia. One-quarter of
nucleoside analogues, rituximab is useful.
patients present with abdominal symptoms due
to splenomegaly; one quarter of patients with
non-specific symptoms of fatigue, weight loss Myelodysplastic syndromes
and fever and the remainder present with fea- Myelodysplastic syndrome (MDS) is a heteroge-
tures of bleeding or recurrent infections. neous group of clonal stem cell disease character-
Peripheral smear shows cytopenia and the ized by dysplasia and ineffective haematopoiesis
presence of hairy cells, cells twice the size of a in one or major cell lineages. Although the
normal lymphocyte with cytoplasmic projections marrow is producing an excess of cells, these are
and an oval nucleus (Figure 21.7). Bone marrow immature and destroyed before reaching the
biopsy is important in definitive diagnosis, which circulation such that the peripheral blood appears
shows an interstitial or focal pattern of infiltra- hypocellular. The median age of occurrence is 70
tion. Immunophenotyping is necessary to distin- years with over 90% patients over the age of 50
guish HCL from other B-cell lymphomas. at the time of diagnosis.
Asymptomatic patients can be observed until There are a number of types including:
the development of cytopenia or systemic symp-
• Refractory anaemia
toms, when treatment is indicated. The mainstay
• Refractory anaemia with ring sideroblasts
of treatment is nucleoside analogues, Pentostatin
• Refractory anaemia with excess blasts
and cladribine, which give a complete remission
• Refractory anaemia with excess blasts in
of >80% with a 10-year overall survival of 95–
transformation
100%. Since both drugs can cause lymphopenia,
• Chronic myelomonocytic leukaemia
patients presenting with cytopenia are treated
either with G-CSF support during nucleoside In the majority of cases, MDS occurs as a de
analogue treatment or initial interferon alfa for novo disorder; recently secondary MDS/AML as
314
 CANCERS OF THE HAEMATOPOIETIC SYSTEM 21
a result of chemotherapy/radiotherapy is increas-
ing. Radiotherapy and alkylating agent related
MDS occurs 5–6 years after treatment whereas
topoisomerase II inhibitor (e.g. etoposide and
teniposide) related MDS develops at a median
interval of 33–34 months after exposure.
Presentation depends on the associated cyto-
penia. Evaluation includes bone marrow biopsy
with iron stain and cytogenetic studies, erythro-
poietin levels and iron studies. The International
Prognostic Scoring System (IPSS) defines four
risk groups for overall survival and AML evolu-
tion, based on the percentage of marrow blasts,
specific cytogenetic abnormalities and number of
cytopenias. Treatment is complex which depends
on the subtype of MDS, IPSS, performance status
and co-morbidities which is not dealt with in this
text-book. In general the initial treatment is sup-
portive but can later involve chemotherapy or
even stem cell transplantation. Median survival
is related to IPSS score and ranges from a few
months to many years.
Figure 21.8
Solitary plasmacytoma MRI scan of the lumbo-sacral spine of a 69-year-old man
who presented with cauda equina syndrome due to L4
The incidence of solitary plasmacytoma is one- compression (arrow). Biopsy of L4 vertebra showed
tenth of myeloma. Solitary plasmacytomas can plasmacytoma and MRI showed another lesion in L1 and
changes in L2 (arrow heads), suggesting myeloma.
occur in bone (solitary bone plasmacytoma –
SBP) or in extramedullary sites (extramedullary
plasmacytoma – SEP). SBP commonly involves
the spine, ribs, femur, humerus, and skull and in all patients as up to one-third of patients may
SEP commonly occurs (80%) in the upper respi- have additional occult lesions that will be missed
ratory tract. In >50% cases solitary plasmacy- on skeletal survey (Figure 21.8). There may be a
toma is a precursor of myeloma. It is more monoclonal gammopathy, which has prognostic
common in men and the median age at diagnosis significance, in 24–72% of patients.
is 10 years younger than patients with multiple
myeloma. Treatment
Radical radiotherapy is the treatment for choice
Clinical features of SPB and SEP (Box 21.7). There is no role for
Pain is the most common clinical symptom of surgery in SPB in the absence of structural insta-
solitary bone plasmacytoma. Spinal plasmacy- bility or neurological compromise. Patients who
toma can present with spinal cord compression. need surgery receive postoperative radiotherapy.
Presentation of extramedullary plasmacytoma There is no data to recommend adjuvant chemo-
depends on the site of origin. therapy. Some consider chemotherapy for patients
at high risk of failure (e.g. tumour >5 cm).
Diagnosis Surgery is avoided in head and neck SEP.
The diagnostic approach is the same as that for Surgery may be considered for SEP at other
myeloma and solitary plasmacytoma is diag- sites. After a complete excision, radiotherapy
nosed when there is no evidence of myeloma. may not be necessary and patients with incom-
MRI of the spine and pelvis should be performed plete excision require radiotherapy. Adjuvant
315
 II SITE-SPECIFIC CANCER MANAGEMENT

Box 21.7: Treatment of solitary plasmacytoma Myeloma

Clinical target volume
• Solitary bone plasmacytoma: Introduction
• Visible tumour on MRI with a margin of at Myeloma accounts for 1–2% of all malignancies
least 2 cm.
• For a lesion in the long bones, there is no need
and 10% of all haematological cancers. About
to include the entire bone marrow. 4000 cases are diagnosed in the UK annually.
• For vertebral disease, the target volume is the The median age at presentation is 70 years and
involved bone with one uninvolved vertebra men are more commonly affected. The aetiology
above and below.
of myeloma is not known.
• Solitary extramedullary plasmacytoma:
Myeloma is the result of clonal proliferation
• Primary tumour with a margin of at least 2 cm.
of plasma cells. 98% cases have production of
• Cervical lymph nodes are included in the target
volume if involved.
paraprotein with IgG being most frequent (60%),
• In SEP of Waldeyer’s ring, first echelon cervical
followed by IgA (20%), light chain (20%), IgD
nodes should be included. (9%) and rarely IgE or IgM. 2% of tumours are
Dose non-secretory.
• Lesion <5 cm – 40 Gy in 20 fractions.
• Lesion >5 cm – 50 Gy in 25 fractions. Clinical features
Monitoring and further treatment The most common presenting symptoms of
• 6-weekly for 6 months and then at long myeloma are fatigue and bone pain. Pain may be
interval. due to bone disease, pathological fracture or
• Patients not responding to radiotherapy should nerve compression. Other presenting features
be treated as multiple myeloma.
include symptoms due to anaemia, renal failure
Patients with apparent SBP with extensive disease (20–30%), hypercalcaemia and infections.
on MRI
• Consider as having multiple myeloma.
Investigations and diagnosis
• Treatment is either with radiotherapy for
symptomatic plasmacytoma followed by Initial investigations for suspected myeloma
observation until progression or as multiple include full blood count with ESR, biochemistry
myeloma.
including albumin, calcium and uric acid, and
electrophoresis of serum and concentrated urine.
Further investigations include serum and urine
chemotherapy may be considered for tumours of
immunofixation to confirm and type monoclonal
>5 cm and high-grade tumours.
protein. Patients with heavy chain myeloma,
Prognostic factors serum electrophoresis (82%) or serum immuno­
Increased serum M protein level and an abnor- fixation (93%) can detect immunoglobulins. Up
mal free light chain ratio are risk factors for to 20% of patients have light chain myeloma
progression to myeloma. The 10-year myeloma which requires detection by urine electrophore-
free survival is 29% in patients with a persistent sis, immunofixation or serum free light chain
serum or urinary M protein compared with 91% test. 1–2% patients have non-secretory myeloma.
in those in whom the M protein was not detect- Serum beta2 microglobulin estimation is impor-
able following radiation therapy. Other factors tant in staging.
associated with progression to myeloma include
Imaging
axial disease, lesion >5 cm and old age.
A skeletal survey reveals lytic bone lesions in
Survival myeloma (Figure 21.9). CT and/or MRI studies
The 10-year overall survival is >50% and DFS is are indicated when symptomatic areas show no
25–50% for SBP. The 10-year DFS for SEP is abnormality on routine radiographs.
70–80% and has a less risk of distant relapse
compared with SBP. Median time to progression Bone marrow
of SBP to myeloma is 2–4 years and the overall A unilateral bone marrow aspirate and trephine
316 survival of SBP varies from 7.5–12 years. is indicated in all patients with myeloma which
 CANCERS OF THE HAEMATOPOIETIC SYSTEM 21

Box 21.8: Diagnostic criteria of myeloma

Myeloma is diagnosed by the following three criteria:
• Bone marrow plasma cells ≥10%, and
• Presence of serum and/or urinary monoclonal
protein (except in patients with true non-secretory
multiple myeloma), and
• Any myeloma-related organ or tissue impairment:
• Bone lesions: lytic lesions, osteoporosis or
pathologic fractures.
• Anaemia: haemoglobin value of >2 g/dL below
the lower limit of normal or a haemoglobin
A value <10 g/dL.
• Hypercalcaemia: corrected serum calcium
>0.25 mmol/L above the upper limit of normal
or >2.75 mmol/L), or
• Renal failure: serum creatinine >195 mg/L.
• Others: symptomatic hyperviscosity, amyloidosis,
>2 episodes of bacterial infection in 12 months.

Table 21.8: International Staging System

for Myeloma
Stage Median
(% of survival
patients) Criteria (months)
I (29) Serum beta2-microglobulin 62
<3.5 mg/L
Serum albumin ≥3.5 g/dL
II (38) Not stage I or III* 44
III (34) Serum beta2-microglobulin 29
≥5.5 mg/L
B
Categories of stage II:
Figure 21.9 • Serum beta2-microglobulin <3.5 mg/L but
Skeletal survey in myeloma. serum albumin <3.5 g/dL
• Serum beta2-microglobulin 3.5 – <5.5 mg/L
irrespective of serum albumin level

will show ≥10% clonal bone marrow plasma

cells.
The diagnostic criteria of myeloma is shown
in Box 21.8. bone marrow involvement, plasmablastic
morphology and lactate dehydrogenase and
Staging cytogenetic changes.
An International Staging System (ISS) has
replaced the Durie–Salmon staging (Table 21.8). Treatment
Myeloma is rarely curable and a minority of
Prognostic factors patients achieve long-term remission following
Performance status is one of the important pre- allogenic stem cell transplantation. Chemother-
dictors of outcome and is a key determinant of apy is indicated for symptomatic myeloma and
transplant eligibility. Other prognostic factors asymptomatic myeloma with myeloma-related
include age, ISS stage, creatinine, calcium, organ damage. The median time to progression
albumin, immunoglobulin subtype, extent of from asymptomatic to symptomatic myeloma is 317
 II SITE-SPECIFIC CANCER MANAGEMENT

Figure 21.10
Symptomatic myeloma Candidates for ASCT
• Age 65 years or less Management of myeloma.
• Good PS
• No comorbidities
Potential candidate for ASCT
Practice in North America

No Yes High risk disease*

65 years
deletion 13
MPT or CDT 6–12 cycles • VAD or VAD type regime deletion 17p
VMP in high risk disease* (4–8 cycles) hypodiploidy
• Thal/dex or Rev/dex t (4; 14)
(2–4 cycles) t (14; 16)

Observation Stem cell harvest Bortezomib based

regime

Mel 200 autograft

Observation or ASCT Continue

maintenance followed by induction till
allogenic plateau and
transplant delayed
if no CR transplant
at relapse

Salvage therapy

12–32 months. Monitoring of asymptomatic Patients not eligible for ASCT are treated with
myeloma includes 3-monthly clinical assessment melphalan-based regimes (Figure 21.2 and Table
and measurement of paraprotein. 21.9). MPT is the preferred regimen for
Treatment of newly diagnosed multiple standard-risk patients who are not candidates
myeloma is rapidly evolving. The North Ameri- for transplantation. ASCT prolongs the median
can approach involves risk categorization of overall survival in myeloma by approximately 12
patients based on molecular cytogenetics and months.
upfront use of novel agents such as bortezomib
(a proteasome inhibitor) and lenalidomide (an Refractory and relapsing myeloma
analogue of thalidomide) whereas such an Almost all patients with myeloma eventually
approach is yet to be adopted in the UK (Figure relapse. If relapse occurs more than 6 months
21.10). Table 21.9 shows regimes in newly diag- after stopping therapy, the initial chemotherapy
nosed myeloma. Treatment response is assessed regimen should be re-instituted. Patients who
by the International Myeloma Working Group have cryopreserved stem cells early in the disease
definitions of response criteria. course can derive significant benefit from ASCT
In patients eligible for autologous stem cell as salvage therapy. In general, patients who have
transplantation (ASCT) prolonged melphalan indolent relapse can often be treated with single
based chemotherapy can interfere with adequate agents whereas those with more aggressive
stem cell mobilization and is therefore avoided. relapse often require a combination of agents.
318
 CANCERS OF THE HAEMATOPOIETIC SYSTEM 21
meniningococci and Haemophilus influenza.
Table 21.9: Regimes in newly diagnosed Prompt treatment of infection is required.
myeloma
• Hyperviscosity syndrome needs plasma­
Regimen Response rate
pheresis.
Regime for patients not eligible for ASCT
Melphalan–prednisolone–
thalidomide (MPT)
75%
Monoclonal gammopathy of
Bortezomib–melphalan- 70% unknown significance (MGUS)
prednisone (VMP) and smouldering myeloma
Cyclophosphamide– 72%
dexamethasone–thalidomide
MGUS is defined by a serum M-protein concen-
(CDT) tration of <3 g/dL, <10% plasma cells in the
bone marrow and absent myeloma-related organ
Regime for patients eligible for ASCT
or tissue impairment (ROTI). Around 1% per
Vincristine–Adriamycin– 52% year will transform to myeloma or another
dexamethasone (VAD)
plasma cell disorder. It does not require any
Thalidomide–dexamethasone 65% treatment but needs life-long monitoring (6–12
(Thal/Dex) monthly) with clinical assessment and quantifica-
Lenalidomide–low dose 70% tion of paraprotein.
dexamethasone (Rev/Dex) Smouldering myeloma is the stage between
Bortezomib–dexamethasone (Vel/ 80% MGUS and myeloma characterized by serum M
Dex) protein of ≥3 g/dL and/or ≥10% plasma cell in
Bortezomib–thalidomide– 90% the bone marrow and no ROTI. Transformation
dexamethasone (VTD) to myeloma or other plasma cell disorders occur
at a rate of 10% per year. Management is 3–4
monthly observation until evidence of progres-
sion to myeloma.
Supportive care Further reading
• Bone disease – all patients with symptomatic Evens AM, Hutchings M, Diehl V. Treatment of Hodgkin
myeloma receive regular bisphosphonate for lymphoma: the past, present, and future. Nat Clin Pract
at least one year from diagnosis. Oncol. 2008;5:543–556.
• Pain control is by analgesics and palliative Peggs KS, Anderlini P, Sureda A. Allogeneic transplantation
for Hodgkin lymphoma. Br J Haematol. 2008;143:
radiotherapy. Percutaneous vertebroplasty
468–480.
and kyphoplasty are useful for vertebral com- Diehl V, Fuchs M. Early, intermediate and advanced
pression fractures that do not respond to Hodgkin’s lymphoma: modern treatment strategies. Ann
standard measures within 6 weeks. Oncol. 2007;18 Suppl 9:ix71–79.
• Hypercalcaemia is treated with Lenz G, Staudt LM. Aggressive lymphomas. N Engl J Med.
2010;362:1417–1429.
bisphosphonates.
Zucca E. Extranodal lymphoma: a reappraisal. Ann Oncol.
• Renal impairment: managed with adequate 2008;19 Suppl 4:iv77–80.
hydration, avoidance of nephrotoxic drugs Estey E, Döhner H. Acute myeloid leukaemia. Lancet.
and prompt treatment of infection and 2006;368:1894–1907.
hypercalcaemia. Hehlmann R, Hochhaus A, Baccarani M. Chronic myeloid
leukaemia. Lancet. 2007;370:342–350.
• Anaemia – transfusions, erythropoietin or
Shanafelt TD, Kay NE. Combination therapies for previously
darbepoietin are useful. untreated CLL. Lancet. 2007;21;370:197–198.
• Infections – all symptomatic patients need Rajkumar SV. Multiple myeloma. Curr Probl Cancer.
vaccination against influenza, pneumococci, 2009;33:7–64.

319
 Paediatric, teenage and
young adult cancers
HM Hatcher
22
Introduction Aetiology
Cancers in this group of patients present specific The majority of older adult cancers are related
challenges in diagnosis, treatment, recruitment to to specific risk factors such as smoking, whereas
clinical trials and survival. Childhood cancers the majority of paediatric malignancies are
have seen a significant improvement in survival thought to be developmental in origin. A number
in the last 30 years from less than 30% to greater of syndromes are associated with childhood
than 70% long-term survival. Unfortunately the cancer (e.g. Down’s syndrome associated with
same is not the case in the teenage and young leukaemia) but the majority arise without an
adult cancers (TYA) with very little improvement underlying genetic predisposition (e.g. Li–
seen over the same time period. Fraumeni and sarcomas). TYA malignancies fall
In addition they have particular social, educa- between the two age extremes and may represent
tional, developmental and psychological needs a late developmental malignancy or an early adult
which, if not addressed, have long-term conse- malignancy due to other factors, e.g. familial
quences for the patient and their family. Those adenomatous polyposis. In most cases the
who survive cancer at a young age may also be aetiology is not known.
left with significant medical late effects which
need to be recognized and managed (p. 58).
Types of cancer
Incidence/epidemiology The types of cancer vary not only between chil-
dren and adults but as the age increases in certain
The incidence of malignancy in the UK is: age group bandings (Table 22.1).
• 12.4 per 100,000 up to 15 years. In children leukaemias represent the most
• 14.4 per 100,000 in those 15–19. common malignancy with acute lymphoblastic
• 22.6 per 100,000 in those 20–24. leukaemia (ALL) being most frequent. Brain
tumours also make up a significant group, but
Those aged 14–24 account for 0.5% of all
the incidence falls as a proportion of cases from
cancer registrations in the UK. In a study from
childhood towards early adulthood. In the 15
the north-west of England the incidence was 174
to 19-year-olds, the most frequent malignancies
cases per million with a male : female ratio of
are lymphomas, leukaemias and carcinomas
1.22 : 1. In the same study the incidence was
(especially thyroid and nasopharyngeal). For the
found to be increasing, particularly for bone
20 to 24-year-olds, lymphomas remain the most
tumours, testicular tumours, thyroid cancer and
common malignancy but with carcinomas (espe-
malignant melanoma.
cially cervix, thyroid and breast) and germ cell
Cancer is the most frequent natural cause of
tumours as next common. Osteosarcomas and
death in this age group, second only to accidents.
germ cell tumours peak in late teenage and
• Male : female ratio is 1.2 : 1. early adulthood.
320 © 2011, Elsevier Ltd
DOI: 10.1016/B978-0-7234-3458-0.00027-0
 PAEDIATRIC, TEENAGE AND YOUNG ADULT CANCERS 22

Table 22.1: Distribution of cancer types according to age

Age 0–14 years Age 15–19 years Age 20–24 years
Leukaemia 35% Lymphoma 27% Lymphomas 24%
Brain tumours 24% Sarcomas 16% Carcinomas 21%
Lymphomas 12% Leukaemia 15% Germ cell tumours 17%
Wilms’ tumour 7% Carcinomas 11% Melanoma 10%
Neuroblastoma 7% Brain tumours 11% Sarcomas 8%
Sarcomas 11% Germ cell tumours 10% Leukaemia 8%
Retinoblastoma 3% Melanoma 6% Brain tumours 8%
Others 1% Others 4% Others 4%

Clinical features Box 22.1: Warning signs of cancer in children

The clinical features in children, teenagers and • Obvious lump or swelling around the head, neck,
abdomen or elsewhere.
young adults are similar to those seen in other
• Increasing and persistent pain in bone or joints,
age groups with the same malignancies, but are often leading to less use of the limb or limping.
often not recognized as such due to the rarity of • Pallor, especially if associated with unexplained
malignancy in these age groups. In addition for bruising or bleeding.
children who are unable to explain symptoms • Worsening headaches, especially if associated with
clearly, the disease has usually progressed so that vomiting in the morning.
symptoms are obvious to their family. Delays in
diagnosis are very common in the adolescent and
young adult and can contribute to reduced
survival at all ages. Delays in diagnosis can occur in children if
In children warning signs may be due to local- symptoms are occult, especially in very young
ized disease, or the manifestations of dissemi- children but are more common in the TYA group.
nated disease are listed in Box 22.1.
In the older child and young adult, the Specific childhood cancers
same warning features apply but also include
additional signs specific to the different Some cancers are specific to children and young
malignancies. adults, or their treatment is different to that in
adults. These tumours will be highlighted below.
Diagnosis and delays For other malignancies, covered by other chap-
ters, only specific changes in management for
Diagnosis of malignancy currently follows the children and young adults will be made.
pathways for either paediatric or adult cancers.
Paediatric cancers are diagnosed and treated in Leukaemias
specialist principal treatment centres with some In childhood acute lymphoblastic leukaemia
care shared with local hospitals. For TYA cancers, (ALL) is by far the most frequently occurring
currently they may be seen in a paediatric or leukaemia representing over 75% cases. (p. 308).
adult setting and treated according to those pro- Presentation is usually with symptoms and
tocols. In the UK TYA cancer will soon be treated signs of bone marrow infiltration and these can
in specialized centres. This may mean referral to appear to occur quite rapidly, although are often
a specialist TYA centre or to an adult cancer preceded by several weeks of general malaise or
specialist in a particular site of the body in a recurrent infections and fevers. Usual features at
designated regional hospital with appropriate the time of diagnosis are pallor, abnormal bruis-
TYA facilities (Figure 22.1). ing or bleeding, bone pain (which may manifest
321
 II SITE-SPECIFIC CANCER MANAGEMENT

Figure 22.1
Suspected cancer
Referral for treatment of childhood
and TYA malignancy.

Childhood cancer TYA cancer

Refer to specialist
paediatric oncology
centre for diagnosis

Diagnosis of Diagnosis at local

childhood cancer hospital or
specialist hospital

Rare Common

Treatment directed and Rare cancer – Common adult cancers tend to be

given at specialist paediatric treat at specialist treated at local hospitals but many
cancer centre with hospital with will now be referred to young adult
shared/supportive care at shared/supportive care specialist cancer centres with
designated district hospitals at local hospital shared care at local hospitals

Box 22.2: Prognostic features in childhood and adolescent ALL

Patients are stratified according to risk by combining age, initial white count, cytogenetics, immunology and
response to initial treatment.
Very high risk (5-year survival <50%).
• Philadelphia chromosome or hypodiploidy or who fail to achieve remission after induction therapy.
High risk (<75% 5-year survival).
• Age greater than 10 years or with unfavourable cytogenetics.
Standard risk (80% 5-year survival).
• Age 1–10, low white count, no unfavourable cytogenetics.
Low risk (90% 5-year survival).
• Age 1–10, low white count, favourable cytogenetics.
Favourable cytogenetics
• Hyperdiploidy, trisomies of 4, 10, 17, t(12;21).
Unfavourable cytogenetics
• Hypodiploidy, tetraploidy, Philadelphia chromosome [t(9;22)], t(1;19), t(4;11).

as limping in young children) and on clinical Treatment of childhood and young adult ALL
examination lymphadenopathy and hepato­ is performed according to risk stratification as in
megaly in some children. Box 22.2. In general treatment involves several
Diagnosis is suspected on the differential blood phases which is similar to that of adult ALL
count but bone marrow examination is essential (p. 308).
to confirm the diagnosis (p. 308), to perform Relapsed ALL may still be curable with high-
immunocytochemical stains and cytogenetics dose chemotherapy and stem cell transplanta-
which are of diagnostic and prognostic signifi- tion, but the chances of long-term cure are
cance (Box 22.2). much lower with the high-risk subgroups and if
322
 PAEDIATRIC, TEENAGE AND YOUNG ADULT CANCERS 22
relapse is within a year of completing initial Overall more than 80% are cured of their disease.
treatment. Treatment for relapse is rarely curative.
In addition certain subgroups such as B-cell
ALL are often treated on different regimens Neuroblastoma
similar to those used for a Burkitt’s lymphoma Neuroblastoma is a neuroendocrine tumour
(p. 305, Burkitt’s lymphoma). Both these malig­ which originates from any neural crest element
nancies are associated with a t(8;14) translocation of the sympathetic nervous system. It predomi-
so may be variations of the same malignancy. nantly occurs in those under 3 years of age. The
highest incidence is in the first 12 months of life
Brain tumours with less than 10% of cases occurring in those
Brain tumours are the second most common over the age of 5 years.
malignancy in children and remain a significant Clinical presentation is varied depending on the
cause of cancer into young adulthood. In location and extent of the tumour. Fatigue, fever
children the majority of tumours occur infra­ and anorexia are the most common initial pre-
tentorially but this proportion changes with senting features with more localizing features
increasing age. dependent on tumour site. Adrenal primaries are
Presenting features include headaches, often often extensive at presentation and may involve
worse in the morning and associated with the IVC. Paravertebral tumours may lead to spinal
morning vomiting, papilloedema (sometimes cord compression. At least 50% of cases are meta-
detected by an optician), ataxia, personality static at presentation. Elevated catechol­amines
change, nerve palsies and nystagmus. are found in over 90%. Staging includes a CT,
Common subtypes of brain tumour include bone scintigram, bone marrow sampling and
astrocytoma, medulloblastoma, glioma, cranio­ radiolabelled MIBG (meta-iodobenzylguanidine)
pharyngioma and ependymoma. In children, scan. MIBG is taken up by 95% of neuro­
particularly in the very young, the emphasis of blastomas and acts as a tool for staging and
treatment is to delay, avoid or minimize the need monitoring disease response.
for radiotherapy to avoid long-term side effects. Poor prognostic features are advanced stage,
These are covered in more detail on p. 264. age over 1 year, and over-expression of N-myc
oncogene.
Wilms’ tumour Treatment may be with surgery alone in early
Wilms’ tumour or nephroblastoma occurs most stage disease, but the majority require combina-
frequently in children under 5 years of age and tion chemotherapy. Trials are examining the role
very rarely in older children or young adults. of intensification of treatment in poor prognosis
Most tumours are unilateral, but are bilateral in disease. The risk of relapse is high and the long-
5% of cases and in a further 5–10% will have term survival for those with metastatic disease at
more than one tumour in the same kidney. Risk presentation is less than 30%.
factors include certain genetic syndromes such as
Beckwith–Weidemann syndrome. They are often Lymphomas
asymptomatic until they present as an abdominal Lymphomas occur in childhood and Hodgkin’s
mass, pain and/or anorexia. disease has a peak in incidence in young adult-
Histologically they are divided into a favoura- hood (p. 298). In general these tumours are
ble group with well-defined elements and the ana- treated similar to their adult counterparts
plastic (or unfavourable group) with poorly except that radiotherapy is avoided, except in
defined cellular morphology. Less than 25% have refractory disease, to reduce the risk of its effect
a mutation within the WT1 (Wilms’ tumour) gene. on growth and the risk of second malignancy.
Staging is undertaken with imaging and Chemotherapy regimens are similar to adults but
treatment is according to stage (Figure 22.2). Ana- trials are ongoing to assess the role of rituximab
plastic tumours are treated with more aggressive in children. The most common subtypes of NHL
chemotherapy except in stage I where their prog- in children are Burkitt-like lymphomas (p. 305)
nosis is similar to favourable histology tumours. and diffuse large B-cell lymphomas (Table 22.2).
323
 II SITE-SPECIFIC CANCER MANAGEMENT

Staging
Ultrasound-blood vessel
involvement CT, bone scan
(surgery)
work up for treatment:
bloods, MUGA/ECHO, GFR

Stage I Stage II Stage III Stage IV Stage V

43% 23% 23% 10% 5%

Limited to the Tumour extends Unresectable primary Lung, liver, Bilateral tumours
kidney beyond the kidney or LN metastases or bone, brain Both sides should
Completely excised but excised extensive or distant LN be staged
Intact capsule May be tumour spillage tumour spillage metastases

Nephrectomy + Nephrectomy Abdominal RT Nephrectomy Treatment variable

combination Abdominal RT Combination chemo Abdominal RT according to stages
chemo Combination chemo Surgery when resectable Combination chemo on both sides and
RT for metastases trials available

4 year survival 4 year survival 4 year survival 4 year survival 4 year survival
98% favourable 96% favourable 95% favourable 90% favourable 76–94%
85% anaplastic 70% anaplastic 56% anaplastic 17% anaplastic

Figure 22.2
Staging and management of Wilms’ tumour.

Table 22.2: Major histopathological categories of non-Hodgkin lymphoma in children

and adolescents
Category (WHO Classification/
updated REAL) Immuno-phenotype Clinical presentation
Burkitt and Burkitt-like Mature B cell Intra-abdominal (sporadic), head and
lymphomas neck (non-jaw, sporadic), jaw (endemic)
Diffuse large B-cell lymphoma Mature B cell; may be CD30+ Nodal, abdomen, bone, primary CNS,
mediastinal
Lymphoblastic lymphoma, Pre-T cell Mediastinal, bone marrow
precursor T-cell/leukaemia, or
Pre-B cell Skin, bone
precursor B-cell lymphoma
Anaplastic large cell lymphoma, CD30+ (Ki-1+) Variable, but systemic symptoms often
systemic prominent
T cell or null cell
Anaplastic large cell lymphoma, CD30+ (Ki-1+usually) Skin only; single or multiple lesions
cutaneous
T cell

324
 PAEDIATRIC, TEENAGE AND YOUNG ADULT CANCERS 22
Anaplastic large cell tumours are rare as are but due to the aggressive nature of these tumours,
other adult subtypes such as cutaneous T-cell combination chemotherapy with e.g. IVADo
lymphoma and MALT lymphoma (p. 306). Prog- (ifosfamide, vincristine, actinomycin and doxo-
nostic factors are similar to adult tumours. rubicin), is given. Radiotherapy is often given if
margins are positive or there has been tumour
Sarcomas regrowth after initial surgery. An Italian pilot
Both bone and soft tissue sarcomas occur in study suggested that maintenance therapy with
children and young adults. These are covered in cyclophosphamide and vinorelbine may prolong
detail in Chapter 15. Some sarcomas, however, progression free survival. In advanced disease
peak in this age group. Osteosarcomas peak in combination chemotherapy is used but the
early adolescence with Ewing’s sarcomas having outlook is poor. Poor prognostic factors include
their peak incidence in older adolescence. increasing age, particularly over age 16, advanced
Rhabdomyosarcoma (RMS), a tumour of stri- stage and alveolar subtype.
ated muscle, is the only soft tissue sarcoma to
peak in children and adolescents. It is divided Germ cell tumours
into two main histological subgroups, embryonal Germ cell tumours of the ovary and testes peak
and alveolar. Alveolar rhabdomyosarcoma in young adulthood and are described in more
(ARMS) is characterized by one of two specific detail in Chapters 12 and 13. Similar treatment
translocations, either t(2;13)(q35;q14) resulting modalities are used in children and young adults,
in fusion of PAX3-FOXO1 in 60% ARMS or but there has been a move to reduce long-term
t(1;13)(q36;q14) resulting in PAX7-FOXO1 in side effects from chemotherapy and to try to
20% ARMS. Embryonal RMS is not associated maintain fertility in ovarian germ cell tumours.
with a specific translocation, but loss in chromo- Trials are underway to examine the role of car-
some 11. Common tumour sites include the head boplatin rather than cisplatin and to reduce the
and neck, paratesticular and limb (Figure 22.3). dose of bleomycin in adolescent germ cell tumours
It frequently presents with advanced disease. If to reduce late effects. Fertility sparing surgery is
localized it can present with a mass or proptosis preferred if possible for ovarian germ cell tumours
if retro-orbital. It can give rise to nodal metas- and many women retain their fertility with this
tases and regional lymph nodes should be exam- type of surgery and BEP chemotherapy (p. 220).
ined. Staging involves local MRI, CT of chest
(and regional), bone scan, and bone marrow Langerhans cell histiocytosis (LCH)
biopsy. Localized disease is treated with surgery,
LCH is a proliferative disorder of histiocytes.
Although not strictly a malignancy it may exhibit
aggressive behaviour and require combination
chemotherapy. Multiple bony lesions can occur
at any site, but can occur within the skull leading
to hypothalamic infiltration and diabetes insip-
idus. Systemic LCH tends to present in infancy
as a widespread rash with bone marrow and soft
tissue involvement. Organ dysfunction is a better
indication of poor prognosis than the number of
involved sites. Treatment of advanced disease is
with chemotherapy.

Hepatoblastomas
Hepatoblastomas are rare but are most common
Figure 22.3
MRI of sagittal section through the foot showing a mass
malignancy of liver in children. There is an asso-
deep to the plantar fascia. Histology showed an ciation with FAP. Hepatocellular carcinoma can
embryonal rhabdomyosarcoma. also occur rarely but in older age groups. Clinical
325
 II SITE-SPECIFIC CANCER MANAGEMENT

presentation is usually with a mass or abdominal an often protracted treatment period. The fact
distension. Jaundice is rare. Alpha-foetoprotein that many children are now cured of their disease
(AFP) is elevated in most cases. Unlike adult liver but with long-term effects from their treatment
tumours, most hepatoblastomas respond to also has a psychological impact on them and
combination chemotherapy (cisplatin and doxo- their family. Adolescents and young adults are at
rubicin) with good long-term survival. a vulnerable stage of development and treatment
for cancer has been shown to have a detrimental
Retinoblastoma long-term psychological impact in many patients.
Retinoblastomas are very rare childhood Appropriate support should be offered to patients
tumours. All bilateral tumours and 20% of uni- and their families to try to prevent some of these
lateral tumours are thought to be hereditary. The conditions occurring later on.
retinoblastoma tumour suppressor gene is on Risk-taking behaviour is also at its greatest in
chromosome 13 with the pattern of inheritance the TYA age group and can affect drug compli-
being autosomal dominant with incomplete pen- ance as well as coping mechanisms.
etrance (Chapter 5, p. 55). Most cases present
before age 3. In children not known to be in a Body image and fertility
retinoblastoma family presentation is with a
squint or white papillary reflex. Those related to Sexual identity and future fertility are important
retinoblastoma families should be part of a considerations for the adolescent or young adult.
screening programme. Surgery may be necessary Loss of hair or a limb will significantly affect
for some but most cases are treated with radio- body image at an age when this is especially
therapy. Long-term survival is over 95%, but vulnerable. The type of cancer or its treatment
second malignancy is common (osteosarcomas in may also affect future fertility, but this is not
radiotherapy field) and in those with hereditary universal so specific knowledge is required for
retinoblastoma other malignancies, especially each patient (p. 59, late effects).
sarcomas can occur elsewhere in the body in
young adulthood up to middle age. Education
The majority of children and young adult patients
Clinical trials will be in full-time education at the time of diag-
Traditionally children have a high recruitment to nosis. If treatment is lengthy or affects the ability
clinical trials (>80%) and there are often avail- to study in the longer term, this can also result
able trials in the most frequent childhood cancers. in difficulties reintegrating into school or obtain-
However, trial recruitment is lowest in the ado- ing a job. Continuing education should be sup-
lescent and young adult population when com- ported throughout treatment.
pared with either children or older adults. This
is partially due to the rarity of cancers concerned, Late effects
but also to the fact that these patients are treated
in a wide range of settings. Many fall between Late effects are an important factor in the treat-
different groups of physicians who may not be ment of children and young adults (p. 58, late
able to provide available trials. It is hoped this effects). Late effects are dependent upon the orig-
will be changed with the evolving changes in the inal cancer, its treatment, the family genetics and
organization of TYA cancer management. the developmental stage of the individual when
treated for cancer. Every organ system can be
affected, but the most significant include the risk
Psychological support of second malignancy, neurocognitive impair-
Children and their families frequently need ment, growth problems, and cardiac and endo-
support to help them manage the consequences crine abnormalities. Many centres run late effects
of a diagnosis of cancer at such a young age, and clinics to monitor for these and other sequelae of
the consequences it will have on the family over cancer treatment.
326
 PAEDIATRIC, TEENAGE AND YOUNG ADULT CANCERS 22

Transition rest of the child or young adult’s treatment, is

essential. Liaison with community services and
Patients in the adolescent age group are at a children’s hospices is an important part of this
critical stage of development between childhood process.
and independent adulthood. Their ongoing care
necessitates an understanding of the transition
Further reading
between these stages. There must be clear com-
munication between different medical teams and Albritton K, Bleyer WA. The management of cancer in the
an agreement to the future care and follow-up of older adolescent. Eur J Cancer 2003;39:2584–2599.
Birch JM, Alston R, Quinn M, Kelsey A. Incidence of
an individual. This can be facilitated by multidis- malignant disease by morphological type in young
ciplinary teams from paediatric, TYA and adult persons aged 12–24 years in England, 1979–1997. Eur J
services as well as joint clinics to facilitate knowl- Cancer 2003;39:2622–2631.
edge and experience. Martin S, Ulrich C, Munsell M, et al. Delays in cancer
diagnosis in underinsured young adults and older
adolescents. The Oncologist 2007;12:816–824.
Terminal care and bereavement Ramanujachar R, Richards S, Hann I, et al. Adolescents with
ALL: outcome on UK national paediatric and adult trials.
Unfortunately many young adults and some chil-
Pediatr Blood Cancer 2007;48:254–261.
dren with cancer will not survive and this will Guidance on Cancer Services – Improving outcomes in
have an enormous impact on their families and children and young people with cancer. August 2005.
friends. Family support at this time, as with the Available from www.nice.org.uk

327
 Oncologic emergencies
J Wrigley and TV Ajithkumar
23
Metastatic spinal tantly, around 17% of patients have two or more
levels of compression at presentation.
cord compression Spinal cord metastases can be of three types
Introduction depending on the location of tumour deposit:
Metastatic spinal cord compression (MSCC) • Extradural – occurs in more than 90%,
occurs in 3–5% of patients with cancer. Prostate, usually due to direct extension of vertebral
breast and lung cancer each account for 15–20% metastases. 75% of these are caused by soft
of cases; lymphoma, myeloma and renal cell tissue extension and 25% by bone collapse
cancer account for 10% and the remainder is due and compression by bony fragments.
to colorectal cancers, sarcomas and cancers of • Intradural extramedullary – occurs in 5% of
unknown primary. Although more frequent in cases and is due to deposit via CSF spaces.
patients with known malignancy, MSCC is the • Intramedullary (0.5–3.5%) – are commonly
presenting feature in up to 20% of patients with associated with brain metastases and lepto­
no prior diagnosis of cancer, particularly lung meningeal disease and can occur in lung,
cancer. breast and renal cell cancers, lymphoma and
myeloma.
Aetiology
The mechanisms by which MSCC may develop Clinical features
include: Back pain is the most frequent (95%) first
symptom, which commonly precedes the diagno-
1. Direct tumour extension into the epidural
sis of MSCC by up to 3 months in patients with
space from a vertebral or paravertebral mass.
known cancer and up to 5 months in those
2. Haematogenous spread to the vertebral spine
without a known malignancy. The pain may be
causing collapse and compression.
localized or neurogenic and is typically worse
3. Direct deposition of tumour cells within the
when the patient is supine.
cord.
Limb weakness is the second most common
Early stage compression of the cord results in symptom. Up to 85% of patients will have
oedema, venous congestion and demyelination, abnormal power in the limbs at presentation,
and neurological recovery may still be possible which depends on the neurologic level of
during this phase with prompt decompression. compression.
Continued compression causes secondary vascu- Sensory deficit may manifest itself as paraes-
lar injury and irreversible infarction. The most thesia or sensory loss and is present in up to 65%
common location of compression is thoracic of patients with MSCC. Up to 50% of patients
(50–70%) followed by lumbo-sacral (20–30%) will have a dermatomal sensory level, although
and cervical spine (10–20%). Up to 85% patients this may vary by several dermatomes above or
have multiple vertebral metastases and impor- below the true level of compression.
328 © 2011, Elsevier Ltd
DOI: 10.1016/B978-0-7234-3458-0.00028-2
 ONCOLOGIC EMERGENCIES 23
Autonomic dysfunction is a late complication when MRI is contraindicated. A sagittal screen-
affecting up to 50% of patients with MSCC. ing of the whole spine with T1 and short T1
It includes impotence, bladder and bowel inversion recovery (STIR) images should be done
dysfunction, with constipation occurring most to ensure that multiple levels of compression are
frequently. not missed and also to identify asymptomatic
There are two clinical variants of MSCC, metastases. T2 weighted images help to detect
which require early recognition: the degree of compression by a soft tissue com-
ponent and intramedullary lesions (Figure 23.1).
• Isolated ataxia: thoracic SCC may present
In patients who have not been previously
with isolated ataxia due to spinocerebellar
diagnosed with cancer, a histological diagnosis
pathway dysfunction.
is required before definitive treatment can be
• Cauda equina syndrome: epidural extension of
planned. Patients should be investigated like
metastases below the level of the spinal cord
any other patient with cancer of unknown
(L1/L2) can present with early sphincter dys-
primary and an appropriate area most amenable
function, saddle anaesthesia (buttocks and
to biopsy should be established. However, treat-
perineal region), flaccid paraparesis of hip
ment should not be delayed during these investi-
extension and abduction, knee flexion and
gations and prompt neurosurgical involvement
movement of feet and toes, and absent ankle
should be established if biopsy is not possible.
reflexes.
Investigations Management
MRI of the whole spine is the investigation of The aim of treatment is to preserve or improve
choice for suspected MSCC. CT is used only neurological function and achieve pain control.

A B

Figure 23.1
Imaging in cord compression. MRI scan shows
spinal cord compression due to a collapsed
C vertebra (A,B) and an intramedullary
metastasis from lung cancer (C).
329
 II SITE-SPECIFIC CANCER MANAGEMENT

70–100% patients who are ambulant at the Box 23.1: Patients with MSCC according to
beginning of treatment remain ambulant with outcome after surgical intervention
prompt treatment, whereas only 30–50% patients Good surgical candidates Poor surgical candidates
who are non-ambulant regain the ability to walk ‘Good prognosis tumours’ ‘Poor prognosis tumours’
and only 5–10% of paraplegic patients become e.g. breast cancer, e.g. lung cancer,
ambulant. Hence it is important to have defini- testicular cancer etc. melanoma
Single level of compression Multiple levels affected
tive treatment within 24 hours of presentation with solitary or few or multiple spinal
with suspected cord compression. Patients with vertebral metastases metastases
MSCC secondary to a vascular event will not Absence of visceral Presence of visceral
metastases metastases
respond to treatment. Good neurological function Poor neurological
function
Initial measures No previous radiotherapy Recurrence following
radiotherapy
All patients with suspected MSCC, except those Minimal co-morbidity Medically unfit for
without known cancer and those who are likely surgery
to have lymphoma, are started on oral dexame- Unknown primary or no Prognosis <3 months
histopathological
thasone 16 mg/day after assessment. This dose of diagnosis
steroid is continued until definitive treatment,
after which the steroids are weaned down as
quickly as neurological symptoms will allow.
Optimal pain control and cervical collar for Box 23.2: Indications for surgical treatment*
patients with suspected cervical spine involve- • Relapse after radiotherapy
ment are advised. • Progression while on radiotherapy
• Radiation resistant tumours
Specific measures
• Unknown primary tumour
Definite treatment of MSCC depends on the • Unstable spine or pathological fractures
histologic type and associated spinal stability. In
patients with no prior history of cancer, surgical *With a single site of cord compression and no total paraplegia for
longer than 48 h.
decompression with histologic confirmation is
appropriate. If surgical decompression is not
possible, a CT guided biopsy is needed.
Surgery may involve decompression, stabiliza- Box 23.3: Radiotherapy in spinal cord
tion and or resection and reconstruction of the compression
spinal canal. The patient’s overall prognosis and • Position – supine or prone
performance status should be taken into consid- • Treatment volume – one vertebra above and
eration and patients who have had no distal below MRI proven compression
neurological function for >24 h should not be • Ensure that all paravertebral disease is enclosed in
the volume if feasible
considered for surgery (Boxes 23.1 and 23.2).
• Direct posterior beam 6 MV (parallel lateral in
Radiotherapy is the treatment most frequently cervical region if feasible)
used and is most effective for patients with radio- • Prescription point – anterior spinal canal (either
sensitive tumours who are ambulatory at the measured from MRI or arbitrary, see Figure 23.2)
beginning of treatment. For those without • Dose – 30 Gy in 10 fractions or 20 Gy in five
mechanical pain or structural instability, radio- fractions
therapy may significantly improve pain control
and neurological function. The most commonly
used regimes are 20 Gy in five fractions (more Patients with established paraplegia are treated
appropriate for patients with expected short sur- with an 8 Gy single fraction for pain control.
vival) or 30 Gy in 10 fractions (Box 23.3). Some The issue of whether surgery or radiotherapy
patients may deteriorate during radiotherapy or a combination of both gives best functional
when the steroid dose may be increased or they outcome is yet to be resolved. A randomized
may be considered for surgery if appropriate. study compared radiotherapy (30 Gy in 10 frac-
330
 ONCOLOGIC EMERGENCIES 23
Figure 23.2
Radiotherapy in spinal cord
compression – anatomical
landmarks and arbitrary
radiotherapy dose prescription
points.
Cervical
Superior thyroid
notch C4 C6 – 7 cm

Sternal notch T2 T2 – 7 cm
Sternal angle T4
T5 – 6 cm

Thoracic
T8 – 5 cm
Xiphisternum T9

T11 – 6 cm

Transpyloric plane L1 (halfway

between xiphoid and umbilicus) L1 – 7 cm
Lumbar Subcostal plane L2/3 L3 – 8 cm
L5 – 8 cm
Transtubercular plane L3

Sacral

tions) started within 24 hours of onset of MSCC unpredictable. Hence MSCC in chemosensitive
with surgery within 24 hours followed by radio- tumours is treated with a combination of radio-
therapy within 2 weeks of surgery. Results therapy and chemotherapy.
showed that initial surgery followed by radio-
therapy offers a longer period with ability to Supportive measures
walk compared with those treated with radio- Supportive care requires a multidisciplinary team
therapy alone (median, 126 days vs. 35 days, approach. Analgesia needs to be optimized and
p = 0.006). This study showed that surgery venous thromboembolism prophylaxis pre-
permits most patients to remain ambulatory and scribed. Urinary or supra-pubic catheters should
continent for the remainder of their lives, while be considered and faecal continence should be
patients treated with radiation alone spend controlled with the use of stool softeners and
approximately two-thirds of their remaining time suppositories every 2–3 days. In patients with
unable to walk and incontinent. However, results bone metastases, there is no evidence that
of this study may not be extended to all patients bisphosphonates can reduce the risk of cord
as the study was limited to patients with less compression.
radiosensitive tumours and with different tumour
types and presentations. Prognosis
Chemotherapy alone is not an option for The median survival following a diagnosis of
treatment even in chemosensitive tumours as MSCC is 3–6 months, with 17% of patients
the response to treatment is often slow and alive at 1 year and 10% alive at 18 months.
331
 II SITE-SPECIFIC CANCER MANAGEMENT

Pre-treatment motor function is an important neurological deficits. Seizures and bleeding into
predictor of the ambulatory outcome. Patients the metastases can result in an acute medical
who develop motor dysfunction more slowly also emergency. Malignant melanoma, renal cell car-
may have a better outcome. cinoma, thyroid cancer and choriocarcinoma are
commonly associated with bleeding into the
Recurrence of spinal cord compression metastases. Initial treatment is dexamethasone
7–14% of patients can present with recurrence 16 mg daily. Patients who present with seizures
of spinal cord compression after initial decom- require anticonvulsants. Role of prophylactic
pression. If the second cord compression is in a anticonvulsants is not known; it may be consid-
different area, treatment is the same as that ered in patients with high risk features of seizure
of the original compression. However, if patients such as metastasis to the motor cortex, bleeding
present with spinal cord compression at the metastasis and leptomeningeal metastasis. Further
initial radiation portal, surgical decompression is management of brain metastasis is given on p. 278.
the initial option, particularly if the recurrence is
within three months of initial treatment. If they Encephalopathy
are not a candidate for surgery, re-irradiation
Introduction
may be considered. It is important to make sure
that the total dose to spinal code is kept below Encephalopathy is an important complication of
100 Gy2 (biologically equivalent dose of 100 Gy cancer, which presents with an acute confusional
when delivered as 2 Gy per fraction). Many clini- state or delirium subsequent to abnormal brain
cians use a dose of 20 Gy in 8–10 fractions. function resulting from interference with brain
metabolism. A number of aetiological factors
Paediatric spinal cord compression can contribute to the development of encepha-
Paediatric MSCC differs from adult MSCC in that lopathy in cancer patients. Generally, these are
it is often caused by chemosensitive histological due to infection, metabolic abnormalities (such
types not seen in adults such as neuro­blastoma, as hyponatraemia, hypercalcaemia) and drugs. A
Wilms’ tumour (p. 323). The usual pathogenesis number of anti-neoplastic agents such as ifosfa-
is the direct invasion of tumour through neural mide, methotrexate, cisplatin, vincristine, cyto-
foramina. The most common histologic type is sine arabinoside etc. can cause encephalopathy.
neuroblastoma, which responds to chemotherapy. Clinical features
Decompressive surgery is offered when patients The usual presentation is cognitive and behav-
present with rapid progression or progress during ioural changes. Patients can present with insom-
chemotherapy. Radiotherapy is only offered when nia followed by acute confusion and delirium.
there is no response after chemotherapy and/or Occasionally focal signs such as ataxia may
surgery and for those who require palliation after predominate.
failure of multiple systemic regimens. Clinical examination shows an altered level
of consciousness, abnormalities of respiration,
Intramedullary spinal cord metastasis
small reactive pupils and spontaneously roving
This is rare (1% incidence) and lung cancer is eye movements. Grading of encephalopathy is as
the most common primary. Sensory deficit (79%), follows:
sphincter dysfunction (60%) and weakness
(91%) are common manifestations. Up to 40% • G1 – mild transient drowsiness or nightmares.
patients will have brain metastases. Treatment is This may not be noticed by the patient at the
with corticosteroids and radiotherapy. time of treatment, but nightmares may be
reported at the next clinic visit.
• G2 – drowsy <50% time.
Raised intracranial pressure • G3 – drowsy >50% time, severe disorientation,
Approximately 25% of patients with cancer tremor, psychosis. Patients will often present
develop brain metastases and can present with with 1 or 2 of these features but not all.
features of raised intracranial pressure and focal • G4 – coma or seizures.
332
 ONCOLOGIC EMERGENCIES 23

Management Clinical examination reveals reduced visual

Investigations include biochemical tests, infec- acuity in the affected eye and there may be
tion screening, MRI brain, EEG and CSF exami- associated field defects. Eye pain can also occur
nation and drug level estimation in selected cases. secondary to optic nerve sheath oedema. If papil-
In most cases of anti-neoplastic induced loedema is present this suggests anterior optic
encephalopathy, the management is cessation of neuritis, but this sign will be absent in retrobul-
the drug and continuation supportive measures bar neuritis.
until recovery, and a re-challenge is seldom Investigations may be normal but MRI can
attempted. One exception is ifosfamide. exclude intracranial metastases. Visual evoked
Ifosfamide encephalopathy can occur within potentials may display reduced amplitudes
minutes or hours of starting ifosfamide, or up to and increased latency suggesting optic nerve
24 hours after the completion of ifosfamide. The involvement.
risk factors for ifosfamide encephalopathy are Treatment of drug-induced optic neuritis
pelvic tumour, low albumin, impaired renal func- involves the immediate withdrawal of the drug
tion, previous cisplatin, high dose of ifosfamide and exclusion of other causes. Intravenous
and CNS disease. In patients on ifosfamide, methylprednisolone has been used but there are no
encephalopathy can be prevented by prophylac- randomized data to support this. Recovery can
tic dose of methylene blue (50 mg IV 4 times occur with drug withdrawal. However, the major-
daily). ity of patients have some permanent visual deficit.
In patients with ifosfamide encephalopathy,
Choroidal metastasis
treatment is based on the grade of the
encephalopathy: Choroidal metastasis can result in sudden loss of
vision. It is most common with breast and lung
• G1 – no action required. cancer and up to 20% may be bilateral. Cancer
• G2 – If on antiemetics such as levomepro- patients presenting with visual symptoms require
mazine (Nozinan), stop the drug and reassess detailed ophthalmologic assessment including a
in 1–2 hours. If there is improvement, replace slit lamp examination. CT scan or MRI of the
the anti-emetics. If there is no improvement, brain is needed to rule out brain metastasis.
give methylene blue (50 mg IV 4 times daily) Urgent radiotherapy is needed to avoid further
and continue ifosfamide if the patient is visual deterioration and maintain useful vision.
undergoing curative treatment. Ensure regular The entire choroid and retina of the affected eye
review so that the patient’s condition does not is treated with a dose of 20 Gy in five fractions
deteriorate. or 30 Gy in 10 fractions at 2.5 cm depth using
• G3/4 – stop ifosfamide infusion (even for a posteriorly angled lateral beam (to avoid
curative treatment) and give or increase meth- opposite lens).
ylene blue (50 mg 6 times daily). Correct any
metabolic abnormalities/infection. If there is Febrile neutropenia
no improvement, consider thiamine 100 mg,
intravenous albumin (in cases of low albumin) Introduction
or haemodialysis. Febrile neutropenia is defined as an oral or tym-
panic membrane temperature of ≥38°C on two
Visual loss occasions, at least one hour apart within a 12 h
period or a single temperature of >38.5°C with
Optic neuropathy an absolute neutrophil count of ≤0.5 × 109/l or
Anti-neoplastic drug-induced optic neuropathy ≤1.0 × 109/l with a predictable decline to ≤0.5 ×
(ON) can be acute with rapidly progressive loss 109/l in 24–48 h.
of vision. Cisplatin, carboplatin, carmustine, Febrile neutropenia is one of the most common
5-fluorouracil, methotrexate, vinca-alkaloids, complications of cancer treatment. 50–60% of
paclitaxel, tamoxifen and bisphosphonates are patients with febrile neutropenia have an estab-
reported to cause optic neuropathy. lished or occult infection and 20% of patients
333
 II SITE-SPECIFIC CANCER MANAGEMENT

with a neutrophil count ≤1.0 × 109/l have (especially in those aged <45 years) and there-
bacteraemia. fore, prompt assessment is essential. Due to lack
Susceptibility to infection increases as the of neutrophils, most infections present with atyp-
neutrophil count drops below 1.0 × 109/l. The ical manifestations.
frequency and severity of infection are inversely It is important to enquire and look for signs
proportional to the absolute neutrophil count, of infection at the following sites:
with the duration of neutropenia also contribut-
• Head and neck – look at the teeth, gums and
ing to overall risk. The timing of the neutrophil
pharynx. Ask about ENT problems, espe-
nadir depends on the type of chemotherapy and
cially involving the sinuses and ears.
generally, it occurs 5–10 days after the last dose.
• Gastrointestinal system – ask about mucosi-
Usually the neutrophil count recovers 5 days
tis, diarrhoea and constipation. The perineal/
after the nadir.
peri-anal area should be inspected and pal-
In the majority of cases, bacterial pathogens
pated gently; but do not perform a rectal
are responsible for febrile neutropenic episodes
examination.
with fungal (Figure 23.3), viral and protozoal
• Respiratory system – ask about cough, short-
infections occurring more commonly as second-
ness of breath and sputum production.
ary events. Currently, Gram-positive bacteria
• Genito-urinary system – ask about symptoms
account for 60–70% of microbiologically
suggestive of infection such as vaginal
detected infections, which may in part be due to
discharge, abdominal pain, urinary frequency
the prevalent use of quinolones as prophylactic
and dysuria.
antibiotics. Other possible causes of this change
• Central nervous system – ask about headache.
in trend include widespread use of intravenous
Examine for altered level of consciousness,
catheters, along with more profound and pro-
cranial nerve lesions and meningism.
longed neutropenia due to intensive and recur-
• Look at vascular access sites and establish
rent treatment regimes.
whether symptoms are related to flushing of
Clinical presentation and assessment the device.
Fever, rigors, hypotension or generalized malaise Antibiotic treatment should not be delayed
may be the only presenting features of infection whilst waiting for results; however, urgent inves-
in the neutropenic patient, and even they may tigations should include:
be masked by concurrent use of NSAIDs or
• FBC and differential, U+E, CRP, LFTs, Ca2+,
steroids. Clinical deterioration can be rapid
coagulation screen and group and save.
• Blood cultures should be taken both peripher-
ally and through any central venous line.
• Stool, urine and throat swabs should be sent
for microscopy, bacterial culture and sensitiv-
ity (viral culture also for throat swab).
• Skin, wound or genital swabs should be
collected when appropriate.
• Sputum sample if possible.
• Chest X-ray.

Management (Figure 23.4)

The mainstay of management is the prompt
administration of broad-spectrum antibiotics.
The Multinational Association for Supportive
Figure 23.3
Care in Cancer (MASCC) scoring system catego-
CT scan of the chest shows diffuse fungal infection in a rizes patients with febrile neutropenia into low
neutropenic patient. and high-risk groups (Box 23.4). Patients with
334
 ONCOLOGIC EMERGENCIES 23
Figure 23.4
Temp ≥ 38°C on 2 occasions at least Absolute neutrophil counts
Management of febrile
1 hr apart within a 12 hr period 0.5x109/l or ≤ 1.0x109/l with a
OR AND predictable decline to ≤ 0.5x109/L in neutropenia.
single temp ≥ 38.5°C 24-48 hrs

Low risk MASCC score > 21 High risk MASCC score ≤ 21

Oral antibiotics IV antibiotics Vancomycin not needed Vancomycin needed

Ciprofloxacin and (A) Monotherapy (B) Dual Therapy Vancomycin with

Co-Amoxidev Aminoglycoside (Gentamicin) A or B
and Anti-pseudomonal penicilin
(Tazocin)
Discharge after
24 hours on oral
antibiotics if
remains clinically Re-assess antibiotics after 2–5 days
well and offer close
outpatient follow-up

Afebrile and no Afebrile and aetiology Persistent fever

aetiology identified identified

High risk Adjust to Change Consider

most appropriate antibiotics antifungals with or
treatment without antibiotic
change
Discontinue IV antibiotics after
72 hours if the neutrophil count If remains well and afebrile,
is >0.5x109/L and rising discharge home

low-risk febrile neutropenia can be managed of broad-spectrum, anti-pseudomonal penicillin

with oral antibiotics and discharged after 24 (e.g. Tazocin) with an aminoglycoside (e.g. Gen-
hours observation, whereas those with high risk tamicin). The synergistic effect of combination
febrile neutropenia require intravenous antibiot- therapy can be beneficial and dual treatment
ics (Figure 23.4). reduces the risk of drug resistant strains emerg-
Although most patients with low-risk febrile ing. Alternatively, a carbopenem (e.g. mero-
neutropenia can be managed in the outpatient penem) can be used as monotherapy in
setting, close follow-up and unrestricted access uncomplicated episodes of neutropenic fever
to health care are essential for institution of such when it has been shown to be equally as effective
a policy. Certain social situations such as a previ- as dual therapy. Vancomycin may be added to
ous history of non-compliance, inability to care mono- or dual-therapy when the patient is felt to
for oneself, lack of caregivers and lack of unre- be at high risk of Gram-positive bacteraemia
stricted healthcare access are contraindications (Staphylococcus aureus bacteraemia in those
to outpatient therapy. with central venous access and severe sepsis
The most commonly used antibiotic regime for with or without hypotension). Gram-positive
high-risk febrile neutropenia is a combination coverage should also be considered in patients
335
 II SITE-SPECIFIC CANCER MANAGEMENT

Box 23.4: The MASCC risk-index score

are often used prophylactically on days 8–15 of
the chemotherapy cycle. Trials have consistently
Characteristic Score
shown that the use of prophylactic antibiotics
Extent of illnessa
in the afebrile neutropenic patient reduces the
• No symptoms 5
• Mild symptoms 5 number of febrile episodes; however, data
• Moderate symptoms 3 demonstrating beneficial effects on mortality are
No hypotension 5 more variable and less convincing. With the
No chronic obstructive airways disease 4
Solid tumour or no fungal infection 4
growing problems of antibiotic resistance and
No dehydration 3 antibiotic associated infection, the use of prophy-
Outpatient at onset of fever 3 lactic antibiotics in all aspects of medicine is
Age <60 yearsb 2
being questioned.
a
Choose 1 item only.
b
Does not apply to patients <16 yrs. Initial monocyte count >1.0 × Haematopoietic colony stimulating factors
109/l, no co-morbidity and normal chest radiograph findings
indicate children at low risk for significant bacterial infections. Haematopoietic colony stimulating factors
Low risk – a score of >21. (CSFs) such as granulocyte CSF (G-CSF) and
High risk – score of ≤21.
granulocyte-macrophage CSF (GM-CSF) are
glycoproteins that stimulate the proliferation
and differentiation of haematopoietic cells. A
pegylated formulation of G-CSF has the benefit
with suspected skin infection or severe mucosal of being given as a one-off dose rather than a
damage and when prophylactic antibiotics daily subcutaneous dose.
against Gram-negative bacteria have been used. CSF use is recommended in both the therapeu-
Along with reverse-barrier nursing, other sup- tic and the prophylactic setting for patients at
portive measures such as the administration of high risk of developing infection-associated com-
fluids and blood or blood products are often also plications or who have prognostic factors predic-
required. tive of a poor clinical outcome (Box 23.5).
The risk of febrile neutropenia and hospitali-
Monitoring zation due to febrile neutropenia is substantially
Intravenous antibiotics should be reviewed daily reduced by the prophylactic use of CSFs. CSFs
and modified depending on organism sensitivities may also have a beneficial effect on infection
and patient response. The median time to clinical related mortality, although effects on overall
response after the administration of antibiotics mortality remain to be established.
to febrile neutropenic patients is 5–7 days and
patients who fail to respond to first-line antibiot- Thrombocytopenia
ics should be discussed with a microbiologist
who may consider anti-fungal or anti-viral treat- Thrombocytopenia (a platelet count of <150 ×
ments. Antibiotic therapy may be discontinued 109/l) can occur due to treatment, bone marrow
when no infection is identified after 3 days of metastasis and in association with disseminated
treatment, if the neutrophil count is ≥0.5 × 109/l intravascular coagulation. The assessment of
for 2 consecutive days and if the patient has been patients with thrombocytopenia is to establish
afebrile for ≥48 h. Recovery of the neutrophil presence of bleeding, whether the bleeding is life
count is the single most important determinant threatening and contributory factors.
of successful antibiotic treatment. Patients without bleeding, and a platelet count
of >10 × 109/l (>20 × 109/l if with ongoing infec-
Prophylactic antibiotics tion) may be managed conservatively. Patients
For regimes that are associated with a high risk with a platelet count of <10 × 109/l (<20 × 109/l
of febrile neutropenia (stem cell transplantation, in those with infection) or those with bleeding
acute leukaemias and neutropenia for greater need random donor platelets. The aim of a
than 10 days), or for patients who have had a platelet transfusion is to maintain platelets above
previous febrile neutropenic episode, quinolones 10 × 109/l (20 × 109/l in those with infection) in
336
 ONCOLOGIC EMERGENCIES 23
the prophylactic setting, to stop bleeding in those to blood flow. Lung cancer is responsible for
with bleeding, and to maintain platelets above nearly three-quarters of cases of malignant SVCO
50 × 109/l in those with life-threatening bleeding. and SVCO occurs in 2–4% of patients with lung
Each five donor unit or one single donor apher- cancer. The remainder of cases is largely due to
esis pack increases the platelet count by approxi- lymphoma (12%) and metastatic malignancies
mately 10 × 109/l at 24-hours post-transfusion. (most commonly from a breast primary).
In the absence of such an increment, platelet
refractoriness should be suspected and managed Clinical presentation
appropriately. Malignant SVCO usually presents insidiously
Chemotherapy dose needs to be reduced for over a period of weeks. The most common symp-
future courses according to the regime and risk toms are cough and dyspnoea (>50%). Clinical
of bone marrow toxicity of individual drugs. examination shows facial puffiness (80%), dis-
tended veins (>60%), and arm oedema (46%).
Superior vena cava obstruction Symptoms are commonly progressive, although
Introduction there may be some clinical improvement with the
formation of a collateral circulation over time.
Superior vena cava obstruction (SVCO) can Symptoms tend to be worse first thing in the
occur as a result of either extrinsic compression morning and can be exacerbated by manoeuvres
of the superior vena cava or intrinsic obstruction that increase venous pressure, e.g. bending for-
wards, coughing, sneezing and straining.

Investigations
Box 23.5: Indications for G-CSF
A plain chest radiograph will often show a right
paratracheal mass or widened mediastinum. A
Prophylactic Germ cell tumour
1. Regimes associated VeIP CT scan will demonstrate SVC compromise
with >20% risk of FN
2. Regimes with 10–20%
and distinguishes between external compression
Breast cancer risk of FN and with and thrombus (Figure 23.5). In patients without
AC followed by factors that may increase a histologic diagnosis, a biopsy is required prior
decetaxel the risk of FN to ≥20%.
The risk factors are:
to deciding treatment.
Paclitaxel followed by AC
TAC • Age ≥65 years
• Advanced disease Management
Lung cancer
Cisplatin-etoposide • Prior FN The management of SVCO depends on the
ACE • No antibiotics underlying aetiology and severity of symptoms.
prophylaxis
ICE In patients with no prior diagnosis of cancer, a
• Multiple
Ovarian cancer co-morbidities histologic diagnosis is essential.
Paclitaxel • Bone marrow General measures include oxygen, dexametha-
Docetaxel involvement sone 16 mg daily, and diuretics. Endovascular
NHL Therapeutic use of G-CSF stent insertion (Figure 23.5) is the gold-standard
DHAP during an episode of treatment which relieves obstruction in 95% of
ESHAP febrile neutropenia cases, usually within 72 h (Box 23.6). Compli­
Patients with ongoing
CHOP-21 neutropenia who do cations of stent placement are in the region
Urothelial not respond to of 3–7% and include: transient chest pain,
Carboplatin/paclitaxel antibiotics infection, misplaced stent, stent migration and
BOP-VIP-B Those with life- pulmonary emboli. SVCO recurs in approxi-
threatening infections
mately 11% of patients (due to stent occlusion
• Shock
secondary to either thrombus or tumour in-
• Severe sepsis
growth). However, secondary patency rates are
• Multi-organ
dysfunction good and long-term patency is achieved in 92%
of patients.
337
 II SITE-SPECIFIC CANCER MANAGEMENT

Box 23.6: Indications for endovascular

stent insertion
• Severe and life-threatening SVCO requiring rapid
relief of symptoms
• Persistent SVCO after radiotherapy or
chemotherapy
• Patients with an underlying disease that is unlikely
to respond well to chemotherapy or radiotherapy
• Patients with symptomatic benign SVCO

A 80% of patients with non-Hodgkin’s lymphoma

or small-cell lung cancer and 40% of patients
with non-small cell lung cancer.
Prognosis
The median survival for patients with SVCO is
generally 6 months; however, this varies widely
depending on the aetiology. Prognosis appears to
be determined by the underlying malignancy
with overall survival being equal between patients
of the same tumour type and stage, with or
without SVCO.

Life-threatening haemoptysis
Approximately 10% of haemoptysis due to
cancers tends to be massive (>500 ml in 24
hours) and <5% of haemoptysis is life-threaten-
ing. The reported in-hospital mortality of bleed-
ing at a rate of >1 litre in 24 hours is 80%. It is
difficult to predict life-threatening haemoptysis
and most patients die suddenly at home.
The immediate management of patients with
B
life-threatening haemoptysis is to maintain a
Figure 23.5 secure airway, adequate ventilation and circula-
Superior vena caval obstruction. CT scan (A) shows tion. Attempts should be made to localize the site
significant compression of SVC (arrow) and SVC stent in of bleeding with bronchoscopy (which can be
situ (B). therapeutic) and/or imaging. Once bleeding is
localized the patient is positioned with the bleed-
ing lung in the dependent position.
Radiotherapy was traditionally used first line Specific measures to control bleeding include
for the treatment of SVCO prior to endovascular bronchoscopy with tamponade using a balloon
stenting. In radiosensitive tumours, radiotherapy catheter, laser photocoagulation or iced-saline
results in symptomatic response rates of up to lavage. Bronchial artery embolization is an
78% at 2 weeks. However, complete resolution option in specialist units.
of obstruction is seen in only 31% on serial veno-
grams with a partial resolution in 23%. Central airway obstruction
Radiotherapy is given to a dose of 20 Gy in
five fractions or 30 Gy in 10 fractions.
and stridor
Chemotherapy is useful in chemosensitive Malignant central airway obstruction produces
338 tumours. Chemotherapy alone relieves SVCO in progressive symptoms of dyspnoea, stridor and
 ONCOLOGIC EMERGENCIES 23
obstructive pneumonia. A central airway nar- cular weakness. If the concentration continues
rowing to <25% cross sectional area is usually to rise above 3.6 mol/l, neurological symptoms
needed to produce dyspnoea and stridor at rest. become more prevalent and patients may become
Airway obstruction can be produced by either confused, leading to coma and death.
extrinsic or intrinsic compression. Hypercalcaemia has few examination findings
Immediate measures are needed for sympto- specific to its diagnosis. However, a thorough
matic relief, which is monitored with pulse oxi- history and physical examination may help yield
metry. These include comfortable positioning, the underlying cause.
high-dose steroid (if known case of cancer, if not
withhold until definitive histologic diagnosis) Investigations
and supplemental oxygen or heliox (heliox is a
Along with serum corrected calcium, baseline
mixture of 80% helium with 20% oxygen; lower
laboratory investigations should include a full
density of helium helps in the easy flow through
blood count, urea, creatinine and electrolytes,
areas of turbulence and may decrease the work
liver function tests, serum phosphate, magnesium
of breathing). Muscle relaxants and respiratory
and PTH concentrations. ECG changes consist-
depressants should be avoided as are attempts
ent with hypercalcaemia include a shortened QT
to instrument airway without expert help and
and prolonged PR interval. At very high levels, a
positive pressure ventilation. CT scan of the
broad QRS complex may develop, T waves may
neck and chest may reveal the area and type of
flatten or invert and a variable degree of heart
obstruction.
block can occur.
Further management is shown in Figure
All further investigations are aimed at estab-
23.6. Stent results in prompt relief of symptoms;
lishing a cause and are likely to include imaging,
with cryotherapy 75% achieve symptomatic
particularly of the chest. In a patient without a
relief. Radiotherapy is given either as 20 Gy in
diagnosis of cancer, a myeloma screen should be
five fractions or 30 Gy in 10 fractions. Radio-
considered and in some patients a bone scan may
therapy response usually occurs within 72 hours
be helpful.
with 70–95% patients becoming symptom-free
by 2 weeks.
Management (Figure 23.7)
Saline rehydration is an important aspect of the
Malignancy associated management of hypercalcaemia. Hydration alone
hypercalcaemia may adequately treat mild hypercalcaemia.
Hypercalcaemic patients are universally de­
Introduction
hydrated as a result of calcium-induced nephro-
Hypercalcaemia (a corrected serum calcium genic diabetes insipidus and poor oral intake.
concentration >2.6 mmol/l) occurs in up to The speed of administration of normal saline
30% of cancer patients during their illness. The depends on the degree of dehydration and renal
mechanisms of hypercalcaemia include secretion impairment, the level of hypercalcaemia and
of parathyroid-related-protein (80%), osteolytic the patient’s underlying cardiac function. Fluid
hypercalcaemia (20%) and rarely due to increased balance must be carefully monitored. The aim of
secretion of 1,25-D3 and ectopic secretion of saline treatment is two-fold, firstly, to increase
PTH. the glomerular filtration rate (GFR) and thereby
increase the filtered load of calcium into the
Clinical presentation tubular lumen from the glomerulus. Secondly,
The symptoms of hypercalcaemia are typically calcium reabsorption is inhibited in the proximal
non-specific and their severity depends on the nephron because of the calciuretic effects of
rapidity with which the calcium level rises. When saline. Once dehydration has been adequately
the serum calcium concentration increases above treated, loop diuretics can be used to increase
2.6 mmol/l, symptoms include fatigue, malaise, calcium excretion. Any drug that may be contrib-
depression, anorexia, nausea, vomiting, bone uting to the hypercalcaemia e.g. thiazide diuret-
pain, polydipsia, polyuria, constipation and mus- ics, lithium and calcium supplements should be 339
 II SITE-SPECIFIC CANCER MANAGEMENT

Central airway
obstruction/stridor

Biopsy if indicated Urgent CT neck/chest

Severe respiratory No respiratory compromise

compromise/stridor (normal oximetry)
(impaired pulse oximetry)

Head and Tracheo-bronchial Head and Tracheo-bronchial

neck/thyroid cancer cancer neck/thyroid cancer cancer

Emergency Small cell cancer/ Non-small cell Appropriate Options:

tracheostomy chemosensitive lung/cancer anticancer treatment • Chemotherapy
tumour tracheal tumour • Radiotherapy
• Stent/cryotherapy/laser

Urgent Intraluminal External

chemotherapy mass compression
± radiotherapy

• Stent/diathermy/laser Options:
• RT if not stentable • Stent
• RT if not stentable

Figure 23.6
Management of central airway obstruction/stridor.

discontinued. Hypophosphataemia is common erally reached at 7–10 days, with the beginnings
and phosphate levels should hence be monitored of a biochemical response evident at 2–4 days.
and replaced as appropriate. Up to 90% of patients will achieve normocalcae-
Bisphosphonates have been shown to be mia after a single dose; however, a second dose
superior to saline alone in the treatment can be given after 7–10 days if the calcium
of malignancy-associated hypercalcaemia. remains elevated. Patients with renal impairment
Bisphosphonates inhibit osteoclastic bone may require a dose reduction and this differs
resorption by adsorbing to the surface of bone between products. Although the administration
hydroxyapatite. The bisphosphonates of choice of bisphosphonates should not be delayed, prior
for the treatment of malignancy-associated rehydration may reduce the risk of further renal
hypercalcaemia are intravenous zoledronate, impairment. Another common adverse effect of
ibandronate and pamidronate. Pamidronate (60– intravenous bisphosphonates is a transient flu-
90 mg IV in 500 ml normal saline over 2 h) or like syndrome with fever, myalgias and chills.
Zoledronate (4 mg IV in 50 ml normal saline For patients in whom bisphosphonates are unsuc-
over 15 min) are the most widely used bisphos- cessful, alternative treatments such as glucocor-
phonates for this indication in the UK. The nadir ticoids, calcitonin and gallium nitrate can be
response to intravenous bisphosphonates is gen- tried following specialist endocrine advice.
340
 ONCOLOGIC EMERGENCIES 23
Figure 23.7
Corrected serum calcium >2.6 mmol/l
Management of hypercalcaemia.

Ca2+ < 3 and asymptomatic Ca2+ > 3 and symptomatic

Hydration: 3-4 litres of saline Improve hydration to 4–6

over 24 hours litres daily

Single dose of intravenous

bisphosphonate

Repeat serum Ca2+ after

48 hours

Ca2+ > 3 Ca2+ normalized

• Maintain hydration (3–4 litres per day) Treat underlying cancer

• Monitor Ca2+ daily

A second dose of bisphosphonates Recurrence of hypercalcaemia

if Ca2+ > 3 after a week

• Regular oral/IV bisphosphonates

Persistent hypercalcaemia Ca2+ normalizes • 3 weekly Ca2+ estimation

Options:
• Hydrocortisone 200 mg daily for 5 days
• Calcitonin 5 IU/kg s/c or IM 12 hourly
• Gallium nitrate 100–200 mg/m2 continuous IV for 5 days
• Dialysis – especially in patients with renal failure/resistant causes

Prognosis dividing tumour cells. Typically, it occurs 12–

Malignancy related hypercalcaemia carries a very 72 h after the initiation of treatment with cyto-
poor prognosis with more than 50% of patients toxic chemotherapy, cytolytic antibody therapy
dying within 30 days of treatment. Overall, and/or radiation therapy.
median survival is less than 12 months. ATLS is most frequent in patients with non-
Hodgkin’s lymphoma (especially Burkitt’s lym-
phoma), acute lymphoblastic leukaemia (ALL)
Acute tumour lysis syndrome and acute myeloid leukaemia (AML). It has also
been rarely reported following the treatment of
Introduction ovarian, breast and small-cell lung cancer. Several
Acute tumour lysis syndrome (ATLS) is a group characteristics inherent to the tumour type pre-
of metabolic abnormalities that occur following dispose to TLS and these include high tumour
the destruction of large quantities of rapidly proliferation rate, large tumour burden, tumour
341
 II SITE-SPECIFIC CANCER MANAGEMENT

chemosensitivity and increased lactate dehydro-

genase (LDH) levels. Pre-existing uraemia or Table 23.1: Biochemical and clinical features
of tumour lysis syndrome
hyperuricaemia, decreased urinary flow, low
Biochemical abnormality Clinical consequence
urinary pH, dehydration, oliguria and renal
impairment have also been identified as risk Hyperuricaemia Renal impairment
(serum uric acid
factors for TLS.
>0.5 mmol/L)
Clinical features Hyperphosphataemia Nausea, vomiting,
(serum phosphate diarrhoea, lethargy,
ATLS is characterized by hyperuricaemia, hyper-
>1.4 mmol/l) seizures
phosphataemia, hypocalcaemia and hyperkal­
aemia. These biochemical abnormalities lead to Hypocalcaemia Cardiac arrhythmias,
(serum Ca2+ <2.12 mmol/l) hypotension, tetany,
a range of non-specific symptoms (Table 23.1). muscular cramps
When the electrolytes are severely deranged,
Hyperkalaemia Cardiac arrhythmias
patients are at risk of seizures, cardiac arrhyth- (serum K+ >6.5 mmol/l) (VT/VF), muscle
mias and sudden death. cramps, paraesthesia

Management
Management is essentially aimed at the prevention
of ATLS. It is important to identify patients at risk
of developing ATLS and to treat them prophylacti- allopurinol in reducing uric acid levels, but
cally with intravenous fluids and allopurinol. significantly more expensive.
Normal saline re-hydration should aim to Specific management of established ATLS
produce a urine output of approximately includes the close monitoring of uric acid, phos-
100 ml/h and diuretics may be required once phate, potassium, creatinine, calcium and LDH
euvolaemia has been achieved. Improving intra- levels. Fluid balance should be measured and
vascular volume, renal blood flow and glomeru- electrolyte abnormalities should be corrected
lar filtration rate promotes the excretion of uric (Table 23.2). Haemodialysis and intensive care
acid and phosphate. Alkalinization of the urine facilities should be available if required.
through the use of sodium bicarbonate is some-
times required. Hypersensitivity reactions
Allopurinol is a xanthine oxidase analogue,
which prevents the conversion of xanthine and Introduction
hypoxanthine to uric acid. It has proven efficacy Nearly all systemic agents used to treat cancer
in the prevention and treatment of hyperuricae- have the potential to cause hypersensitivity reac-
mia in patients with or at risk of ATLS. Allopu- tions; however, severe reactions are rare. Pro-
rinol prevents the formation of uric acid and vided patients receive appropriate pre-medication,
should be commenced prior to starting treatment close monitoring and prompt intervention when
with intensive chemotherapy. It has been associ- required, severe hypersensitivity reactions occur
ated with hypersensitivity reactions and reduces in less than 5% of patients. Platinum compounds,
the clearance of other purine-based chemothera- taxanes and monoclonal antibodies are most
peutic agents such as 6-mercaptopurine and likely to cause a reaction, although the timing of
azathioprine. such reactions may differ, as do their likely
Rasburicase is a recombinant urate oxidase underlying aetiology (Table 23.3).
that promotes the catabolism of uric acid to Platinum compounds such as cisplatin, carbo-
allantoin. Unlike allopurinol, there is no risk of platin and oxaliplatin classically cause reactions
xanthine nephropathy or calculi. It is licensed for following multiple cycles of treatment, typically
the treatment and prophylaxis of acute hyper­ after 6–8 doses. This is consistent with a type 1
uricaemia in patients who have high tumour hypersensitivity reaction following repeated
burden haematological malignancies and are at exposure to the drug and leads to IgE-mediated
high risk of ATLS. It is more effective than release of histamine, leukotrienes and prostag-
342
 ONCOLOGIC EMERGENCIES 23

Table 23.2: Management of electrolyte Table 23.3: Showing the incidence of any
abnormalities grade hypersensitivity in a range of
chemotherapy agents
Electrolyte
abnormality Management Drug Incidence
Hyperphosphataemia Avoidance of additional Carboplatin or oxaliplatin 12–19%
phosphate
Paclitaxel 8–45%
Administration of a
phosphate binder e.g. Docetaxel 5–20%
calcium carbonate
Trastuzumab 40%
Haemodialysis/
haemofiltration Rituximab Up to
77%
Hypocalcaemia Calcium gluconate (10 ml
10% IV administered Cetuximab 16–19%
slowly with ECG
monitoring)
Hyperkalaemia Avoidance of additional
potassium
Cardiac monitoring less likely with each subsequent infusion. Delayed
Calcium resonium (15 g po reactions are still seen in 10–30% however, the
tds) underlying aetiology of these reactions is largely
Calcium gluconate
unknown.
(as above) for
cardio-protection
Insulin–dextrose (10–15
Clinical features
units insulin with 50 ml The National Cancer Institute Common Toxicity
50% dextrose) Criteria (NCI-CTC) distinguish between hy­
Haemodialysis/
persensitivity and acute infusion reactions
haemofiltration
(Table 23.4).
Clinical features of hypersensitivity include
pruritis, rash, urticaria, rigors/chills/fevers, head-
ache, arthralgia/myalgia, tumour pain, fatigue,
landins from mast cells in the tissues and dizziness, sweating, nausea/vomiting, cough, dys-
basophils in the peripheral blood. This causes pnoea, bronchospasm, hypotension/hypertension
smooth muscle contraction and peripheral vaso­ and tachycardia.
dilatation, leading to urticaria, rash, angioedema,
bronchospasm and hypotension. Management
Although a similar clinical picture can be pro- Prophylaxis with antihistamines and corticoster-
duced following administration of a taxane, 95% oids is recommended for infusions that carry a
of these reactions occur during the first or second high risk of hypersensitivity reactions and for any
exposure to the drug and 80% occur within the patient that shows early signs of a hypersensitiv-
first 10 minutes of the infusion. In this scenario, ity reaction. Pre-medication for paclitaxel would
IgE-mediated type-1 hypersensitivity is unlikely, likely include 20 mg dexamethasone (preferably
and it is postulated that direct effects on mast given several hours before the infusion), chlor­
cells and basophils lead to release of immu- pheniramine 10 mg and cimetidine 300 mg.
nomodulators and an anaphylactoid reaction. Patients should be closely monitored throughout
The solvent used in paclitaxel, but not docetaxel all infusions.
(Cremophor EL) has been shown to cause hista- Treatment of anaphylaxis is outlined in
mine release and hypotension and is felt to be Figure 23.8.
partly responsible for the hypersensitivity reac- Re-challenging patients following a hypersen-
tions seen with paclitaxel. sitivity reaction depends on the aim of treatment
Monoclonal antibody infusions can also and the severity of the reaction. The majority of
produce hypersensitivity reactions, which become patients who have a mild–moderate reaction
343
 II SITE-SPECIFIC CANCER MANAGEMENT

Table 23.4: Grading of hypersensitivity reactions according to the NCI-CTC for adverse events
Grade
1 2 3 4 5
Hypersensitivity Transient Rash, flushing, Symptomatic Anaphylaxis Death
(allergic reaction) flushing or urticaria, dyspnoea, bronchospasm, with
rash, fever fever ≥38°C or without urticaria,
<38°C parenteral medication
indicated, allergy-
related oedema/
angioedema,
hypotension
Acute infusion Mild reaction, Requires therapy or Prolonged recurrence Life-threatening, Death
reaction infusion infusion interruption of symptoms following pressor or
(cytokine interruption but responds promptly initial improvement, ventilatory
mediated) not indicated, to symptomatic hospitalization support
intervention treatment, prophylactic indicated for other indicated
not indicated medication indicated clinical sequelae (e.g.
for ≥24 h renal impairment,
pulmonary infiltrates)

Secure airway and administer high flow oxygen usually less successful with approximately 50%
of patients experiencing recurrent hypersensitiv-
ity reactions.
Stop the infusion and cautiously recline the patient

Extravasation
Give 0.5 mg (0.5 ml of 1:1000) adrenalin IM
Repeat after 5 min if there is no clinical improvement Introduction
or there is further deterioration
An extravasation injury is any tissue damage that
occurs as a result of leakage of cytotoxic drugs
Give 10 mg Chlorpheniramine and 200 mg Hydrocortisone IV into the surrounding tissue.
• An irritant is a chemotherapeutic agent
Rapid infusion of IV fluids if required capable of producing venous pain at the ven-
Nebulized salbutamol if evidence of bronchoconstriction opuncture site or along a vein, with or without
an inflammatory reaction.
Figure 23.8
Management of anaphylaxis.
• A vesicant is an agent capable of blister for-
mation and/or tissue destruction.
Vesicant drugs are more likely to lead to
extravasation because of their potential for
during their first drug exposure (often seen with endothelial damage (Table 23.5). The risk of
taxanes and monoclonal antibodies) are likely to vesicant extravasation is very low, in the range
tolerate re-challenge of the drug if pre-medica- of 0.01–6% and although the use of implanted
tion is used with a slower rate of infusion. Desen- ports reduces the risk of extravasation, it can still
sitization protocols have been used with some occur.
success in patients who have a reaction to taxanes, Tissue damage occurs due to three main
however, re-challenge of platinum compounds is factors:
344
 ONCOLOGIC EMERGENCIES 23
• Erythema, blotching, blistering, swelling and
Table 23.5: Vesicant vs non-vesicant drugs tenderness.
Non-vesicant/irritant/ • Early firm induration is often an indication of
Vesicant drugs exfoliant drugs
eventual ulceration.
Busulfan Bevacizumab • The skin may become white and cold, later
Carmustine Bleomycin developing into a black eschar.
Dactinomycin Carboplatin • Ulceration does not usually occur until at
(Actinomycin D) least 48 h, but may be delayed until one or
Daunorubicin Cisplatin
more weeks after the injury.
Doxorubicin Cyclophosphamide Management
Epirubicin Cytarabine Prevention is the key. The technique of cannula-
Mitomycin C Cetuximab tion and administration of the drug is important.
Treosulfan Docetaxel
Cannulas should ideally be inserted in the back of
the hand where they are readily accessible and
Vinblastine Etoposide
extravasation can be easily detected. Use of a
Vincristine Fludarabine central venous access device is preferable; however,
Vinorelbine Fluorouracil vesicant administration should only proceed
Gemcitabine
when there is blood return through the device.
Management of extravasation includes stop-
Ifosfamide
ping the infusion and aspirating from the intra-
Irinotecan vascular device. Extravasation of anthracyclines
Liposomal doxorubicin is initially managed with cooling of the area,
Methotrexate
however, heat application is generally used fol-
lowing the extravasation of plant alkaloids. Early
Oxaliplatin
review by the plastic surgeons for consideration
Paclitaxel of surgical debridement is vital when tissue
Rituximab necrosis is possible.
Topotecan
Hyaluronidase increases the permeability of
connective tissue and can be injected into the
Trastuzumab
extravasation sites of plant alkaloids. Used in
combination with a saline flush out of the area,
it aids the dispersion of the vesicant drug.
Dexrazoxane is a derivative of EDTA that
chelates iron. It has shown benefit in the treat-
1. Direct cellular toxicity of the antineoplastic ment of extravasation from intravenous anthra-
drug causing cellular necrosis. cycline therapy; although the exact mechanism
2. Differences in osmotic pressures between the of action is unknown. It is a systemic treatment
infused solution and the tissue environment. that is infused over 1–2 h each day for three days
3. Cellular damage due to the alkalinity or into a large vein, away from the extravasation
acidity of the solution. site. Side effects include nausea and vomiting,
diarrhoea, stomatitis, bone marrow suppression,
Clinical features elevated liver enzymes and infusion site burning.
Symptoms and signs of extravasation include:
Bone fractures or impending
• Pain, discomfort and burning sensations at or
around the cannula site.
fractures
• Reduced flow rate of the infusion. Bone metastasis is the third most common site of
• Lack of blood return through the cannula. metastatic disease. Bone metastasis can be lytic,
345
 II SITE-SPECIFIC CANCER MANAGEMENT

Table 23.6: Mirel scoring for impending

fracture
Score
Variable 1 2 3
Site Upper Lower limb Peritrochanteric
limb
Pain Mild Moderate Functional
Lesion Blastic Mixed Lytic
Size* <1/3 1/3–2/3 >2/3

*Indicates maximal cortical destruction as seen on plain X-ray

in any view.
Score and fracture rate:
0–6: 0%
7: 5%
8: 33%
9: 57%
10–12: 100%

for prophylactic surgical fixation. However, sur-

gical fixation of a pathological fracture in a
weight-bearing bone may be considered even
with a lesser life expectancy to improve pain. In
Figure 23.9 solitary bone metastases, a radical excision may
A lytic lesion in the femur with high risk features of
impending fracture.
be feasible especially in renal cell carcinoma.
Surgical repair of non-axial pathological frac-
tures can be achieved by a variety of different
methods.
sclerotic and mixed. Risk of pathological fracture
is highest in lytic lesions. 50% of pathological
fractures are due to metastatic breast cancer and
Other emergencies
the commonest site is femur. A lesion involving Chemotherapy induced haemorrhagic
50% of the cortex, 2.5 cm in diameter, or which cystitis
remains painful after weight-bearing after radio-
High-dose cyclophosphamide as a marrow abla-
therapy is at risk of a pathological fracture
tive regime as well as ifosfamide can produce
(Figure 23.9).
significant haemorrhagic cystitis. It is produced
The common presentation is bone pain at the
by a metabolite of these agents, acrolein, by an
site of bone destruction. 10–15% patients present
unknown mechanism. Sodium 2-mercaptoethane
with hypercalcaemia. Pathological fracture of
sulfonate (mesna) is used as a uroprotective agent
long bones presents with pain and loss of func-
along with these agents. Mesna needs to be
tion whereas that of vertebrae presents with pain
started prior to the chemotherapy and continued
and neurological deficits.
after the last dose of chemotherapy.
Plain X-ray will reveal bone metastases in long
bones, and it is helpful in deciding Mirel’s scoring • In patients with frank haematuria, urology
(Table 23.6). consultation should be sought as there is a
Surgery is the main treatment for patients with risk of clot retention. A 3-way continuous
fracture or impending fracture of long bones. All irrigation may be needed to maintain urine
patients with a Mirel score of ≥8 and expected flow. If urine flow cannot be established,
survival of at least 3 months should be referred cystoscopy with clot wash out is indicated.
346
 ONCOLOGIC EMERGENCIES 23
• Patients with 1+ blood on urine dipstix can Malignant obstructions and bleeding
be managed without any intervention. The management of malignant obstructions and
• Patients with 2+ or 3+ blood on urine dipstix. bleeding is dealt in individual chapters.
Ensure that it is current urine void (within last
hour) as there will be some haematuria during Further reading
chemotherapy. If there is uncertainty about Scott-Brown M, Spence R, Johnston P. Emergencies in
dipstix results, repeat the test on a fresh urine Oncology, Oxford University press, 2007.
sample. If the abnormal treatment is early Samphao S, Eremin JM, Eremin O. Oncological emergencies:
during mesna treatment, continue monitoring clinical importance and principles of management. Eur J
Cancer Care. 2009 Dec 17. [Epub]PMID: 20030695.
and give the remaining mesna. If there is per- Walji N, Chan AK, Peake DR. Common acute oncological
sistent 2+ reading at the end of mesna treat- emergencies: diagnosis, investigation and management.
ment, additional mesna is needed and patient Postgrad Med J. 2008;84:418–427.
should be discharged only after the dipstix is Marti FM, Cullen MH, Roila F; ESMO Guidelines Working
1+ or less. At discharge patients are given oral Group. Management of febrile neutropenia: ESMO
clinical recommendations. Ann Oncol. 2009;20 Suppl
mesna 1200 mg/m2 every 4 hours for three 4:166–169.
doses and asked to take along with 2 litres Innes H, Marshall E. Outpatient therapy for febrile
water over 12 hours. neutropenia. Curr Opin Oncol. 2007;19:294–298.

347
 Management of
common radiotherapy
side effects
TV Ajithkumar
24
General side effects Radiation reaction heals in 3–4 weeks fol-
lowed by tanning of the skin which takes a few
Skin more days to subside. Patients are asked to
Radiation dermatitis generally starts 10–14 days protect irradiated skin with sun block when sun
after the first fraction of radiotherapy and peaks exposure is unavoidable.
at the end or within one week of completion of Late skin reactions include atrophy and fibro-
radical treatment. It progresses from skin ery- sis of skin and telangiectasia. Radiation recall is
thema, to dry desquamation (dry, itchy, flaky), the phenomenon of skin reaction occurring in the
moist desquamation (raw painful area which previous radiation field when exposed to certain
may drain serous exudates) and finally necrosis chemotherapy (e.g. anthracyclines and gemcitab-
(rare). Skin reaction is intense when skin dose is ine). This is usually more severe than previous
high (e.g. electrons, bolus over the field), over radiation reaction and subsides in 2 weeks.
areas with skin folds (e.g. inframammary fold,
groin, perineum etc.), when radiotherapy is given Fatigue
concurrently with chemotherapy (particularly Fatigue (a subjective feeling of tiredness) is a
with anthracyclines, methotrexate, and 5-fluor- common side effect of radiotherapy and the exact
ouracil) and over areas of surgical wounds. cause is not known. Fatigue may increase pro-
Measures to minimize skin reaction include gressively during the radiotherapy and may take
avoiding mechanical, chemical and thermal irri- weeks or months to subside after radiotherapy
tations such as pat drying rather than rubbing, treatment. Measures to improve fatigue include
using simple soap, avoiding perfumes, powders, frequent periods of rest, regular minimal aerobic
deodorants over the irradiated area, shaving with exercise, and stress management. A study showed
razor blade, heat, cold and sun and using loose that 20–30 minutes of brisk walking 4–5 times
fitting and cotton clothes. 1% hydrocortisone per week improved fatigue level, symptom inten-
cream is useful for itchy areas. sity and physical functioning.
During dry desquamation, hydrophilic mois-
turizing ointment with no heavy metals (e.g. Anorexia
aqueous cream) can be applied to the skin after Some patients experience anorexia and the exact
radiation treatment every day. For moist desqua- cause is not known. A number of factors such as
mation, dress the moist area with hydrogel, the primary cancer itself and its systemic treat-
hydrocolloid or alignate dressing and continue ment as well as concurrent medications can influ-
applying aqueous cream to other areas. When ence the degree of anorexia. Measures to improve
radiotherapy is stopped, zinc oxide or silver sul- anorexia include frequent small meals, high
fadiazine (flamazine) may be applied to the skin energy high protein diet, and sometimes appetite
with non-adhesive dressing. Superadded infec- stimulants like megestrol acetate (400–800 mg
tion may need antibiotics depending on culture daily) or steroids. Anorexia can cause clinically
and sensitivity. significant weight loss (loss of ≥10% prediagnosis
348 © 2011, Elsevier Ltd
DOI: 10.1016/B978-0-7234-3458-0.00029-4
 MANAGEMENT OF COMMON RADIOTHERAPY SIDE EFFECTS 24
weight loss) in which case enteral feeding is • Mouth wash – sterile water, 0.9% saline
advised, particularly to those receiving radical or sodium bicarbonate solutions. Normal
radiotherapy. saline can be prepared by adding one tea-
spoon of salt to 1 litre of water and 1–2
Bone marrow suppression tablespoons of sodium bicarbonate can be
Irradiation of a large area of marrow bearing added if the saliva is viscous.
bones can result in bone marrow suppression. • Benzydamine (Difflam) is recommended
The degree of bone marrow suppression is high for prevention of oral mucositis whereas
if concurrent myelosuppressive chemotherapy is chlorhexidine, sucralfate and antimicro-
used. All patients at risk of bone marrow sup- bial lozenges are not.
pression need weekly blood counts and appropri- • Pain – controlled by topical anaesthetics and
ate action. analgesics and systemic analgesics.
• Diet – soft bland diet and in severe mucositis,
enteral feeding.
Site-specific side effects
Xerostomia
Brain
During radiotherapy, dry mouth starts within
Cerebral oedema 1–2 weeks of radiotherapy which involves the
Radiotherapy can cause cerebral oedema which region of salivary glands. Later saliva becomes
manifests as headache, vomiting, seizures, neuro- thick and sticky which causes problems of retch-
logical deficit and altered mental function. Ster- ing, coughing, nausea and vomiting, difficulty in
oids are the treatment of choice. talking and disturbed sleep. Dry mouth can
become chronic. Measures include:
Alopecia
• Mouth care – frequent cleansing.
Alopecia depends on the dose and extent of radi- • Improve moisture – frequent sips of fluids and
ation. Alopecia starts when the radiation dose is saliva substitutes.
above 25–30 Gy and is permanent when the dose • Stimulate saliva – sucking candies, pharmaco-
is >40 Gy. If regrowth occurs it usually starts 2–3 logical measures (e.g. oral pilocarpine 5 mg
months after completion of radiotherapy. 3–4 times daily).
• In suitable patients, intensity modulated radi-
Head and neck cancer otherapy (IMRT) delivery (p. 85) can avoid
Mucositis irradiation of at least one salivary gland and
The initial reaction is tenderness in the mouth thereby reduce the degree of xerostomia.
with associated erythema and oedema of the Taste change
mucosa. Subsequently a whitish membrane is
formed, which progresses to a painful ulcer with Radiation can change taste sensation, which may
continuation of radiotherapy. Bleeding and persist for years. It usually starts after doses
superadded infection can occur. Concurrent >20 Gy and around 90% patients receiving
chemotherapy and metallic fillings in teeth (by radical radiotherapy are affected. Measures
electron back scatter) can enhance mucosal skin include mouth care before and after meals and
reaction. Dental assessment prior to radiother- modification of food and preparation. An
apy is important (p. 79). Measures to prevent unpleasant taste of meat is one of the common
and manage mucositis include: problems, which can be masked by trying addi-
tional seasoning, marinating meat in wine or
• Radiotherapy planning – use of midline radia- sweet and sour sauce before and during cooking
tion blocks wherever appropriate and 3D and serving food cold or at room temperature.
planning reduce mucosal injury.
• Mouth care – frequent cleansing, tooth Hypopituitarism and hypothyroidism
sponges and swabbing rather than use of a Patients who received radiotherapy to the pitui-
toothbrush. tary and thyroid regions are at risk of hormonal
349
 II SITE-SPECIFIC CANCER MANAGEMENT

insufficiency. Patients need hormone replacement needed. Dietary modifications with low fat, low
treatment. sugar diet and high fluid intake are also useful.
Thoracic region Diarrhoea
Diarrhoea can occur 2–3 weeks after starting
Cough
treatment. The pattern of diarrhoea may be
Cough is initially productive which becomes dry either increased frequency of stool or watery
as treatment progresses. Treatment is sympto- stools with abdominal cramps. Sulfasalazine
matic with adequate fluid intake, humidification 500 mg twice orally is suggested to reduce the
of air, cessation of smoking, cough suppressants incidence and severity of radiation-induced enter-
and antibiotics if there is superadded infection. opathy in patients receiving pelvic radiotherapy.
Pneumonitis A low-residue, low fat (<40 g) diet and avoid-
ance of milk products can be useful in reducing
Acute pneumonitis usually occurs 1–3 months
diarrhoea. Antidiarrhoeal medications such as
after radiotherapy and rarely earlier (‘hyper­
codeine and loperamide are useful when dietary
acute’). It manifests initially with dry cough and
modifications are ineffective.
later with productive cough, fever and dyspnoea.
Treatment includes bed rest, steroids (pred- Proctitis
nisolone 1 mg/kg for 4–6 weeks) and antibiotics Patients with tenesmus benefit from antispas-
if superadded infection. modics and anticholinergics. Pain can be control-
led by frequent sitz baths and local creams
Oesophagitis such as haemorrhoidal preparations. Patients
Oesophagitis develops 2–3 weeks after starting with chronic proctitis are treated with sucralfate
radiotherapy and the severity is high with con- enema.
current chemotherapy, long length of oesopha-
gus in the radiation field and increased dose per Cystitis
fraction. Patients develop progressive painful Cystitis manifests with dysuria, nocturia, urgency,
swallowing. Measures to improve dysphagia hesitancy and frequency. Patients are encouraged
include liquid high calorie, high protein diet, to have an adequate fluid intake. Bladder infec-
local anaesthetics, liquid analgesics and systemic tion should be treated. Bladder analgesics (e.g.
analgesics. Patients may develop superadded can- phenazopyridine) and antispasmodics are useful
didiasis and need antifungal treatment. in pain. Patients receiving prostatic radiotherapy
can develop bladder outflow irritation which
Radiation fibrosis manifests with hesitancy, decreased force of flow
Radiation fibrosis develops 6–12 months after and frequency. In these situations, alpha blockers
completion of radiotherapy and can manifest such as terazocin (Hydrin) and tamsulosin
with dyspnoea. Treatment is essentially symp­ (Flomax) result in better symptom control than
tomatic. NSAIDs.
Vaginal stenosis and dryness
Abdomen and pelvis
Vaginal stenosis and dryness are late effects.
Vomiting Treatment is symptomatic with lubricants and
Vomiting is common with radiation involving vaginal dilatators.
the upper abdomen. Vomiting can occur within
Erectile dysfunction
6 hours of radiotherapy and may last for 3–6
Erectile dysfunction results from damage of
hours. Patients receiving treatment to the upper
pelvic nerves and fibrosis of pelvic vasculature.
abdomen, large single fractions and total body
Pharmacological interventions, devices and pros-
or lower hemibody irradiation are advised to
thesis are useful.
have prophylactic anti-emetics with a serotonin
receptor antagonist (e.g. ondansetron 8 mg, 30 Gonadal failure
minutes prior to radiotherapy). In severe vomit- Ovarian failure can induce symptoms of meno-
ing continual administration of antiemetics is pause and permanent sterility (>8 Gy fractionated
350
 MANAGEMENT OF COMMON RADIOTHERAPY SIDE EFFECTS 24
dose). HRT is useful if not contraindicated. In appropriate the testes should be shielded from
young people needing pelvic radiotherapy, laparo- radiation.
scopic oophoropexy (surgically placing ovaries
outside radiation field), may be protective. Further reading
Testicular irradiation (>12 Gy of fractionated Faithfull S, Wells M (ed). Supportive Care in Radiotherapy.
RT) causes permanent sterility and hence if Edinburgh: Churchill Livingstone, 2004.

351
Clinical trials in cancer
TV Ajithkumar and HM Hatcher
25
Introduction Preclinical stage
Research and development is an important aspect The preclinical stage involves screening of poten-
of cancer management. Cancer drugs have to tial agents and their testing on animal models.
undergo rigorous evaluation before approval for Initial testing may be performed on cell lines or
clinical use. However, technological develop- tumour explants before moving to an animal
ments, such as a new surgical or radiotherapy model. Preclinical studies establish that the
technique, often do not undergo such complex potential agent is not lethal, safe to use and that
procedures. They are approved if they are proven there is some indication of activity in the medical
not to be harmful and they meet the appropriate condition studied.
quality control measures. In fact, many of the
new radiotherapy techniques are approved for
clinical use without any robust comparative data Clinical trials
on the clinical efficacy.
Traditionally the clinical efficacy of drugs is Phase I
studied through several phases of clinical trial Phase I studies are the first human application of
after initial pre clinical studies. Each of these a new drug or drug combination. The aim of this
trials is aimed at generating sufficient evidence phase is to establish the dose and schedule of the
on the safety, dosing, efficacy and feasibility of experimental agent for efficacy testing in a phase
use. This process is expensive and time consum- II study based on the maximum tolerated dose
ing (Figure 25.1), which often leads to very (MTD) of the new agent. Phase I studies are typi-
high costs of effective treatments preventing cally single arm, open label, sequential studies
their general use and often prompting policy that include patients with good performance
makers to adopt rationing strategies based on status (PS 0-2) and for whom there is no standard
cost-effectiveness. treatment option. The MTD is determined by
New methods of trial design are constantly progressively increasing the dose in small cohorts
evolving, both to address the length of time to until the dose limiting toxicity (DLT) is achieved.
take a drug from development into practice and DLT is defined as grade 4 non-haematological
to answer questions which apply to newer drugs. toxicity or a grade 3 or more haematological
For example targeted treatments may incorpo- toxicity graded according to the National Cancer
rate an assessment of the efficiency in affecting Institute Common Terminology Criteria for
that target or in measuring the sub-population Adverse Events (CTCAE) (p. 38). MTD dose is
who may benefit most from an effective but defined as the dose below the level the DLT is
expensive treatment. met or the dose level at which the DLT is seen.

© 2011, Elsevier Ltd 355

DOI: 10.1016/B978-0-7234-3458-0.00030-0
 III RESEARCH IN ONCOLOGY

Figure 25.1
Concept and discovery Drug approval, Process of drug discovery.
Pre-clinical studies Clinical trials
launch and sale
Synthesis Registration
Research of active Screening Preclinical Preclinical Phase I Phase II Phase III with drug Production
target substance trials I trials II studies studies studies authority and sale
PRE-DISCOVERY

TOTAL COST = $1 BILLION TO 1.4 BILLION

1–2 year 2–4 years 6–7 years 2–4 year

20–30 18 10 4–7 2–3 1

8,000–10,000 substances 1 substance
substances substances substances substances substances substance

There are a number of components to the design Box 25.1: Components of phase I study design
of a phase I study and there are various dose and methods of dose escalation
escalation methods to find out the maximum tol- Design components of a phase I study
erated dose (Box 25.1). Phase I trial design is a • Starting dose – usually 110 of the animal dose
specialized topic and is beyond the scope of this • Dose increment
chapter (see Further reading). • Dose escalation method
• Number of patients per dose level
• Specification of dose-limiting-toxicity (DLT)
Phase II • Target toxicity level
Phase II studies are done to assess the activity, • Definition of maximum tolerated dose (MTD)
safety and feasibility of new drug. There are • Recommended dose and patient selection for
many options for the design of a phase II trial. phase II trial
A phase II study can either be completed in a Dose escalation methods
single stage or as two stages. In two stage study, • Rule-based design – based on no prior assumption
of the dose-toxicity curve and allows dose
the first stage is to evaluate the treatment efficacy escalation and de-escalation of dose with
(phase IIA) and in the second stage (phase IIB) is diminishing fractions of preceding dose depending
to identify promising agents to send to phase III on the absence or presence of severe toxicity in
the previous cohort of patients treated.
for additional evaluation. Phase IIA design is to
• 3 + 3 design – most frequently used method.
test short-term tumour response, whereas phase The classical assumption is toxicity increases
IIB design compares two or more regimes which with dose. It starts with a cohort of three
have demonstrated some initial efficacy. patients and subsequent cohorts are treated at
increasing level.
Randomized phase II trials are increasingly
• Accelerated titration design
being used in cancer. These studies randomize
• Pharmacologically guided dose escalation
patients to new treatment or standard treatment
• Model based designs – are complex and use
or to a number of new treatments. Randomi­ statistical models that actively seek a dose level
zation is to ensure a similar patient population that produces a pre-specified probability of dose
in each group and not to do a statistical test to toxicity using dose-toxicity curve calculated from
all enrolled patients. Examples include:
compare treatment groups. These trials are not
• Continual reassessment method
adequately powered to do this and this is the
• Escalation with overdose control
purpose of a phase III trial. Treatment outcomes
• Designs that use time-to-event endpoints
are ranked according to activity, safety and fea-
• Designs that use toxicity and efficacy as
sibility to take the drug forward to phase III endpoints
study.
356
 CLINICAL TRIALS IN CANCER 25

Phase III context than in clinical trial. The various study

The aim of a phase III study (also called rand- designs are given in Box 25.3.
omized controlled trials) is to establish the
efficacy of a new treatment compared with Ethics and good clinical practice
an existing standard treatment or observation/ In order to protect patient safety and to ensure
placebo where there is no standard treatment. It the reliability of any trial data all trials should be
also helps to establish whether the new treatment conducted according to good clinical practice
has less toxicity compared with the standard (GCP) which has been developed according
treatment. Randomization reduces bias by bal- to international guidelines. Part of this process
ancing the characteristics of study population. means that the trials must be peer reviewed and
Design of a phase III study is complex (Box reviewed by an ethics committee to ensure that
25.2). It requires large patient numbers to ensure the trial seems appropriate, safe and adheres to
adequate statistical power which frequently these international guidelines (International Con-
necessitates international cooperation and is very ference on Harmonization ICH). These have now
costly. Modern trials are incorporating transla- been incorporated into the 2004 Medicines for
tional studies to try to target the new drug to the Human Use (Clinical Trials) Regulations and the
population most likely to benefit. This may affect recent EU Directive on Good Clinical Practice,
the inclusion criteria e.g. presence of an EGFR which apply to all trials within Europe. Similar
mutation for entry into a trial for an antibody practices have also been adopted in North
against the EGFR receptor. America.
Phase IV studies
Recruiting patients into
Phase IV studies are post-marketing studies done
to learn more about the side effects, safety, and a clinical trial
long term risk-benefits of the drug in a wider A number of issues need to be considered when
recruiting patients into clinical trial ranging from
explaining the trial itself to giving a realistic
picture of the potential risks and benefits. Consent
Box 25.2: Phase III study is a complex process which does not simply refer
• Identify a select group of patients and define to the signing of a form but with good clinical
eligibility criteria. practice has to ensure that the patient has ade-
• Identify meaningful and reliable outcome quately understood what is involved and has
measures (endpoints).
• Randomization process and stratification of study
group.
• Statistical considerations – sample size based on Box 25.3: Phase IV study designs
expected benefit, method of data analysis etc. • Post-phase III ‘continuation’ trial – is done to
• Phase III study designs: identify the long-term efficacy, common dose-
• Parallel-group design – patients are randomized related adverse effects (AEs) and reasons for
to two or more treatment group. discontinuation.
• Cross-over design – patients will receive both • Phase V ‘naturalistic’ trial – done to analyse
the new and control treatment. effectiveness and common dose-related AEs and
also can assess patient reported outcomes.
• Factorial design – includes double
randomization so that the same study group is • Prospective cohort design – to assess long-term
used to answer two research questions. effectiveness in routine practice (>2 years)
• Adaptive design – starts with a number of new • Retrospective cohort – rapid study of a
treatments, and the treatments found to be representative patient sample, often poor quality.
inactive can be dropped. • Case control – to identify rare AEs.
• Discontinuation design – only patients who • Large computerized databases and record linkage
respond to treatment remain in the trial and – to identify rare idiosyncratic AEs and to correlate
then randomized to a continuation or AEs with laboratory value and prescribing data.
discontinuation of treatment. This design needs >10,000 patients.

357
 III RESEARCH IN ONCOLOGY

given their consent freely. It should be made Advances in clinical trials

clear that consent can be withdrawn at any
time without affecting their future care to avoid The current process of cancer clinical trial design
pressurizing already vulnerable individuals into is costly and lengthy. Studies show that the
believing they have to agree to please their medical overall cost of introduction of a drug to clinical
carers. Good clinical practice also states that use is approximately 1 billion dollars and that
patients should be given adequate time to reflect for a target molecule is 1.4 billion dollars. This
on the information received and be able to discuss process also takes an average of 12–14 years. The
with family, friends or their general practitioner. phase 0 trial design has been proposed as a solu-
Key areas to be covered when discussing a trial tion (Box 25.5). This may expedite the identifica-
with a patient are listed in Box 25.4. tion of new target molecules and bring potentially
active molecules into routine clinical use faster.
Other advances include development of novel
trial designs or the use of alternative statistical
Box 25.4: Cancer clinical trials – what to tell methods. Translational studies are now integrat-
the patient? ing biological questions with clinical develop-
• Type of study and objective – should be clear and ments. In terms of drugs, trials are now moving
properly explained to patients. This is important
to get a right balance in the beginning in the
on to examine the best way to combine novel
minds of patients and their families. They should agents, either with other novel agents or
not be left with an impression that either they are chemotherapy.
simply ‘guinea pigs’ or the treatment is going to
give them an imminent cure.
• Phase I studies – is to decide toxicity and
maximum tolerated dose and only a small Box 25.5: Phase 0 trial
percentage is expected to respond. Classically Phase 0 trial – are first-in-human trials with no
less than 5% of patients would benefit. This therapeutic or diagnostic intent, in a limited number
has improved by a few percent with targeted of patients (<15) using subtherapeutic doses over a
treatments. limited period to establish a drug-target effect. (See
• Phase II studies – is to test the activity of a new Figure 25.2). These are established as means to
drug for a particular type of cancer. address the pitfalls of phase I–III studies and to
• Phase III studies – standard treatment is expedite the development of new investigational
compared with a new treatment and it may targeted agents. These methods may also be included
take years to show any benefit or even, harm. within a classical phase I trial.
• Purpose of clinical trials – it is important to tell These studies help to:
patients that though, in many situations we have • Study whether the investigational drug affects the
standard treatments, most of the treatments may alleged target in the desired manner.
not be the best. Hence there is a continuous • Provide further pharmacokinetic (PK) and
attempt to improve the success of existing pharmacodynamic (PD) data.
treatment with new clinical studies.
• Validate biomarker assays for target modulation
• All the studies discussed with patients have effects.
undergone rigorous ethical procedures before
approval to ensure participants’ safety and to • Select most promising molecule based further
safeguard their human rights. evaluations using very sensitive imaging
technologies.
• Patients have the right to decline to participate
which does not compromise future care and they Under these studies, dose escalation is allowed
can withdraw from the trial at any point without provided it is to modulate the target, not to
affecting their future treatment. determine MTD. Phase 0 trials provide critical human
PK and PD data which help to directly proceed to
• Need to explain the trial process – such as type of phase I/II study or a combination with an established
study, cannot choose the treatment in phase III agent, thus expediting the development of agents or
study, need for frequent tests, follow-up combination of agents likely to have clinical activity.
appointments, complete a number of forms etc. Using the new design, the National Cancer Institute
• Funding of trial – even if a trial is funded by evaluated the effect of a PARP inhibitor, ABT 888
pharmaceutical companies, the trial process is in tumour tissue which led to a phase I study of
done according to national/international ABT-888 with chemotherapy. The phase 0 study met
regulations. There is no financial incentive for the its primary objective within 5 months, even before
doctors or other healthcare professionals enrolling any of the planned phase I study started patient
patients into the study. accrual (see Figure 25.2).

358
 CLINICAL TRIALS IN CANCER 25

Phase 0: Proof of concept

Oncology remains one of the most evidence-
(10–15 patients)
Preclinical studies based specialties at the forefront of clinical trial
development.

Further reading
Target modulation No target modulation Phase I
(30 patients) Le Tourneau C, Lee JJ, Siu LL, Dose escalation methods
in phase I cancer clinical trials. J Natl Cancer Inst
2009;101(10):708–720.
Phase I/II No further Kummar S, Doroshow JH, Tomaszewski et al. Phase 0
Dose escalation and studies Phase II clinical trials: recommendations from the Task Force on
efficacy and target (300 patients) Methodology for the Development of Innovative Cancer
assessment (around
Therapies. Eur J Cancer 2009;45(5):741–746.
100 patients)
Eisenhauer EA, O’Dwyer PJ, Christian M, Humphrey JS.
Phase I clinical trial design in cancer drug development.
Phase III
(3000 patients) J Clin Oncol 2000;18:684–692.
Phase II/III Lee JJ, Feng L. Randomized phase II designs in cancer
efficacy and target clinical trials: current status and future directions. J Clin
qualification (around Oncol 2005;23(19):4450–4457.
1000 patients) Green S, Bendetti J, Crowley J. Clinical Trials in Oncology.
Second edition. London: Chapman and Hall, 2003.
Eisenhauer EA, Twelves C, Buyse M. Phase I cancer clinical
trials. Oxford: Oxford University Press, 2006.
Drug approval

Figure 25.2
Phases of the clinical trials.

359
 26
Understanding the
strengths and
weaknesses of clinical
research in cancer
C Williams

‘I hope that the cares of medical practice What are the important
have not obliterated your interest on
solving deductive problems.’ elements when assessing
Sherlock Holmes to Watson in the reports of trials?
Stockbroker’s Clerk* By far the most important elements are the design
and conduct of the trial. The methods of analysis,
Introduction while still important, are generally less likely to
lead to inappropriate conclusions than inappro-
This chapter briefly discusses cancer clinical trials priate design and management of a trial. This
and systematic reviews of the cancer literature, chapter is based on the methods recommended
together with the concept of critical appraisal by various EBM groups (Box 26.1).
and evidence-based medicine (EBM). Much of Because there is such a huge volume of medical
literature appraisal requires a common sense, but literature published each year, it is important to
systematic, approach to ascertaining answers to take a systematic approach to what you appraise
key questions about potential biases in the design, thoroughly (Box 26.2). The first step in appraisal
conduct and reporting of a study or review. is to screen the paper to see if it is worthy of
careful reading. It may be possible to answer
Appraising reports of these screening questions on reading the title and
abstract.
cancer clinical trials
The difficulty in appraising clinical trials lies in Step 1 – Screening questions
assessing the strength of the evidence. On cursory • Was there a clearly focused question? Impor-
reading the author of the report may seem to tant aspects include the population studied,
present a strong case for the trial, but you need the interventions and the outcomes used.
to see beyond the rhetoric, the eminence of the • Did the investigators use the right type of
author or institution/trials group and the status study design for the question being asked? If
of the journal publishing the paper, to assess the there is a clearly focused question that
evidence and to see if it is strong enough to stand is addressed by a trial of appropriate design
on its own. Very strong evidence may be enough it is worth continuing on to a full appraisal
to influence practice by itself, but more com- of the results. However, do not save time
monly the evidence is weaker and needs support by simply reading the abstract (Example
from further studies. Box 26.1).
Step 2 – Appraising a paper
*Quotes in this chapter are as those cleverly used by Jorgen reporting a trial
Nordenstrom in his book ‘Evidence based medicine in Sherlock
Holmes’ Footsteps’ (Wiley Black-well, 2006). There are a number of crucial questions that need
to be answered (Box 26.2):
360 © 2011, Elsevier Ltd
DOI: 10.1016/B978-0-7234-3458-0.00031-2
UNDERSTANDING THE STRENGTHS AND WEAKNESSES OF CLINICAL RESEARCH IN CANCER 26

Box 26.1: Evidence-based medicine Box 26.2: Systematic method of

web resources research appraisal
Centre for Evidence-Based Medicine, Oxford, UK – Step 1 – Screening questions
http://www.cebm.net/?o=1013 • Was there any clearly focused question?
Centre for Evidence-Based Evidence, University of • Did the investigators use the right type of study
Toronto, Canada – http://www.cebm.utoronto.ca/ design?
Centre for Health Evidence – http://www.cche.net/ Step 2 – Appraising the study report
about.asp
1. Was there an appropriate comparison group?
The Cochrane Collaboration – http://www.cochrane.
• Concurrent or historic controls?
org/
• Was the study randomized?
Users’ Guides Interactive Learner Web site – http://
www.usersguides.org/ 2. Was the study based on a pre-specified protocol?
• Did the study have a narrow focus?
• Did the study have appropriate end points?
• Did the investigators stick to the protocol?
Example Box 26.1: Abstracts 3. Who knew, what and when?
• Blinding?
There is a tendency in abstracts to report only the • Allocation concealment?
statistically significant outcomes. Authors may ignore
clinically important outcomes and may fail to report 4. Which patients were included or excluded and
or discuss issues important to the validity of the what happened to those lost to follow-up or who
study. went off protocol or were left out?
Piver MS, Barlow JJ, Vongtama V, et al. Hydroxyurea: • Representative sample for the intervention
A radiation potentiator in carcinoma of the uterine studied?
cervix: A randomized double-blind study. Am J Obstet • Whether all patients randomized are included
Gynecol 1983;147:803–808. in the final analysis?
In this trial the authors reported in the abstract and 5. How much did the outcomes change and were
text, a highly significant benefit from the addition of they measured and reported appropriately?
hydroxyurea to radiation therapy for cervix cancer. • Whether appropriate endpoints and validated
Only when reading the table on side effects does it instruments were used?
become evident that data on patients dying from
causes other than cancer were censored. These • Were measurements appropriate and done
included a significant excess of deaths from infection, properly?
bowel perforation and leukaemia in the hydroxyurea • Which treatment is better and how much?
group. If these patients, whose deaths were • Appropriate sample size?
potentially due to treatment toxicity, are included in
an uncensored analysis the highly significant
advantage for hydroxyurea disappears. These facts
are not mentioned in the abstract or discussion.

patients and will then compare the outcomes

with those obtained from the records of similar
1. Was there an appropriate comparison patients treated in the past – so-called historical
group? controls. Any such comparison is fraught with
‘Though most of the facts were familiar to danger as factors other than the new treatment
me, I had not sufficiently appreciated their may have change over time.
relative importance, nor their connection Did the authors use randomization?
to each other.’ The purpose of randomization is to ensure, as far
Watson in Silver Blaze as possible, that all factors (known and unknown)
The main aim is that the control group be identi- that may influence the treatment outcome are
cal to the intervention group in everything apart balanced between the treatment groups. This
for the intervention itself. is done to reduce the risk of a chance bias.
Randomization requires the use of a random
Concurrent or historical controls? device; this is normally a table of random numbers.
When a new therapy is being tested some inves- Systematic allocation; i.e., alternating between
tigators will give the new treatment to all the treatments, odd or even birth date or hospital
361
 III RESEARCH IN ONCOLOGY

number is not an acceptable method, though it is life are often of major importance; they are fre-
sometimes referred to as pseudo-randomization. quently ignored in the primary research.
Since the researchers know which treatment each
person is allocated to before they consent, selec- Optimal cut points and the problem with
tive allocation can occur, which will skew the multiple comparisons.
results. Hence the process used for randomization ‘While the individual man is an insoluble
must ensure that neither the trial subjects nor the problem, in aggregate he becomes a
investigator can influence the treatment arm each mathematical certainty. For example you
person ends up in (‘allocation concealment’). can never foretell what any one man will
Despite their pre-eminence, RCTs do, however, do, but you can say with some precision
have their limitations. They are usually carried what an average number will be up to.
out in a narrowly defined research setting. Pro- Individuals vary, but percentages remain
tocols require careful selection of patients with constant.’
specific characteristics. There may be a propor- Sherlock Holmes, in The Sign of The Four
tion of patient eligible who chooses not to par-
ticipate. Because of these factors, patients in an Where there is a continuous outcome measure, it
RCT may not be typical of patients in routine is common to simplify analysis by defining one
health practice. or more points that are used to characterize risk.
The way that these points are selected may have
2. Was the study based on a major effect on the analysis.
a pre-specified protocol?
Subgroup analysis
A protocol written before the trial starts is a
Subgroup analyses are fairly common in trials;
prerequisite to good research and some journals
they use the data from a study to compare one
are now recommending that the original protocol
endpoint across different subgroups. There are
be submitted with the final paper to ensure that
three major problems with this approach:
there was such a protocol and to identify any
deviations from the original design. Any devia- • The comparison is not randomized.
tion from the original study design can result in • The comparison is less precise as there are
skewed observation of clinical benefit. numbers of patients and those reaching end
When reading a paper bear in mind the fol- points is smaller.
lowing elements of trial design: • The power calculations for the size in a study
may be invalidated by a large number of
Was there a clearly defined research question?
subgroups.
A good study has limited objectives that are
based on a biological hypothesis. Studies with no Where a subgroup is found to behave differ-
focus and without a clearly defined question are ently, you should consider if there is a plausible
in danger of becoming a ‘fishing expedition’ with biological mechanism for this and whether other
multiple comparisons. trials have found a similar finding. Where there
The chances of multiple testing increases when is a statistical analysis, this should be done as a
there is numerous subgroups or endpoints or formal test of interaction. Strong empirical evi-
when data are reported on multiple side effects. dence suggests that post hoc subgroup analyses
This is particularly problematic when such com- often lead to false positive results (Example Box
parisons are unplanned. 26.2).
Did the study have appropriate end points?
Most RCTs in cancer therapy concentrate on 3. Did the investigators stick to the protocol?
reporting response rates (a surrogate end point Clinical research is rarely predictable, so changes
of clinical benefit), disease free survival and or alterations to a protocol are often needed.
overall survival. However, accepting that cure is However, they should be clearly reported, as
out of the reach of many patients with cancer, major deviations may reduce the reliability of
information on symptom control and quality of the data.
362
UNDERSTANDING THE STRENGTHS AND WEAKNESSES OF CLINICAL RESEARCH IN CANCER 26

Example Box 26.2: International study of

There is also an increase in trend towards
infarct survival stopping the trials too early after an interim anal-
ysis. The ethical reason for this decision is to
Sleight P. Subgroup analyses in clinical trials: fun to
look at – but don’t believe them! Curr Control Trials minimize the number of patients receiving an
Cardiovasc Med 2000;1(1):25–27. unsafe, ineffective or inferior treatment. However,
Analysis of subgroup results in a clinical trial is stopping trials for apparent benefit will system-
surprisingly unreliable, even in a large trial. This is atically overestimate treatment effects, especially
due to a combination of reduced statistical power,
increased variance and the play of chance. Reliance when the sample size is small. The best strategy
on such analyses is likely to be erroneous. Plausible to minimize the problems associated with early
explanations can usually be found for effects that stopping is not to stop early. Alternative strate-
are, in reality, simply due to the play of chance.
When clinicians believe such subgroup analyses, there gies include a low p-value as the threshold for
is a real danger of harm to the individual patient. stopping at the time of interim analysis, not to
In order to study the effect of examining subgroups analyse before a sufficiently large number of
the investigators of the ISIS trial, testing the value of
aspirin and streptokinase after MI, analysed the
events had accrued and continuation of enrol-
results by astrological star sign. All of the patients ment and follow-up for further period.
had their date of birth entered as an important
‘identifier’. They divided population into 12 Fraudulent conduct of clinical research
subgroups by astrological star sign. Even in a highly Although we all hope that such fraud is very rare,
positive trial such as ISIS-2, in which the overall
statistical benefit for aspirin over placebo was
there are too many instances where there has
extreme (p < 0.00001), division into only 12 been clear fraud (Example Box 26.3). Detecting
subgroups threw up two (Gemini and Libra) for such fraud is very difficult. Peer review may help,
which aspirin had a non-significantly adverse effect
(9% ± 13%).
but in many instances journals do not have the
ISIS-2 was carried out in 16 countries. For the
original protocol and access to the raw data is
streptokinase randomization, two countries had extremely unusual. In the above example, it was
non-significantly negative results, and a single an independent outside review that revealed the
(different) country was non-significantly negative for
aspirin.
fraud. The review was carried out as the trial was
There is no plausible explanation for such findings at variance with other literature and the subject
except for the entirely expected operation of the was of great importance.
statistical play of chance. It is very important to
realize that lack of a statistically significant effect is 4. Who knew what and when?
not evidence of lack of a real effect.
Blinding
While it is often not possible to blind patients
and clinicians about which arm a trial patient
is in, anyone who evaluates patient outcomes
Changes in a protocol that may cause major
should be blinded to the treatment allocation.
problems includes, introducing new exclusion
This is especially important when there is a
criteria after the trial has finished or during the
‘surrogate’ endpoint subject to individual inter-
course of the trial and introducing new end
pretation, e.g. imaging to assess response or
points. So, for instance, new exclusion criteria
measurement of toxicity.
may improve the results by leaving only those
patients who get apparent benefit. The addition The effect of blinding on the patient
of unplanned end points may turn a negative Blinding removes the placebo effect. There are
study around by concentrating the focus on posi- three specific situations where the placebo effect
tive results for the new end points, when the old is of particular concern. It is most important
endpoints were negative. when doctors and patients are enthusiastic about
Without access to the original protocol, it may the treatment being tested, when outcomes
be difficult for the reader to know if there were use patient’s self-assessment (e.g. quality of life
major protocol deviations. Where a deviation is studies), and when the primary aim is symptom
known the acid test is to ask if the change would control. When there is an objective outcome such
have made sense if it had been considered when as survival, the placebo effect is much less
the protocol was being designed. important.
363
 III RESEARCH IN ONCOLOGY

Example Box 26.3: On-site audit for high-dose

ment each patient is allocated before they consent,
chemotherapy selective allocation may occur which results in
skewing of results. Similarly, if the patients know
Weiss RB et al. An on-site audit of the South African
Trial of high-dose chemotherapy for metastatic breast the treatment they are receiving, it can introduce
cancer and associated publications. J Clin Oncol bias in reporting the outcomes. Hence, it is
2001;19:2771–2777. important to conceal the randomization list from
This article reported the results of an on-site audit to those recruiting patients. Only when an eligible
verify the results of a randomized study reported by
Bezwoda et al. on high-dose chemotherapy (HDC) for patient has agreed to participate should the treat-
treatment of metastatic breast cancer. In the original ment allocation be carried out. Unblinded alloca-
study, 90 patients were reported to have been tion methods show an average bias of 30–40%.
randomized and treated. However, even after
searching more than 15,000 sets of medical records The only safe method of randomization is to
only 61 of the 90 patients could be found. Of these carry out allocation, for a single patient at a time,
61, only 27 had sufficient records to verify eligibility by a central trials office or pharmacy.
for the trial by the published criteria. Of these 27, 18
did not meet one or more eligibility criteria. Only 25 5. Which patients were included or
patients appeared to have received their assigned
therapy temporally associated with their enrolment excluded and what happened to those lost
date, and all but three of these 25 received HDC. The to follow up or who went off protocol or
treatment details of individual patients were at great
variance from the published data. were left out?
In the accompanying editorial (High-dose There is a major problem when studies, parti­
chemotherapy for breast cancer: ‘how do you know?’ cularly RCTs, become unrepresentative of the
J Clin Oncol 2001;19(11):2769–2770) Larry Norton
wrote ‘In this regard, Dr Weiss et al. … have done a population or setting which the treatment is
great service. They offer us unequivocal evidence that potentially suitable for. Frequently, patients in
Dr Werner Bezwoda’s critical study in high-dose trials are fitter and younger than those encoun-
chemotherapy for advanced breast cancer is fake and
completely inadmissible information regarding the tered in routine practice.
safety and efficacy of such treatment was included. Who was lost to follow-up or dropped out
This work was previously and wrongly reported as
positive at ASCO’s 1992 Annual Meeting, in the during the study?
Journal in 1995, and in multiple subsequent Loss of some patients in a study is inevitable.
publications [six] … That the original publication,
now being retracted by the Journal, has influenced
These patients may have a different prognosis
major thinkers in this field and may have put patients than those remaining in the trial. Excluding those
in danger raises the stakes as we consider how we lost to follow-up or dropped out will often result
can improve the process to make sure that this never
happens again.’
in overestimate of treatment benefit.
All patients should be analysed in the groups
they were randomized to, regardless of whether
they crossed over or changed treatment, were lost
Blinding of investigators to follow up or dropped out. This is known as
Clinicians caring for the patients may also influ- ‘intention to treat’ analysis and should always
ence a trial outcome by their attitude and the be reported, even if the authors also choose
way that they manage the disease overall. When to present analyses excluding selected patients
unblinded studies were compared to blinded (Box 26.3). Intention to treat analysis is the only
studies, the former studies tended to estimate a way we can ensure that the original randomiza-
treatment effect that was (on average) 11% to tion has retained and thereby, the groups are
17% higher than in blinded studies. Blinding is comparable.
of less importance where there is an objective end 6. How much did the outcomes
point such as survival. change and were they measured and
Allocation concealment reported appropriately?
For randomization to be effective, neither the It is important to ensure that the end points used
trial subjects nor the investigators can influence are appropriate. There is a tendency to measure,
the treatment each person is allocated. If either easier and quicker, surrogate end points, rather
the patients or the investigators know the treat- than those that are important to the patient or
364
UNDERSTANDING THE STRENGTHS AND WEAKNESSES OF CLINICAL RESEARCH IN CANCER 26

Box 26.3: Sample size slippages in

change, it is important to consider if the investi-
randomized trials gators should have been measuring long-term
• All randomized participants should be included in effectiveness. For instance, several treatments in
the primary analysis (an intent-to-treat analysis). the review ‘Non-surgical interventions for late
Participants might ignore follow-up, leave town, radiation proctitis in patients who have received
or take aspartame when instructed to take aspirin.
radical radiotherapy to the pelvis,’ (Denton et al.,
• Exclusions before randomization do not bias the
treatment comparison, but they can hurt 2008), were often only given for one month and
generalizability. then response was assessed at one time point.
• Eligibility criteria for a trial should be clear, Although less of a problem in cancer studies,
specific, and applied before randomization. when compared with the general medical litera-
Readers should assess whether any of the criteria
make the trial sample atypical or unrepresentative ture, it is sometimes difficult to obtain accurate
of the people in which they are interested. measurements in certain types of study. If the
• In reality, patients will lose follow-up. measurement error concerns an important factor
Investigators should, therefore, commit adequate predictive of an outcome, this is of major concern.
resources to develop and implement procedures to
maximize retention of participants. An example in the field of cancer would be the
• Researchers should provide clear, explicit difficulty in accurately measuring dietary fat
information on the progress of all randomized intake when studying the effect of diet on devel-
participants through the trial by use of, for
instance, a trial profile.
opment of breast cancer.
• Investigators can also do secondary analyses on,
for instance, per-protocol or as-treated Which is the better treatment and how
participants. Such analyses should be described as much difference?
secondary and non-randomized comparisons.
It is not sufficient to know that one treatment is
• Mishandling of exclusions causes serious
methodological difficulties. Unfortunately, some better than another, it is important to quantify
explanations for mishandling exclusions intuitively how much better the treatment is than the other.
appeal to readers, disguising the seriousness of While a p-value may tell you which treatment is
the issues. Creative mismanagement of exclusions
can undermine trial validity. better, the confidence interval is a better measure.
Schulz KF and Grimes DA. Sample size slippages in It not only tells you which is the better treatment,
randomized trials: exclusions and the lost and but quantifies the difference (Box 26.4). This
wayward. Lancet 2002;359:781–785. is particularly important where any gain has
to be balanced against the side effects of that
treatment.
their clinicians. Patients want information on Just because a statistical test shows an inter-
what effect an intervention will have on their vention to be superior this does not tell you
chance of survival, what the side effects will be, whether the difference is clinically important.
and whether it will change their quality of life. This requires, in addition, an estimate of the
Use of surrogate measures, such as a fall in a numbers of patients seen in routine practice who
tumour marker, will fail to answer these ques- might benefit from the ‘better’ treatment, the tox-
tions; even if they may provide evidence support- icity of the treatment, its ease of administration
ing potential benefit. and cost. Assessing clinical significance requires
sound judgment. The decision whether to use
Were measurements appropriate and that treatment will also ultimately depend on the
well done? personal preferences of patients.
Although it is probably less of a problem in
cancer studies than some other areas of medicine, Were there sufficient subjects?
be wary of end points that measure short-term There has been a tendency for cancer RCTs to
outcomes. For instance, in studies concerned have too few subjects, or more accurately patients
with management of complications of cancer or reaching the end point of the study. Investigators
the side effects of its treatment, trials may report should provide an a priori justification of the
effectiveness of an intervention after, say, six- sample size in the paper itself. If there are no
week therapy. Since it is easier to get a short-term power calculations, it is useful to look at the
365
 III RESEARCH IN ONCOLOGY

Box 26.4: Is the result important? Example Box 26.4: Publication bias
In any study, the beneficial effect/risk of the Stern JM, Simes RJ. Publication bias: evidence of
experimental arm can be due to three possible delayed publication in a cohort study of clinical
reasons: research projects. BMJ 1997;315:640–645.
• Bias – excluded by assessing the validity of study. This retrospective study was undertaken to determine
• Chance variation between the treatment groups the extent to which publication is influenced by study
– excluded by analysing p-value and confidence outcome. Of the 218 studies analysed with tests of
interval. significance, those with positive results (p < 0.05)
• The real benefit/risk – quantified by calculating were much more likely to be published than those
various event rates. with negative results (P ≥ 0.10) (hazard ratio 2.32
(95% confidence interval 1.47 to 3.66), p = 0.0003),
P-value is used to measure the probability of with a significantly shorter time to publication
occurring the benefit/risk by a chance, e.g. a p-value (median 4.8 vs. 8.0 years). Studies with indefinite
of 0.01 means that there is a 1 in 100 (1%) conclusions (0.05 ≤ P < 0.10) tended to have an even
probability of the result occurring by chance. lower publication rate and longer time to publication
Conventionally, a p value of <0.05 (<1 in 20 than studies with negative results (hazard ratio 0.39
probability) is set as the statistically significant result. (0.13 to 1.12), p = 0.08).
Confidence interval (CI) is used to measure the
sampling error. Since any study can only examine a
sample of a population, we would expect the sample
to be different from the population (sampling error). ing the results of a meta-analysis, you should ask
Conventionally a 95% CI is used, which specifies that the following questions:
there is a 95% chance that the population’s true
value lies between the two limits. If the 95% CI • Were all the available studies included? An
crosses the ‘line of no difference’ between
interventions, the result is not statistically significant.
incomplete search of the literature can bias
Once the bias and chance have been ruled out, the
the findings of a meta-analysis or systematic
benefit/risk of intervention can be quantified using review.
the following measures: • Was it appropriate to pool the data? Hetero-
• Relative risk (RR) – the ratio of the risk in the geneity among studies may make any pooled
experimental group divided by the risk in the
control group.
estimate meaningless.
• Absolute risk reduction (ARR) – the difference
• Was the quality of the trials good? The quality
between the control event rate and experimental of a meta-analysis cannot be any better than
event rate. This is a more clinically relevant the quality of the studies it is summarizing.
measure.
• Relative risk reduction (RRR) – calculated by Did the reviewers find all of the trials?
dividing ARR with control event rate. One of the greatest risks of bias in a meta-
• Number needed to treat (NNT) – is the inverse of
ARR and is the most useful measure of clinical
analysis is omitting relevant studies. Often studies
benefit. It tells you the absolute number of are never published; evidence suggests that such
patients who need to be treated to prevent one studies are likely to be negative. This is known
adverse outcome.
as publication bias (Example Box 26.4). Regis-
tration of trials, before they start, is being intro-
duced as a way of avoiding publication bias.
width of the confidence intervals. If there is an
inadequate sample size, the confidence intervals Duplicate publication
will be abnormally wide. Studies which are positive are more likely to
appear more than once in publication. This is
Systematic reviews especially problematic for multi-centre trials
where an individual centres may publish results
and meta-analyses specific to their site.
Introduction The limitations of a Medline search
A systematic review is one carried out in While a Medline search is the most convenient
accordance with a written protocol and using way to identify published research, it should not
methodology designed to reduce the risk of bias. be the only source of publications for a meta-
Meta-analysis is the quantitative pooling of data analysis. Medline searches cover only about a
from two or more studies. When you are examin- quarter of the medical literature.
366
UNDERSTANDING THE STRENGTHS AND WEAKNESSES OF CLINICAL RESEARCH IN CANCER 26
Foreign language publications
Box 26.5: NICE appraisal on addition of
Some meta-analyses restrict their attention to paclitaxel to platinum in ovarian cancer
English language publications only. This makes ‘While design differences between the four trials,
life easier for the reviewers, but there is evidence in terms of severity of disease of included patients,
that researchers tend to publish reports of posi- differences in treatment and control drugs and
doses, length of follow-up, and the extent of
tive trials in English language journals. Con- cross-over (before and after disease progression),
versely, they publish negative reports in a native may hamper statistical pooling of results, meta-
language journal where the citation index is analyses have been undertaken … These take
account of statistical heterogeneity as far as
likely to be lower. possible, and their results appear consistent,
reporting that the findings for progression-free
Heterogeneity survival (hazard ratios = 0.84, 95% CI = 0.70 to 1.02
[MRC] and 0.87, 95% CI 0.72 to 1.05 [BMS]) and
Even when the trials do not have obvious clinical overall survival (hazard ratios = 0.82, 95% CI 0.66
heterogeneity the results may turn out to be very to 1.01 [MRC] and 0.82, 95% CI 0.68 to 1.00 [BMS])
different. An example is RCTs testing the efficacy across the trials do not show statistically significant
differences between paclitaxel/platinum and the
of adding paclitaxel to platinum therapy for the alternatives.’
primary chemotherapy of ovarian cancer. The ‘The four trials showed consistently that treatment
initial two studies, GOG 111 and OV10, showed with paclitaxel in combination with platinum leads to
an advantage for the addition of paclitaxel. Two more side effects …’
subsequent trials, GOG132 and ICON3 (by far ‘The Committee took account of this range of trial
evidence as well as other factors that would
the biggest trial), have failed to show an advan- differentiate between the two regimens including
tage for the addition of paclitaxel. Examining the the side-effect profiles of the treatments … On this
results there appears to be such an extreme het- basis the Committee considered that paclitaxel/
platinum combination treatment should no longer be
erogeneity that pooling of the data in a meta- recommended exclusively as standard therapy for
analysis should be avoided. Despite this NICE women receiving first-line chemotherapy for ovarian
in its appraisal did include a meta-analysis cancer. [The original recommendation was made
when ICON3 had not been published.] … both
(Box 26.5). platinum therapy alone and a combination of
The main areas where heterogeneity occurs paclitaxel and a platinum compound were
include: appropriate first-line treatments for women with
ovarian cancer.’
Heterogeneity of the treatment and control This guidance allows clinicians to exercise their
groups: prejudice, either to believe the two positive trials or
the two negative trials, containing many more
• Varying inclusion and exclusion criteria. patients. The meta-analysis, although showing no
• Variation in general health of patients or statistical benefit for the addition of paclitaxel, has
geographical differences. not added to the guidance since its conclusion has
been ignored. The statistical heterogeneity was
• Differences in dose or timing of a drug or so great that it would have been better to have
co-medication. discussed the two pairs of trials in narrative fashion,
Heterogeneity in the design of the study: rather than to have produced a meta-analysis of the
four trials.
• Variation in length of follow-up.
• Variation in proportion of drop outs and
how they are handled.
Heterogeneity in the management of the jects, increases confidence in that treatment.
patients and in the outcome: Where there is excessive heterogeneity pooling
• Variation in the management of of data should be avoided. The results can be
co-morbidity. explored in various ways.
• Variation in managing side effects.
Subgroup analysis
Managing heterogeneity When there is substantial heterogeneity, you can
A degree of heterogeneity is to be expected and look and compare subgroups of the studies. As
is acceptable. Showing that a treatment gives the case in Box 26.5, of the use of paclitaxel
consistent results, with some variation, across a chemotherapy in ovarian cancer, suggests rather
variety of trials, and in a large number of sub- than pooling all the data, the review could have
367
 III RESEARCH IN ONCOLOGY

pooled the data from the two groups of positive number of positive studies exceeds the negative
and negative trials and then discussed the reasons group or vice versa. However, there is a major
for the different outcomes. flaw with this approach as it ignores the possibil-
ity that some studies are negative because they
Meta-regression are simply too small.
You can try to adjust for heterogeneity in a meta-
analysis. This works similarly to the adjustment How to avoid bias from exclusion
for covariates in a regression model. of publications
The major bibliographic databases, registries for
Sensitivity analysis clinical trials, and the grey literature should all
Another approach to heterogeneity is to examine be searched. In addition the bibliographies of all
the sensitivity of the results by looking at selected articles found should be checked to see if there
groups of studies. This may mean only including are relevant trial reports.
those trials selected to be of good quality factor
or some other element likely to reduce bias. Intentional exclusion of studies
In any meta-analysis, you have to draw a line
Was the quality of the trials good?
somewhere. Studies that fail to meet your criteria
Meta-analysis cannot correct or compensate for will not be included in the results. Where the
poorly designed or conducted studies. It is for cut-off point is based on judgment, such as trial
this reason that poor quality trials should be quality, this can sometimes cause serious contro-
excluded or a sensitivity analysis carried out versy. A Cochrane Review of mammographic
based on trial quality. screening for breast cancer found seven eligible
Reporting of trials is often poor so that it is studies, but only two were deemed to be of suf-
impossible to assess the quality of the study. ficient quality to include in the review; meta-
There is evidence that poorly reported trials are analysis of the two studies found no benefit from
more likely to be of poor quality and incomplete screening. If all seven studies were included the
reporting is associated with poor quality. outcome was positive. This Cochrane review
provoked a furious response and intense debate
Taking the easy option – over the rights and wrongs of excluding most of
a narrative review the available trials (Example Box 26.5).
‘The temptation to form premature
theories upon insufficient data is the bane Objectivity in a systematic review
of our profession.’ ‘It is capital mistake to theorize before one
Sherlock Holmes in the Tragedy has data. One begins to twist the facts to
of Birlstone fit theories, instead of theories to fit facts.’
Sherlock Holmes in Scandal in Bohemia
A classical narrative review frequently suffers
from a lack of systematic ways of avoiding bias. A systematic review or meta-analysis should have
There is also a worrying tendency to choose a written protocol, though most published meta-
papers that support the reviewer’s own point of analyses do not state if a protocol was used. This
view. This is fine in an opinion piece designed to protocol should state: the inclusion/exclusion
make people think, but is very dangerous if the criteria for studies, how quality will be assessed,
reviewer purports to give a balanced assessment a detailed search strategy and the statistical
of the literature. methods used to combine results. The protocol
Traditional narrative reviews generally do not is there to reduce bias, increase transparency and
use meta-analysis, but will often undertake an to make it possible to see how the review was
exercise often referred to as vote counting. In done. As well as including information on
such a process, there is a sum of the number of included studies, a systematic review should
positive and negative studies; the overall inter- report on which studies were excluded and on
pretation depending on whether or not the what grounds.
368
UNDERSTANDING THE STRENGTHS AND WEAKNESSES OF CLINICAL RESEARCH IN CANCER 26

Example Box 26.5: Screening for breast cancer

• Clinicians need valid information about
with mammography patient management up to five times per
in-patient and twice for every three
Olsen O and Gøtzsche PC. Screening for breast cancer
with mammography. Cochrane Database Syst Rev out-patients.
2001;(4):CD001877. • While our diagnostic skills and clinical judg-
MAIN RESULTS: Seven completed and eligible trials ment increase with experience, our up-to-date
involving half a million women were identified. The knowledge declines.
two best trials provided medium-quality data and,
when combined, yield a relative risk for overall • There is too little time to see patients or
mortality of 1.00 (95% CI 0.96–1.05) after 13 years. to look for information and to keep
However, the trials are underpowered for all-cause up-to-date.
mortality, and confidence intervals include a possible
worthwhile effect as well as a possible detrimental EBM has helped to find ways to support clini-
effect. If data from all eligible trials (excluding
flawed studies) are considered then the relative risk cians through:
for overall mortality after 13 years is 1.01 (95% CI
0.99–1.03). The best trials failed to show a significant • The creation of systematic reviews, with
reduction in breast cancer mortality with a relative succinct summaries, by groups such as the
risk of 0.97 (95% CI 0.82–1.14). If data from all Cochrane Collaboration.
eligible trials (excluding flawed studies) are
considered then the relative risk for breast cancer • The creation of evidence-based journals that
mortality after 13 years is 0.80 (95% CI 0.71–0.89). publish summaries of the small proportion of
However, breast cancer mortality is considered to be clinical papers that are valid and useful to us
an unreliable outcome and biased in favour of
screening. Flaws are due to differential exclusion of in seconds.
women with breast cancer from analysis and
differential misclassification of cause of death. Further reading
Moher D, Schulz KF and Altman DG. The CONSORT
statement: revised recommendations for improving the
Evidence-based medicine (EBM) quality of reports of parallel-group randomised trials.
Lancet 2001;357(9263):1191–1194.
Evidence-based medicine (EBM) brings together Denton AS, Clarke N and Maher J. Non-surgical
best research evidence with clinical expertise and interventions for late radiation proctitis in patients who
patient expectations. Best research evidence have received radical radiotherapy to the pelvis. Cochrane
Database of Systematic Reviews 2008; Issue 4.
means clinically relevant research (basic sci- Straus SE and Sackett DL. Using research findings in clinical
ences), clinical research into the accuracy of diag- practice. BMJ 1998;317(7154):339–342.
nostic tests (includes clinical examination), the Montori VM and Guyatt GH. Intention-to-treat principle.
power of prognostic and predictive markers, and CMAJ 2001;165(10):1339–1341.
the efficacy and safety of all types of interven- Straus SE and Sackett DL. Applying evidence to the
individual patient. Ann Oncol 1999;10(1):29–32.
tions. Clinical expertise includes the ability to use Straus SE and McAlister FA. Evidence-based medicine:
our clinical skills and past experience to recog- a commentary on common criticisms. CMAJ
nize a patient’s individual diagnosis and general 2000;163(7):837–841.
health, the potential risks and benefits of inter- Jackson R, Ameratunga S, Broad J et al. The GATE frame:
ventions, and to integrate this with their personal critical appraisal with pictures. Evid Based Med
2006;11(2):35–38.
expectations. Sackett DL and Straus SE. Finding and applying evidence
during clinical rounds: the ‘evidence cart’. JAMA
Why do we need EBM? 1998;280(15):1336–1338.
Clinicians are hungry for edible sized bites of Williams CJ. The pitfalls of narrative reviews in clinical
reliable information: medicine. Ann Oncol 1998;9:601–605.

• Traditional sources are often out-of-date,

frequently wrong, overly didactic and too
unfocused.

369
 Appendix:
A glossary of common targets
with examples
HM Hatcher

There is now a better understanding of the

molecular mechanisms involved in the develop- Table A.1 Toxicities of common
targeted agents
ment of cancer. In addition to specific genetic
Drug Action Common toxicity
changes seen in individual cancers, some cellular
pathways are common to many types of cancer Cetuximab EGFR Rash, diarrhoea
antibody
and have been the focus of targeted therapies.
This glossary highlights two of these processes Erlotinib, EGFR TKIs Rash
and gives examples of where and how new drugs gefitinib
work in specific malignancies. Bevacizumab VEGF Hypertension,
It should also be noted that the toxicities of antibody bleeding, clots
(arterial + venous)
these targeted agents are different from those of
traditional chemotherapy (Table A.1). Transtuzumab HER-2 Anaphylaxis,
antibody cardiac failure

Epidermal growth factor Sunitinib TKI multi Skin changes,

target stomatitis
receptor (EGFR) Imatinib TKI (SCF/c-KIT) Peripheral
The EGFR is a cell surface growth factor receptor oedema, rash,
which is activated by the binding of an EGFR diarrhoea
ligand. This activation causes the formation of a
dimer (Figure A.1), leading to phosphorylation
of the intracellular kinases and a cascade of
signal transduction proteins which regulate DNA
synthesis and cell proliferation (Figure A.2).
EGFR is part of the ErbB family of receptors activity, both with chemotherapy or as a single
which also includes HER-2 (also known as agent, in metastatic colorectal cancer (p. 169).
ErbB2). Used in combination with irinotecan and 5-FU it
In many types of cancer there are mutations showed a benefit in progression free survival over
within part of the EGFR which make it a poten- chemotherapy without cetuximab. Erlotinib and
tially useful target for novel treatments. Increased gefitinib are selective tyrosine kinase inhibitors
HER-2 expression is also seen in breast cancer. (TKIs) (p. 102) which have shown improvements
There are several areas within this signalling in clinical symptoms and response rates in meta-
process which can be targeted, such as the recep- static lung cancer. Their use in the adjuvant
tor binding site, the tyrosine kinases or any of setting combined with chemotherapy has only
the downstream signalling proteins. been shown to be of benefit in a small subset of
Figure A.3 shows the location of some of the patients (lifelong non-smokers, adenocarcinoma,
drugs developed to date. Cetuximab is a mono- females and those of Asian origin). Further anal-
clonal EGFR antibody which has demonstrated ysis has shown that the greatest benefits are seen
370 © 2011, Elsevier Ltd
DOI: 10.1016/B978-0-7234-3458-0.00032-4
 APPENDIX: A GLOSSARY OF COMMON TARGETS WITH EXAMPLES

Figure A.1
EGFR EGFR receptor showing the extracellular binding domain (pink)
and intracellular tyrosine kinases (blue). When the EGF (ligand)
(purple) binds the receptor it causes heterodimerization and
EGF autophopsphorylation (yellow P symbols) of the tyrosine kinase
domains within the cell.

Extracellular domain

Intracellular domain

P P
P P

EGF EGF-R

Extracellular domain

Intracellular domain
P P
DAG PIP2 PLCα P P Sos-1 Ras
Grb2
PI3K Shc
Raf MEKK-1
IP3 JAK1

PKC STAT 3 STAT 1 MEK MKK-7

Ca2+
STAT 3 STAT 1

ER STAT 3 STAT 3 EFK NK

Ca2+

Transcription Nucleus
factors ELK-1 ELK-1
C-jun
STAT 3 STAT 1

STAT 3 STAT 3

Figure A.2
The complex signalling pathways following activation of EGFR.
371
 APPENDIX: A GLOSSARY OF COMMON TARGETS WITH EXAMPLES

Pertuzumab Figure A.3

Areas of the EGFR or HER-2 for
which targeted drugs have been
Cetuximab developed and examples of drugs
Trastuzumab HER2/neu EGFR
Panitumumab acting at these sites.
Extracellular domain

Intracellular domain

Tyrosine kinase region mutations Gefitinib

Erlotinib

Ligand Tyrosine kinase

Figure A.4
The effect of angiogenesis on
tumour growth (above) and the
effect of inhibiting angiogenesis
Tumour (below).

Angiogenesis
Tumour growth

Blood supply

Anti-angiogenic activity Antitumour action

with those who have specific EGFR mutations. VEGF. VEGF is another growth factor receptor
Transtuzumab (Herceptin™) is an antibody which, like EGFR, leads to an intracellular cascade
against HER-2 and has shown significant activity of proteins which regulate cell growth. Increased
in breast cancer. In the adjuvant setting, com- VEGF expression is also observed in many cancers
bined with chemotherapy, it has shown signifi- (e.g. ovarian and renal). Interfering with this
cant improvements in progression free survival process by reducing VEGF expression or its sub-
(p. 128). Lapatinib is a small molecule which has sequent signalling has been another major target
activity against both HER-2 and EGFR and is of drug developers (Figures A.4 and A.5).
also active in breast cancer. As with EGFR, antibodies can be developed
to the receptor and bevacizumab is a VEGFR
Vascular endothelial growth antibody which has shown activity in breast,
colorectal and renal cancer and investigations
factor (VEGF) are underway for other malignancies. TKIs which
Angiogenesis is an important process by which work on this pathway include sorafenib and
tumours gain increased vasculature allowing sunitinib both of which have shown significant
them to grow and spread. A major contributory improvements in survival in metastatic renal
factor to angiogenesis is increased expression of cancer (Figure A.6).
372
 APPENDIX: A GLOSSARY OF COMMON TARGETS WITH EXAMPLES

Figure A.5
Potential downstream effects of
Vascular endothelial VEGF VEGFR-2 VEGF.
cell plasma membrane

Extracellular domain

Intracellular domain
P13K P P Raf

P P MEK

Akt/PKB p38MAPK ErK

Vascular Endothelial cell Endothelial cell Endothelial cell

permeability survival migration proliferation

Figure A.6
Sites of action of various drugs
which work in the VEGF/
VEGF-receptor 2 angiogenesis pathway.

Bevacizumab VEGF

Extracellular domain

Intracellular domain
PKC
Sunitinib
Sorafenib
SPK Ras

P13K Raf
Sorafenib

Akt/PKB MEK

ErK

Endothelial cell Vascular Endothelial cell

survival permeability proliferation

Angiogenesis

against the c-KIT and PDGF (platelet derived

Other molecules growth factor) receptors.
Sorafenib and sunitinib are also examples of Other new target developments include target-
TKIs which can target more than one receptor ing small intracellular proteins further down the
pathway. For example, sunitinib also has activity signalling cascades described above, e.g. mTOR
373
 APPENDIX: A GLOSSARY OF COMMON TARGETS WITH EXAMPLES

inhibitors and PI3K inhibitors which are under the bcl-2 antisense Oblimersen sodium which in
investigation. The mTOR inhibitor Terosilimus early trials has shown activity in pre-clinical and
has already shown activity in metastatic renal pilot studies of lung cancer and melanoma.
cancer. Future areas involve targeting many parts of
Antisense agents are those which recognize the signalling pathway at the same time to see if
abnormal proteins or products of transcription, this leads to synergistic activity and is safe.
bind to them and inactivate them. An example is

374
Index

prostate, 183 ovarian tumours, 220

A small intestine, 158–159 testicular tumours, 189–190
Abdominoperineal resection stomach, 142 5-alpha reductase inhibitors,
(APR), 167 vagina, 229 prostate cancer, 187
Absolute risk reduction (ARR), Adenoid carcinoma, cutaneous, Amitriptyline, 67–69, 70t
366b 241 AML see acute myeloid leukaemia
Abstracts, 360, 361b Adenoid cystic carcinoma, head Anaemia, 27–28, 39b
ABVD chemotherapy, Hodgkin’s and neck, 88 Anal cancer, 170–172, 170t, 172t
disease, 300–301, 300b Adenosquamous carcinoma HIV-positive patients, 171,
ACE chemotherapy, small cell skin, 241–242 297
lung cancer, 101b vagina, 229 Anal intraepithelial neoplasia
Acoustic neuroma, 269t, 275 Adjuvant treatment, 31b (AIN), 170
Active surveillance assessing response, 42 Analgesic nephropathy, 173
prostate cancer, 184–185 chemotherapy, 34b Analgesics, 66–67, 68t
testicular cancer, 190–192 Adrenal insufficiency, cancer adjuvant, 67–69, 70t
Acute lymphoblastic leukaemia survivors, 63–64, 64t Anaphylaxis, management, 344f
(ALL), 308–311 Adrenal metastases Anaplastic lymphoma, 303t
aetiology, 308–309 lung cancer, 106 Anaplastic thyroid carcinoma,
childhood, 321–323, 322b surgical resection, 13b 282, 285
clinical features, 309, 321–322 Adrenocortical carcinoma, Angiogenesis, 372, 372f–373f
diagnosis, 309, 322 285–286, 285f Angiosarcomas, 259b
late effects of treatment, 63 Adriamycin see doxorubicin Ann Arbor staging system,
pathology, 309 AFP see alpha-fetoprotein Cotswold modification,
prognosis and risk classification, Agitation, terminal, 73 299, 299t
310 AIDS-defining malignancies, Anorexia, 348–349
treatment, 310–311, 322–323 295–297, 296b see also Anterior resection (AR), 167
tumour lysis syndrome, human immunodeficiency Anthracyclines
341–342 virus (HIV) infection breast cancer, 125, 128, 130
Acute myeloid leukaemia (AML), Airway obstruction, central, extravasation, 345
308–311 338–339, 340f leukaemia, 311
aetiology, 308–309 Alcohol consumption, 77, 147 Anti-androgens, prostate cancer,
clinical features, 309 Alemtuzumab, leukaemia, 311, 187
diagnosis, 309 313 Anti-angiogenesis inhibitors, 372,
pathology, 309, 309f Alfentanil, 70f 373f
prognosis and risk classification, Alkaline phosphatase (ALP), 246 as radiation modulators, 29
310 Alkylating agents, 32b, 35 see also bevacizumab; sorafenib;
secondary, 309, 314–315 Ewing’s sarcoma, 251 sunitinib
treatment, 311 ALL see acute lymphoblastic Anti-epileptic drugs (AEDs), 268,
tumour lysis syndrome, leukaemia 332
341–342 All-trans-retinoic acid (ATRA), Antibiotics
Acute promyelocytic leukaemia 311 antitumour, 32b, 35
(APML), 311 Allocation concealment, 364 febrile neutropenia, 334–336
Adenocarcinoma Allopurinol, 342 prophylactic, 336
anal, 170 Alopecia (hair loss), 39b, 349 Antibodies, therapeutic, 41
cervix, 213 Alpha-fetoprotein (AFP), serum Antidepressants, 72
colorectal, 160 brain tumours, 275 Antihistamines, 343
lung, 90 hepatocellular carcinoma, 148, Antimetabolites, 32b, 33–34
oesophagus, 134 150 Antipsychotic agents, 72
375
 INDEX

Antiretroviral therapy (ART), 295 Basal cell carcinoma (BCC), Blumer’s shelf, 142
see also highly active cutaneous, 237–239, Body image, children and young
antiretroviral therapy 238b–239b, 238f adults, 326
Antisense agents, 374 Basal naevus syndrome, 264 Bone
APC gene mutations, 52 BCG, intravesical, 178–179 fractures/impending fractures,
Apocrine carcinoma, 244 Bcl-2 antisense molecule, 314, 374 345–346, 346f, 346t
Aromatase inhibitors (AI) BCR-ABL1 fusion gene, 311–312 late effects of cancer treatment,
breast cancer, 127–128 BEAM chemotherapy, 305t 61–62, 61b
endometrial cancer, 211–212 Benzydamine, 349 lymphoma, 306
mechanism of action, 127 BEP chemotherapy, ovarian solitary plasmacytoma, 315–316
ovarian cancer, 204 tumours, 222–223, 223b Bone marrow
side effects, 61, 127–128 Bereavement care, 73, 327 examination in leukaemia, 309,
Arrhythmias, cancer survivors, 63, Betel quid chewing, 77 309f, 312, 314
64t Bevacizumab, 41, 372, 373f failure, 309
Arsenic trioxide, 311 brain tumours, 270 response to chemotherapy, 33b,
Asbestos, 89, 107 breast cancer, 132 33f
Ascites, ovarian cancer, 198, colorectal cancer, 169 suppression, treatment-induced,
204 kidney cancer, 176 39b, 349
Astrocytoma, 270–271 lung cancer, 103 transplantation see stem cell
anaplastic, 266t, 270–271, malignant melanoma, 236 transplantation
273 mesothelioma, 110 Bone metastases
grade II (diffuse), 266t, 267f, toxicity, 370t breast cancer, 130–131
270–272 Bexarotene, 308 lung cancer, 106
pilocytic, 266t, 270–271 Bias, 366b lytic, 345–346, 346f
spinal cord, 280–281 Bicalutamide, prostate cancer, 187 malignant melanoma, 235
Ataxia, isolated, 329 Bile duct cancer, 152–154, 153f men with sclerotic, 288
Ataxia telangiectasia, 48t Biliary tract tumours, 150–154 prostate cancer, 183, 188f, 189
Atumumab, 308 Biological agents Bone pain
Atypical adenomatous hyperplasia head and neck cancer, 82 lung cancer, 91
(AAH), 90 lung cancer, 102–103 management, 69
Atypical ductal hyperplasia, 115 mesothelioma, 110 myeloma, 316
Atypical hyperplasia, oesophageal cancer, 141 Bone scan
endometrium, 205 as radiation modulators, 29 bone tumours, 246, 250, 251f
Atzpodien chemotherapy, 175 see also targeted systemic lung cancer, 92
Auer rods, 309, 309f therapy prostate cancer, 188f
Autonomic dysfunction, 329 Biopsy see tissue diagnosis Bone tumours, primary, 245–254
Axillary dissection, breast cancer, Bisphosphonates, 41 clinical features, 246, 246b
123–124, 128 breast cancer, 130–131 staging, 246, 247t
Axillary lymphadenopathy, hypercalcaemia of malignancy, Bortezomib
women with isolated, 287 340 myeloma, 318, 319t
Axillary nodes, 116–117, 117f myeloma, 319 oesophageal cancer, 141
prostate cancer, 189 Bowel Cancer Screening
Bladder cancer, 177–182 Programme (BCSP), 169
B investigations and staging, 177, Bowen disease, 239–241
Back pain, 328 179f, 179t management, 243
Baclofen, 70t, 71 management, 178–182, 178b, penis, 194
Bacterial infections, 334 180f vulva, 226
Bad news, breaking, 5–6, 6b secondary, 59t Bowenoid papulosis, 194
Barium enema, double contrast small cell, 182 Brachytherapy, 17, 18f
(DCBE), 161, 161f Bleomycin, 35 cervical cancer, 214, 217b
Barium studies, gastric cancer, lymphoma, 300b endometrial cancer, 207–211
142, 143f ovarian tumours, 223b head and neck cancer, 81
Barium swallow, 136, 136f testicular cancer, 192b penile cancer, 195–196
Barrett’s oesophagus, 134, 141 Blinding, 363–364 prostate cancer, 186, 187b
376
 INDEX

Brain metastases, 278–281 G-CSF indications, 337b Cancers of unknown primary

breast cancer, 130, 279f hormone treatment, 40–41, 41t (CUP), 287–289
diagnosis, 278, 279f inflammatory, 128, 131–132 evaluation, 287, 288b, 288t
imaging, 266t inherited, 46t, 47–50, 47b, 48f, management, 287–289
lung cancer, 91, 104, 106, 279f 54 Candidiasis, oral, 71
malignant melanoma, 235, 279f initial (triple) assessment, Cannonball lung metastases, 179f,
presentation, 278–280 117–119 182
prognosis, 278, 278t investigations, 119–120 CAP chemotherapy, thymoma,
raised intracranial pressure, 332 locally advanced, 128–129, 113, 114b
single or solitary, 279–280, 129f Capecitabine, 33–34
279b male, 132 breast cancer, 126b, 130
surgical resection, 13b metastatic, 129–130, 129f, colorectal cancer, 163, 165t,
treatment, 278–280 279f 168–169
Brain tumours, 264–281 palliative care, 130–131 gastric cancer, 146b
aetiology, 264 pathogenesis and pathology, oesophageal cancer, 140, 140b
follow-up, 270 115–116, 116b–117b pancreatic cancer, 157
imaging, 265–267, 266t precursor lesions, 115 Carbamazepine, 70t
investigations, 265–267 pregnancy, 292–293 Carboplatin, 35
late effects of treatment, 62–63, presentation, 117 combination therapy, 34b
270 prognostic factors and outcome, endometrial cancer, 211, 211b
management, 267–270 131 lung cancer, 101b, 104
paediatric, teenage and young prophylactic mastectomy, 13, mechanism of action, 34b, 34f
adult, 323 13b mesothelioma, 109
presentation, 264 radiotherapy, 19 ovarian cancer, 200–203, 201b
prognostic factors, 267 recent advances, 132 prescribing, 37, 37b
radiotherapy, 19, 268–270, recurrent, 130 testicular cancer, 190–191
269t, 272, 274–275 resection margins, 12t Carcinoembryonic antigen (CEA),
radiotherapy side effects, 349 screening and prevention, 131 161–162, 169, 198
WHO classification and grading, secondary, 59, 59t, 301–302 Carcinoid tumours
264, 265b staging, 120, 120b atypical, lung, 91, 105
Brainstem gliomas, 273–274 triple negative, 132 lung, 90, 105
BRCA1/BRCA2 mutations, 48–50, Breast feeding, 291 pancreas, 158
48t Breathlessness, 71, 106–107 small intestine, 159
breast cancer, 115 Breslow thickness, 233 Carcinoma, poorly differentiated,
diagnosis, 45–46, 49, 49b Bronchoalveolar carcinoma, 90 with unknown primary,
genetics, 45, 47–49 Bronchoscopy, 92, 136 289
management, 50, 50f Buprenorphine, 68t Carcinoma-in-situ
ovarian cancer, 197 Burkitt’s lymphoma, 303t, 305 bladder, 177
prophylactic surgery, 13, 13b, breast, 121
49 penis, 194–195, 241
Breaking bad news, 5–6, 6b
C testes, 189
Breakthrough analgesia, 69b, 70f CA-125, serum see also Bowen disease
Breast cancers with unknown primary, Cardiac failure, cancer survivors,
conserving surgery, 123–124 287 63, 64t
imaging, 118–119, 119f–120f ovarian cancer, 198, 202–205 Cardiac late effects of treatment,
reconstruction surgery, 123 ovarian germ cell tumours, 221 63, 64t
surgical anatomy and lymphatic CA19.9, serum, 153, 155–156, Carmustine, 35, 273
drainage, 116–117, 117f 198 Cauda equina syndrome, 329
Breast cancer, 48t, 115–133 Cachexia, cancer, 72 Causes of death, after cancer
aetiology, 115, 116t Caelyx, ovarian cancer, 201b, treatment, 64–65
bilateral, 132 203–204 CAV chemotherapy, small cell
carcinoma-in-situ, 121 Calvert formula, 37, 37b lung cancer, 101b
case presentation, 118b Camptothecans, 32b, 35 CCNU, brain tumours, 270b,
early stage invasive, 121–128 Cancer cachexia, 72 274–275
377
 INDEX

Centigray (cGy), 25 brain tumours, 270, 270b, prostate cancer, 188

Central nervous system (CNS) 272–273, 275 rectal cancer, 167
tumours, 264–281 breast cancer, 122f, 125, 126b, research see clinical trials
Cerebral oedema, radiotherapy- 128, 130 routes of administration, 37–38
associated, 349 carcinoid tumours, 158 sanctuary sites, 35b
Cerebrospinal fluid (CSF) cervical cancer, 216–219 second malignancies after,
evaluation, 266 classes of agents, 30, 32b, 32f 58–59, 59t
Cervical cancer, 212–219 colorectal cancer, 164–165, skin cancer, 242
evaluation and staging, 213, 165t, 168–169 soft tissue sarcomas, 258–261,
214f, 215t combination, 32–33, 34b 258b–259b, 325
HIV-related, 296 complementary therapy spinal cord compression, 331
management, 213–218, 216f interactions, 40 superior vena cava obstruction,
pathogenesis and pathology, cycles, 34b 338
213b delivery, 35–40 testicular cancer, 190–192, 192b
pregnancy, 292 dose adjustment, 38–39 thymoma, 112–113, 114b
presentation, 213 endometrial cancer, 209, toxicities, 39b, 40f
prevention, 219 211–212, 211b toxicity recording, 38
prognosis, 219 Ewing’s sarcoma, 251–252 tumour cell responses, 31–32,
recurrence, 218–219 extravasation, 344–345 33b, 33f
screening, 219 gallbladder cancer, 151 see also chemoradiation
Cervical lymph nodes, 78f gastric cancer, 145–147, 146b Chest wall sarcomas, management,
Cervical lymphadenopathy, with gestational trophoblastic disease, 257
unknown primary, 288 225–226, 225b Chest X-ray
Cetuximab, 370–372, 372f HAART interactions, 297 bladder cancer, 177, 179f
brain tumours, 270 head and neck cancer, 81–82, head and neck cancer, 79
colorectal cancer, 169 84b Hodgkin’s disease, 298–299,
head and neck cancer, 82, history of development, 30, 31f, 299f
84b 32b lung cancer, 92, 94f
oesophageal cancer, 141 hypersensitivity reactions, mesothelioma, 107–108, 108f
as radiation modulator, 29 342–344, 343t pregnancy, 290
toxicity, 343t, 370t informed consent, 35–36, 36b thymoma, 111, 112f
CHART see continuous Kaposi’s sarcoma, 296, 297b Child–Pugh grading system, 149b
hyperfractionated kidney cancer, 176 Childhood cancers see paediatric
accelerated radiotherapy late effects, 58–65 cancers
Chemoradiation (CRT), 29, 101 leukaemia, 310–311, 313 Chlorambucil, 35
anal cancer, 171–172, 172t liver cancer, 150 leukaemia, 313
bladder cancer, 181–182 lung cancer, 101–105, 101b lymphoma, 304, 308
cervical cancer, 215 lymphoma, 300–301, 300b, Chlorpheniramine, 343
colorectal cancer, 165t 304–306, 305t, 308 Chlorpromazine, 71
gastric cancer, 145 malignant melanoma, 233–236, Cholangiocarcinoma (CCA),
head and neck cancer, 81, 84b 236t 152–154
lung cancer, 101–103 mesothelioma, 109–110 Cholangiography, 153, 155
oesophageal cancer, 137–140 myeloma, 317–318, 319t Cholecystectomy, radical, 151,
pancreatic cancer, 156–157 oesophageal cancer, 137, 152f
rectal cancer, 167 139–141, 140b Choledochal cysts, 152
vaginal cancer, 230 osteosarcoma, 247–249 Chondrosarcoma, 245, 253–254
Chemotherapy, 30–40 ovarian cancer, 200–203, 201b imaging, 253, 253f–254f
actions of specific drug classes, ovarian tumours, 222–223, management, 246, 254
33–35, 35f 223b, 325 myxoid, 255b
adrenocortical carcinoma, 286 pancreatic cancer, 156–157 risk factors, 245
anal cancer, 172 penile cancer, 196 staging, 247t
bile duct cancer, 154 phases of treatment, 31b CHOP chemotherapy, 304–305,
bladder cancer, 178, 181–182, pregnancy, 291–292 305t, 313
181b prescribing, 36–37, 36f, 37b Choriocarcinoma, 224
378
 INDEX

Choroid plexus tumour, 274 heterogeneity of results, 367, endometrial cancer, 206
Choroidal metastasis, 333 367b gallbladder carcinoma, 151
Chronic health conditions, cancer patient recruitment, 357–358, gastric cancer, 143
survivors, 64 358b head and neck cancer, 79
Chronic lymphocytic leukaemia phases, 355–357, 359f kidney cancer, 174, 174f
(CLL), 312–314, 313t quality assessment, 368 lung cancer, 92, 94f
Chronic myeloid leukaemia stopping early, 363 lymphoma, 298, 302, 304f,
(CML), 311–312 CMV chemotherapy, 181, 181b 306f
Chronic myelomonocytic Co-morbidities, assessment of, 7 malignant melanoma, 232–233,
leukaemia, 314 Codeine, 68t 236
Cimetidine, 343 CODOX-M chemotherapy, 305, mesothelioma, 107–108, 108f
Cirrhosis of liver, 147–148, 150 305t oesophageal cancer, 136
Cisplatin, 35 Coeliac disease, 158 ovarian tumours, 198, 199f,
anal cancer, 171–172 Colectomy, prophylactic, 52–53, 221, 221f
bladder cancer, 181–182, 181b 52t pancreatic cancer, 155, 155f
brain tumours, 270b, 274–275 Colon cancer radiotherapy planning, 19–21,
cervical cancer, 215, 219 management, 53, 164f 21f
endometrial cancer, 211 resection margins, 12t small intestinal tumours, 159
gastric cancer, 146b, 147 see also colorectal cancer soft tissue sarcomas, 255
head and neck cancer, 81–82, Colonoscopy superior vena cava obstruction,
84b diagnostic, 161, 161f 337, 338f
lung cancer, 100–101, 101b, screening/surveillance, 52–53, testicular cancer, 190, 192f
104 169 thymoma, 111, 112f
mesothelioma, 109–110 Colony stimulating factors (CSFs), Concurrent controls, 361–362
oesophageal cancer, 138–140, 336, 337b Cone biopsy, 213, 292
140b Colorectal cancer (CRC), 159–170 Confidence intervals (CI), 365,
osteosarcoma, 247–249 aetiology, 160 366b
ovarian tumours, 223b epidemiology, 159–160 Conformal (3D) radiotherapy
skin cancer, 242 follow-up, 169 beam shaping, 22–23, 22b
testicular cancer, 192b inherited, 46t, 50–53, 51b, 160 planning, 21
thymoma, 113, 114b investigations, 161–162, Confusional state, acute, 332
Citalopram, 72 161f–162f Consent, informed
CK7, 288t management, 162–165, 164f, chemotherapy, 35–36, 36b
CK20, 288t 165t clinical trials participants,
Cladrabine, 314 pathogenesis and pathology, 357–358, 358b
Clark level, 233 160, 160f radiotherapy, 17
Clear cell carcinoma presentation, 160–161 Consolidation chemotherapy, 31b
endometrium, 205–206, 207t, prognosis and outcome, 169 Constipation, 39b, 69
212 screening, 169 Consultation, patient, 5–6, 6b
ovary, 197 secondary, 59t Continuous hyperfractionated
Clear-cell sarcoma, 255b staging, 162, 163f accelerated radiotherapy
Clinical approach, cancer patients, Complementary therapy, 40 (CHART), 26b, 28–29, 98
3–9 Complete response (CR), 44t Control groups, 361
Clinical Benefit, 42–43 Computed tomography (CT), 4, 4f Controls, concurrent or historical,
Clinical significance, clinical trial assessing response to treatment, 361–362
results, 365, 366b 43f Core biopsy, 10
Clinical target volume (CTV), bone tumours, 246 Coronary artery disease, cancer
20b brain metastases, 278, 279f survivors, 64t
Clinical trials, 355–359 brain tumours, 265, 266t, 276f Corticosteroids
advances, 358–359 cervical cancer, 213 adrenalectomized patients, 286
children and young adults, 326 cholangiocarcinoma, 153 brain tumours, 267–268
critical appraisal, 360–366, colonography, 161, 161f hypersensitivity reactions, 343
361b colorectal cancer, 161, 162f, leukaemia, 310
ethics, 357 169 myeloma, 319t
379
 INDEX

prostate cancer, 188–189 Digitally reconstructed images

skeletal effects, 61–62
D (DRRs), 19–21, 26, 26b
spinal cord compression, 330 Dacarbazine, 235, 300b Dihydrocodeine, 68t
Cough, 72, 350 Dactinomycin, 225–226, 225b Dimethicone, 71
Cowden syndrome, 54–55, 54t Dasatinib, 312 Disseminated intravascular
breast cancer, 47–48, 48t Daunorubicin, 297b, 310 coagulation (DIC), 311
Cranial irradiation, small cell lung De Gramont chemotherapy, Docetaxel
cancer, 104 modified (MdG), 165, 165t, breast cancer, 126b, 128, 130
Craniopharyngioma, 266t, 269t, 168–169 head and neck cancer, 81–82,
277, 277f Death(s) 84b
Craniospinal axis, evaluation, 266, cancer, numbers, 3 hypersensitivity reactions, 343,
267f causes of, after cancer 343t
Craniospinal radiotherapy, 269t, treatment, 64–65 lung cancer, 101b, 102
274–275 place of, 73 prostate cancer, 188
Critical appraisal, 360–366, 361b Death certificate, 73 soft tissue sarcomas, 259b,
screening questions, 360–361 Death rattle, 73 261
study report, 361–366 Debulking surgery, 13 Dose density, 31b
Crohn’s disease, 158 endometrial cancer, 210 Dose intensity, 31b
Cryotherapy ovarian tumours, 201, 221 Dose limiting toxicity, 355–356,
prostate cancer, 188 Delirium, 72, 332 356b
skin cancer, 241 Dental assessment, pre-treatment, Dose volume histogram (DVH),
Cryptorchidism, 189 39b, 61–62 23–24, 24b
CT see computed tomography Depression, 65, 72 Doxorubicin (Adriamycin)
Curative treatment, 31b Dermatitis, radiation, 348 bladder cancer, 181, 181b
chemotherapy, 34b Desmoid tumours, 254 breast cancer, 126b
radiotherapy, 15 Desmoplastic small round-cell carcinoid tumours, 158
surgery, 11–13 tumour, 255b endometrial cancer, 211, 211b
Cushing’s syndrome, 285–286 Dexamethasone, 71 Ewing’s sarcoma, 251
Cutaneous B cell lymphoma brain tumours, 267–268 Kaposi’s sarcoma, 297b
(CBCL), 244, 307 hypersensitivity reactions, 343 lymphoma, 300b
clinical features, 307 myeloma, 319t myeloma, 319t
management, 308 pain management, 70t osteosarcoma, 247–249
Cutaneous T cell lymphoma, 244, prostate cancer, 188–189 pegylated see caelyx
307 spinal cord compression, 330 soft tissue sarcomas, 258–259,
clinical features, 307, 307f Dexrazoxane, 345 259b, 261
management, 307–308 Diagnosis of cancer, 3, 4f Drop-outs, clinical trials, 364,
CVP chemotherapy, 305t, 308 breaking the news, 5–6, 6b 365b
Cyclophosphamide investigations, 3–4 Drug discovery, 355, 356f
breast cancer, 126b psychological impact, 65 Dry mouth, 349
Ewing’s sarcoma, 251 surgical techniques, 10 Ductal adenocarcinoma, pancreas,
haemorrhagic cystitis, 346–347 Diamorphine, 68t, 70f 154
leukaemia, 313 Diarrhoea, 39b, 69, 350 Ductal carcinoma, invasive,
myeloma, 319t Diazepam, 70t 115–116
Cystectomy, radical, 178b, Diclofenac, 68t Ductal carcinoma-in-situ (DCIS),
179–180 Diffuse idiopathic pulmonary 115
Cystitis neuroendocrine cell imaging, 118
chemotherapy induced hyperplasia (DIPNECH), 90 management, 121
haemorrhagic, 346–347 Diffuse large B-cell lymphoma Ductal hyperplasia, atypical, 115
radiation-induced, 350 (DLBCL), 303t Dukes’ staging system, 162,
Cystoscopy, 177 International Prognostic Index, 163f
Cytoreduction surgery see 302–303, 304b Duodenal obstruction, 157
debulking surgery treatment, 305 Duodenal tumours, 159
Cytosine arabinoside (cytarabine), Diffusion tensor imaging (DTI), Dysgerminomas, ovarian, 220–
33–34, 311 brain tumours, 265–266 223, 221f
380
 INDEX

Dysphagia presentation, 205 Erlotinib, 370–372, 372f

gastric cancer, 142, 146 prognostic factors, 206, 207t bile duct cancer, 154
oesophageal cancer, 134, synchronous cancers, 212 lung cancer, 102–103
140–141 Endometrial intraepithelial mesothelioma, 110
carcinoma, 205 pancreatic cancer, 157
Endometrial sampling, 206 toxicity, 370t
E Endometrial stromal sarcoma Erythroplasia of Queyrat, 194,
Eccrine carcinoma, 244 (ESS), 260–261 241
EDP chemotherapy, adrenocortical Endometrioid carcinoma, ESHAP chemotherapy, 305t
carcinoma, 286 endometrium, 205–206, Ethics, clinical trials, 357
Education, children and young 207t Etoposide (VP-16), 35
adults, 326 Endometrioid tumours, ovary, 197 Ewing’s sarcoma, 251
Elderly patients Endoscopic mucosal resection leukaemia, 311
basal cell carcinoma, 238 (EMR), 137, 144 lung cancer, 104
primary CNS lymphoma, Endoscopic retrograde ovarian tumours, 223b
276–277 cholangiopancreatography testicular cancer, 192b
prostate cancer, 187 (ERCP), 151, 153, 155, thymoma, 113, 114b
Electron beam radiation, 16, 16b, 155f Evidence-based medicine (EBM),
18f, 23 Endoscopic ultrasound (EUS) 360, 369
Eligibility criteria, clinical trials, gastric cancer, 143 appraising reports of clinical
364, 365b oesophageal cancer, 136, 136f trials, 360–366, 361b
EMA/CO chemotherapy, pancreatic cancer, 155 defined, 369
gestational trophoblastic Endoscopy, oesophageal cancer, rationale, 369
disease, 225b, 226 136 systematic reviews and meta-
EMA/EP chemotherapy, Environmental risk factors, lung analyses, 366–369
gestational trophoblastic cancer, 89 web resources, 361b
disease, 225b, 226 EP chemotherapy, thymoma, 113, Ewing’s sarcoma, 245, 250–252
Embryonal carcinoma, 220 114b children and young adults, 325
Emergencies, oncologic, 328–347 Ependymoma, 274 clinical features, 246, 246b,
Encephalopathy, 332–333 imaging, 266t, 267f 250
End-of-life care, 72–73, 327 radiotherapy, 269t, 274 extraskeletal, 258–259
End points, clinical trial, 362, spinal cord, 267f, 280 imaging, 250, 251f
364–366 Epidermal growth factor receptor late effects of treatment, 58–59,
Endo-oesophageal ultrasound (EGFR), 370–372, 371f 59b, 60f
(EUS), lung cancer, 95 Epidermal growth factor receptor management, 246, 251–252,
Endobronchial ultrasound (EBUS), (EGFR) inhibitors, 370– 251f–252f, 253b
95, 98f 372, 372f pathogenesis, 245–246, 255b
Endocrine disorders, cancer head and neck cancer, 82 prognostic factors, 250b, 252
survivors, 63–64, 64t lung cancer, 102–103 recurrent, 252
Endocrine therapy see hormone mesothelioma, 110 risk factors, 245
treatment as radiation modulators, 29 staging, 246, 247t
Endocrine tumours, 282–286 see also cetuximab; tyrosine Examination under anaesthesia
Endodermal sinus tumours (EST), kinase inhibitors (EUA)
220 Epipodophyllotoxins, 32b, 35 gynaecological cancers, 206,
Endoluminal procedures, Epirubicin, 35 213
colorectal cancer, 168 breast cancer, 126b head and neck cancer, 79
Endometrial cancer, 205–212 gastric cancer, 146b Excision biopsy, 10
aetiology, 205, 205t oesophageal cancer, 140, 140b Exclusion criteria, clinical trials,
diagnosis, 206, 206f Epithelial ovarian cancer see 363–364, 365b
FIGO staging, 206, 207b ovarian cancer, epithelial Exemestane, breast cancer, 127
follow-up, 212 Epratuzumab, 308 Exenteration
inherited, 46t, 205 Epstein–Barr virus (EBV), 77, gynaecological cancers, 212,
management, 207–212, 208f, 297–298 218–219, 230
210b Erectile dysfunction, 350 rectal cancer, 167–168
381
 INDEX

External beam radiotherapy oesophageal cancer, 138–140, malignant potential, 262, 262b,
(EBRT), 15–16 140b 262t
External ear canal tumours, 85 pancreatic cancer, 156–157 management, 262–263, 262b
Extrapleural pneumonectomy penile cancer, 195 small intestine, 159, 262
(EPP), 108 rectal cancer, 167 stomach, 261f, 262
Extravasation, 344–345 Folinic acid (FA) Gastrointestinal system
Eye tumours, 85 breast cancer, 126b cancers, 134–172
malignant melanoma, 85, colorectal cancer, 163, 165t, late effects of treatment, 63, 63b
236–237 168–169 metastases in melanoma, 235
Follicular carcinoma of thyroid, Gefitinib, 370–372, 372f
282–283 lung cancer, 102–103
F Follicular lymphoma, 303–304, mesothelioma, 110
Faecal occult blood (FOB), 169 303t oesophageal cancer, 141
Familial adenomatous polyposis Follicular Lymphoma International toxicity, 370t
(FAP), 51–52, 51t, 158, Prognostic Index (FLIP Gemcitabine, 33–34
160 score), 302–303, 304b bladder cancer, 181, 181b
Familial cancer see inherited Follow-up combination therapy, 34b
cancer after treatment, 8–9 lung cancer, 101b
Fatigue, 39b, 72, 348 losses to, clinical trials, 364, mechanism of action, 34b, 34f
Febrile neutropenia see 365b ovarian cancer, 203
neutropenia, febrile during treatment, 7–8 pancreatic cancer, 156–157
Female genital system, cancers of, Fractionation, radiotherapy, 17, soft tissue sarcomas, 259b, 261
197–230 20b, 28–29 Gemtuzumab ozogamicin, 311
Fentanyl, 68t, 70f advances in, 28–29 Genetic counselling, 46–47, 47b
Fertility schedules, 25, 26b Genetic screening, 8, 45–46
children and young adults, see also continuous Genetic testing, predictive, 45–46
326 hyperfractionated Genetics, cancer, 45–57
female cancer survivors, 61b accelerated radiotherapy see also inherited cancer
preserving surgery, ovarian Fractures/impending fractures, Genitourinary system cancers,
tumours, 199–200, 221 345–346, 346f, 346t 173–196
see also infertility Fraudulent clinical research, 363, Germ cell tumours (GCTs)
Fibromas, ovarian, 224 364b central nervous system, 275
Fibromatosis, aggressive, 254 Frozen section, 10 children and young adults, 325
Fibrosarcoma, 259b Fungal infections, 334, 334f G-CSF indications, 337b
Fine needle aspiration (FNA), ovary, 220–223, 222f
10–11 testes, 189
Fitness for treatment, assessing,
G Germinoma, 269t, 275
6–7, 7t Gabapentin, 67–69, 70t Gestational trophoblastic disease
Flavopiridol, 314 Gallbladder carcinoma, 150–151, (GTD), 224–226, 225b,
Fludarabine 151b 225t
leukaemia, 313 Gallstones, 150, 152 Giant cell tumours of bone, 254
lymphoma, 304 Gamma-radiation therapy, 17 Gleason grading system, 183,
5-fluorouracil (5-FU), 33–34 Gastric cancer, 141–147 183b
administration, 37–38 investigations and staging, Gliadel wafers, 273
anal cancer, 171–172 142–143, 143b, 143f Glioblastoma multiforme (GBM),
bladder cancer, 181–182 management, 144–147, 145f, 266t, 270–271
breast cancer, 126b 146b biological agents, 270
carcinoid tumours, 158 resection margins, 12t, 144 recurrence and progression, 273,
colorectal cancer, 163, 165t, Gastric stump cancer, 147 274f
168–169 Gastrinoma, 158 treatment, 272–273
gallbladder cancer, 151 Gastrointestinal stromal tumours Gliomas, 270–274
gastric cancer, 146b, 147 (GIST), 159, 261–263 aetiology, 264
head and neck cancer, 81–82, assessing response to treatment, anaplastic (grade 3), 272–273
84b 42, 263 biological agents, 270
382
 INDEX

brainstem, 273–274 Haemorrhagic cystitis, gynaecological cancers, 197,

chemotherapy, 270b chemotherapy induced, 205
high grade (grade 3 and 4), 346–347 Hereditary papillary renal cell
272–274 Hair loss, 39b, 349 carcinoma (HPRC), 173
imaging, 265–266 Hairy cell leukaemia (HCL), 314, Herpes simplex virus infections,
low grade (grade 2), 271–272 314f oral, 71
radiotherapy, 269t Haloperidol, 72 Heterogeneity, clinical trials
spinal cord, 280–281 Head and neck cancer, 77–88 results, 367–368
see also astrocytoma; aetiology, 77 Hiccups, 71
oligodendroglioma anatomy, 78, 78f High frequency ultrasound
Gliomatosis cerebri, 271–272 clinical evaluation, 79 (HiFU), prostate cancer,
Gliomatosis peritonei, 220 follow-up, 85 188
Glucagonoma, 158 investigations, 79, 80f Highly active antiretroviral
Gonadal failure, 60, 64t, 350–351 malignant melanoma, 237 therapy (HAART), 295,
see also infertility management, 79–82, 81b, 84f 297
Gonadotropin-releasing hormone presentation, 79 chemotherapy interactions, 297
(GnRH; LHRH) agonists prognosis, 85 Kaposi’s sarcoma, 296
breast cancer, 127 radiotherapy side effects, Histological diagnosis see tissue
endometrial cancer, 211 349–350 diagnosis
prostate cancer, 186–187 recurrent, treatment, 83–84 Historical controls, 361–362
side effects, 187b resection margins, 12t HIV infection see human
Good clinical practice (GCP), 357 squamous cell see under immunodeficiency virus
Gorlin’s syndrome, 237 squamous cell carcinoma infection
Goserelin, breast cancer, 127 TNM staging, 79, 80b HMLH1 mutations, 52–53
Granulocyte colony-stimulating uncommon types, 88 HMSH2 mutations, 52–53
factor (G-CSF), 38–39, 336, WHO classification, 78b HMSH6 mutations, 52–53
337b Hearing loss, cancer survivors, 63 Hodgkin and Reed–Sternberg cells
Granulocyte-macrophage colony- Helicobacter pylori, 142 (H-RS), 298
stimulating factor (GM- Heliox, 339 Hodgkin’s disease (HD), 298–302
CSF), 336 Hepatitis, viral, 147 classical, 298, 300–301
Granulosa cell tumours, ovarian, Hepatoblastoma, 325–326 HIV-positive patients, 297
224 Hepatocellular carcinoma (HCC), imaging, 298–299, 299f
Gray (Gy), 25 147–150, 148b, 149f International Prognostic Score,
Gross tumour volume (GTV), 20b children and young adults, 299, 300b
Gynaecological cancers, 197–230 325–326 lymphocyte-rich classical
Gynaecomastia, 187 HIV-positive patients, 297 (LRCHL), 298
Gynandroblastomas, 224 HER-2, as therapeutic target, management, 299–301, 300t,
370–372, 372f 301f, 302b
HER2+ breast cancer, 115–116 nodular lymphocyte
H management, 122f, 125, 128, 130 predominant (NLP), 298,
HAART see highly active scoring, 117 300
antiretroviral therapy Herceptin see trastuzumab nodular sclerosis, 298, 299t
Haematologic malignancies, Hereditary breast/ovarian cancer paediatric, teenage and young
298–319 syndrome, 48–50 adult, 323–325
phases of chemotherapy, 30, Hereditary cancer see inherited pregnancy, 293
31b cancer second malignancies, 59,
secondary, 58–59, 314–315 Hereditary diffuse gastric cancer 301–302
see also leukaemia; lymphoma (HDGC) syndromes, 47–48, staging, 299, 299t
Haematology toxicity chart, 40f 48t WHO classification, 298,
Haematuria, 177 Hereditary non-polyposis colon 299t
Haemoglobin levels, 27–28 cancer (HNPCC) (Lynch Hormone treatment, 40–41, 41t
Haemoptysis, 72 syndrome), 51–53, 160 breast cancer, 122f, 125–130
life-threatening, 338 clinical features, 51b, 51t, 52 endometrial cancer, 211–212
lung cancer, 106 diagnosis, 52–53, 53b late effects, 61, 61b
383
 INDEX

ovarian cancer, 204 Hypocalcaemia Immunoglobulins, intravenous,

prostate cancer, 40–41, 41t, management, 343t 313–314
186–187 tumour lysis syndrome, 330b, Immunohistochemistry, cancers of
Human chorionic gonadotrophin 342 unknown primary, 287,
(hCG; beta-hCG) Hyponatraemia, lung cancer, 288t
brain tumours, 275 91–92 Incisional biopsy, 10
gestational trophoblastic disease, Hypopharyngeal tumours, 81b, Inclusion criteria, clinical trials,
224, 226 87–88 364, 365b
ovarian germ cell tumours, Hypopituitarism, radiation- Induction chemotherapy, 31b
220 induced, 64t, 349–350 Infections
testicular germ cell tumours, Hypothyroidism, radiation- chemotherapy-related, 39b
189–190 induced, 64t, 349–350 see also neutropenia, febrile
Human immunodeficiency virus Hysterectomy Infertility
(HIV) infection, 295–297 modified radical, 209–210, 214 cancer survivors, 59–61,
AIDS-defining malignancies, radical, 214–215 60b–61b, 64t
295–297, 296b simple, 213 radiation-induced, 350–351
anal cancer, 171, 297 total abdominal (TAH), 207, see also fertility; gonadal
chemotherapy–HAART 224 failure
interactions, 297 vaginal, 207 Inflammatory bowel disease, 160
non-AIDS-defining malignancies, Hysteroscopy, 206 Inguinal lymphadenectomy, penile
296b, 297 cancer, 196
pathogenesis of cancers, 295 Inguinal lymphadenopathy, with
primary CNS lymphoma, 297,
I unknown primary,
306 Ifosfamide 288–289
Human papillomaviruses (HPV) encephalopathy, 333 Inherited cancer, 45–57, 46t
anal cancer and, 170 Ewing’s sarcoma, 251 diagnosis, 45–46
gynaecological cancers and, haemorrhagic cystitis, 346–347 genetic counselling, 46–47,
212–213, 226, 229 osteosarcoma, 248–249 47b
head and neck cancer and, 77 ovarian tumours, 223b mechanisms, 45, 47f
vaccines, 219 soft tissue sarcomas, 258–259, risk reduction surgery, 13, 13b
Hutchinson’s freckle, 231 259b, 261 Inhibin, 223
Hyaluronidase, 345 Image guided radiotherapy Insulinomas, 157
Hydromorphone, 68t, 70f (IGRT), planning, 21, 22f Intensity modulated radiotherapy
Hyoscine butylbromide, 70t Imaging (IMRT)
Hypercalcaemia of malignancy, diagnostic, 3–4 head and neck cancer, 81, 84f,
339–341 staging, 4, 4f 349
management, 106, 339–340, see also specific modalities planning, 21, 22f
341f Imatinib, 37 prostate cancer, 185
pathogenesis, 91–92, 339 gastrointestinal stromal Intention to treat analysis, 364,
Hyperkalaemia tumours, 262, 262b 365b
management, 343t leukaemia, 310, 312 Interferon-α
tumour lysis syndrome, 330b, toxicity, 370t kidney cancer, 175
342 Immune therapy, 41 malignant melanoma, 233–236
Hyperphosphataemia bladder cancer, 178–179 Interferons, 41
management, 343t malignant melanoma, 235–236 Interleukin-2 (IL-2)
tumour lysis syndrome, 330b, osteosarcoma, 248–249 kidney cancer, 175
342 Immunocompromised patients, malignant melanoma, 235–236
Hypersensitivity reactions, 295 Interleukins, 41
342–344, 343t–344t, anal cancer, 170 Internal mammary nodes, 117
344f oral infections, 71 International Study of Infarct
Hyperuricaemia primary CNS lymphoma, 276 Survival (ISIS), 363b
management, 342 skin cancers, 231, 242 Intestinal obstruction, 71
tumour lysis syndrome, 330b, see also human immunodeficiency bowel cancer, 160–161
342 virus infection ovarian cancer, 204
384
 INDEX

Intra abdominal metastases, soft paediatric, 321–323, 322b

tissue sarcomas, 259, 259b
L phases of chemotherapy, 30,
Intracranial pressure, raised, 332 Lacrimal gland tumours, 85 31b
Intraductal papillary mucinous Lactate dehydrogenase (LDH), secondary to previous
neoplasms (IPMNs), 189–190, 221, 233, 246 chemotherapy, 58–59, 59t
pancreas, 158 Langerhans cell histiocytosis see also specific types
Intraperitoneal chemotherapy, 38, (LCH), 325 Li–Fraumeni syndrome (LFS),
38b, 39f Lantreotide, thymoma, 113 53–54, 54t
ovarian cancer, 202 Laparoscopy brain tumours, 264
Intrathecal (IT) chemotherapy, 38, cholangiocarcinoma, 153 breast cancer, 47–48, 48t, 54
38b, 38f gastric cancer, 143 Chompret criteria, 54b
leukaemia, 310 oesophageal cancer, 136 osteosarcoma, 245
Intratubular germ cell neoplasia, pancreatic cancer, 156 Limb perfusion, isolated see
189 Lapatinib, 370–372 isolated limb perfusion
Intravenous chemotherapy, 37–38 bile duct cancer, 154 Limb soft tissue sarcomas,
Intravesical therapy, bladder breast cancer, 130 management, 257, 257f,
cancer, 178–179 Large cell carcinoma, lung, 90 259–260
Investigations, 3–4 Large cell neuroendocrine Limb sparing surgery, bone
Irinotecan, 35 carcinoma, lung, 91 tumours, 246, 250f
colorectal cancer, 164–165, Large loop excision of Limb weakness, 328
165t, 168–169 transformation zone Linear accelerators (LINACs), 16,
Irradiated volume (IrV), 20b (LLETZ), 213 16b, 17f
Irritant drugs, 344, 345t Laryngeal cancer, 81–82, 81b, 88 Lip cancer, 87, 243
Isolated limb perfusion, 236, Late effects of cancer treatment, Liposarcoma, 259b, 260
259–260 58–65, 326 myxoid, 255b, 260
Ivor–Lewis oesophagectomy, medical, 58–64, 59b retroperitoneal, 260f, 261
138 psychological, 65 Liver cancer, 147–150
on relationships, 65 HIV-positive patients, 297
social, 65 Liver disease, chronic, 147
J Laxatives, 69 Liver flukes, 152
Jaundice, obstructive Leiomyosarcomas, 260 Liver metastases
biliary tract cancer, 151–154 chemotherapy, 259b colorectal cancer, 162, 162f,
pancreatic cancer, 154–157 prognostic factors, 259b 164–165, 169
retroperitoneal, 261 malignant melanoma, 235–237
uterine, 260–261 soft tissue sarcomas, 259
K Lenalidomide surgical resection, 12, 13b
K-ras gene, 169 chronic lymphocytic leukaemia, Liver transplantation, 149, 154
Kaposi’s sarcoma (KS), 295–296, 314 Liverpool Care Pathway for the
296b–297b, 296f myeloma, 318, 319t Dying Patient (LCP), 73
Karnofsky performance status Lentigo maligna melanoma, 231 Lobectomy, pulmonary, 97, 100t
(KPS), 6–7, 7t Leptomeningeal carcinomatosis, Lobular carcinoma, invasive, 116
Keratoacanthoma, 241, 243 280, 280f Lobular carcinoma-in-situ, 115,
Ketamine, 67–69 Leser–Trelat, sign of, 142 121
Kidney cancer, 173–176 Letrozole Lomustine, 35
investigations and staging, 174, breast cancer, 127–128, 130 Losses to follow-up, clinical trials,
174f, 175t ovarian cancer, 204 364, 365b
management, 174–176 Leukaemia, 308–314 Lung cancer, 89–107
pathology, 173–174 acute, 308–311 aetiology, 89
C-KIT gene mutations, 41–42, chemotherapy, 30 classification, 90–91, 90b
262, 262b chronic lymphocytic (CLL), epidemiology, 89
Klatskin tumours, 152 312–314, 313t follow-up, 106–107
Knudson two-hit hypothesis, 45, chronic myeloid (CML), G-CSF indications, 337b
47f 311–312 investigations and staging,
Kruckenberg’s tumour, 142 hairy cell (HCL), 314, 314f 92–96, 93f, 95b
385
 INDEX

management, 96 testicular, 306–307 prophylactic, 13, 13b, 49

multiple primary tumours, see also Hodgkin’s disease; radiotherapy after, 124–125
106 non-Hodgkin’s lymphoma; Maximum tolerated dose (MTD),
in never smokers, 106 specific types 355–356, 356b
palliative care, 106–107 Lynch syndrome see hereditary MEA chemotherapy, gestational
paraneoplastic syndromes, non-polyposis colon cancer trophoblastic disease, 225b
91–92, 91b Measurable lesions, 43b
pathogenesis and pathology, Measurement error, 365
89–91
M Mediastinal nodes, 96f
pathology, 90–91 M protein, 316, 319 Mediastinoscopy, 95–96
pre-invasive lesions, 90 Magnetic resonance cholangio- Medical late effects of cancer
presentation, 91–92 pancreatography (MRCP), treatment, 58–64, 59b
prognostic factors and survival, 153, 155 Medline searches, limitations,
105 Magnetic resonance imaging 366–367
resection margins, 12t (MRI) Medroxyprogesterone acetate, 72
secondary, 59t, 301–302 bladder cancer, 177 endometrial cancer, 211
superior sulcus, 105–106 bone tumours, 246, 247f, 254f kidney cancer, 175
Lung diseases, previous, 89 brain metastases, 278, 280 Medullary carcinoma of thyroid,
Lung metastases brain tumours, 265–266, 266t, 282, 284–285
bladder cancer, 179f, 182 267f Medulloblastoma, 266t, 274–275
colorectal cancer, 164–165 breast cancer, 118–119, 120f chemotherapy, 270b, 274–275
Ewing’s sarcoma, 252 cervical cancer, 213, 214f radiotherapy, 269t, 274–275
kidney cancer, 176 colorectal cancer, 161–162, Megestrol acetate, 72, 348–349
malignant melanoma, 235–237 162f endometrial cancer, 211
osteosarcoma, 248–249, 250f endometrial cancer, 206, 206f Melanoma, malignant, 231–237
soft tissue sarcomas, 259b gallbladder carcinoma, 151 aetiology, 231
surgical resection, 12, 13b head and neck cancer, 79, 80f cutaneous, 231–236
Lung resection lung cancer, 95 epidemiology, 231
bronchoplastic or sleeve, 97 ovarian tumours, 221 follow-up, 236
wedge or segmental, 97 penile cancer, 194–195, 195f initial assessment, 232, 232f
Luteinizing hormone releasing pregnancy, 290 investigations, 232–233
hormone (LHRH) agonists solitary plasmacytoma, 315, management, 233–236
see gonadotropin-releasing 315f mucosal, 237
hormone agonists spinal cord compression, 329, non-cutaneous, 236–237
Lymph nodes 329f ocular, 85, 236–237
dissection, 11–12 thymoma, 111 pathology, 231–232
sampling, 11 thyroid cancer, 282, 283f pregnancy, 293
sentinel biopsy see sentinel node Magnetic resonance spectroscopy presentation, 232
biopsy (MRS), 265 prognostic factors, 232b, 236
surgery of regional, 11–12 Maintenance chemotherapy, 31b resection margins, 12t, 233
Lymphangitis carcinomatosis, Mainz II diversion, 180 staging, 233, 234t
71 Malignant peripheral nerve sheath vaccine, 234
Lymphoedema, 228 tumours (MPNST), 254, vagina, 229
Lymphoma, 298–308 254f, 259b Melphalan
bone, 306 Mammography melanoma, 236
cutaneous, 244, 307–308, diagnostic, 118, 119f myeloma, 319t
307f screening, 131, 368, 369b Menin, 56
HIV-related, 296–297 Mantle cell lymphoma (MCL), Meningioma, 266t, 275–276,
paediatric, teenage and young 303t, 305–306 276f–277f
adult, 323–325, 324t Margins, resection, 11, 12t radiotherapy, 269t, 276
pregnancy, 293 Mastectomy spinal cord, 281
primary CNS see primary CNS breast reconstruction after, 123 treatment, 276
lymphoma carcinoma-in-situ, 121 Menopause, premature, 60,
small intestine, 158–159 invasive carcinoma, 123, 128 350–351
386
 INDEX

Mercaptopurine, leukaemia, 310 Mitotane, 286 smouldering, 319

Merkel cell carcinoma, 243–244, Mitrofanoff diversion, 180 staging, 317, 317t
243f Mixed adenocarcinomas, Myelosuppression, treatment-
Mesenchymal tumours endometrium, 205 induced, 39b, 349
endometrium, 205 Mixed carcinomas, ovarian, 197 Mylotarg, 311
see also sarcomas Mixed germ cell tumours, ovarian, Myocardial infarction (MI), cancer
Mesna, 346–347 220 survivors, 63, 64t
Mesothelioma, 107–110 Mixed small and non-small cell Myxoid chondrosarcoma, 255b
aetiology, 107 lung cancer, 105–106 Myxoid liposarcoma, 255b, 260
future directions, 110 Mohs’ micrographic surgery, 239,
investigations and staging, 242
107–108, 109t Mole, invasive, 224
N
management, 108–109 Monoclonal gammopathy of Naevi, multiple benign, 231
medicolegal implications, 109 unknown significance Naloxone, 66–67
pathogenesis and pathology, 107 (MGUS), 319 Narrative reviews, 368
peritoneal, 110 Morphine Nasal cavity tumours, 85–86
presentation, 107 breathlessness, 71 Nasopharyngeal cancer, 86
prognostic factors and survival, pain management, 66, 68t, 70f imaging, 80f, 86
109, 110t Mouth care, 349 management, 81b, 86
Meta-analyses, 366–369 Mouth infections, 71 National Cancer Institute
Meta-regression, 368 Mouth washes, 349 Common Toxicity Criteria
Metaiodobenzylguanidine (MIBG) MPT chemotherapy, myeloma, 318 and Adverse Events version
scan, 323 MRI see magnetic resonance 3 (NCI CTCAE v3), 38
Metastases imaging Nausea and vomiting, 69, 71t
curative resection, 12, 13b MTOR inhibitors, 373–374 chemotherapy-induced, 39b
diagnosis, 4, 4f Mucinous cystic neoplasms, radiotherapy-induced, 350–351
see also specific sites of pancreas, 158 Neoadjuvant treatment, 31b
metastasis Mucinous tumours, ovarian, 197 assessing response, 42
Methadone, 68t Mucosa-associated lymphoid tissue Nephrectomy, 174–175
Methotrexate, 33–34 (MALT) lymphoma, 306 Nephroblastoma (Wilms’ tumour),
bladder cancer, 181, 181b Mucositis, 39b, 349 323, 324f
breast cancer, 126b Multidisciplinary management, 5 Neuroblastoma, 323
gestational trophoblastic disease, Multiple endocrine neoplasia Neurocognitive impairment, 63
225–226, 225b (MEN) syndromes, 55–57, Neuroendocrine carcinomas,
leukaemia, 310 56t poorly differentiated, 289
osteosarcoma, 247–249 type 1 (MEN1), 56, 56t, 158 Neuroendocrine tumours
primary CNS lymphoma, type 2 (MEN2), 56, 56t, lung, 90–91
276–277 284–285 skin, 243–244
Methylene blue, 333 Muramyl tripeptide (MTP), see also small cell lung carcinoma
Methylguanine-DNA osteosarcoma, 248–249 Neurofibromatosis
methyltransferase (MGMT) Muscle spasm, 70t type I (NF1), 254, 254f, 264
gene promoter, Musculoskeletal system cancers, type II (NF2), 264, 275
methylation, 273 245–263 Neurological late effects of
Metoclopramide, 71 MVAC chemotherapy, 181, 181b treatment, 62–63, 62b–63b,
Microcystic adnexal carcinoma, Myasthenia gravis, 111–112 62f
244 Mycosis fungoides (MF), 244, Neuropathic pain, 67–69, 70t
Microsatellite instability (MSI), 53 307–308, 307f Neutropenia, febrile, 38–39,
Middle ear tumours, 85 Myelodysplastic syndromes 333–336, 334f
Minimal access surgery, 13–14 (MDS), 314–315 management, 334–336, 335f
Mirtazapine, 72 secondary, 58–59, 314–315 MASCC risk-index score, 336b
Mitomycin C (MMC) Myeloma, 316–319 Neutrophil counts, 27–28
anal cancer, 171 diagnosis, 316–317, 317b, 317f NHL see non-Hodgkin’s
bladder cancer, 178, 181–182 management, 317–318, 318f, lymphoma
mesothelioma, 110 319t Nifedipine, 70t, 71
387
 INDEX

Nitrosoureas, 32b, 35 Oblimersen sodium, 314, 374 Orbital tumours, 85

Non-alcoholic fatty liver disease Occupational risk factors Organs at risk (OARs) (in
(NAFLD), 147 bladder cancer, 177 radiotherapy), 21
Non-dysgerminomas, ovarian, head and neck cancer, 77 tolerance dose, 24, 25t
220–223 kidney cancer, 173 treatment plan evaluation,
Non-Hodgkin’s lymphoma (NHL), lung cancer, 89 23–25, 24b
302–308 mesothelioma, 107 Oropharyngeal tumours, 81b, 87
AIDS-related, 296–297 Octreotide, 69 Osteonecrosis, 61–62
follow-up, 308 carcinoid tumours, 158 Osteopenia, 61, 127–128
high-grade, 304–306 thymoma, 113 Osteoporosis, 61, 127–128
paediatric, teenage and young Oesophageal cancer, 134–141 Osteoradionecrosis, 61
adult, 323–325, 324t aetiology, 134, 135b Osteosarcoma, 245–250,
pathology, 302, 303t clinical features, 134–135 247f–248f
pregnancy, 293 evaluation, 135 children and young adults, 325
primary extra-nodal, 306–308 investigations and staging, localized, 247–248
prognostic factors, 302–303, 136–137, 137b management, 246–250,
304b management, 137–141, 138f 249f–250f
treatment, 303–308 pathogenesis and pathology, metastatic, 248–249, 248b, 250f
tumour lysis syndrome, 134 pathogenesis, 246
341–342 resection margins, 12t prognostic features, 248b
Non-measurable lesions, 43b Oesophagitis, radiation, 350 recurrent, 250
Non-seminomatous germ cell Oesophagogastroduodenoscopy risk factors, 245
tumours (NSGCT), 189, (OGD), 142 staging, 246, 247t
194 Oesophagus, anatomy, 134, 135f Outcomes, clinical trial, 362,
investigations and risk Oestrogen 364–366
classification, 189–190, 190t breast cancer and, 127 Outer ear (pinna) tumours, 85
postoperative management, endometrial cancer and, 205 Ovarian cancer, epithelial (EOC),
192–194, 193f prostate cancer, 187 197–205
Non-small cell lung carcinoma Oestrogen receptors (ER) aetiology, 197
(NSCLC), 90 breast cancer, 115–117, 125 familial, 46t, 197
management, 96–103, 99f, 100t, endometrial cancer, 205, 211 FIGO staging, 198, 199b
101b ovarian cancer, 204 follow-up, 204–205
palliative care, 106–107 Offspring, cancer survivors, 60–61 G-CSF indications, 337b
prognostic factors and survival, Oligodendroglioma, 266t, 271, heterogeneity of paclitaxel trials,
105 271f 367, 367b
with solitary metastases, 106 anaplastic, 266t, 273 investigations, 198, 199f
staging, 94–96, 95b, 96f mixed, 271–272 management, 198–202, 200f
Non-steroidal anti-inflammatory treatment, 271–272 pathogenesis and pathology,
drugs (NSAIDs), 68t Ommaya reservoir, 38b, 38f, 280f 197
Normal tissue complication Oncogenes, 45 pattern of spread, 197–198
probability (NTCP), 26b, Oncoplastic surgery, 13 pregnancy, 293–294, 294f
27f Ondansetron, 350 presentation, 198
Nose, tumours of, 85–86 Onion skin appearance, 250, 251f prognosis, 202, 202t
Nottingham grading, breast Oophorectomy relapse, 202–204, 203f
cancer, 117b breast cancer, 127 synchronous endometrial cancer,
Nottingham prognostic index, prophylactic, 13b, 49 212
breast cancer, 122f, 131 Opioids, 66–67 Ovarian failure, premature, 60,
Number needed to treat (NNT), dose titration, 66, 69b 350–351
366b side effects and toxicity, 66–67 Ovarian tumours
switching, 66–67, 70f germ cell tumours (GCTs),
Optic neuropathy, drug-induced, 220–223, 222f
O 333 risk of malignancy index (RMI),
Obesity Oral cavity tumours, 81b, 87 198, 198b
cancer survivors, 64 Oral chemotherapy, 38 sex cord stromal tumours,
388 renal cancer and, 173 Oral infections, 71 223–224
 INDEX

Oxaliplatin colorectal cancer, 168–169 PCV chemotherapy, gliomas, 270b

colorectal cancer, 163–165, endometrial cancer, 211 PDGFR gene mutations, 262b
165t, 168–169 gallbladder cancer, 151 PEB chemotherapy, testicular
oesophageal cancer, 140 gastric cancer, 146–147 cancer, 191–192, 192b
Oxycodone, 68t, 70f head and neck cancer, 82–84 Pelvic lymph node dissection
hepatocellular carcinoma, 150 cervical cancer, 214–215
kidney cancer, 174–175 endometrial cancer, 207
P lung cancer, 106–107 Pemetrexed, mesothelioma,
P-values, 365, 366b oesophageal cancer, 137, 109–110
Packer regime, 270b, 274–275 140–141, 140b Penile cancer, 194–196, 195f, 196t
Paclitaxel, 34 ovarian cancer, 203–204 Pentostatin, 314
breast cancer, 126b, 130, 132 pancreatic cancer, 157 Percutaneous ablation
combination therapy, 34b penile cancer, 196 hepatocellular carcinoma,
endometrial cancer, 211, 211b prostate cancer, 188–189 149–150
heterogeneity of trial results, radiotherapy, 15, 69 liver metastases, 169
367, 367b surgery, 13 Percutaneous transhepatic
hypersensitivity reactions, 343, Pamidronate, 340 cholangiography, 155
343t Pancoast’s tumour, 105 Performance status (PS), 6–7, 7t
Kaposi’s sarcoma, 297b Pancreatic cancer, 154–158 Peritoneal carcinoma, primary,
lung cancer, 101b diagnosis and staging, 155–156, 197
ovarian cancer, 200–204, 201b 155f Peritoneal carcinomatosis, women
Paediatric cancers, 320–327 inherited, 46t, 154 with, 287
aetiology, 320 management, 156–157, 156b Peritoneal mesothelioma, 110
body image and fertility, 326 staging, 156b Perluzumab, 372f
clinical features, 321, 321b Pancreatic cystic tumours, 158 PET see positron emission
clinical trials, 326 Pancreatic endocrine tumours, tomography
diagnosis and delays, 321, 322f 157–158 Peutz–Jeghers syndrome
education, 326 Pancreatic intra-epithelial breast cancer, 47–48, 48t
incidence/epidemiology, 320 neoplasia (PanIN), 154 gastrointestinal cancer, 51
late effects, 58, 326 Pancreaticoduodenectomy, 156 Phaeochromocytoma, 284
cardiac dysfunction, 63 Pancreatitis Phase 0 trial, 358, 358b
fertility, 59 chronic, 154 Phase I studies, 355–356, 356b,
obesity, 64 hereditary, 154 358b
psychological problems, 65 Panitumumab, 372f Phase II studies, 356, 358b
see also late effects of cancer colorectal cancer, 169 Phase III studies, 357, 357b–358b
treatment oesophageal cancer, 141 Phase IV studies, 357, 357b
psychological support, 326 Papillary adenocarcinoma, vagina, Philadelphia chromosome,
specific, 321–326 229 310–311
spinal cord compression, 332 Papillary carcinoma of thyroid, Photon beam radiation, 16, 16b,
transitional care, 327 282–283 18f, 23
types, 320, 321t Papillary serous carcinoma, Pineal tumours, 275
Paget’s disease of the nipple, 131 peritoneum, 197 Pinna tumours, 85
Pain Papillary serous tumours, ovarian, Pituitary adenomas, 277–278
assessment, 66, 67b 197 imaging, 266t, 277f
breakthrough, 69b, 70f Paracetamol, 68t management, 269t, 277–278
complex, 66–69 Paragangliomas, head and neck, Pituitary carcinoma, 278
management, 66–69 88 Pituitary dysfunction, cancer
non-pharmacological measures, Paranasal sinuses, tumours of, survivors, 63–64, 64t
69 85–86 Placebo effect, 363–364
Palliative care, 31b, 66–73 Paraneoplastic syndromes Placental alkaline phosphatase
bile duct cancer, 154 gastric cancer, 142 (PLAP), 221, 275
bladder cancer, 181 lung cancer, 91–92, 91b Placental site trophoblastic tumour
breast cancer, 130–131 Parasternal nodes, 117f (PSTT), 224, 226
cervical cancer, 219 Parinaud’s syndrome, 275 Planning organ at risk volume
chemotherapy, 34b Partial response (PR), 44t (PRV), 20b 389
 INDEX

Planning target volume (PTV), management principles, 290 Prostatectomy, radical, 185
20b, 23–25, 24b, 24f postpartum care, 292 Protocol, clinical trial
Plasmacytoma, solitary, 315–316, psychosocial support, 294 changes to original, 362–363
315f, 316b radiotherapy, 291, 291b pre-specified, 362
Platelet counts, 27–28, 336–337 surgery, 290–291 Psychological problems, cancer
Platelet transfusion, 336–337 systemic treatment, 291–292 survivors, 65
Platinum-based chemotherapy timing of delivery, 291 Psychosocial support see support
hypersensitivity reactions, in cancer survivors, 60–61, 60f, during treatment
342–343, 343t 61b PTEN mutations, 54–55
Merkel cell carcinoma, 243 termination, 290 Publication
ovarian tumours, 202–203, 223 Primary CNS lymphoma (PCNSL), duplicate, 366
see also carboplatin; cisplatin; 276–277, 306 foreign language, 367
oxaliplatin HIV-associated, 297, 306 Publication bias, 366, 366b, 368
Pleomorphic adenoma, parotid imaging, 266t, 306f Pulmonary function tests, 97,
gland, 86 Primary sclerosing cholangitis 100t, 299
Pleural effusions (PSC), 152–153 Pulmonary late effects of
lung cancer, 102, 108 Primitive neuroectodermal tumour treatment, 63
mesothelioma, 107–109, 108f (PNET), 245, 274–275
Plummer–Vinson syndrome, 135b, chemotherapy, 270b
141 staging, 246
Q
Pneumonectomy, 97, 100t Procarbazine, gliomas, 270b Question, clearly defined research,
extrapleural (EPP), 108 Proctitis, radiation, 350 362
Pneumonitis, radiation, 350 Proctocolectomy, prophylactic,
Poly (ADP-ribose) polymerase 13b, 52t
(PARP) inhibitors, ovarian Progesterone receptors (PgR)
R
cancer, 204 breast cancer, 115–117 R0, R1, R2 resections, 11
Poorly differentiated carcinoma, endometrial cancer, 205, 211 Radiation dermatitis, 348
with unknown primary, Progestogens, 72 Radiation dose
289 endometrial cancer, 211 bolus, 23
Positron emission tomography see also medroxyprogesterone foetal, 290–291, 291b
(PET) acetate; megestrol acetate prescription, 25, 27f
cervical cancer, 213 Prognostic factors, 5 tolerance, organs at risk (OAR),
colorectal cancer, 161–162 Progressive disease (PD), 44t 24, 25t
endometrial cancer, 206 Prophylactic cranial irradiation Radiation fibrosis, 350
gastric cancer, 143 (PCI), small cell lung Radiation recall, 348
head and neck cancer, 79 cancer, 104 Radiofrequency ablation (RFA)
Hodgkin’s disease, 299 Prostate cancer, 182–189 liver cancer, 150
lung cancer, 94–95, 97f aetiology, 183 liver metastases, 169
lymphoma, 308 hormone refractory (HRPC), malignant melanoma, 236
mesothelioma, 108 188 Radioimmunotherapy (RIT),
oesophageal cancer, 136 hormone treatment, 40–41, 41t, lymphoma, 308
ovarian tumours, 221 186–187 Radioiodine ablation
radiotherapy planning, 19–21, inherited, 46t, 183 side effects, 284b
21f investigations and staging, thyroid cancer, 283–284
Preclinical studies, 355 183–184, 184t Radionuclide treatment, 17
Prednisolone, myeloma, 319t management, 184–187 carcinoid tumours, 158
Prednisone, myeloma, 319t palliative treatment, 188–189 prostate cancer, 189
Pregabalin, 70t pathology, 183 Radiotherapy, 15–29, 16b
Pregnancy presentation, 183, 183b advances, 28–29
cancer during, 290–294 prognosis and survival, 189 beam shaping, 22–23, 22b,
care of baby, 292 Prostate specific antigen (PSA), 183 23f
diagnostic work-up, 290, cancer with unknown primary, bladder cancer, 180–181
291b 288 bone tumours, 249
future pregnancies, 292 predictive value, 183–184 brain metastases, 278
390
 INDEX

brain tumours, 19, 268–270, second malignancies after, 28, resection margins, 12t, 167
269t, 272–275 58–59, 59t see also colorectal cancer
breast cancer, 121, 124–125, side effects, 17, 28 Recurrence
124b–125b, 129 management, 348–351 management, 8–9
central airway obstruction, 339 simulators, 19–21, 21f re-irradiation after, 29
cervical cancer, 214–218, 217b, skin cancer, 239, 240b, salvage surgery, 13
218f 241–244 Reed–Sternberg (RS) cells, 298
chemotherapy with see soft tissue sarcomas, 257–259, Refractory anaemia, 314
chemoradiation 261 Relationships, cancer survivors,
choroidal metastasis, 333 solitary plasmacytoma, 315, 65
colorectal cancer, 168 316b Relative risk (RR), 366b
curative, 15 spinal cord compression, Relative risk reduction (RRR),
delivery methods, 15–17 330–331, 330b, 331f 366b
endometrial cancer, 207–212, spinal cord tumours, 280–281, Renal cancer see kidney cancer
209b 281b Renal cell carcinoma (RCC),
errors in treatment set up, superior vena cava obstruction, 173–176
26–27 338 aetiology, 173
Ewing’s sarcoma, 252 supportive care, 27–28 hereditary papillary, 173
external beam (EBRT), 15–16 systemic, 42 management, 174–176
follow-up care, 28 testicular cancer, 190–191, pathology, 173–174
fractionation, 17, 20b, 25, 26b 192b, 192f prognosis and survival, 176
future directions, 29 thymoma, 112, 114b staging, 175t
gallbladder cancer, 151 thyroid cancer, 284–285 Renal pelvis, cancer of, 173–174,
gap correction, 28 treatment verification and 177, 182, 182t
gastric cancer, 146 corrections, 25–27, 26b, Research, cancer
gynaecomastia prophylaxis, 27f clinical trials, 355–359
187 vaginal cancer, 230 critical appraisal, 360–369
head and neck cancer, 19, volumes, 20b, 21f fraudulent, 363, 364b
80–81, 81b, 82t, 83b vulval cancer, 227–228 Research question, clearly defined,
indications, 15 see also brachytherapy; 362
informed consent, 17 chemoradiation Resection margins, 11, 12t
kidney cancer, 176 Radon, 89 Respiratory secretions, 73
late effects, 58–65 Randomization, 361–362 Respiratory symptoms, lung
lung cancer, 98, 100t, 101–102, allocation concealment, 364 cancer, 91
104 phase II studies, 356 Response Evaluation Criteria in
lymphoma, 300–301, 300b, Randomized controlled trials Solid Tumours (RECIST)
307–308 (RCTs) criteria, 42–43, 43b, 44t
malignant melanoma, 235, 237 critical appraisal, 360–366 Response to treatment, assessing,
mesothelioma, 108–109 design, 357, 357b 42–43, 43f
mode of action, 19b, 19f Rapirnase, mesothelioma, 110 RET proto-oncogene, 56, 285
oesophageal cancer, 137–138, Rasburicase, 342 Retinoblastoma, 45, 55, 326
139b, 141 RB1 gene mutations, 55 osteosarcoma, 245
osteosarcoma, 248 RECIST criteria see Response Retroperitoneal sarcomas, 260f,
ovarian tumours, 222 Evaluation Criteria in Solid 261
palliative, 15, 69 Tumours (RECIST) criteria Reviews
penile cancer, 195–196, 196b Reconstructive surgery, 13 narrative, 368
planning, 18–28, 22b, 22f, 24b, Rectal bleeding, cancer survivors, systematic, 366–369, 369b
24f 63 Rhabdomyosarcoma (RMS)
pregnancy, 291, 291b Rectal cancer alveolar, 255b, 325
prostate cancer, 185–189, 185b, investigations and staging, 161, children and young adults, 325
186f 161f–162f embryonal, 325, 325f
rectal cancer, 167, 168t management, 165–168, 166f, late effects of treatment, 58–59
repeat, 29 168t management, 258–259
sarcomas, 253b presentation, 160–161 Richter’s syndrome, 313
391
 INDEX

Risk of malignancy index (RMI), Sertoli–Leydig cell tumours, Sodium valproate, 70t
ovarian tumours, 198, 198b ovarian, 224 Soft tissue sarcomas (STS),
Risk reduction surgery, 13, 13b Sex cord stromal tumours, 254–263
Rituximab, 41 223–224 aetiology, 254
hypersensitivity reactions, 343t Sezary syndrome (SS), 307–308 children and young adults, 325
leukaemia, 311 Shields, radiation, 23 diagnosis, 255
lymphoma, 300, 304–306 Sigmoidoscopy, 161 management, 253b, 255–260,
Roach formula, 183, 183b Signs of cancer, warning, 3, 3b 257f
Robotic assisted surgery, 14 Sister Mary Joseph nodule, 142 pathology, 255, 255b
Rodent ulcer, 237 Skin, radiation reactions, 348 presenting features, 255
Roswell Park, modified Skin cancers, 231–244 prognostic factors, 258, 259b
chemotherapy, 165t adnexal carcinomas, 244 specific subtypes, 260–263
basal cell carcinoma, 237–239 staging, 255, 256t
eyelids, 85 Solitary plasmacytoma, 315–316,
S lymphoma, 244, 307–308, 307f 315f, 316b
Salivary gland tumours, 86 malignant melanoma, 231–236 Somatostatin analogues, thymoma,
Salpingo-oophorectomy, bilateral Merkel cell carcinoma, 243–244 113
(BSO), 207, 224 squamous cell carcinoma, 12t, Sorafenib, 372–373, 373f
Salvage surgery, 13 239–243, 241f kidney cancer, 176
Sample size Skin metastases, malignant liver cancer, 150
adequacy, 365–366 melanoma, 235–236 malignant melanoma, 236
slippages, 364, 365b Small and non-small cell lung mesothelioma, 110
Sanctuary sites, chemotherapy, cancer, mixed, 105–106 Sperm banking, 60
35b Small cell carcinoma Spinal cord compression,
Sarcomas, 245–263 bladder, 182 metastatic (MSCC),
head and neck, 88 oesophagus, 141 328–332
orbital, 85 Small cell lung carcinoma (SCLC), intramedullary, 328, 332
paediatric, teenage and young 90 investigations, 329, 329f
adult, 325 management, 101b, 103–105, management, 329–331
radiotherapy, 253b 103f paediatric, 332
secondary, 58, 59t palliative care, 106–107 prognosis, 331–332
small intestine, 159 paraneoplastic syndromes, recurrence, 332
Screening 91–92 Spinal cord tumours, 280–281,
cancer, 8 prognostic factors and survival, 280b–281b
genetic, 8 105 Spindle cell carcinoma, skin,
Sebaceous carcinoma, 244 staging, 95b 241–242
Second cancers, 28, 58–59, 59b, Small intestine Splenectomy, 314
59t, 60f lymphoma, 158–159 Sputum cytology, 92
brain, 264 malignant tumours, 158–159 Squamous cell carcinoma (SCC)
Hodgkin’s disease, 59, 301–302 metastases, 159 anal canal, 170
Seminomas, 189, 194 obstruction, ovarian cancer, cervix, 213
investigations, 189–190 204 cutaneous, 12t, 239–243,
postoperative management, Small molecule drugs, 41–42 241f
190–194, 191f, 192b Smoking head and neck, 77
Sensitivity analysis, 368 gastrointestinal cancers and, aetiology, 77
Sensory deficits, 328 152, 154, 170 management, 81–82
Sentinel node biopsy (SNB), 11, head and neck cancer and, 77 pathogenesis and pathology,
12f lung cancer and, 89 77–78
breast cancer, 123–124 renal cancer and, 173 see also head and neck cancer
malignant melanoma, 233 Smooth muscle spasm, 70t kidney, 174
Serous cystic neoplasms, pancreas, Social issues, cancer survivors, 65 lip, 243
158 Socioeconomic status, head and lung, 90
Serous papillary carcinoma, neck cancer, 77 middle ear, 85
uterine (UPSC), 205–206, Sodium 2-mercaptoethane nose and paranasal sinuses, 85
392 207t, 212 (mesna), 346–347 oesophagus, 134
 INDEX

penis, 194 brain tumours, 268, 271–272, Symptom clusters, 72

vagina, 229 276 Syndrome of inappropriate
vulva, 226 breast cancer, 121–124, 128 secretion of antidiuretic
St John’s wort, 40 cervical cancer, 213–215 hormone (SIADH), 91–92
Stable disease (SD), 44t colorectal cancer, 163–165 Synovial sarcoma, 255b, 259b,
Staging, 4–5, 5b, 5f curative, 11–13 260
investigations, 4 diagnosis and staging, 10–11 Systematic reviews, 366–369,
surgical procedures, 10–11 endometrial cancer, 207, 369b
Stem cell transplantation (SCT) 209–210, 212 Systemic therapy, 30–44, 31b
leukaemia, 310–312 Ewing’s sarcoma, 251–252 aims, 30, 31b
lymphoma, 301, 305–306, 308 fractures/impending fractures, assessing response, 42–43, 43f
myeloma, 318 346 breast cancer, 125–128
Stents gallbladder cancer, 151, 152f dose intensity and dose density,
airway, 339 gastric cancer, 144–145, 144f, 31b
biliary, 155, 157 146b, 146f future prospects, 43, 43b
endovascular, 337, 338b, 338f gestational trophoblastic disease, gastric cancer, 147
gastrointestinal, 141, 146, 163, 226 lymphoma, 304, 308
168 head and neck cancer, 80–81 malignant melanoma, 235–236
Steroids see corticosteroids kidney cancer, 174–176 oesophageal cancer, 140
Streptozocin, 158, 286 liver cancer, 148 pregnancy, 291–292
Stridor, 338–339, 340f lung cancer, 97, 101, 103–104 see also chemotherapy; hormone
lung cancer, 106 malignant melanoma, 233, 235 treatment; targeted systemic
Subclavicular nodes, 117f mesothelioma, 108 therapy
Subependymoma, 274 minimal access, 13–14
Subgroup analyses, 362, 363b, oesophageal cancer, 137–140
368 ovarian tumours, 199–201,
T
Suicide, cancer survivors, 65 201b, 221–222 Tamoxifen
Sulfasalazine, 350 palliative, 13 breast cancer, 121, 122f,
Sunburn, 231 pancreatic cancer, 156, 156b 125–130
Sunitinib, 372–373, 373f penile cancer, 195 endometrial cancer, 211
breast cancer, 132 pregnancy, 290–291 gynaecomastia prophylaxis, 187
gastrointestinal stromal primary tumour, 11 mechanism of action, 127
tumours, 262b, 263 reconstructive (oncoplastic), 13 side effects, 127
kidney cancer, 176 rectal cancer, 167 Tarceva, brain tumours, 270
toxicity, 370t regional lymph nodes, 11–12 Targeted systemic therapy,
Superior sulcus tumours, 105 risk reduction, 13 370–374
Superior vena cava obstruction robotic assisted, 14 colorectal cancer, 169
(SVCO), 337–338 salvage, 13 kidney cancer, 176
aetiology, 91, 337 skin cancer, 239, 241–244 toxicities of common agents,
investigations, 337, 338f soft tissue sarcomas, 255, 370t
management, 106, 337–338, 258–259, 259b see also biological agents
338b spinal cord compression, Taste changes, 39b, 349
Support during treatment, 8 330–331, 330b Taxanes, 32b, 34
cancer during pregnancy, 294 spinal cord tumours, 280–281 breast cancer, 125, 130
children, teenagers and young testicular cancer, 190 hypersensitivity reactions, 343,
adults, 326 thymoma, 112 343t
radiotherapy, 27–28 thyroid cancer, 282–284 soft tissue sarcomas, 259b
Surface area, body, 37 vaginal cancer, 229–230 Taxotere, breast cancer, 126b
Surgery, 10–14 vulval cancer, 227 Teenage and young adult (TYA)
anal cancer, 171–172 Surrogate end points, clinical cancers, 320–327
bile duct cancer, 153–154 trials, 364–365 aetiology, 320
bladder cancer, 178b, 179–180 Survivorship, 9, 58–65 body image and fertility, 326
bone tumours, 246, 249, 250f, radiotherapy, 28 clinical features, 321
254 Swallowing difficulties, 134 clinical trials, 326
brain metastases, 279 Sweat gland carcinoma, 244 diagnosis and delays, 321, 322f 393
 INDEX

education, 326 Thyroidectomy, 282–284 Trastuzumab (Herceptin), 41,

incidence/epidemiology, 320 prophylactic, 13b 370–372, 372f
late effects, 326 Thyroxine (T4), 282–283 breast cancer, 122f, 128, 130
psychological support, 326 Tissue diagnosis, 3–4, 4f toxicity, 128, 343t, 370t
transitional care, 327 bone tumours, 246 Treated volume (TV), 20b
types, 320, 321t brain tumours, 267 Treatment
Temozolamide breast cancer, 119 assessing fitness for, 6–7, 7t
gliomas, 270b, 273 cholangiocarcinoma, 153 assessing response to, 42–43,
malignant melanoma, 235 head and neck cancer, 79 43f
Temsirolimus, kidney cancer, 176 liver cancer, 148 causes of death after, 64–65
Tenesmus, 70t lung cancer, 92 clinical trials see clinical trials
Teratogenic effects, cytotoxic lymphoma, 298, 302 follow-up after, 8–9
drugs, 291–292 mesothelioma, 108 follow-up during, 7–8
Teratomas oesophageal cancer, 136 implementing planned, 7
immature ovarian, 220–221 ovarian tumours, 198 late effects, 58–65, 326
testes, 189–190 pancreatic cancer, 155 research and development,
Terminal care, 72–73, 327 during pregnancy, 290 355–359
Termination of pregnancy, 290 skin cancer, 233, 238, 241 successful, 9
Terosilimus, 373–374 small intestinal tumours, 159 support during, 8
Testicular cancer, 189–194 soft tissue sarcomas, 255, 261 Triiodothyronine (T3), 282–284
management, 190, 191f techniques, 10 Troisier’s sign, 155
staging and risk classification, thymoma, 111 Trophoblastic disease, gestational
190, 190t Tissue expanders, reconstructive (GTD), 224–226, 225b,
Testicular failure, radiation- surgery, 123 225t
induced, 351 TNM staging system, 4–5, 5b Tropical sprue, 158
Testicular intraepithelial neoplasia Tobacco use Tuberous sclerosis, 264
(TIN), 194 head and neck cancer, 77 Tumorigenesis, 45, 47f
Testicular lymphoma, 306–307 see also smoking Tumour control probability (TCP),
Thalidomide, 319t Tolerance dose (TD), organs at 26b, 27f
Thecoma, 224 risk, 24, 25t Tumour localization, radiotherapy
Therapeutic ratio, radiotherapy, Topoisomerases, 35 planning, 19–21, 21f
26b Topotecan, 35 Tumour lysis syndrome, acute,
Thorax, cancers of, 89–114 ovarian cancer, 201b, 204 305, 341–342, 342t–343t
Thorotrast, 152 Total mesorectal excision (TME), Tumour necrosis factor-alpha
Thrombocytopenia, 336–337 167 (TNF-alpha), isolated limb
Thrombosis, ovarian cancer, Total skin electron beam therapy perfusion, 236
201b (TSEBT), 307–308 Tumour suppressor genes, 45
Thymoma, 110–114 TP53 gene, germline mutations, Turcot syndrome, 264
management, 111–113, 113f 53–54 Tylosis, 135b, 141
Masaoka staging, 111, 112b Trabectedin, soft tissue sarcomas, Typhoid, chronic, 152
WHO classification, 110, 111b 258, 259b Tyrosine kinase inhibitors (TKIs),
Thyroglobulin (TG), serum, Trachelectomy, radical, 214 41–42, 42f, 370–373
282–284 Tramadol, 68t gastrointestinal stromal
Thyroid cancer, 282–285 Trans-vaginal ultrasound scan tumours, 262, 262b
evaluation, 282, 283f (TVUSS), endometrial leukaemia, 312
management, 282–285, 284f cancer, 206 see also erlotinib; gefitinib;
staging and MACIS score, 282, Transbronchial needle aspiration sorafenib; sunitinib
283b (TBNA), 95
Thyroid dysfunction, cancer Transitional cell carcinoma (TCC),
survivors, 63–64, 64t 177
U
Thyroid-stimulating hormone renal pelvis, 173–174, 177, Ulcerative colitis, 160
(TSH), 283–284 182 Ultrasound scanning (USS)
Thyroid transcription factor-1 ureter, 177, 182 breast, 118, 119f
(TTF-1), 90, 288t see also bladder cancer cholangiocarcinoma, 153
394
 INDEX

head and neck cancer, 79 Vesicant drugs, 344, 345t Whole brain radiotherapy
lung cancer, 95, 98f Vestibular schwannoma (WBRT), brain metastases,
ovarian cancer, 198 (acoustic neuroma), 269t, 278–279
pancreatic cancer, 155 275 Wide local excision (WLE)
small intestinal tumours, 159 VHL gene, 55 basal cell carcinoma, 239
Ultraviolet (UV) radiation Video-assisted thoracoscopy breast cancer, 123–124
head and neck cancer risk, 77 (VATS), 96, 111 Wilms’ tumour, 323, 324f
skin cancer risks, 231, 237, 239 Vinblastine World Health Organization
Ureter, carcinoma of, 177, 182, bladder cancer, 181, 181b (WHO)
182t lymphoma, 300b analgesic ladder, 66, 67f
Urinary diversion, 180 ovarian tumours, 223b performance score, 6–7, 7t
Uterine cancer, secondary, 59t Vinca alkaloids, 32b, 34
Uterine sarcomas, 205, 260–261 Vincristine, 34
leiomyosarcomas (LMS), brain tumours, 270b, 274–
X
260–261 275 X-rays
undifferentiated, 261 Ewing’s sarcoma, 251 external beam radiotherapy,
Uterine serous papillary carcinoma leukaemia, 310 15–16
(UPSC), 205–206, 207t, myeloma, 319t impending fractures, 346,
212 Vinorelbine, lung cancer, 100– 346f
101, 101b myeloma, 316, 317f
Viral infections, head and neck primary bone tumours, 246,
V cancer risk, 77 248f, 250, 251f, 253f
VAC chemotherapy, Ewing’s Virchow’s node, enlarged, 142 see also chest X-ray
sarcoma, 251 Visual loss, acute, 333 Xerostomia, 349
Vaginal cancer, 228–230, 229b Vomiting see nausea and
Vaginal vault, endometrial cancer vomiting
recurrence, 212 Von Hippel–Lindau syndrome
Y
Vascular endothelial growth factor (VHL), 55, 56t, 173 Yolk sac tumours (YST), 220
(VEGF), 372, 373f Vote counting, 368 Young adults
Vasoactive intestinal polypeptide Vulval cancer, 226–228, 227b cancers see teenage and young
tumour (VIPoma), 158 Vulvar intraepithelial neoplasia adult (TYA) cancers
Vatalanib, mesothelioma, 110 (VIN), 226 poorly differentiated carcinoma
VelP chemotherapy, ovarian with midline distribution,
tumours, 223b 289
Venlafaxine, 72
W
Venous thromboembolism, Warning signs of cancer, 3, 3b
ovarian cancer, 201b Watchful waiting, prostate cancer,
Z
Verrucous carcinoma 185 Zolendronic acid, 61–62
penis, 194 Wedges, radiotherapy, 23 hypercalcaemia of malignancy,
skin, 241 Weight loss, 5, 348–349 340
vulva, 226 Whipple procedures, 156 prostate cancer, 189

395