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Note to the reader
The information in this volume has been carefully reviewed for accuracy of
dosage and indications. Before prescribing any drug, however, the clinician
should consult the manufacturer’s current package labeling for accepted
indications, absolute dosage recommendations, and other information perti-
nent to the safe and effective use of the product described. This is especially
important when drugs are given in combination or as an adjunct to other forms
of therapy. Furthermore, some of the medications described herein, as well
as some of the indications mentioned, had not been approved by the US Food
and Drug Administration at the time of publication. This possibility should be
borne in mind before prescribing or recommending any drug or regimen.

The views expressed are the result of independent work and do not
necessarily represent the views or findings of the US Food and Drug
Administration or the United States.

Copyright © 2003 by The Oncology Group. All rights reserved. This book is protected
by copyright. No part of it may be reproduced in any manner or by any means, electronic
or mechanical, without the written permission of the publisher.

Library of Congress Catalog Card Number 2002111548

ISBN Number 189148317X

For information on obtaining additional copies of this volume, contact the publishers,
The Oncology Group, a division of SCP Communications, Inc., 134 West 29th Street,
5th Floor, New York, NY 10001-5399

Printed on acid-free paper

The Oncology Group

A DIVISION OF
S C P C O M M U N I C AT I O N S , I N C .

Publishers of
ONCOLOGY
Oncology News International
Contributors
Thomas E. Ahlering, MD Eduardo Bruera, MD
Urology Division Department of Symtom Control
University of California, Irvine and Palliative Care
Medical Center M. D. Anderson Cancer Center
Steven R. Alberts, MD Ephraim S. Casper, MD
Department of Medical Oncology Department of Medical Oncology
Mayo Clinic Memorial Sloan-Kettering
Cancer Center at Saint Clare’s
Penny R. Anderson, MD
Denville, New Jersey
Department of Radiation Oncology
Fox Chase Cancer Center Dennis S. Chi, MD
Richard R. Barakat, MD Gynecology Service
Memorial Sloan-Kettering
Gynecology Services
Cancer Center
Memorial Sloan-Kettering
Cancer Center Warren Chow, MD
Bart Barlogie, MD, PhD Department of Medical Oncology
Division of Hematology/Oncology City of Hope National Medical Center
University of Arkansas Lawrence B. Cohen, MD
for Medical Sciences Department of Gastroenterology
Al B. Benson III, MD Mt. Sinai School of Medicine
Division of Hematology/Oncology New York City
Northwestern University Lawrence R. Coia, MD
Charles D. Blanke, MD Community Medical Center
Department of Medicine Toms River, New Jersey
Oregon Health Sciences University An Affiliate of Saint Barnabas
Portland, Oregon Health Care System
Steven R. Bonin, MD Jay S. Cooper, MD
Department of Radiation Oncology Division of Radiation Oncology
Wyoming Cancer Center New York University Medical Center
Medical Group
Jorge E. Cortes, MD
Mission Viejo, California
Division of Medicine
Steven T. Brower, MD M. D. Anderson Cancer Center
Department of Surgical Research
Carey A. Cullinane, MD
Memorial Medical Center
Department of General
Savannah, Georgia
Oncologic Surgery
City of Hope National Medical Center

CONTRIBUTORS XI
John P. Curtin, MD Robert J. Friedman, MD
Division of Gynecology Department of Dermatology
NYU School of Medicine New York University Medical Center
Lisa M. DeAngelis, MD Michael J. Gazda, MS
Department of Neurology Department of Radiation Oncology
Memorial Sloan-Kettering North Shore Cancer Center
Cancer Center Miami, Florida

George D. Demetri, MD Bonnie S. Glisson, MD

Division of Medical Oncology Division of Medicine
Dana-Farber Cancer Institute M. D. Anderson Cancer Center
Raman Desikan, MD Smitha V. Gollamudi, MD
Myeloma and Transplant Program Department of Radiation Oncology
St. Vincent’s Comprehensive Monmouth Medical Center
Cancer Center Long Branch, New Jersey
New York, New York
Leo I. Gordon, MD
James H. Doroshow, MD Division of Hematology/Oncology
Department of Medical Oncology Robert H. Lurie Comprehensive Cancer
City of Hope National Medical Center Center Feinberg School of Medicine/
Northwestern University
Lawrence Driver, MD
Pain Symptom Management Section Richard J. Gralla, MD
M. D. Anderson Cancer Center Department of Medical Oncology
New York Presbyterian Hospital
Joshua D. I. Ellenhorn, MD
Department of General Frederic W. Grannis, Jr., MD
Oncologic Surgery Section of Thoracic Surgery
City of Hope National Medical Center City of Hope National Medical Center
Carmen P. Escalante, MD Kathryn M. Greven, MD
Division of Medicine Department of Radiation Oncology
M. D. Anderson Cancer Center Bowman Gray School of Medicine
Paul Fisher, MD Bruce G. Haffty, MD
Department of Radiology
Department of
Stony Brook University Hospital
Therapeutic Radiology
and Medical Center
Yale-New Haven Hospital
East Setauket, New York
John D. Hainsworth, MD
Stephen J. Forman, MD
Sarah Cannon Cancer Center
Department of Medical
Nashville, Tennessee
Oncology/Hematology
City of Hope National Medical Center John Hoffmann, MD
Department of Surgical Oncology
Ralph S. Freedman, MD, PhD
Fox Chase Cancer Center
Department of Gynecology/Oncology
M. D. Anderson Cancer Center

XII CANCER MANAGEMENT: A MULTIDISCIPLINARY APPROACH

Eric M. Horwitz, MD John J. Kavanagh, MD
Department of Radiation Oncology Section of Gynecologic Medical Oncology
Fox Chase Cancer Center M. D. Anderson Cancer Center
William J. Hoskins, MD Mark Kawachi, MD
Curtis and Elizabeth Anderson Cancer Department of Urology
Institute at Memorial Health City of Hope National Medical Center
University Medical Center
Fadlo R. Khuri, MD
Savannah, Georgia
Department of Thoracic/Head
Mark Hurwitz, MD and Neck Medical Oncology
Department of Radiation Oncology M. D. Anderson Cancer Center
Harvard Medical School
Howard Koh, MD
Jimmy J. Hwang, MD Division of Public Health Practice
Department of Hematology/Oncology Harvard School of Public Health
Lombardi Cancer Center
Alfred W. Kopf, MD
James Ito, MD Department of Dermatology
Department of Infectious Diseases New York University Medical Center
City of Hope National Medical Center
Andrzej P. Kudelka, MD
Sundar Jagannath, MD Division of Medicine
Myeloma and Transplant M. D. Anderson Cancer Center
St. Vincent’s Comprehensive
Cancer Center Lily Lai, MD
New York, New York Division of Surgery
City of Hope National Medical Center
Ishmael Jaiyesimi, DO
Division of Hematology/Oncology Rachelle M. Lanciano, MD
William Beaumont Hospital Department of Radiation Oncology
Royal Oak, Michigan Delaware County Memorial Hospital
Drexel Hill, Pennsylvania
Lori Jardines, MD
Department of Surgery Alan List, MD
Cooper Health Services Bone Marrow Transplant
Camden, New Jersey University of Arizona Cancer Center
Javid Javidan, MD
Jay S. Loeffler, MD
Department of Urology
Department of Radiation Oncology
University of Michigan Medical Center
Harvard Medical School
James T. Kakuda, MD
Patrick J. Loehrer, MD
Department of General
and Oncologic Surgery Department of Hematology/Oncology
City of Hope National Cancer Center Indiana University Medical Center

Hagop Kantarjian, MD Charles Loprinzi, MD

Division of Medicine Department of Medical Oncology
M. D. Anderson Cancer Center Mayo Clinic

CONTRIBUTORS XIII
Robert Lustig, MD Benjamin Movsas, MD
Department of Radiation Oncology Department of Radiation Oncology
Hospital of University Fox Chase Cancer Center
of Pennsylvania
Nikhil C. Munshi, MD
Adam N. Mamelak, MD Department of Adult Oncology
Department of General Dana-Farber Cancer Institute
Oncologic Surgery
City of Hope National Medical Center Robert J. Myerson, MD, PhD
Department of Radiation Oncology
Gary N. Mann, MD Washington U Medical School
Department of Surgery
Nicos Nicolaou, MD
University of Washington
Department of Radiation Oncology
Ellen Manzullo, MD Fox Chase Cancer Center
Section of General Medicine
Susan O’Brien, MD
M. D. Anderson Cancer Center
Department of Medicine
Kim A. Margolin, MD M. D. Anderson Cancer Center
Department of Medical Oncology
Margaret R. O’Donnell, MD
City of Hope National Medical Center
Department of Hematology/Bone
Maurie Markman, MD Marrow Transplant
Department of Hematology/Oncology City of Hope National Medical Center
Cleveland Clinic Foundation
Bert O’Neil, MD
John L. Marshall, MD Division of Hematology/Oncology
Department of Hematology/Oncology University of North Carolina
Lombardi Cancer Center at Chapel Hill
Todd McCarty, MD Brian O’Sullivan, MD
Department of Surgery Department of Radiation Oncology
Baylor University Medical Center Princess Margaret Hospital
Toronto, Ontario, Canada
Robert J. McKenna, Jr., MD
Department of Thoracic Surgery Ray Page, DO, PhD
Cedars Sinai Medical Center Department of Pharmacology
University of North Texas Health
Michael O. Meyers, MD Science Center
Department of Surgery Fort Worth, Texas
Fox Chase Cancer Center
I. Benjamin Paz, MD
Ronald T. Mitsuyasu, MD Division of Surgery
Department of Medicine City of Hope National Medical Center
University of California, Los Angeles
Richard Pazdur, MD
Arturo Molina, MD Division of Oncology Drug Products
Department of Hematology/ Center for Drug Evaluation
Bone Marrow Transplant and Research
City of Hope National Medical Center US Food and Drug Administration

XIV CANCER MANAGEMENT: A MULTIDISCIPLINARY APPROACH

Kenneth J. Pienta, MD Paul Sabbatini, MD
Department of Medicine/Urology Gynecologic Section
University of Michigan Solid Tumor Division
Comprehensive Cancer Center Memorial Sloan-Kettering
Peter W. T. Pisters, MD Cancer Center
Division of Surgery Martin G. Sanda, MD
M. D. Anderson Cancer Center Department of Urology
Alan Pollack, MD, PhD University of Michigan
Division of Radiation Oncology Comprehensive Cancer Center
Fox Chase Cancer Center
Howard Sandler, MD
Stephen P. Povoski, MD Department of Radiation Oncology
Department of Surgery University of Michigan
James Cancer Hospital and Solove Comprehensive Cancer Center
Research Institute at Ohio
State University Kim Andrews Sawyer
American Cancer Society
Marcus E. Randall, MD
Atlanta, Georgia
Department of Radiation Oncology
Indiana University Medical Center Roderich E. Schwarz, MD, PhD
Bruce G. Redman, DO Department of Surgery
Division of Hematology/Oncology Robert Wood Johnson
University of Michigan Comprehensive University Hospital
Cancer Center New Brunswick, New Jersey
Dong M. Shin, MD
Paul Richardson, MD
Department of Medicine
Department of Adult Oncology University of Pittsburgh Cancer Institute
Dana-Farber Cancer Institute
Richard T. Silver, MD
John Andrew Ridge, MD, PhD Division of Hematology/Oncology
Department of Surgical Oncology Weill Medical College
Fox Chase Cancer Center of Cornell University
Darrell S. Rigel, MD Robert A. Smith, PhD
Department of Dermatology American Cancer Society
New York University Medical Center Atlanta, Georgia
John M. Robertson, MD Vernon K. Sondak, MD
Department of Radiation Oncology Department of General Surgery
William Beaumont Hospital University of Michigan
Comprehensive Cancer Center
Steven Rosen, MD
Division of Hematology/Oncology David Straus, MD
Robert H. Lurie Comprehensive Cancer Department of Medicine
Center Feinberg School of Medicine/ Memorial Sloan-Kettering
Northwestern University Cancer Center
Stephen C. Rubin, MD Mohan Suntharalingam, MD
Division of Gynecologic Oncology Department of Radiation Oncology
University of Pennsylvania University of Maryland

CONTRIBUTORS XV
Catherine Sweeney, MD Mark A. Weiss, MD
Department of Palliative Care Department of Hematology
and Rehabilitation Medicine Memorial Sloan-Kettering Cancer Center
M. D. Anderson Cancer Center
Jeffrey Weitzel, MD
Chris Takimoto, MD, PhD
Department of Clinical Cancer Genetics
Department of Pharmacology
University of North Texas City of Hope National Medical Center
Health Science Center Jane N. Winter, MD
Fort Worth, Texas Division of Hematology/Oncology
Alan Valentine, MD Robert H. Lurie Comprehensive Cancer
Department of Neuro-Oncology Center Feinberg School of Medicine/
M. D. Anderson Cancer Center Northwestern University
Rena Vassilopoulou-Sellin, MD Joachim Yahalom, MD
Division of Medicine Department of Radiation Oncology
M. D. Anderson Cancer Center
Memorial Sloan-Kettering
Lawrence D. Wagman, MD Cancer Center
Division of Surgery
City of Hope National Medical Center Alan W. Yasko, MD
Division of Surgical Oncology
Sharon M. Weinstein, MD M. D. Anderson Cancer Center
Department of Anesthesiology
Huntsman Cancer Institute

Publishing Staff

Melissa Warner President

James F. McCarthy Senior Vice President, Editorial
Cara H. Glynn Editorial Director
Gail van Koot Senior Project Manager, Editorial
Susan Reckling Editor
Terri Gelfand Editorial Administrative Assistant
Lisa Katz Creative Director
Jeannine Coronna Director of Operations

XVI CANCER MANAGEMENT: A MULTIDISCIPLINARY APPROACH

Preface
The concept for Cancer Management: A Multidisciplinary Approach arose nearly
10 years ago. This seventh annual edition reflects the ongoing commitment of
the authors, editors, and publishers to rapidly disseminate to oncologists the
most current information on the clinical management of cancer patients.
Each chapter in this seventh edition has been updated to keep pace with the
most current diagnostic and treatment recommendations. In addition, and in
accordance with the recommendations of users of previous editions of this
treatment handbook, the common chemotherapy regimens have again been
included within the treatment sections of each chapter, rather than as a sepa-
rate Appendix as in the fifth and previous editions. Information on biological
therapies, too, is now included in the treatment sections of appropriate chap-
ters, rather than as a separate chapter. Again, readers tell us this reorganization
makes the treatment guide easier to use.
The current volume also provides information on newly approved drugs, such
as gefitinib (Iressa), lonafarnib (Sarasar), pemetrexed (Alimta), flavorpiridol
(cyclin-dependent kinase inhibitor), epirubicin (Ellence), citalopram
hydrobromide (Celexa), oxandrolone (Oxandrin), infliximab (Remicade),
troxacitabine (Troxatyl), temozolomide (Temodar), tariquidar, antithymocyte
globulin (Atgam), voriconazole (Vfend), micafungin, as well as new indica-
tions for alemtuzumab (Campath), capecitabine (Xeloda), darbepoetin alfa
(Aranesp), zoledronic acid (Zometa), Actiq (oral transmucosal fentanyl citrate),
and rituximab (Rituxan). Reports on newer clinical trials with imatinib mesylate
(Gleevec), oxaliplatin (Eloxatin), erlotinib (Tarceva), thalidomide (Thalomid),
raloxifene (Evista), anastrozole (Arimidex), letrozole (Femara), and others also
are included.
The 49 chapters, one Addendum, and 2 Appendices in the latest edition repre-
sent the efforts of 120 contributors (9 of whom are new) from 60 institutions in
the United States and Canada.
Three consistent goals continue to guide our editorial policies:
■ To provide practical information for physicians who manage cancer
patients
■ To present this information concisely, uniformly, and logically, em-
phasizing the natural history of the malignancy, screening and diagno-
sis, staging and prognosis, and treatment
■ To emphasize a collaborative multidisciplinary approach to patient
management that involves surgical, radiation, and medical oncologists,
as well as other health care professionals, working as a cohesive team
As with the first six annual editions, each chapter (as appropriate) in the cur-
rent volume has been authored jointly by practicing medical, surgical, and
radiation oncologists. In some cases, other specialists have been asked to con-
tribute their expertise to a particular chapter.

PREFACE XVII
All of our contributors personally manage patients using a multidisciplinary ap-
proach in their respective institutions. Thus, these chapters reflect the recom-
mendations of practitioners cognizant that therapies must be based on evidence-
based research directed at practical patient care in a cost-effective manner.
To write, edit, and publish a 1,000-page text in less than 6 months requires the
dedication of all of the authors, as well as a professional publication staff to
coordinate the technical aspects of editing and publishing. We, the authors and
editors, are indebted to the following individuals: especially Gail van Koot,
senior project manager for the book; Susan Reckling, managing editor of the
volume; Jim McCarthy, Senior Vice-President/Editorial; Cara Glynn, Edito-
rial Director; and Melissa Warner, President of The Oncology Group. We also
thank Andrea Bovee Caldwell, Angela Cibuls, Jeannine Coronna, Christina
Fennessey, Ed Geffner, Terri Gelfand, Lisa Katz, Andrew Nash, and Stacey
Cuozzo for their efforts. We extend our special thanks to Robert A. Smith, PhD,
and Kim Andrews Sawyer of the American Cancer Society for their guidance
in helping us to update screening guidelines.
We were able to produce this edition in such a short time frame by drawing
on the oncology expertise of the editors of ONCOLOGY and Oncology News
International. These periodic publications, the seventh annual edition of this
book, and continuously updated, clinically relevant oncology information can
be accessed, at no charge, at The Oncology Group website, CancerNetwork.com.
The background of this text’s cover should look familiar to readers. It is iden-
tical to that of ONCOLOGY, the flagship publication of The Oncology Group,
which has provided continuing medical information to oncology professionals
for the past 16 years and is consistently ranked as the most widely read oncol-
ogy journal by an independent readership audit. This cover symbolizes the
ongoing commitment to oncology education of The Oncology Group and the
editors and authors of this text.

Richard Pazdur, MD
Division of Oncology Drug Products
Center for Drug Evaluation and Research
US Food and Drug Administration
Lawrence R. Coia, MD
Community Medical Center
Toms River, New Jersey
An affiliate of Saint Barnabas Health Care System
William J. Hoskins, MD
Curtis and Elizabeth Anderson Cancer Institute
Memorial Health University Medical Center
Savannah, Georgia
Lawrence D. Wagman, MD
Division of Surgery
City of Hope National Medical Center
Duarte, California

XVIII CANCER MANAGEMENT: A MULTIDISCIPLINARY APPROACH

 SURGICAL ONCOLOGY
CHAPTER 1

Principles of surgical
oncology
Lawrence D. Wagman, MD

Surgical oncology, as its name suggests, is the specific application of surgical

principles to the oncologic setting. These principles have been derived by adapt-
ing standard surgical approaches to the unique situations that arise when treat-
ing cancer patients.
The surgeon is often the first specialist to see the patient with a solid malig-
nancy, and, in the course of therapy, he or she may be called upon to provide
diagnostic, therapeutic, palliative, and supportive care. In each of these areas,
guiding paradigms that are unique to surgical oncology are employed.
In addition, the surgical oncologist must be knowledgeable about all of the
available surgical and adjuvant therapies, both standard and experimental, for
a particular cancer. This enables the surgeon not only to explain the various
treatment options to the patient but also to perform the initial steps in diagno-
sis and treatment in such a way as to avoid interfering with future therapeutic
options.

Invasive diagnostic modalities

As the surgeon approaches the patient with a solid malignancy or abnormal
nodal disease or the rare individual with a tissue-based manifestation of a leu-
kemia, selection of a diagnostic approach that will have a high likelihood of a
specific, accurate diagnosis is paramount. The advent of high-quality invasive
diagnostic approaches guided by radiologic imaging modalities has limited the
open surgical approach to those situations where the disease is inaccessible, a
significant amount of tissue is required for diagnosis, or a percutaneous ap-
proach is too dangerous (due, for example, to a bleeding diathesis, critical in-
tervening structures, or the potential for unacceptable complications, such as
pneumothorax).

Lymph node biopsy

The usual indication for biopsy of the lymph node is to establish the diagnosis
of lymphoma or metastatic carcinoma. Each situation should be approached
in a different manner.

PRINCIPLES OF SURGICAL ONCOLOGY 1

SURGICAL ONCOLOGY

Lymphoma The goal of biopsy in the patient with an abnormal lymph node
and suspected lymphoma is to make the general diagnosis and to establish
the lymphoma type and subtype. Additional analyses of the cells in the
node, its internal architecture, and the subpopulations of cells are critical for
subsequent treatment. Although advances in immunocytochemical and his-
tochemical analyses have been made, adequate tissue is the key element in
accurate diagnosis.
Consequently, the initial diagnosis of lymphoma should be made on a com-
pletely excised node that has been minimally manipulated to ensure that there
is little crush damage. When primary lymphoma is suspected, the use of needle
aspiration does not consistently allow for the complete analyses described above
and can lead to incomplete or inaccurate diagnosis and treatment delays.
When recurrent lymphoma is the primary diagnosis, the analysis of specific
cell type is very important for assessing changes in the type of lymphoma and
whether a transformation has occurred. In the rare situation in which recurrent
Hodgkin’s disease is suspected, a core biopsy may be adequate if the classic
Reed-Sternberg cells are identified. However, in the initial and recurrent set-
tings, biopsy of an intact node is often required.
Carcinoma The diagnosis of metastatic carcinoma often requires less tissue
than is needed for lymphoma. Fine-needle aspiration (FNA), core biopsy, or
subtotal removal of a single node will be adequate in this situation. For meta-
static disease, the surgeon will use a combination of factors, such as location of
the node, physical examination, and symptoms, to predict the site of primary
disease. When this information is communicated to the pathologist, the patho-
logic evaluation can be focused on the most likely sites so as to obtain the
highest diagnostic yield. The use of immunocytochemical analyses can be suc-
cessful in defining the primary site, even on small amounts of tissue.
Head and neck adenopathy The head and neck region is a common site of
palpable adenopathy that poses a significant diagnostic dilemma. Nodal zones
in this area serve as the harbinger of lymphoma (particularly Hodgkin’s dis-
ease) and as sites of metastasis from the mucosal surfaces of the upper
aerodigestive tract, nasopharynx, thyroid, lungs, and, occasionally, from intra-
abdominal sites, such as the stomach, liver, and pancreas.
Since treatment of these nodal metastases varies widely, and since subsequent
treatments may be jeopardized by inconveniently placed biopsy incisions, the
surgical oncologist must consider the most likely source of the disease prior to
performing the biopsy. FNA or core biopsy becomes a very valuable tool in
this situation, as the tissue sample is usually adequate for basic analysis (cyto-
logic or histologic), and special studies (eg, immunocytochemical analyses) can
be performed as needed.

Biopsy of a tissue-based mass

Several principles must be considered when approaching the seemingly sim-
ple task of biopsying a tissue-based mass. As each of the biopsy methods has
unique risks, yields, and costs, the initial choice can be a critical factor in the

2 CANCER MANAGEMENT: A MULTIDISCIPLINARY APPROACH

timeliness and expense of the diagnostic process. It is crucial that the physician
charged with making the invasive diagnosis be mindful of these factors.
Mass in the aerodigestive tract In the aerodigestive tract, biopsy of a lesion
should include a representative amount of tissue taken preferably from the
periphery of the lesion, where the maximum amount of viable malignant cells
will be present. Since the treatment of in situ and invasive disease varies greatly,
the biopsy must be of adequate depth to determine penetration of the tumors.
This is particularly true for carcinomas of the oral cavity, pharynx, and larynx.
Breast mass Although previously a common procedure, an open surgical
biopsy of the breast is rarely indicated today. Palpable breast masses that are
highly suspicious (as indicated by physical findings and mammography) can
be diagnosed as malignant with close to 100% accuracy with FNA. However,
because the distinction between invasive and noninvasive disease is often re-
quired prior to the initiation of treatment, a core biopsy, performed either
under image guidance (ultrasound or mammography) or directly for palpable
lesions, is the method of choice.
The spectrum of therapeutic options guides the method of tissue diagnosis. For
example, the woman who chooses preoperative chemotherapy for a breast
lesion is best served with a core biopsy. This biopsy method establishes the
histologic diagnosis, provides adequate tissue for analyses of hormone-recep-
tor levels and other risk factors, causes little or no cosmetic damage, does not
perturb sentinal analyses, and does not require extended healing prior to the
initiation of therapy. In addition, a small radio-opaque clip can be placed in the
tumor to guide the surgical extirpation. This is important because excellent
treatment responses can make it difficult for the surgeon to localize the original
tumor site.
Mass in the trunk or extremities For soft-tissue or bony masses of the trunk
or extremities, the biopsy technique should be selected on the basis of the
planned subsequent tumor resection. The incision should be made along ana-
tomic lines in the trunk or along the long axis of the extremity. When a sar-
coma is suspected, FNA can establish the diagnosis of malignancy, but a core
biopsy will likely be required to determine histologic type and plan neoadjuvant
therapy.

Preoperative evaluation
As with any surgical patient, the preoperative evaluation of the cancer patient
hinges primarily on the individual’s underlying medical condition(s). Because
most new cancers occur in older patients, careful attention must be paid to
evaluation of cardiovascular risks. Adequate information usually can be ob-
tained from a standard history, physical examination, and electrocar-
diogram (ECG), but any concerns identified should be subjected to a full
diagnostic work-up.

PRINCIPLES OF SURGICAL ONCOLOGY 3

The evaluation should also include a detailed history of previous therapies.
Previous use of doxorubicin (Adriamycin and others) may be associated with
cardiac dysfunction and the use of bleomycin (Blenoxane) with severe lung
sensitivity to oxygen concentrations > 30%. Prior radiation therapy is associ-
ated with fibrosis and delayed healing. An appreciation of potential postopera-
tive problems secondary to these factors is important in planning the surgical
extirpation and reconstruction.
For example, in a patient who requires mastectomy after failed breast-conserv-
ing surgery, the zone of tissue damage from the original radiation therapy can
be assessed by reviewing the port and boost site films or by examining the
irradiated site for tattoo marks used to align the radiation field. Plans for re-
section of heavily irradiated tissues should be made preoperatively in concert
with the reconstructive surgeon, and the relative increased risk of postopera-
tive problems should be discussed with the patient. This evaluation should
include the type of tissue to be transferred, analysis of potential donor and
recipient sites and vessels, and assurance that the appropriate microvascular
equipment is available, in the event that it is needed during surgery.

Pathologic confirmation of the diagnosis

The treatment of cancer is based almost exclusively on the organ of origin and,
to a lesser degree, on the histologic subtype. Unless the operative procedure is
being performed to make a definitive diagnosis, review of the pathologic mate-
rial is needed to confirm the diagnosis preoperatively.
There are few exceptions to this doctrine, and it behooves the surgeon to have
a confirmed diagnosis, including the in situ or invasive nature of the cancer,
prior to performing an operation. This tenet assumes paramount importance
when one is performing procedures for which there is no recourse once the
specimen is removed, eg, laryngectomy, mastectomy, removal of the anal
sphincter, and extremity amputation.
Ironically, in some situations, a preoperative or intraoperative diagnosis can-
not be confirmed, despite the fact that the preoperative and intraoperative
physical findings, laboratory data, and radiologic studies (pre- and intraop-
erative) overwhelmingly suggested the cancer diagnosis. The classic example
of this dilemma is the jaundiced patient with a firm mass in the pancreatic
head. The Whipple procedure (pancreaticoduodenectomy) causes significant
morbidity but is required to make the diagnosis and treat the cancer. In any of
these situations, the preoperative discussion with the patient must include the
possibility that the final diagnosis may be a benign lesion.

Resection
The principles of resection for malignant disease are based on the surgical goal
(complete resection vs debulking), degree of functional significance of the in-
volved organ or structure, and the ability to reconstruct the involved and sur-
rounding structures. Also important are the technical abilities of the surgeon

4 CANCER MANAGEMENT: A MULTIDISCIPLINARY APPROACH

or availability of a surgical team, adequacy of adjuvant and neoadjuvant thera-
pies, and the biological behavior (local and systemic) of the disease. The defi-
nition of “resectable” varies, and this term can be defined only in the context
of the aforementioned modifying parameters.

Wide excision
A wide excision includes the removal of the tumor itself and a margin of nor-
mal tissue, usually exceeding 1 cm in all directions from the tumor. The mar-
gin is quite variable in a large, complex (multiple tissue compartments) speci-
men, and the limiting point of the resection is defined by the closest approxi-
mation of cancerous tissue to the normal tissue excised.
Wide margins are recommended for tumors with a high likelihood of local
recurrence (eg, dermatofibrosarcoma protuberans) and for tumors without any
reliable adjuvant therapeutic options.
Breast The use of adjuvant radiation therapy has permitted the use of
breast-conserving surgery, which limits the excision of wide margins of
normal breast tissue.
Colon and rectum For carcinoma of the colon and rectum, the width of exci-
sion is defined by the longitudinal portion of the bowel and the inclusion of
adjacent nodal tissue. The principles of wide resection of normal bowel
include at least 5 cm of uninvolved tissue, the associated mesenteric leaf,
and adjacent rectal soft tissue (mesorectum).
This general principle has been modified in the distal rectum, where longitudi-
nal bowel margins of 2 cm are accepted. This modification reflects the empha-
sis on functional results (ie, maintenance of anal continence) and the availabil-
ity of adequate adjuvant radiation therapy to improve local control.

No touch technique
This principle is based on the concept that direct contact with the tumor during
resection can lead to an increase in local implantation and embolization of
tumor cells. Theoretically, the metastatic potential of the primary lesion would
be enhanced by the mechanical extrusion of tumor cells into local lymphatic
and vascular spaces. There may be some validity to this theory with respect to
tumors that extend directly into the venous system (eg, renal cell tumors with
extension to the vena cava) or that extensively involve local venous drainage
(eg, large hepatocellular carcinomas).
Extensive palpation and manipulation of a colorectal primary have been shown
to result in direct shedding of tumor cells into the lumen of the large bowel.
The traditional strategy to lessen this risk was to ligate the proximal and distal
lumen of the segment containing the tumor early in the resection. These areas
were then included in the resection, limiting the contact of shed tumor cells
with the planned anastomotic areas.
Neither of the above theoretical situations (ie, manipulation of the tumor and
direct contact of the tumor with the anastomotic area) has been definitively

PRINCIPLES OF SURGICAL ONCOLOGY 5

tested in controlled, prospective, randomized trials. However, the risk-benefit
ratio clearly favors adherence to the general principles of minimal tumor ma-
nipulation, protection of the anastomotic areas, and exclusion of the resection
bed from potential implantation with tumor cells.

Lymphadenectomy
Early surgical oncologic theory proposed that breast cancer progressed from
the primary site to the axillary lymph nodes to the supraclavicular nodes and
nodes of the neck. This theory led to the radical surgical approach that in-
cluded resection of all of the breast tissue and some or all of the above-noted
draining nodal basins (ie, modified radical or radical mastectomy).
Absent in this approach was an appreciation of the nodes not only as a deposit
of regional metastatic disease but also as a predictor of systemic disease. Mod-
ern treatment approaches view nodal dissection as having a triple purpose: the
surgical removal of regional metastases, the prediction of prognosis, and the
planning of adjuvant therapy.
The surgical technique for lymphadenectomy is based on nodal basins that are
defined by consistent anatomic structures. For example, dissection of the neck
is defined by the mandible, anterior strap muscles of the neck, clavicle, trape-
zius muscle, carotid artery, vagus nerve, brachial plexus, and fascia overlying
the deep muscles of the neck.
Modifications of classic techniques Each of the classic anatomic lymph-
adenectomies has been modified along lines that consider the predicted posi-
tivity and functional impact of the dissection. To use the example of radical
neck dissection, the modifications include supraomohyoid dissection for tu-
mors of the floor of the mouth (a high-risk zone) and sparing of the spinal
accessory nerve (functional prevention of shoulder drop and loss of full ab-
duction of the shoulder).
As alluded to in the previous paragraphs, lymph node dissection has thera-
peutic value only in patients with positive nodes. In individuals with pathol-
ogically negative nodes, the benefit is limited to prediction of prognosis and
documentation of pathologic negativity. Therefore, in the pathologically nega-
tive nodal basin, there is minimal benefit to outweigh the risks and untoward
sequelae of the dissection.

Sentinel node biopsy

Technique The technique of sentinel node identification is being developed to
address clinically negative nodal basins. With this technique, node or nodes
that preferentially drain a particular primary tumor are identified by mapping
and then surgically excised. The mapping agents include radiolabeled materi-
als and vital dyes that are specifically taken up by, and transported in, the
lymphatic drainage systems. These mapping and localizing agents, used alone
or in combination, are critical in defining the unique flow patterns to specific
lymph node(s) and in defining ambiguous drainage patterns (eg, a truncal mela-
noma that may drain to the axilla, supraclavicular, or inguinal spaces).

6 CANCER MANAGEMENT: A MULTIDISCIPLINARY APPROACH

Unresolved issues As this field of directed diagnostic node biopsy and dissec-
tion develops, many technical issues related to the timing and location of the
injections are being evaluated. In addition, the type of pathologic evaluation
(ie, the number of sections examined per node, and the use of immunohis-
tochemical analysis) is undergoing intense scrutiny.
A study of 200 consecutive patients who had sentinel lymph node biopsies
performed for breast cancer examined the concepts of injecting dye and radio-
active tracer into either the breast or the overlying dermis. The authors be-
lieved that the technical aspects of intradermal injection were simpler and more
easily reproduced than those of injections into the breast. Injections were per-
formed in group 1 intraparenchymally, and in group 2 intradermally. The com-
bination of blue dye and isotope localization produced a 92% success rate
in group 1 and a 100% success rate in group 2. The authors concluded that
dermal and parenchymal lymphatics of the breast drain to the same lymph
node and that the more simple approach of dermal injection may simplify and
optimize sentinel lymph node localization.
For melanoma, for which these techniques were originally developed, researchers
are studying the feasibility and clinical relevance of evaluating nodal material
with polymerase chain reaction (PCR) techniques. These techniques also are
being studied in breast cancer, where the clinical relevance of the presence of
micrometastases or PCR-only metastases is highly controversial and, therefore,
questions the need for this intense level of pathologic scrutiny.
Elective lymph node dissection has limited value in intermediate-thickness
melanoma. In clinically node-negative patients, the use of the sentinel node
technique can avoid postoperative complications, increase confidence about
the better prognosis, and avoid the significant side effects of adjuvant immu-
nologic therapy. However, the identification of histologically positive nodes
via sentinel node biopsy technique is expected to have significant benefit, as it
will result in a complete therapeutic dissection and adjuvant therapy with in-
terferon-α (Intron A, Roferon-A).

Palliation
In the continuum of care for the cancer patient, aspects of palliation, or the
reduction of suffering, are delegated to the surgeon. This text includes many
examples of palliative surgical procedures: venous access, surgical relief of as-
cites with shunt procedures, neurosurgical intervention for chronic pain, fixa-
tion of pathologic fractures, and placement of feeding tubes to deliver food
and medications. The surgeon must be versed in the techniques of and indica-
tions for such interventions and discuss their risks and benefits with the patient,
caregivers, and referring physician. The barriers to the initiation and practice
of palliative surgery include the reluctance of patients, family and referring
physicians, health care system administrative obstacles, and cultural factors.
Resuscitation issues An ethical issue of resuscitation must be addressed when
considering palliative surgical intervention. Some may take the position that if

PRINCIPLES OF SURGICAL ONCOLOGY 7

a patient is to have surgery, he or she must be willing to undergo full resuscita-
tion if required. That tenet may be set aside in the palliative setting, in which
the operative intervention is planned only to relieve suffering. In such a situa-
tion, a frank discussion with the patient and appropriate family members can
avoid the distressing situation of the patient being placed on unwanted, fruit-
less life support. Again, the surgeon is called upon not only to provide a tech-
nical service but also to achieve a comprehensive understanding of the disease
process and how it affects each individual cancer patient.

Suggested reading
Fortner JG: Inadvertent spread of cancer at surgery. J Surg Oncol 53:191–196, 1993.
Krouse RS, Nelson RA, Farrell BR, et al: Surgical palliation at a cancer center. Arch
Surg 136:773–778, 2001.
McCahill LE, Krouse R, Chu D, et al: Indications and use of palliative surgery–results of
Society of Surgical Oncology survey. Ann Surg Oncol 9:104–112, 2002.
McIntosh SA, Purushotham AD: Lymphatic mapping and sentinel node biopsy in breast
cancer. Br J Surg 85:1347–1356, 1998.

8 CANCER MANAGEMENT: A MULTIDISCIPLINARY APPROACH

CHAPTER 2

Principles of

RADIATION THERAPY
radiation therapy
Michael J. Gazda, MS, and Lawrence R. Coia, MD

This chapter provides a brief overview of the principles of radiation therapy.

The topics to be discussed include the physical aspects of how radiation works
(ionization, radiation interactions) and how it is delivered (treatment machines,
treatment planning, and brachytherapy). Recent relevant techniques of radia-
tion oncology, such as conformal and stereotactic radiation, also will be pre-
sented. These topics are not covered in great technical detail, and no attempt is
made to discuss the radiobiological effects of radiation therapy. It is hoped that
a basic understanding of radiation treatment will benefit those practicing in
other disciplines of cancer management.

How radiation works

IONIZING RADIATION
Ionizing radiation is energy sufficiently strong to remove an orbital electron
from an atom. This radiation can have an electromagnetic form, such as a
high-energy photon, or a particulate form, such as an electron, proton, neu-
tron, or alpha particle.
High-energy photons By far, the most common form of radiation used in
practice today is the high-energy photon. Photons that are released from the
nucleus of a radioactive atom are known as gamma rays. When photons are
created electronically, such as in a clinical linear accelerator, they are known as
x-rays. Thus, the only difference between the two terms is the origin of the
photon.
Inverse square law The intensity of an x-ray beam is governed by the inverse
square law. This law states that the radiation intensity from a point source is
inversely proportional to the square of the distance away from the radiation
source. In other words, the dose at 2 cm will be one-fourth of the dose at 1 cm.
Electron volt Photon absorption in human tissue is determined by the
energy of the radiation, as well as the atomic structure of the tissue in
question. The basic unit of energy used in radiation oncology is the elec-
tron volt (eV); 103 eV = 1 keV, 106 eV = 1 MeV.

PRINCIPLES OF RADIATION THERAPY 9

 PHOTON-TISSUE INTERACTIONS
Three interactions describe photon absorption in tissue: the photoelectric ef-
fect, Compton effect, and pair production.
Photoelectric effect In this process, an incoming photon undergoes a colli-
sion with a tightly bound electron. The photon transfers practically all of its
RADIATION THERAPY

energy to the electron and ceases to exist. The electron departs with most of
the energy from the photon and begins to ionize surrounding molecules. This
interaction depends on the energy of the incoming photon, as well as the atomic
number of the tissue; the lower the energy and the higher the atomic number,
the more likely that a photoelectric effect will take place.
An example of this interaction in practice can be seen on a diagnostic x-ray
film. Since the atomic number of bone is 60% higher than that of soft tissue,
bone is seen with much more contrast and detail than is soft tissue. The energy
range in which the photoelectric effect predominates in tissue is about 10-25 keV.
Compton effect The Compton effect is the most important photon-tissue
interaction for the treatment of cancer. In this case, a photon collides with a
“free electron,” ie, one that is not tightly bound to the atom. Unlike the pho-
toelectric effect, in the Compton interaction both the photon and electron are
scattered. The photon can then continue to undergo additional interac-
tions, albeit with a lower energy. The electron begins to ionize with the
energy given to it by the photon.
The probability of a Compton interaction is inversely proportional to the en-
ergy of the incoming photon and is independent of the atomic number of the
material. When one takes an image of tissue using photons in the energy range
in which the Compton effect dominates (~25 keV-25 MeV), bone and soft-
tissue interfaces are barely distinguishable. This is a result of the atomic num-
ber independence.
The Compton effect is the most common interaction occurring clinically, as
most radiation treatments are performed at energy levels of about 6-20 MeV.
Port films are films taken with such high-energy photons on the treatment
machine and are used to check the precision and accuracy of the beam; be-
cause they do not distinguish tissue densities well, however, they are not equal
to diagnostic films in terms of resolution.
Pair production In this process, a photon interacts with the nucleus of an
atom, not an orbital electron. The photon gives up its energy to the nucleus
and, in the process, creates a pair of positively and negatively charged elec-
trons. The positive electron (positron) ionizes until it combines with a free
electron. This generates two photons that scatter in opposite directions.
The probability of pair production is proportional to the logarithm of the en-
ergy of the incoming photon and is dependent on the atomic number of the
material. The energy range in which pair production dominates is ≥ 25 MeV.
This interaction does occur to some extent in routine radiation treatment with
high-energy photon beams.

10 CANCER MANAGEMENT: A MULTIDISCIPLINARY APPROACH

ELECTRON BEAMS
With the advent of high-energy linear accelerators, electrons have become a
viable option in treating superficial tumors up to a depth of about 5 cm. Elec-
tron depth dose characteristics are unique in that they produce a high skin
dose but exhibit a falloff after only a few centimeters.
Electron absorption in human tissue is greatly influenced by the presence of
air cavities and bone. The dose is increased when the electron beam passes
through an air space and is reduced when the beam passes through bone.
Common uses The most common clinical uses of electron beams include the
treatment of skin lesions, such as basal cell carcinomas, and boosting of (giving
further radiation to) areas that have previously received photon irradiation,
such as the postoperative lumpectomy or mastectomy scar in breast cancer
patients, as well as select nodal areas in the head and neck.

MEASURING RADIATION ABSORPTION

The dose of radiation absorbed correlates directly with the energy of the beam.
An accurate measurement of absorbed dose is critical in radiation treatment.
The deposition of energy in tissues results in damage to DNA and diminishes
or eradicates the cell’s ability to replicate indefinitely.
Gray The basic unit of radiation absorbed dose is the amount of energy (joules)
absorbed per unit mass (kg). This unit, known as the gray (Gy), has replaced
the unit of rad used in the past (100 rads = 1 Gy; 1 rad = 1 cGy).
Exposure In order to measure dose in a patient, one must first measure the
ionization produced in air by a beam of radiation. This quantity is known as
exposure. One can then correct for the presence of soft tissue in the air and
calculate the absorbed dose in Gy.
Percentage depth dose The dose absorbed by tissues due to these inter-
actions can be measured and plotted to form a percentage depth dose
curve. As energy increases, the penetrative ability of the beam increases and
the skin dose decreases.

How radiation is delivered

TREATMENT MACHINES

Linear accelerators
High-energy radiation is delivered to tumors by means of a linear accelerator.
A beam of electrons is generated and accelerated through a waveguide that
increases their energy to the keV to MeV range. These electrons strike a tung-
sten target and produce x-rays.
X-rays generated in the 10–30-keV range are known as grenz rays, whereas
the energy range for superficial units is about 30–125 keV. Orthovoltage units
generate x-rays from 125–500 keV.

PRINCIPLES OF RADIATION THERAPY 11

Orthovoltage units continue to be used today to treat superficial lesions; in
fact, they were practically the only machines treating skin lesions before the
recent emergence of electron therapy. The maximum dose from any of these
low-energy units is found on the surface of patients; thus, skin becomes the
dose-limiting structure when treating patients at these energies. The depth at
which the dose is 50% of the maximum is about 7 cm. Table 1 lists the physical
characteristics of several relevant x-ray energies.
Megavoltage units The megavoltage linear accelerator has been the standard
radiotherapy equipment for the past 20-30 years. Its production of x-rays is
identical to that of lower-energy machines. However, the energy range of
megavoltage units is quite broad—from 4 to 20 MeV. The depth of the maxi-
mum dose in this energy range is 1.5-3.5 cm. The dose to the skin is about
30%-40% of the maximum dose.
Most megavoltage units today also have electron-beam capabilities, usually in
the energy range of about 5-20 MeV. In order to produce an electron beam,
the tungsten target is moved away from the path of the beam. The original
electron beam that was aimed at the tungsten target is now the electron beam
used for treatment. Unlike that of photons, the electron skin dose is quite high,
about 80%-95% of the maximum dose. A rule of thumb regarding the depth of
penetration of electrons is that 80% of the dose is delivered at a depth (in cm)
corresponding to one-third of the electron energy (in MeV). Thus, a 12-MeV
beam will deliver 80% of the dose at a depth of 4 cm.
Altering beam intensity and field size When measurements are made at the
point just past the target, the beam is more intense in the center than at the
edges. Optimal treatment planning is obtained with a relatively constant inten-
sity across the width of the beam. This process is accomplished by placing a
flattening filter below the target.
In order for the radiation beam to conform to a certain size, high atomic num-
ber collimators are installed in the machine. They can vary the field size from
4 × 4 cm to 40 × 40 cm at a distance of 100 cm from the target, which is the
distance at which most treatments are performed.

TABLE 1: Depth dose characteristics for clinical

radiotherapy beams

Nominal energy Depth of maximum dose (cm) Skin dose (%)

240 kV(p) Surface 100

Cobalt-60 0.500 50
6 MeV 1.500 35
10 MeV 2.500 25
18 MeV 3.000 15

kV(p) = kilovolt (peak)

12 CANCER MANAGEMENT: A MULTIDISCIPLINARY APPROACH

If it is decided that a beam should be more intense on one side than the other,
high atomic number filters, known as wedges, are placed in the beam. These
filters can shift the dose distribution surrounding the tumor by 15º-60º. Wedges
can also be used to optimize the dose distribution if the treatment surface is
curved or irregular.
Shielding normal tissue Once the collimators have been opened to the de-
sired field size that encompasses the tumor, the physician may decide to block
out some normal tissue that remains in the treatment field. This is accomplished
by placing blocks (or alloy), constructed of a combination of bismuth, tin, cad-
mium, and lead, in the path of the beam. In this way, normal tissues are shielded,
and the dose can be delivered to the tumor at a higher level than if the normal
structures were in the field. These individually constructed blocks are used in
both x-ray and electron treatments. A more modern technique involves multileaf
collimators mounted inside the gantry. They provide computerized, custom-
ized blocking instead of having to construct a new block for each field. (See
“Intensity-modulated radiation therapy.”)

PRETREATMENT PROCEDURES
Certain imaging procedures must be done before radiation therapy is begun:
Pretreatment CT Before any treatment planning can begin, a pretreatment
CT scan is often performed. This scan allows the radiation oncologist to iden-
tify both tumor and surrounding normal structures.
Simulation The patient is then sent for a simulation. The patient is placed on
a diagnostic x-ray unit that geometrically simulates an actual treatment ma-
chine. With use of the CT information, the patient’s treatment position is simu-
lated by means of fluoroscopy. A series of orthogonal films are taken, and
block templates that will shield any normal structures are drawn on the films.
These films are sent to the mold room, where technicians construct the blocks
to be used for treatment. CT simulation is a modern alternative to “conven-
tional” simulation and is described later in this chapter.
Guides for treatment field placement Small skin marks, or tattoos, are
placed on the patient following proper positioning in simulation. These
tattoos will guide the placement of treatment fields and give the physician
a permanent record of past fields should the patient need additional treat-
ment in the future.
It is imperative that the patient be treated in a reproducible manner each day.
In order to facilitate this, Styrofoam casts that conform to the patient’s contour
and place the patient in the same position for each treatment are constructed.
Lasers also help line up the patient during treatment.

TREATMENT PLANNING AND DELIVERY

Determining optimal dose distribution The medical physicist or dosimetrist
uses the information from CT and simulation to plan the treatment on a com-
puter. A complete collection of machine data, including depth dose and beam
profile information, is stored in the computer. The physics staff aids the radia-

PRINCIPLES OF RADIATION THERAPY 13

tion oncologist in deciding the number of beams (usually two to four) and
angles of entry. The goal is to maximize the dose to the tumor while minimiz-
ing the dose to surrounding normal structures.
Several treatment plans are generated, and the radiation oncologist chooses
the optimal dose distribution. The beam-modifying devices discussed earlier,
such as blocks and wedges, may be used to optimize the dose distribution
around the tumor.
Establishing the treatment plan The planning computer will calculate the
amount of time each beam should be on during treatment. All pertinent data,
such as beam-on time, beam angles, blocks, and wedges, are recorded in the
patient’s treatment chart and sent to the treatment machine. The radiation thera-
pist will use this information, as well as any casts, tattoos, and lasers, to set up
and treat the patient consistently and accurately each day.
Port films As part of departmental quality assurance, weekly port films are
taken for each beam. They ensure that the beams and blocks are consistently
and correctly placed for each treatment. Port films are images generated by the
linear accelerator at energies of 6-20 MeV. Because of the predominance of the
Compton effect in this energy range, these images are not as detailed as those at
diagnostic film energies (as mentioned earlier), but they still add important infor-
mation on treatment accuracy and ensure the quality of setup and treatment.

BRACHYTHERAPY
Brachytherapy is the term used to describe radiation treatment in which the ra-
diation source is in contact with the tumor. This therapy contrasts with external-
beam radiotherapy, in which the radiation source is 80-100 cm away from the
patient.
In brachytherapy, dose distribution is almost totally dependent on the in-
verse square law because the source is usually within the tumor volume. Be-
cause of this inverse square dependence, proper placement of radiation sources
is crucial.

TABLE 2: Physical characteristics of commonly

used radioisotopes

Isotope Energy (MeV) Half-life

Radium-226 0.830 1,600 yr

Cesium-137 0.662 30 yr
Cobalt-60 1.250 5.26 yr
Iridium-192 0.380 74.2 d
Iodine-125 0.028 60.2 d
Gold-198 0.412 2.7 d

14 CANCER MANAGEMENT: A MULTIDISCIPLINARY APPROACH

Isotopes Table 2 lists commonly used isotopes and their properties. In the past,
radium was the primary isotope used in brachytherapy. Recently, because of its
long half-life and high energy output, radium has been replaced with cesium
(Cs), gold (Au), and iridium (Ir). These isotopes have shorter half-lives than ra-
dium and can be shielded more easily because of their lower energies.
Types of implants Brachytherapy procedures can be performed with either
temporary or permanent implants. Temporary implants usually have long half-
lives and higher energies than permanent implants. These sources can be manu-
factured in several forms, such as needles, seeds, and ribbons.
All temporary sources are inserted into catheters that are placed in the tumor
during surgery. A few days after surgery, the patient is brought to the radiation
clinic and undergoes pretreatment simulation. Wires with nonradioactive metal
seeds are threaded into these catheters. Several films are taken, and the images
of the seed placement can be digitized into a brachytherapy treatment plan-
ning computer.
Once the treatment plan is complete and the physician has chosen the optimal
dose rate (usually 50-60 cGy/h), the sources can be implanted. The actual im-
plantation takes place in the patient’s private room. The duration of treatment is
usually 1-3 days. The majority of temporary implants are loaded interstitially.
Common uses Interstitial low-dose-rate (LDR) brachytherapy is commonly
used for cancer of the oral cavity and oropharynx and sarcoma. Prostate can-
cer is probably the most common site for which LDR brachytherapy “seeds”
are used today. Intracavitary LDR brachytherapy is frequently used in gyne-
cologic applications. High-dose-rate (HDR) brachytherapy is used with remote
afterloading techniques, as described below.

Remote afterloading brachytherapy

Because brachytherapy requires numerous safety precautions and entails un-
necessary exposure of personnel and family members to radiation, remote after-
loading of temporary implants has become popular in recent years. The two
types of remote afterloading that can be used for treatment are LDR and HDR
sources. The most popular LDR source used today is Cs-137, which has a dose
rate of about 1 cGy/min. The most widely used HDR source is Ir-192. This
isotope has a dose rate of about 100 cGy/min.
General procedures The pretreatment brachytherapy procedures outlined
above are also implemented in remote afterloading brachytherapy. Once the
treatment plan has been approved by the physician, the patient is brought into
the treatment room. The LDR cesium source or HDR iridium source is con-
nected to the end of a cable inside its respective afterloading unit. This unit is
programmed with the data from the planning computer. The cable is sent out
from the unit into one of the patient’s catheters. Several catheters can be con-
nected to the unit. Each catheter is irradiated, one at a time, until the pre-
scribed dose has been delivered.

PRINCIPLES OF RADIATION THERAPY 15

The motor that drives the source out of the treatment unit is connected elec-
tronically to the door of the treatment room. If the treatment must be stopped
for any reason, simply opening the door triggers an interlock that draws the
source back into the unit. Because of this device, oncology personnel will not
be exposed to any radiation should they need to see the patient during treat-
ment. This interlock is the main safety advantage of remote afterloading over
manual afterloading.
LDR treatment Uterine cancer is the most popular site for intracavitary treat-
ment with LDR remote afterloading brachytherapy. These procedures are per-
formed in the patient’s room. The interlock is connected to the patient’s door
so that nurses can take vital signs and give medication and family members can
visit the patient without risk of radiation exposure.
HDR treatment The most common applications of HDR brachytherapy are
for tumors of the vaginal apex, esophagus, lungs, and, most recently, breast
and prostate. Most HDR treatments are performed on an outpatient basis.
Allowing the patient to return home the same day after therapy is one advan-
tage of HDR afterloading brachytherapy. Patients with prostate cancer are the
exception. They may remain in the hospital for 2-3 days during the treatment.

Recent advances in planning and treatment

CT SIMULATION
Until recently, CT and simulation were separate pretreatment procedures. Within
the past decade, many cancer centers have combined CT and simulation into a
single diagnostic-treatment planning unit, known as a CT-simulator. The major
advantage of this combination is that both procedures can be performed by one
unit and, thus, the patient does not have to make two separate visits to the clinic.
Also, CT simulation is bringing the radiation clinic into the digital age, with hos-
pitals reporting an increase in speed, efficiency, and accuracy of treatment plan-
ning and delivery.
Procedure In brief, in the first step of this new procedure, the patient is placed
on the CT-simulator table and undergoes a normal CT study. The physician
has the capability of outlining the tumor and any normal structures on each
CT slice. A computer performs a three-dimensional (3D) transformation of the
CT slices and creates a digitally reconstructed radiograph (DRR).
The DRR resembles a normal diagnostic film, except that it is digital and can
be manipulated to achieve better contrast and detail than regular film. The
outlines of the tumor and organs are displayed on the DRRs for any viewing
angle. The physician can then draw blocks on the DRRs with a more accurate
idea of where the tumor and normal tissues actually lie.
The DRRs are digitized into the treatment planning computer, and any CT
slices and their contours drawn by the physician are transferred as well. These
DRRs are either sent to the mold room for block construction or are trans-

16 CANCER MANAGEMENT: A MULTIDISCIPLINARY APPROACH

ferred to the treatment planning software for multileaf collimator optimiza-
tion. Treatment plans are generated as discussed earlier.
At the time of the patient’s first treatment, DRRs and port films are digitized
and saved on a local area network (LAN). Physicians can then call up these
images on their desktop computers for weekly patient quality assurance.

CONFORMAL RADIATION THERAPY

Conformal radiation therapy is a geometric shaping of the radiation beam that
conforms with the beam’s eye view of the tumor. Conformal therapy utilizes the
outlining capabilities of the CT-simulator. The physician outlines the tumor vol-
ume, generates DRRs, and draws an appropriate margin from 1-2 cm around the
tumor. These fields conform closely to the shape of the tumor and, thus, shield
more critical structures than do normal blocks. The margin allows for setup er-
rors of a few millimeters each day. Appropriate immobilization of the target vol-
ume must be achieved in each patient through the use of devices that constrain
movement (“casts”) so that the target is accurately localized.
These films are sent to the mold room for block construction. Since the fields
are “tighter” around the tumor, the prescribed dose can be increased. Clinicians
believe that by increasing the dose to the tumor, local control will be improved.
Intensity-modulated radiation therapy (IMRT), an extension of conformal
therapy, allows for shaping of the intensity of the radiation beam. This is an
important improvement, especially when the target is not well separated from
normal tissues.
A uniform dose distribution can be created around the tumor by either modu-
lating the intensity of the beam during its journey through the linear accelera-
tor or by the use of multileaf collimators. Multileaf collimators consist of 80 or
more individual collimators, or “leaves,” located at the head of the linear ac-
celerator, which can be adjusted to the shape of the tumor. (For a technical
description, the reader is referred to the text by Khan; see “Suggested Reading.”)
Both of these methods alter the fluence of radiation exiting the accelerator.
The final result is a uniform dose distribution around the tumor and minimal
dose to the surrounding normal tissues, often below tolerance levels. This im-
proves the risk-benefit ratio.
The clinical use of IMRT has grown as computer power increases and costs
decline. Preliminary clinical data have shown that prostate doses can be in-
creased significantly without increasing the complication rate. IMRT must
be administered within a closely monitored program with rigorous quality
assurance since it can potentially cause significant injury if not appropriately
applied.
Several types of IMRT delivery are now becoming standard in radiation on-
cology clinics. Dynamic conformal therapy with multileaf collimators is being
used routinely in hospitals around the country. With this approach, collima-
tors conform to the tumor volume with the beam on while the treatment unit is

PRINCIPLES OF RADIATION THERAPY 17

rotating around the patient. This is an example of totally computer-controlled
radiation delivery.
Another method of IMRT delivery—serial tomotherapy—is an enhancement of
the method described above. An accelerator is equipped with mini-multileaf
collimators that form a “slit” of radiation (normally 2 × 20 cm). The gantry is
rotated through an entire arc around the patient while the mini-multileaf colli-
mators are driven in and out of the field, thus modulating the intensity of the
beam. The treatment couch is advanced by a few millimeters and the next arc
is treated. An entire treatment is given once all the adjoining arcs have been
delivered.
Instead of treating the patient on a normal linear accelerator, with helical
tomotherapy the patient travels continuously through a modified CT ring. This
CT ring has the capability of administering 6-mV x-rays, as in a standard linear
accelerator, while at the same time performing a conventional diagnostic CT
scan. Any anatomic or position changes that might require replanning can be
performed before that day’s treatment. Following treatment, a daily, real-time
image of the dose distribution can be obtained.

PROTON THERAPY
Protons, a form of particulate radiation, have been investigated recently as a
means to improve tumor control. A proton has a charge of +1, is a stable
particle, and, together with the neutron, makes up the atomic nucleus.
Protons are delivered to the tumor in the same manner as are photons and
electrons. The dose deposited by protons remains relatively constant as they
travel through the normal tissues proximal to the target.
The kinetic energy of the protons is transferred to the tumors by electrons
knocked out of atoms. These electrons ionize DNA, and their biological ef-
fectiveness resembles that of megavoltage photons.
Bragg peak At the end of the path, biological effectiveness increases sharply
as the protons slow down and eventually stop. This increase in dose is called
the Bragg peak. The size of the Bragg peak is usually smaller than the tumor,
however. This problem can be resolved by scanning the Bragg peak through
the tumor volume by sequentially irradiating the target with lower energies.
The dose falloff of the Bragg peak is sharp enough that the normal tissues distal
to the tumor receive a negligible radiation dose.
Current clinical applications Uveal melanomas and skull-base sarcomas ad-
jacent to CNS tissues are two areas that have been under clinical study with
promising results. Clinical studies have also begun recently in treating non–
small-cell lung, hepatocellular, and paranasal sinus carcinomas.

STEREOTACTIC RADIOSURGERY
Stereotactic radiosurgery is a 3D technique that delivers the radiation dose in
one fraction. Specially designed collimators are attached to a linear accelera-
tor, which delivers a high dose of radiation to a small volume, usually about

18 CANCER MANAGEMENT: A MULTIDISCIPLINARY APPROACH

3 cm in diameter. Several stationary beams or multiple arc rotations concen-
trate the radiation dose to the lesion while sparing surrounding normal tissue.
Use in treating arteriovenous malformations Stereotactic radiosurgery is
used to treat certain patients with arteriovenous malformations. These in-
tracranial lesions arise from the abnormal development of arteries and venous
sinuses. Surgical excision is the standard treatment of choice for operable le-
sions, but stereotactic radiosurgery has become a viable option for inoperable
malformations.
Use in treating brain tumors As with conformal radiotherapy, clinical trials
involving stereotactic radiosurgery for brain tumors are being conducted at
major cancer centers. However, based on positive early results, many commu-
nity centers have begun instituting a stereotactic radiosurgery program, either
with a dedicated cobalt unit (gamma knife) or a linear accelerator–based sys-
tem. Small (< 4 cm) tumors of the brain, whether primary, metastatic, or recur-
rent, may benefit from this treatment technique.

SUGGESTED READING
Coia LR, Schultheiss TE, Hanks GE: A Practical Guide to CT Simulation. Madison,
Wisconsin, Advanced Medical Publishing, 1995.
IMRT CWG: Intensity modulated radiotherapy: Current status and issues of interest. Int
J Radiat Biol Phys 51:880–914, 2001.
Khan FM: Treatment Planning in Radiation Oncology. Baltimore, Maryland, Williams &
Wilkins, 1998.
Perez CA, Brady LW: Principles and Practice of Radiation Oncology. Philadelphia,
Lippincott-Raven, 1998.
Suit H: The Gray Lecture: Coming technical advances in radiation oncology. Int J Radiat
Biol Phys 53:798–809, 2002.
Van Dyk J: The Modern Technology of Radiation Oncology. Madison, Wisconsin, Medi-
cal Physics Publishing, 1999.

PRINCIPLES OF RADIATION THERAPY 19

CHAPTER 3

Principles of
chemotherapy
Ray Page, DO, PhD, and Chris Takimoto, MD, PhD

The effective use of cancer chemotherapy requires an understanding of the

principles of tumor biology, cellular kinetics, pharmacology, and drug resis-
tance. Thanks to the development of new, effective chemotherapeutic agents,
coupled with our expanding knowledge about the administration and combi-

CHEMOTHERAPY
nation of these agents, we now are able to cure almost 20% of all new cases of
cancer through chemotherapy alone.
This chapter focuses on the principles responsible for the development of mod-
ern combination chemotherapy regimens. This discussion is followed by de-
scriptions of the major classes of chemotherapeutic drugs and their mecha-
nisms of action.

Cellular kinetics
Cytokinetic studies have shown how the kinetics of cellular growth defines the
characteristics of tumor growth and, in part, explains the biological behavior
and heterogeneity of tumors.

Normal cell cycle

Inherent to cytokinetic principles is the concept of the cell cycle. Daughter
cells formed as a result of mitosis consist of three subpopulations: (1) cells that
are nondividing and terminally differentiated, (2) cells that are continually pro-
liferating, and (3) cells that are resting but may be recruited into the cell cycle
(ie, stem cells). All three populations exist simultaneously in tumors.
The cell cycle is composed of four phases during which the cell prepares for
and effects mitosis. Cells that are committed to divide again enter the G1 phase.
Preliminary synthetic cellular processes occur that prepare the cell to enter the
DNA synthetic (S) phase. Specific protein signals regulate the cell cycle and
allow replication of the genome where the DNA content becomes tetraploid
(4N). After completion of the S phase, the cell enters a second resting phase,
G2, prior to undergoing mitosis. The cell progresses to the mitotic (M) phase,
in which the chromosomes condense and separate and the cell divides, pro-
ducing two daughter cells.
Chemotherapeutic agents can be classified according to the phase of the
cell cycle in which they are active (Table 1). Agents that are cell-cycle-phase–

PRINCIPLES OF CHEMOTHERAPY 21
 TABLE 1: Cell-cycle-phase–specific drugs

S phase–dependent M phase–dependent
Antimetabolites Vinca alkaloidsa
Capecitabine Vinblastine
Cytarabine Vincristine
Doxorubicin Vinorelbine
Fludarabine Podophyllotoxins
Floxuridine Etoposide
Fluorouracil Teniposide
Gemcitabine Taxanes
Hydroxyurea Docetaxel
Mercaptopurine Paclitaxel
Methotrexate G2 phase–dependent
CHEMOTHERAPY

Prednisone Bleomycin
Procarbazine Irinotecan
Thioguanine Mitoxantrone
Topotecan
G1 phase–dependent
Asparaginase
Corticosteroids
a Have greatest effects in S phase and possibly late G2 phase; cell blockade or death, however, occurs in
early mitosis.
Adapted, with permission, from Dorr RT, Von Hoff DD (eds):The Cancer Chemotherapy Handbook, 2nd
ed, p 5. East Norwalk, Connecticut, Appleton & Lange, 1993.

nonspecific (eg, alkylating agents) have a linear dose-response curve; that is,
the greater the dose of drug, the greater is the fraction of cell kill. However,
cell-cycle-phase–specific drugs have a plateau with respect to cell killing abil-
ity, and cell kill will not increase with further increases in drug dosage.

Tumor kinetics
The rate of growth of a tumor is a reflection of the proportion of actively divid-
ing cells (the growth fraction), the length of the cell cycle (doubling time), and
the rate of cell loss. Variations in these three factors are responsible for the
variable rates of tumor growth observed among tumors of differing histolo-
gies, as well as among metastatic and primary tumors of the same histology.
Tumors characteristically exhibit a sigmoid-shaped Gompertzian growth curve,
in which tumor doubling time varies with tumor size. Tumors grow most rap-
idly at small tumor volumes. As tumors become larger, growth slows based on a
complex process dependent on cell loss and tumor blood and oxygen supply.

22 CANCER MANAGEMENT: A MULTIDISCIPLINARY APPROACH

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