CURRENT CLINICAL UROLOGY

Eric A. Klein, MD, Series Editor

Professor of Surgery
Cleveland Clinic Lerner College of Medicine Head,
Section of Urologic Oncology
Glickman Urological and Kidney Institute
Cleveland, OH

For further volumes:

http://www.springer.com/series/7635
Steven C. Campbell ●
Brian I. Rini
Editors

Renal Cell Carcinoma

Clinical Management
Editors
Steven C. Campbell, MD, PhD Brian I. Rini, MD, FACP
Center for Urologic Oncology Cleveland Clinic Lerner College
Glickman Urological and Kidney Institute of Medicine
Cleveland Clinic Case Western Reserve University;
Cleveland, OH, USA Cleveland Clinic Taussig Cancer Institute
Department of Solid Tumor Oncology
Cleveland, OH, USA

ISBN 978-1-62703-061-8 ISBN 978-1-62703-062-5 (eBook)

DOI 10.1007/978-1-62703-062-5
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Preface

Kidney cancer, more than any other malignancy, has undergone a fundamental
transformation over the past decade, with seminal discoveries related to tumor
biology and prognostication, molecular genetics, and pathologic classification.
The evaluation and management of this disease has likewise been revolutionized
by the introduction of novel targeted agents and innovative surgical
approaches. This textbook provides a timely update on these advances with a
strong emphasis on clinical management.
A greater appreciation of the importance of renal function and competing
risks have complicated management for patients with localized disease, and
there are now a wide spectrum of options ranging from active surveillance to
surgical excision, much of which can now be accomplished through mini-
mally invasive techniques. Partial nephrectomy is now established as the ref-
erence standard, but overtreatment remains a major concern. The role of
biopsy is still debated, and efforts to provide truly rational care for this size-
able group of patients remain a work in progress.
Locally advanced kidney cancer has always been primarily a surgical
domain, yet increased response rates with targeted agents, particularly in the
primary tumor, have stimulated efforts to reassess treatment paradigms, with
neoadjuvant protocols followed by consolidative surgery being investigated
more intensively. The optimal approaches to integrate surgery and targeted
therapies remain controversial, although there is a strong consensus that there
are great opportunities to improve management for this challenging patient
population.
Advanced kidney cancer has seen perhaps the greatest transformation with
extended survival and better quality of life now a reasonable expectation for
many patients with metastatic disease. A fundamental comprehension of the
VEGF, mTOR, and related pathways is a key to understanding where we are
now and how we will move into the future. Again, integration of surgery has
been revisited with new perspectives. While targeted molecular agents have
moved to the forefront, immunotherapy, both conventional and investiga-
tional, still holds promise for many patients. All of these advances are
reviewed with an emphasis on routine clinical management along with the
many unique challenges that are often encountered in this field.
We are grateful to all of our authors for their outstanding contributions and
trust that you will find this textbook up-to-date and informative. We have
been fortunate to have international leaders in each branch of the field participate

v
vi Preface

and provide their expertise for this textbook, which should serve as a resource
for educating physicians about kidney cancer and ultimately should advance
the care of patients with this malignancy.

Cleveland, OH, USA Steven C. Campbell, MD, PhD

Brian I. Rini, MD, FACP
Contents

Part I Localized Disease

1 Etiology of Renal Cell Carcinoma: Incidence,
Demographics, and Environmental Factors ............................. 3
Frédéric D. Birkhäuser, Nils Kroeger, and Allan J. Pantuck
2 Pathology of Renal Cell Carcinoma .......................................... 23
Ming Zhou and Huiying He
3 Familial Renal Cell Carcinoma ................................................. 43
Simon P. Kim and Bradley C. Leibovich
4 Imaging of Renal Cell Carcinoma ............................................. 53
Andrei S. Purysko, Erick M. Remer, and Brian R. Herts
5 Prognostic Factors for Localized Renal
Cell Carcinoma............................................................................ 83
Brian R. Lane
Part II Management of Localized RCC
6 Assessment of Oncologic Risk for Clinical Stage
T1 Renal Tumors and the Emerging Role of
Renal Mass Biopsy ...................................................................... 105
Matthew N. Simmons and Steven C. Campbell
7 Radical Nephrectomy for Localized Renal Tumors:
Oncological and Renal Functional Considerations.................. 119
Paul Russo
8 Nephron-Sparing Surgery for Renal Cancer ........................... 133
Alon Z. Weizer, Jeffery S. Montgomery,
and Khaled S. Hafez
9 Thermal Ablation ........................................................................ 155
Surena F. Matin and Kamran Ahrar
10 Active Surveillance of the Small Renal Mass ........................... 167
Marc C. Smaldone, Daniel Canter, Alexander Kutikov,
and Robert G. Uzzo

vii
viii Contents

Part III Locally Advanced Disease

11 Locally Advanced Renal Cell Carcinoma ................................. 197
Stephen H. Culp and Christopher G. Wood
12 Neoadjuvant Targeted Therapy
and Consolidative Surgery ......................................................... 219
Sean P. Stroup and Ithaar H. Derweesh
Part IV Advanced Disease
13 Biology of Renal Cell Carcinoma
(Vascular Endothelial Growth Factor,
Mammalian Target of Rapamycin,
Immune Aspects)......................................................................... 231
Alexandra Arreola and W. Kimryn Rathmell
14 Prognostic Factors in Advanced
Renal Cell Carcinoma................................................................. 249
Michael M. Vickers and Daniel Y.C. Heng
15 Integration of Surgery in Metastatic
Renal Cancer ............................................................................... 257
Tom Powles and Axel Bex
16 Immunotherapy for Renal Cell Carcinoma.............................. 279
Diwakar Davar, Moon Fenton, and Leonard J. Appleman
17 Targeted Therapy: Vascular Endothelial
Growth Factor ............................................................................. 303
Linda Cerbone and Cora N. Sternberg
18 Mammalian Target of Rapamycin
in Renal Cell Carcinoma ............................................................ 317
Eric Jonasch and Michel Choueiri
19 Palliative and Supportive Care
for Renal Cancer ......................................................................... 339
Armida Parala-Metz and Mellar Davis

Index ..................................................................................................... 349

Contributors

Kamran Ahrar Department of Diagnostic Radiology and Section of

Interventional Radiology, The University of Texas MD Anderson Cancer
Center, Houston, TX, USA
Leonard J. Appleman Division of Hematology/Oncology, UPMC Cancer
Pavilion, University of Pittsburgh Physicians, Pittsburgh, PA, USA
Alexandra Arreola Departments of Medicine and Genetics, Lineberger
Comprehensive Cancer Center, University of North Carolina, Chapel Hill,
NC, USA
Frédéric D. Birkhäuser Department of Urology, David Geffen School of
Medicine, University of California, Los Angeles, Los Angeles, CA, USA
Steven C. Campbell Center for Urologic Oncology, Glickman Urological
and Kidney Institute, Cleveland Clinic, Cleveland, OH, USA
Daniel Canter Division of Urologic Oncology, Department of Surgical
Oncology, Fox Chase Cancer Center, Philadelphia, PA, USA
Michel Choueri Division of Genitourinary Medical Oncology, University
of Texas MD Anderson Cancer Center, Houston, TX, USA
Stephen H. Culp Department of Urology, University of Virginia Health
System, Charlottesville, VA, USA
Mellar Davis Taussig Cancer Institute, Cleveland Clinic, Cleveland Clinic
Lerner School of Medicine, Case Western Reserve University, Cleveland,
OH, USA
Ithaar H. Derweesh Division of Urology, Department of Surgery, Moores
UCSD Cancer Center, University of California San Diego Medical Center, La
Jolla, CA, USA
Khaled S. Hafez Division of Urologic Oncology, Department of Urology,
University of Michigan, Ann Arbor, MI, USA
Huiying He Department of Pathology, Health Science Center, Peking
University, Beijing, China
Daniel Y.C. Heng Department of Oncology, Tom Baker Cancer Centre,
University of Calgary, Calgary, AB, Canada

ix
x Contributors

Brian R. Herts Section of Abdominal Imaging, Imaging & Glickman

Urological and Kidney Institute, Cleveland Clinic, Cleveland, OH, USA
Eric Jonasch Department of Genitourinary Medical Oncology, The
University of Texas MD Anderson Cancer Center, Houston, TX, USA
Simon P. Kim Department of Urology, Mayo Clinic, Rochester, MN, USA
Nils Kroeger Department of Urology, David Geffen School of Medicine,
University of California, Los Angeles, Los Angeles, CA, USA
Alexander Kutikov Division of Urologic Oncology, Department of Surgical
Oncology, Fox Chase Cancer Center, Philadelphia, PA, USA
Brian R. Lane Michigan State University College of Human Medicine, Van
Andel Research Institute, Minimally Invasive Surgery Program, Spectrum
Health, Department of Urologic Oncology, Spectrum Health Cancer Program,
Urology Division, Spectrum Health Medical Group, Grand Rapids, MI,
USA
Bradley C. Leibovich Department of Urology, Mayo Clinic, Rochester,
MN, USA
Surena F. Matin Departments of Urology and Minimally Invasive New
Technology in Oncologic Surgery (MINTOS), The University of Texas MD
Anderson Cancer Center, Houston, TX, USA
Jeffery S. Montgomery Division of Urologic Oncology, Department of
Urology, University of Michigan, Ann Arbor, MI, USA
Allan J. Pantuck Department of Urology, Institute of Urology Oncology,
David Geffen School of Medicine, University of California, Los Angeles,
Los Angeles, CA, USA
Armida Parala-Metz The Harry R. Horvitz Center for Palliative Medicine
and Supportive Oncology, Taussig Cancer Institute, Cleveland Clinic Health
Systems, Cleveland, OH, USA
Thom Powles Department of Medical Oncology, Barts Cancer Institute, St
Bartholomew’s Hospital, Queen Mary University of London, London, UK
Andrei S. Purysko Section of Abdominal Imaging, Imaging Institute,
Cleveland Clinic, Cleveland, OH, USA
W. Kimryn Rathmell Departments of Medicine and Genetics, Lineberger
Comprehensive Cancer Center, University of North Carolina, Chapel Hill,
NC, USA
Erick M. Remer Section of Abdominal Imaging, Imaging Institute,
Cleveland Clinic, Cleveland, OH, USA
Brian I. Rini Department of Solid Tumor Oncology, Cleveland Clinic
Taussig Cancer Institute, Case Western Reserve University, Cleveland Clinic
Lerner College of Medicine, Cleveland, OH, USA
Contributors xi

Paul Russo Department of Surgery, Urology Service, Memorial Sloan

Kettering Cancer Center, Weill Medical College, Cornell University, New
York, NY, USA
Matthew N. Simmons Center for Urologic Oncology, Glickman Urological
and Kidney Institute, Cleveland Clinic, Cleveland, OH, USA
Marc C. Smaldone Division of Urologic Oncology, Department of Surgical
Oncology, Fox Chase Cancer Center, Philadelphia, PA, USA
Cora N. Sternberg Department Medical Oncology, San Camillo-Forlanini
Hospital, Rome, Italy
Sean P. Stroup Division of Urology, Department of Surgery, Moores UCSD
Cancer Center, University of California San Diego Medical Center, La Jolla,
CA, USA
Robert G. Uzzo Division of Urologic Oncology, Department of Surgery,
Fox Chase Cancer Center, Philadelphia, PA, USA
Michael M. Vickers Department of Oncology, Tom Baker Cancer Center,
University of Calgary, Calgary, AB, Canada
Alon Z. Weizer Division of Urologic Oncology, Department of Urology,
University of Michigan, Ann Arbor, MI, USA
Christopher G. Wood Department of Urology, The University of Texas MD
Anderson Cancer Center, Houston, TX, USA
Ming Zhou Department of Pathology, New York University Tisch Hospital,
New York, NY, USA
 Part I
Localized Disease
 Etiology of Renal Cell Carcinoma:
Incidence, Demographics, and 1
Environmental Factors

Frédéric D. Birkhäuser, Nils Kroeger,

and Allan J. Pantuck

cer cases [1]. Worldwide, the incidence of kidney

Incidence cancer rose 2.4% per year from 1975 to 1990 and
1.3% per year from 1990 to 2001 [3] and is still
Kidney cancer was estimated to be the 14th most reported to be rising. Particularly in the Western
common malignancy worldwide in 2008 [1], world, kidney cancer has been among the tumors
although this cancer is much more common in with the highest upward trend in incidence, both
certain countries or regions of the world. More for men and for women (Fig. 1.3) [1, 4–6].
than 85% of kidney cancers arise in the renal
parenchyma, with the overwhelming majority
representing renal cell carcinomas (RCCs), while United States of America
the remainder arise in the renal pelvis, of which
the vast majority are urothelial carcinomas [2, 3]. In the United States of America (USA), the
RCC is considered to be the most lethal of all the American Cancer Society estimated that 58,240
common urologic cancers. Worldwide incidence cases of kidney cancer (35,370 in men, 22,870 in
rates vary considerably by geographical region, women) were diagnosed in 2010 [7]. From 1988
age, and ethnicity. The highest incidences are to 2006, the overall age-standardized incidence
observed in Northern America, Europe, and rate for kidney cancer was 9.4 per 100,000 per-
Australia/New Zealand, while substantially lower son-years. Temporal trends showed that incidence
incidence rates are found in Africa, the Pacific rates rose from 7.6 per 100,000 person-years in
and Asia (Figs. 1.1 and 1.2) [1]. The World Health 1988 to 11.7 per 100,000 person-years in 2006
Organization (WHO) has estimated the world- (Fig. 1.4) [8]. For localized stages, the rate was
wide incidence of kidney cancers to be 273,500 5.7 per 100,000 person-years, while for regional
cases (169,000 in men, 104,500 in women) for and distant stages, the rates were 1.8 and 2.0 per
the year 2008, representing 2.2% of all adult can- 100,000 person-years, respectively. Also stage-
specific incidence rates have revealed changes
over time, with the greatest increase being noted
for localized tumors. In localized stages, the inci-
dence rate rose from 3.8 in 1988 to 8.2 per
F.D. Birkhäuser, MD • N. Kroeger, MD 100,000 person-years in 2006. Among distant
• A. J. Pantuck, MD, MS, FACS () stages, the rate slightly decreased from 2.1 in
Department of Urology, David Geffen School of 1988 to 1.8 per 100,000 person-years in 2006.
Medicine, Institute of Urologic Oncology, University
However, during the same time period, the inci-
of California-Los Angeles, 924 Westwood Boulevard,
Suite 1050, Los Angeles, CA 90095-7207, USA dence rate of regional stages remained stable with
e-mail: [email protected] 1.6 per 100,000 person-years from 1988 to 2006 [8].

S.C. Campbell and B.I. Rini (eds.), Renal Cell Carcinoma: Clinical Management, Current Clinical Urology, 3
DOI 10.1007/978-1-62703-062-5_1, © Springer Science+Business Media New York 2013
Fig. 1.1 Map of estimated age-standardized incidence and Parkin DM. GLOBOCAN 2008, Cancer Incidence
rates of kidney cancer per 100,000 person-years world- and Mortality Worldwide: IARC CancerBase No. 10
wide, by countries, including both sexes and all ages [Internet]. Lyon, France: International Agency for
(from Ferlay J, Shin HR, Bray F, Forman D, Mathers C Research on Cancer; 2010)

Fig. 1.2 Estimated age-

11.8
standardized incidence and Northern America 2.6
mortality rates per 100,000 Western Europe 9.2
2.9
person-years of kidney cancer
8.6
worldwide, by regions, including More developed regions 2.8
both sexes and all ages (from 8.1
Central and Eastern Europe 3.6
Ferlay J, Shin HR, Bray F, 8.1
Forman D, Mathers C and Parkin Australia/New Zealand 2.7
7.9
DM. GLOBOCAN 2008, Cancer Northern Europe 3.1
Incidence and Mortality 6.3
Southern Europe 2.2
Worldwide: IARC CancerBase
4
No. 10 [Internet]. Lyon, France: World 1.6
International Agency for Central America
3.4
1.8
Research on Cancer; 2010) 3.3
Micronesia 1.1
3.1
South America 1.7
Eastern Asia 2.8
1
2.8
Polynesia 0
2.6
Western Asia 1.6
1.9
Less developed regions 1
1.9
Caribbean 1.1
1.9
South-Eastern Asia 1.3
Northern Africa 1.6
1.3
1.4
Middle Africa 1.1
1.2
Southern Africa 0.9
0 2 4 6 8 10 12 14
ASR (W) per 100,000 Incidence
Mortality
Fig. 1.3 Estimated worldwide incidence of kidney can- Incidence and Mortality Worldwide: IARC CancerBase
cer, including both sexes and all ages (adapted with per- No. 10 [Internet]. Lyon, France: International Agency for
mission from Ferlay J, Shin HR, Bray F, Forman D, Research on Cancer; 2010)
Mathers C and Parkin DM. GLOBOCAN 2008, Cancer

Fig. 1.4 Age-standardized incidence and mortality rates National Cancer Institute. Bethesda, MD, http://seer.can-
per 100,000 person-years of kidney cancer in the United cer.gov/csr/1975_2007/, based on November 2009 SEER
States, by race and sex (Altekruse SF, Kosary CL, Krapcho data submission, posted to the SEER web site, 2010)
M, et al. SEER Cancer Statistics Review, 1975–2007,
6 F.D. Birkhäuser et al.

Overall, the lifetime risk of developing cancer of regional differences and trends between regions
the kidney for men and women born in the USA and countries over time. Countries of Central and
today, based on rates from 2005 to 2007, is 1 in Eastern Europe have the highest rates, with the
67, or 1.49% [9]. Czech Republic having the highest incidence and
mortality rates for many years. In contrast, coun-
tries from Western and Southern Europe report
Europe substantially lower rates (Fig. 1.5) [1].
Interestingly, if one considers only the last
In Europe, the incidence of malignant tumors of 10 years, a shift towards stabilization or even to a
the kidney was estimated to be 102,000 cases decrease in incidence could be observed in some
(62,800 in men, 39,200 in women) for the year countries in both sexes. Moreover, as an outlier to
2008 [1]. This corresponds to an age-standard- the general European trends, Sweden showed a
ized incidence rate of 8.1 per 100,000 person- decreasing incidence rate for both sexes for the
years for both sexes (11.3 in men, 5.5 in women). last 30 years (Fig. 1.6) [1].
For the European Union (EU-27), 73,200 new
diagnosed cases (46,200 men, 27,000 women)
and an age-standardized rate of 8.0 per 100,000 Future Worldwide RCC Incidence
person-years for both sexes (11.2 in men, 5.2 in
women) has been estimated for the same year The World Health Organization predicts a rising
2008 [1]. However, in Europe kidney cancer inci- incidence of RCC for the entire world until at
dence and mortality rates show substantial least 2030, with a faster rise in the incidence for

Fig. 1.5 Map of estimated age-standardized incidence Parkin DM. GLOBOCAN 2008, Cancer Incidence and
rates per 100,000 person-years of kidney cancer in Europe, Mortality Worldwide: IARC CancerBase No. 10 [Internet].
by countries, including both sexes and all ages (from Lyon, France: International Agency for Research on
Ferlay J, Shin HR, Bray F, Forman D, Mathers C and Cancer; 2010)
1 Etiology of Renal Cell Carcinoma: Incidence, Demographics, and Environmental Factors 7

Fig. 1.6 Trends of age-standardized incidence and mortality rates per 100,000 person-years of kidney cancer in 14
different countries around the world
8 F.D. Birkhäuser et al.

Fig. 1.7 Prediction of future worldwide incidence of kidney cancer until 2030

men compared to women. In 2030, a total inci- 2007 [11, 12], and that approximately 13–27% of
dence of 466,000 cases is expected to occur, rep- abdominal imaging studies will incidentally iden-
resenting 290,500 new cases for men and 175,500 tify some type of kidney lesion [13, 14], though
new cases in women (Fig. 1.7). The steepest rise the majority of these lesions will be small simple
in incidence is predicted to occur in the Americas cysts that will not require treatment.
and the Western Pacific region, whereas in the However, increased abdominal imaging and
European region the incidence will rise more enhanced detection does not explain the continued
slowly but will remain near the top regarding increase of larger and more advanced tumors, or
absolute incidence numbers [1]. the increase in tumor size-specific mortality noted
among kidney cancer patients [5, 6]. In the SEER
data, nearly one-third of new cases will still pres-
Incidence Rate, Tumor Size, and Stage ent with advanced disease at the time of first diag-
nosis [15]. Thus, the increased incidence rate likely
As noted above, the most pronounced increase in reflects both a real increase and increased detec-
the incidence of new RCC cases was for localized tion, which, however, varies considerably among
and small tumors <2.0 cm. According to recent demographic groups. The failure to detect a true
data from the surveillance, epidemiology, and end stage migration with both increased small tumors
results (SEER) program, the percentage of kidney and with fewer advanced tumors may be due to
cancer diagnosed in the localized stage ranges other reasons, such as the concomitant rise in the
between 59% and 73%, depending on race and presence of environmental or other RCC risk fac-
sex. This trend for small, low-stage tumors has tors like obesity [16] and hypertension [17].
been proposed to be a reflection of earlier diagno-
sis primarily as a result of the widespread and
increasing use of noninvasive abdominal imaging Prevalence
modalities such as ultrasound (US), computerized
tomography (CT), and magnetic resonance imag- Included in disease prevalence calculations are
ing (MRI) [10]. This trend becomes even more the numbers of all patients alive who had previ-
obvious when considering that, in just the USA ously been diagnosed with kidney cancer, includ-
alone, the total number of CT examinations per- ing both patients with active disease and those
formed annually has risen from approximately who had already been cured of their disease. At
three million in 1980 to nearly 70 million in the beginning of 2007, there were approximately
1 Etiology of Renal Cell Carcinoma: Incidence, Demographics, and Environmental Factors 9

281,000 patients (165,000 men, 116,000 women) United States of America

alive in the USA having a history of kidney can-
cer [9]. In the USA, paralleling the incidence of The American Cancer Society estimated that in
new cases, prevalence rates have increased over 2010 there would be 13,040 deaths due to malig-
the last decades. However, the stage-specific nant tumors of the kidney (8,210 in men, 4,830 in
prevalence has varied significantly. From 1988 to women) [7], making RCC the tenth leading cause
2006, the prevalence for localized RCCs rose of cancer deaths in men. Over the past 30 years,
from 51.2% to 70.8%. Conversely, reflecting the the death rate for kidney cancer increased slightly
enhanced detection of low-stage RCC with a from 3.6 per 100,000 person-years in 1975 to 4.3
greater propensity to be cured and for patients to per 100,000 person-years in 2001 [3]. Based on
live longer, the prevalence of regional stages patients who died in 2003–2007 in the USA, the
declined from 20.9% to 13.6%, and for distant age-standardized death rate for cancer of the
stages from 27.9% to 15.6%, for the same time kidney and renal pelvis was 4.1 per 100,000 men
points [8]. Looking to the next several years, at and women per year [9]. However, in the last
least in the more developed countries, RCC prev- decade this trend seems to have stabilized or even
alence is likely to further increase, reflecting to have slightly decreased [18]. Mortality rates
increased incidence, longer survival rates, as well vary considerably according to different geo-
as aging of the population, which will lead in the graphic states, as shown in (Fig. 1.8). The 5-year
future to even more kidney cancer diagnoses. overall survival of kidney cancer has nearly
doubled from 34% in 1954 to 67% in 1996–2004
[18]. Current data from the USA indicate a
Mortality median age at death for cancer of the kidney and
renal pelvis of 71 years. Approximately 0.5%
Worldwide, the number of deaths due to malignant died under the age of 20; 0.5% between 20 and
tumors of the kidney was estimated to be 116,500 34; 2.2% between 35 and 44; 10.0% between 45
(72,000 in men, 44,500 in women) in 2008 [1]. and 54; 20.2% between 55 and 64; 25.0%
Mortality rates show important variations when between 65 and 74; 28.0% between 75 and 84;
countries around the world are analyzed (Fig. 1.6). and 13.6% at 85 years of age or above [9].

Fig. 1.8 Age-standardized death rates per 100,000 per- Cancer Institute. Bethesda, MD, http://seer.cancer.gov/
son-years of kidney cancer in the USA, by States, includ- csr/1975_2007/, based on November 2009 SEER data
ing both sexes (Altekruse SF, Kosary CL, Krapcho M, submission, posted to the SEER web site, 2010)
et al. SEER Cancer Statistics Review, 1975-2007, National
10 F.D. Birkhäuser et al.

Europe
Demographics
In Europe, it was estimated that there were 45,100
deaths due to kidney cancer in 2008, including Age
28,300 deaths occurring in men and 16,800 in
women [1]. For the European Union (EU-27), Incidence rates worldwide, and especially in the
31,300 deaths (19,600 in men, 11,700 in women) USA and Europe, increase consistently with age
were estimated for the same time period. Mortality [1]. The steepest increase has been noted in young
from kidney cancer increased throughout the men and women between 25 and 50 years of age.
European Union until the late 1980s or early With age up to 70–75 years, the velocity of increase
1990s. Thereafter, it tended to stabilize or even slows, which may be a result of less frequent and
decline. In men, age-standardized mortality rates rigorous diagnostic testing in elderly people
from kidney cancer peaked at 4.8 per 100,000 per- (Fig. 1.9). The vast majority of kidney cancers are
son-years in 1990–1994, and then declined to 4.1 diagnosed at age over 65 [3]. As the population
(−13%) in 2000–2004. In women, the correspond- ages in several regions worldwide, further increases
ing values were 2.1 in 1990–1994, and 1.8 (−17%) of incidence are expected (Fig. 1.7). From 2003 to
in 2000–2004 [19]. The greatest decreases took 2007 in the USA, the median age at diagnosis for
place in Scandinavian and other Western European cancer of the kidney and renal pelvis was 64 years
countries. In most countries of Central and Eastern of age. For men, the median age was 64 years, and
Europe, kidney cancer mortality rates tended to for women it was 66 years [9]. Approximately
stabilize, even if values remained exceedingly 1.3% of kidney cancers were diagnosed under age
high, e.g., in the Czech Republic, Hungary, Poland, 20; 1.6% between 20 and 34; 6.1% between 35
and the Baltic countries (Fig. 1.6) [20]. and 44; 16.4% between 45 and 54; 24.9% between

Fig. 1.9 Estimated world-incidence rates per 100,000 per- 2008, Cancer Incidence and Mortality Worldwide: IARC
son-years of kidney cancer, by age (from Ferlay J, Shin HR, CancerBase No. 10 [Internet]. Lyon, France: International
Bray F, Forman D, Mathers C and Parkin DM. GLOBOCAN Agency for Research on Cancer; 2010)
1 Etiology of Renal Cell Carcinoma: Incidence, Demographics, and Environmental Factors 11

55 and 64; 24.2% between 65 and 74; 19.8% higher among women (Figs. 1.6 and 1.10) [1].
between 75 and 84; and 5.8% at years of age 85 In various regions worldwide, a trend to steeper
and above [9]. rising incidence rates in women compared to men
has been observed. In the USA between 1975 and
1995, the incidence rate of kidney cancer increased
Sex annually by 2.3% among white men, 3.1% among
white women, 3.9% among black men, and 4.3%
Both age-standardized incidence and mortality among black women (Fig. 1.4) [10]. In the USA in
rates of kidney cancer, in particular from the more 2009, kidney cancer was expected to be the sev-
developed regions of the world, have consistently enth leading cause of cancer in men and the eighth
been reported to be higher among men than leading cause of cancer in women, corresponding
women. This pattern is likewise observed through- to about 5% of all cancers in men and 3% of all
out the rest of the world, with the exception of cancers in women [18]. Over the last 20 years,
some Western and Central Africa countries, where 62% of all cases of kidney cancer were in men and
reported incidence rates appear to be equal or even 38% were in women [8].

Fig. 1.10 Estimated age-standardized incidence rates per 2008, Cancer Incidence and Mortality Worldwide: IARC
100,000 person-years of kidney cancer by World regions, CancerBase No. 10 [Internet]. Lyon, France: International
by men and women (from Ferlay J, Shin HR, Bray F, Agency for Research on Cancer; 2010)
Forman D, Mathers C and Parkin DM. GLOBOCAN
12 F.D. Birkhäuser et al.

Ethnicity age above 60 years, survival for African

Americans was worse [3]. The reasons underly-
Wide differences in incidence and mortality rates ing this observation are not well understood, but
in many countries and regions around the world may be due to either different biological behavior
have been well documented. However, these data, of the disease between ethnicities, to underlying
usually collected in national or regional cancer somatic genetic differences in various ethnic
registries, may be difficult to compare strictly in populations, or to different comorbid conditions
regards to differences in ethnicity due to various occurring in various ethnic groups [21].
concomitant biasing factors, including access to When migrating to nonnative geographic
and quality of health care, lifestyle-associated or regions, ethnic populations may eventually either
environmental risk factors, and to differences in change or preserve their native incidence rates. An
socioeconomic status. Another general limitation unchanged and low incidence rate has been
to most large cancer data sets is that they often observed in Asians, both in the majority of Asian
indicate overall but not disease specific survival. countries and in the USA [1, 4, 5]. In contrast,
Thus, ethnical disparities in comorbidities may incidence rates are highest among African
bias survival data. Fortunately, the SEER data- Americans in the USA [5, 9], whereas they have
base in the USA compares different demographic been reported to be much lower in the same groups
groups in a single country, which potentially may living in many African countries [1, 4]. These
reduce biasing factors. Considering the therein- observations provide indirect evidence that the risk
recorded demographic groups, the incidence rates of developing kidney cancer may not only vary
of kidney cancer have clearly been rising for all between ethnicities, but may also involve gene–
demographic groups during the last decades. environment interactions, as well as differences in
However, both incidence rate and velocity of rise access to health care, frequency of diagnostic
have differed significantly between different eth- imaging, and to the prevalence of lifestyle-associ-
nic groups. American Indians and Alaska Natives ated or environmental risk factors.
had the highest incidence rate, but the slowest
rise. On the other hand, Asian and Pacific
Islanders had the lowest incidence rate. Between Environmental Risk Factors for RCC
the extremes of those two ethnical groups, African
Americans, Caucasians, and Hispanics showed Smoking
similar incidence rates and trends. When age and
race are considered together, African American Smoking and RCC: Biological Background
men under 60 had the most rapid rise in incidence Cigarette smoke contains more than 4,500 chem-
of kidney cancer (Fig. 1.4) [21]. ical compounds of which more than 60 are well-
When looking at the mortality rate, a significant established carcinogens [22], including various
increase in RCC-related deaths in both African chemical classes such as polycyclic aromatic
Americans and Caucasians was observed until hydrocarbons (PAHs), N-nitrosamines, aromatic
the 1990s, with African Americans having the amines, aldehydes, volatile organic hydrocar-
steepest increase in mortality rate over the last bons, and metals. Many other, less well investi-
years (Fig. 1.11) [3, 9]. Since that time, the trend gated carcinogens are also components of
appears to have stabilized for all ethnicities cigarette smoke [23]. Chemical components of
reflected in the SEER database [3]. Compared to tobacco smoke are generally metabolized by
Caucasians, however, African Americans have phase I and phase II enzymes through the liver,
experienced worse survival; from 1975 to 1990, and cleared through the urinary tract. Carcinogenic
the survival for African Americans under 60 years components are therefore concentrated in the
of age presenting with localized tumors was kidneys. Because of this excretory pathway, the
190 months, while for Caucasians having the urinary tract is exposed to much higher concen-
same age and stage, it was 259 months. Also for trations of the carcinogenic substances present in
1 Etiology of Renal Cell Carcinoma: Incidence, Demographics, and Environmental Factors 13

Fig. 1.11 Age-standardized incidence and mortality from 1992 to 2007 (Altekruse SF, Kosary CL, Krapcho
rates of kidney cancer in the USA for various ethnic M, et al. SEER Cancer Statistics Review, 1975–2007,
groups, including both sexes. Joint analyses for Whites National Cancer Institute. Bethesda, MD, http://seer.can-
and Blacks from 1975 to 2007 and for Asian/Pacific cer.gov/csr/1975_2007/, based on November 2009 SEER
Islanders, American Indians/Alaska Natives and Hispanics data submission, posted to the SEER web site, 2010)

tobacco smoke than many other organ systems in epoxide (BPDE). From four known enantiomers,
humans (even, surprisingly, the respiratory sys- one (BPDE-N2-deoxyguanosine) has been reported
tem). The major established pathway of cancer to be strongly carcinogenic [24]. Two critical tar-
causation by smoking is described by a report of gets of the BPDE adducts are known: mutational
the US Surgeons General as follows [23]: (1) the spots in the p53 tumor-suppressor gene and the
exposure to carcinogens from tobacco smoke KRAS oncogene [23]. Zhu et al. recently reported
leads to (2) formation of covalent bonds between a higher frequency of BPDE-associated 3p dele-
the carcinogens and DNA (DNA adduct forma- tions in the lymphocytes of RCC patients. 3p
tion), and (3) the resulting accumulation of per- deletions are known as the most commonly chro-
manent somatic mutations in critical genes mosomal aberrations in RCC. The authors con-
leading to conversion of the affected cells to can- cluded that chromosome 3p may be a specific
cerous cells (Fig. 1.12). These pathological target of cigarette carcinogens like BPDE [25]. Other
changes are followed by clonal outgrowth, addi- authors have shown an N-nitrosdimethylamine
tional mutations, and genetic instability that ulti- (NMDA) dosage-dependent induction of kidney
mately leads to the development of cancer [23]. tumors in rats [26, 27]. Furthermore,
One example of a carcinogenic component 4-(methylnitrosamino)-1-(3-pyridiyl)-1-butanone
found in tobacco smoke is benzo[a]-pyrene diol (NNK)-induced DNA damage is associated with a
14 F.D. Birkhäuser et al.

Protein Kinase A and B

Receptor binding ativation and other
changes

Mutations in
oncogenes
Regular and tumor- Loss of normal
Initiation of cigarette Uptake of Metabolic DNA Persistence suppressor growth control Cancer
smoking carcinogens adducts genes mechanisms
uptake activation miscoding

Metabolic
detoxification Repair

Normal DNA Apoptosis

Excretion

Uptake of co carcinogens Tumor suppressor

and tumor promoters gene inactivation
gene promoter hypermethylation and other changes

Fig. 1.12 Relationship between cancer and smoking (from How Tobacco Smoke Causes Disease: The Biology and
Behaviroal Basis for Smoking Attributable Disease: A Report of the Surgeon General. Rockville, MD: Department of
Health and Human Services; 2010: 221–350)

higher risk for kidney cancer [28]. In general, differences are notable: whereas women smokers
because tobacco smoke contains such a high num- had an RR of 1.22 (95% CI: 1.09–1.36), men
ber and variety of carcinogens, it is difficult to who had smoked had a greater RR of 1.54 (95%
fully tease out the RCC-causative effect of any one CI: 1.42–1.68). Furthermore, the authors demon-
single component of cigarette smoke. Together, strated a dose-dependent effect of smoking on the
however, epidemiological and biological data development of kidney cancer, showing a 1.60
strongly support the conclusion that kidney cancer (95% CI: 1.21–2.12), 1.83 (95% CI: 1.30–2.57),
is a smoking-related disease. and 2.03 (95% CI: 1.51–2.74) higher risk in men
who smoked, 1–9, 10–20, and 21 or more ciga-
Smoking and RCC: Cancer Development rettes/day, respectively. The impact of the same
Tobacco smoking has been declared a causal risk dosage exposure is different for women than for
factor for the development of RCC by both the men; women who smoked the same dosage of
International Agency for Research on Cancer 1–9, 10–20, and 21 or more cigarettes/day had no
[29] and the US Surgeon General [30]. Numerous higher risk (RR 0.98, 95% CI: 0.71–1.35), 38%
studies have investigated the relationship between higher risk, (RR 1.38; 95% CI: 0.90–2.11), and
smoking and the development of RCC. Despite 58% (RR1.58%; 95% CI: 1.14–2.20) higher risk,
having differing study designs (cohort studies, respectively, than nonsmoking women for devel-
hospital- and population-based case–control oping kidney cancer. Smoking cessation is
studies, etc.), the majority of these studies have reported to be associated with a reduction in the
shown consistent results in both sexes: tobacco RR for developing kidney cancers, but the risk
exposure is linked to a higher risk for developing does not seem to diminish until a long latency
RCC [29, 31]. period of over 10 years [31].
In a meta-analysis of 24 studies, Hunt et al. It has been estimated that 1.3 billion people in
found that the relative risk (RR) for smokers was the world are currently smokers. If the trends of
1.38 (95% CI: 1.27–1.50) that of lifetime non- smoking and population growth continue, the
smokers [31]. Their findings of gender-specific number of smokers is expected to reach two billion
1 Etiology of Renal Cell Carcinoma: Incidence, Demographics, and Environmental Factors 15

worldwide in 2030. The prevalence of tobacco Obesity

consumption, however, has shifted from developed
countries to the developing world: the highest Obesity and RCC: Biological Background
prevalence of smoking currently is found in The mechanisms that are associated with kidney
Eastern Europe, the former Soviet Union, China, cancer development potentially related to obesity
and Indonesia. About 50% of the men and 9% of are poorly understood. To date, however, both
women in developing countries, compared to 35% in vitro and in vivo studies have provided evidence
of the men and 22% of women in developed coun- that key pathways for cancer development and
tries, are currently smokers. On average, the con- progression are altered through host factors asso-
sumption of tobacco will continue to fall in ciated with obesity and the “metabolic syndrome.”
developed countries, but rise in low- and medium- These host factors include leptin, adiponectin, ste-
resource countries [32]. These developments raise roid hormones, reactive oxygen species (ROC),
concern that the number of RCC cases in develop- insulin, and insulin-like growth factor [35].
ing countries will increase in the future. Furthermore, obesity is associated with a state of
chronic, low-grade systemic inflammation, and
Smoking and RCC: Cancer-Specific inflammation is in turn associated with both can-
Survival Outcome cer and cancer progression. The levels of several
While most of the studies which have investi- cytokines, such as tumor necrosis factor (TNF)-a,
gated the relationship between smoking and kid- soluble TNF receptor, IL-1b, IL-6, IL-1 receptor
ney cancer have focused on the development of antagonist, and C-reactive protein, have been
kidney cancer, few studies have investigated the found to be two- to threefold increase in obese
relationship between smoking and the outcome people compared to nonobese people [36].
of kidney cancer patients. Sweeny et al. reported Metabolic stress and the special cytokine environ-
in a case–control study of 555 patients that cur- ment associated with inflammatory changes pro-
rent smokers experienced a worse overall and voke oxidative stress, resulting in higher levels of
cancer-specific survival than nonsmokers (HR ROS. ROS are highly reactive radicals, which lead
1.7, 95% CI: 1.2–2.5). However, when smoking to damage of lipids, proteins, and nucleic acids.
was considered in this study as part of a multi- Interestingly, the P13K/akt pathway, an important
variate Cox hazard proportional model, it was not activator of the mTOR pathway whose function
retained as an independent factor of survival out- has implications for both the pathogenesis and the
come. The authors explained the survival differ- treatment of RCC [37–39], can be activated
ences with reference to the higher pT stages of through ROS [35].
the patients [33]. In another study, Parker et al. Insulin resistance and hyperinsulinemia are
also reported a worse cancer-specific survival conditions typically found in obese patients. Both
outcome of current smokers compared to non- have been shown to increase the risk for tumor
smokers (HR 1.31; 95% CI: 1.09–1.58). However, progression in different cancer types [40, 41].
again, after adjustment for TNM stage group and The effects of insulin and IGF-1 occur through
tumor grade, this difference was no longer their binding to cell surface receptors on tumors
significant [34]. Many studies of smoking and or precancerous cells, and represent another
RCC outcomes have been limited by small cohort mechanism for the subsequent activation of the
size, limited follow-up, and inability to substrat- P13/Akt pathway [40, 42]. Furthermore, IGF-1
ify patients according to RCC histological sub- has been shown to interact with the p53 tumor
type and according to tobacco exposure dosage. suppressor [43]. The (mal)-function of the p53
Furthermore, since many studies have been epi- tumor suppressor has been implicated in the
demiologically based, they have generally been development of RCC, as it has been in many
unable to further investigate the genetic and other cancers [44, 45].
molecular mechanisms that might underlie the The metabolic function of the liver is a crucial
worse survival outcome seen in smokers. factor in the inactivation of environmental and
16 F.D. Birkhäuser et al.

dietary carcinogens. Epidemiologic studies have prospective observational studies that 40% of the
suggested that 1–3% of the western population RCC cases in the USA and 30% in Europe are
has nonalcohol-related liver disease, and that a associated with excessive bodyweight [53]. The
considerable percentage of these patients suffer risk for the development of kidney cancer has
eventual progression towards liver inflammation, been reported to be directly correlated with
fibrosis, and cirrhosis. These processes result in a increased weight. Comparisons between obese
restriction of the metabolic and detoxification and nonobese patients have shown a 48% higher
functions of the liver [46]. Many toxic substances, risk for RCC in obese patients, with each unit
whether in original form or as metabolic byprod- increase in body mass index (BMI) leading to a
ucts of phase I and phase II metabolism, are 4% increased risk of developing RCC (HR 1.04,
cleared through the urinary tract. Impaired liver 95% CI: 1.02–1.06, p = 0.001) [54]. Interestingly,
function may in some situations result in higher clear cell RCC is the histological subtype that
concentrations of toxic substances that are in turn appears to be the most obesity associated [54].
delivered to the kidney [27]. Many hormones, The role of fat distribution in RCC development
including steroid hormones (estrogens, proges- was investigated in one study. Among women, an
terone, and adrenal steroids), leptin, and adi- increased risk of RCC was observed with respect
ponectin have been shown to be associated with to elevated body weight (highest vs. lowest quin-
carcinogenesis and tumor progression [47]. tile, RR 2.13, 95% CI: 1.16–3.90, p = 0.003),
Consistent with studies showing the association BMI, (2.25, 1.14–4.44, p = 0.009), wider waists
of estrogens and carcinogenesis with tumor pro- (1.67, 0.94–2.98, p = 0.003), and wider hip cir-
gression, Nicodemus et al. found that women cumference (2.30, 1.22–4.34, p = 0.01), but waist
who reported estrogen use in the past had a 62 and hip circumference was not longer significant
higher risk for the development of RCC. Elevated after controlling for body weight [52].
estrogen levels have also been reported to be Individual macro and micronutrient variation
associated with obesity [48]. in the diet may further modify the risk associated
with excessive caloric intake alone. For example,
Obesity and RCC: Cancer Development a high fruit and vegetable intake has been reported
Obesity is a complex disease, which is influenced to be associated with a decreased risk of RCC in
by underlying genetic factors, as well as lifestyle a pooled analysis of 13 prospective studies [55].
factors such as high caloric intake and low physi- The authors were able to show a reduction or
cal activity. It is difficult to distinguish the impact RCC risk with the consumption of six or more
and individual influence of each of these inter- servings of fruits and vegetables a day. Lindblad
twined factors on the risk of kidney cancer devel- et al. observed a 50–60% reduction in risk of
opment. The evaluation of obesity, therefore, RCC (highest vs. lowest quartile of intake) with
necessarily includes consideration of all of its respect to consumption of total fruit, apple, and
associated risk factors. Nevertheless, diet alone is citrus fruits [56]. However, data from the
considered an important risk factor for the devel- European Prospective Investigation into cancer
opment of cancer in general [47, 49]. The follow- and nutrition, the largest prospective population-
ing paragraphs investigate the role of obesity, and based study of diet and disease, has found no
the factors which are involved in the development consistent correlation between fruit and vegetable
of obesity and which therefore may indirectly intake and RCC risk [57].
affect the development of RCC. Fat and protein intake of animal origin is a risk
Obesity has been rising in prevalence through factor for a number of cancer types, especially
the last few decades in the USA and many others colon cancer. However, in a pooled study as well
countries [50]. Several studies worldwide have as in a large prospective cohort study, neither fat
demonstrated the influence of body weight on the nor protein was found to be associated with a
risk of kidney cancer development [51, 52]. higher risk of RCC [58, 59]. Allen et al. con-
Renehan et al. demonstrated in a meta-analysis of cluded that there is no association between these
1 Etiology of Renal Cell Carcinoma: Incidence, Demographics, and Environmental Factors 17

macronutrients and the risk of RCC. However, participants and 1,238 cases, Moore et al. found a
Mellemgaard et al. reported in a smaller study of reduction of RCC incidence of 23% [95% CI:
351 RCC cases and 340 controls, that both high 0.64, 0.92; p(trend) = 0.10] for women cur-
caloric and fat intakes are associated with a higher rently exercising, 16% [95% CI: 0.57, 1.22;
risk of RCC in both men and women [60]. p(trend) = 0.03] for routine physical activity, and
For a long time, it was hoped that a high intake 18% [95% CI: 0.68, 1.00; p(trend) = 0.05] for
of antioxidant vitamins such as vitamins A, C, activity during adolescence [67]. However, other
and E could be associated with a reduction in studies did not find evidence of a protective effect
cancer risk. However, data from studies focusing for physical activity and the risk of RCC. A pro-
on the influence of antioxidant nutrients has spective cohort study of 17,241 Swedish twins
delivered inconsistent results. Lee et al., for having a follow-up of 30 years identified 102
example, were able to demonstrate that vitamin cases of RCC. In that study, neither occupational
A, C, and carotenoid intake correlated with a nor leisure physical activity was associated with
decreased risk of RCC, though vitamin E did not a decreased risk for RCC [68]. Data from the
appear to influence the risk of RCC development Netherlands Cohort Study on Diet and Cancer
[61]. On the other hand, other studies have dem- showed a slight risk reduction of RCC for occu-
onstrated a positive relationship between vitamin pational physical activity in men, for work com-
C and E intake and RCC risk [48, 62, 63]. parable to 8–12 kJ/min (RR 0.98; 95% CI:
The consumption of fatty fish (such as salmon 0.64–1.49) and >12 kJ/min (RR 0.86; 95% CI:
and tuna) has been considered to be an important 0.50–1.46). For nonoccupational physical activ-
protective factor in cardiovascular diseases. A ity, risk reduction was demonstrated for
study on 61,433 Swedish women reported a 44% 30–60 min/day (RR 0.46; 95% CI: 0.28–0.77),
decrease in the risk of RCC for a consumption of 60–90 min/day (RR 0.67; 95% CI; 0.38–1.17)
one or more servings of fatty fish per week. and >90 min/day (RR 0.66; 95% CI: 0.41–1.07),
Moreover, women who reported consistent con- respectively. For women, a risk reduction at
sumption of at least 1–3 servings of fatty fish per 30–60, 60–90 and >90 min/day of nonoccupa-
month, over at least 10 years, had a 74% lower risk tional physical activity of RR 0.95 (95% CI: 0.54,
of developing RCC [64]. However, another study 1.68), RR1.07 (95% CI: 0.59, 1.94) and RR 0.85
did not find a protective effect of fatty fish con- (95% CI; 0.44, 1.63) was found. For both men
sumption with respect to RCC development [60]. and women, these results were considered
Another confounding lifestyle and dietary fac- significant by p trend [68].
tor to consider is alcohol consumption. Moderate In conclusion, the influence of obesity, irre-
consumption of alcohol has been reported to spective of the fat distribution, on the develop-
decrease the risk of RCC. In a pooled analysis of ment of RCC has moderate support in the
12 studies, Lee et al. reported a decreased risk of epidemiological literature. Dietary factors such
28% (95% CI: 0.60–0.86) for moderate alcohol as high energy intake, low physical activity, and
consumption of ³15 g/day, equivalent to slightly low consumption of fatty fish, vegetables, and
more than one alcoholic drink per day [65]. The fruit that are more common in patients with obe-
alpha-tocopherol, beta carotene (ATBC) cancer sity are associated with an increased risk for
prevention study suggested that these findings development of RCC. Moderate alcohol con-
were particularly true for the highest quartile of sumption may decrease the risk. The field of
alcohol intake (RR 0.53, 95% CI: 0.34–0.83). nutrition, diet and lifestyle modification warrants
Another study showed that these findings in men further prospective interventional study.
are in agreement with the data for women (RR
0.50, 95% CI: 0.2–0.9). Obesity and RCC: Cancer-Specific
Lower physical activity has been reported to Survival Outcome
be associated with an increased risk of RCC for The overweight, obesity, and mortality from can-
women [66]. In a prospective study of 482,386 cer study, a prospective study of US adults, found
18 F.D. Birkhäuser et al.

higher mortality rates from all types of cancer tive damage which are risk factors for the
(52% higher for men and 62% higher for women) development of kidney cancer [72]. One of the
for the heaviest members of the study cohort hallmarks of hypertension is rarefaction of
(BMI > 40) compared to men and women of nor- microvessels and increased expression of angio-
mal weight. Compared to the group of normal genic growth factors such as VEGF, and this may
weight women (BMI 18.5–24.9), the RRs of predispose to malignancy in the kidney [73]. In
female patients with a BMI of 25.0–29.9, 30.0– addition, rarefaction of microvessels induces tis-
34.9, 35.0–39.9, and ³40 were, 1.33 (95% CI: sue hypoxia, and in this setting, hypoxia induc-
1.08–1.63), 1.66 (95% CI:1.23–2.24), 1.70 (95% ible factor (HIF) is not degraded and is instead
CI: 0.94–3.05), and 4.75 (95% CI: 2.50–9.04), expressed constitutively [73]. Of interest, both
respectively. For men in the same BMI groups, the angiogenic growth factors and HIF are key play-
RRs were 1.18 (95% CI: 1.02–1.37), 1.36 (95% ers in the development of RCC; however, further
CI: 1.06–1.74), and 1.70 (95% CI: 0.99–2.92). investigation into the potential biological effects
Several studies, conversely, have demonstrated of hypertension that may predispose to RCC is
a favorable overall and cancer-specific survival necessary.
outcome in patients who presented with obesity
[69–71]. In contrast to the overweight, obesity, Hypertension and RCC: Cancer
and mortality from cancer study, however, these Development, Use of Antihypertensive
studies were all case–control studies. The biggest Medication and Cancer-Specific Outcome
of these studies, with 1,338 clear cell RCC Prospective cohort studies have shown an asso-
patients, retained obesity as an independent pre- ciation between hypertension and risk for RCC
dictor for cancer-specific survival in localized [74–76]. One of the largest prospective cohort
RCC; in metastatic patients, obesity was not studies, involving 363,992 Swedish men, investi-
retained as an independent factor predicting sur- gated RCC risk in relation to hypertension. Over
vival in multivariate analysis. This study, how- a follow-up period of 25 years, workers under-
ever, had several limitations. The authors did not went physical examination with blood pressure
control their study population for important con- measurement every 2–5 years. Overall, 759 men
founders, such as smoking and ECOG perfor- developed RCC. The authors found that those
mance status [69]. Parker et al. reported that with diastolic blood pressure of 90 mm Hg or
obesity retained only borderline significance in more had twice the risk for RCC compared to
their analysis (HR 0.77, 95% CI: 0.57–1.05, patients with a diastolic blood pressure of 70 mm
p = 0.096), after adjustment for TNM stage group, Hg or less. Further, compared to patients with a
nuclear grade, and necrosis [71]. In particular, the median systolic blood pressure of 120 mm Hg,
results of Parker et al. suggest that the role of patients with a median systolic blood pressure of
obesity is of at most minor importance for the 150 mm Hg or more were at 60–70% higher risk
survival outcome of RCC patients. of RCC. Even after controlling for other risk fac-
tors, the authors were able to demonstrate a cor-
relation between hypertension and the
Hypertension development of RCC. Furthermore, this investi-
gation also showed a “dose–response” relation-
Hypertension and RCC: Biological ship between hypertension and the risk of RCC
Background [74]. Vatten et al. showed similar results for
The biological mechanisms that mediate the epi- women in a study of 36,688 women from Norway.
demiological association between hypertension Women with a systolic blood pressure of 130–
and RCC risk are poorly understood. Hypertension 149 mm Hg had an RR of 1.7 (95% CI: 0.9–3.5);
is associated with cell proliferation and lipid per- with levels of 150–169 mm Hg, the RR was 2.0
oxidation in the renal tubule. These processes can (95% CI: 0.9–4.2), and with levels ³170 mm Hg,
lead to inflammation, angiogenesis, and oxida- it reached 2.0 (95% CI: 0.9–4.6). Interestingly,
1 Etiology of Renal Cell Carcinoma: Incidence, Demographics, and Environmental Factors 19

women who had never used antihypertensive hypertension on the survival of RCC patients is
medication and had a systolic blood pressure of fraught with difficulty. It is possible, therefore,
³170 mm Hg had an RR of 3.4 (95% CI: 0.8–2.2) that the observed effect was more likely an effect
compared to those with a blood pressure of of smoking than an effect of hypertension.
<130 mm Hg. This result raises the possibility for In summary, the data to date has shown
using effective blood pressure management as a uncertain results in terms of demonstrating an
strategy for the reduction of RCC risk [77]. independent relationship between the use of anti-
The investigation of an independent influence hypertensive medication and an increased risk of
of hypertension on RCC risk is complicated by the RCC. Experimental studies and better controls
inevitable use of antihypertensive medication in for other risk factors in epidemiological studies
patients with hypertension [78]. Moreover, the use are necessary to determine whether there indeed
of particular types of antihypertensive medication is a relationship. Nevertheless, the results from
itself has also been implicated in increasing the epidemiological cohort studies appear to be
risk of RCC. Numerous studies have investigated sufficient to support a relationship between
the relationship between diuretics and the risk of hypertension and the risk of RCC.
RCC. While Flaherty et al. did not find an increased
RCC risk associated with the use of thiazide diuret-
ics [75]; other studies have shown a positive asso- Summary
ciation between diuretic use and RCC. A pooled
meta-analysis of 18 studies has shown an increased The worldwide incidence of kidney cancer has
risk of RCC for diuretic (RR 1.43; 95% CI: 1.12– been increasing and is expected to continue to rise
1.83) and nondiuretic hypertensive medications for the next several decades. The increased inci-
(RR 1.51; 95% CI: 1.21–1.87). However, further dence of RCC likely reflects numerous factors,
analysis suggested that the effect of diuretics was including increased utilization of abdominal
significant only in women but not in men [79]. imaging leading to the increased incidental diag-
Other large studies have suggested, on the other nosis of small renal tumors, as well as the aging of
hand, that hypertension alone rather than the use of the population and the increased prevalence of
antihypertensive medication, increases RCC risk environmental and lifestyle risk factors for RCC
[76, 80, 81]. For example, Shapiro et al. reported a such as obesity, hypertension, and smoking. The
higher risk of RCC for women on antihypertensive number of new cases presenting at advanced
medications (OR = 1.8; 95% CI: 1.0–3.1), but only stages, however, has remained at a stable but rela-
in univariate analysis. tively high level, comprising approximately one-
The role of hypertension in the outcome of third of all newly diagnosed cases. Regardless of
RCC patients was investigated in a cohort study this trend, both 5-year survival and mortality rates
of 576,562 Korean men. An increased risk for for RCC have improved. A wide variability in
cancer-specific mortality was found only for cur- geographic, gender, and ethnic differences has
rent smokers who were also hypertensive (RR been observed relative to RCC around the world.
2.80; 95% CI: 1.64–4.79). For nonsmokers and The majorities of these gene/environment interac-
former smokers, on the other hand, hypertension tions remain poorly understood and are still a
was not found to be an independent risk factor for matter of ongoing research. Tobacco use, obesity,
cancer-specific mortality [82]. This study is, to and hypertension have emerged as the primary
our knowledge, the only one which found a environmental factors that predispose to RCC.
significant effect of hypertension on the survival However, since many of these risk factors are
of RCC patients. The result of this study, how- modifiable, future investment in research directed
ever, is questionable because other studies have at the biological mechanisms that underlie the
reported worse cancer-specific survival for cur- pathogenesis of RCC and the development of evi-
rent smokers alone [33, 34], and the ability to dif- dence-based screening and prevention programs
ferentiate between the effects of smoking and are warranted.
20 F.D. Birkhäuser et al.

18. Jemal A, Siegel R, Ward E, Hao Y, Xu J, Thun MJ.

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 Pathology of Renal Cell Carcinoma
2
Ming Zhou and Huiying He

Arising from the renal tubular epithelial cells, tumors was introduced by WHO in 2004
renal cell carcinoma (RCC) accounts for more (Table 2.1) [1]. It is based primarily on mor-
than 90% of primary kidney tumors in adults. It phology but has also incorporated characteristic
encompasses a group of heterogeneous tumors genetic and molecular features of renal tumors.
with diverse clinical, pathological, and molecular These ten tumors represent the most common
characteristics as well as distinct prognosis and RCC subtypes encountered clinically. However,
therapeutic responses. It is therefore of para- many other less common subtypes of RCC have
mount importance to accurately classify renal been described with distinct clinical, pathologi-
tumors. In this chapter, we review the pathologi- cal, and genetic features, and it is likely that
cal and molecular characteristics of major histo- additional ones will be identified in the future.
logical subtypes of RCC that are recognized by As the molecular mechanisms of renal tumors
the 2004 World Health Organization (WHO) have been increasingly elucidated, molecular
classification of renal tumors [1]. We also discuss classification will eventually replace morpho-
several newly described subtypes of RCC and logical classification [2–4].
RCC associated with inherited cancer syndromes.
The prognostic significance of various histologi-
cal parameters will also be highlighted [2–4]. Pathologic and Molecular
Characteristics of RCC Histologic
Subtypes
Pathological Classification of RCC
Renal Cell Carcinoma, Clear
In addition to rendering an accurate diagnosis, Cell (CCRCC) Type
pathological classification of RCC also provides
relevant prognostic information and guidance to Clinical Features
therapy. The current classification of renal CCRCC type is the most common histological
subtype and accounts for 60–70% of all RCCs.
Although it may occur in all age groups, it most
M. Zhou, MD, PhD () commonly affects patients in their sixth to seventh
Department of Pathology, New York University Langone decades of life and the majority are males with a
Medical Center, 560 First Avenue, TCH-461, New York,
NY 10016-6497, USA
ratio of approximately 2:1 [5]. Most CCRCC
e-mail: [email protected] arises sporadically, with only 2–4% of the cases
H. He, MD, PhD
presenting as part of an inherited cancer syn-
Department of Pathology, Health Science Center, drome, including von Hippel–Lindau (VHL)
Peking University, Beijing, China syndrome, Birt–Hogg–Dube (BHD) syndrome,

S.C. Campbell and B.I. Rini (eds.), Renal Cell Carcinoma: Clinical Management, Current Clinical Urology, 23
DOI 10.1007/978-1-62703-062-5_2, © Springer Science+Business Media New York 2013
24 M. Zhou and H. He

Table 2.1 2004 World Health Organization classification Pathology

of renal cell carcinoma Grossly, CCRCC usually presents as a unilateral
Renal cell carcinoma and unicentric, round and well-demarcated mass
Clear cell renal cell carcinoma with a fibrous capsule. The cut surface often has
Multilocular clear cell renal cell carcinoma characteristic golden yellow color with variable
Papillary renal cell carcinoma degree of hemorrhage, necrosis, cystic degenera-
Chromophobe renal cell carcinoma tion, and calcification (Fig. 2.1a). Bilaterality
Carcinoma of the collecting ducts of Bellini
and/or multicentricity occur in <5% of sporadic
Renal medullary carcinoma
CCRCC cases but are more common in inherited
Xp11 translocation carcinomas
cancer syndromes.
Carcinoma associated with neuroblastoma
Mucinous tubular and spindle cell carcinoma
Microscopically the tumor cells are arranged
Renal cell carcinoma, unclassified in compact nests, sheets, alveolar, or acinar struc-
tures separated by thin-walled blood vessels.
Tumor cells have clear cytoplasm (Fig. 2.1b) due
to loss of cytoplasmic lipid and glycogen during
and constitutional chromosomal 3 translocation tissue processing and slide preparation. In high-
syndrome [6, 7]. As a general rule, familial grade and poorly differentiated tumors, cells lose
CCRCC presents at a younger age and is much their cytoplasmic clearing and acquire granular
more likely to be multifocal and bilateral. eosinophilic cytoplasm (Fig. 2.1c).

Fig. 2.1 (a) Large clear cell renal cell carcinoma with posed of compact nests of tumor cells with clear cyto-
characteristic bright golden yellow color extends into plasm separated by delicate arborizing vasculature (b).
perinephric and sinus fat. Adrenal metastasis is also seen High-grade clear cell RCC can show eosinophilic and
on the bottom of the image (a). Clear cell RCC is com- granular cytoplasm (c)
2 Pathology of Renal Cell Carcinoma 25

Molecular Genetics vast majority of CCRCC showing somatic VHL

Seventy to ninety percent of CCRCCs harbor mutations also exhibit allelic loss or LOH at the
chromosome 3p alterations which comprise dele- VHL locus, consistent with Knudson’s two-hit
tion, mutation, or methylation of several impor- model of tumorigenesis.
tant genes, including von Hippel–Lindau (VHL) VHL protein plays a critical role in the cellu-
gene on chromosome 3p25-26, RASSF1A on lar response to hypoxia (Fig. 2.2). Hypoxia-
3p21 and FHIT on 3p14.2. Duplication of 5q22 is inducible factor (HIF) is a transcriptional factor
the second most common cytogenetic finding and whose cellular level is regulated by VHL. Under
may be associated with better prognosis. Other normoxic condition, HIF is hydroxylated, and the
cytogenetic alterations involve loss of chromo- wild-type VHL protein binds and targets this
somes 6q, 8p12, 9p21, 9q22, 10q, 17p, and 14q form of HIF for degradation in proteosomes.
[3, 8, 9]. Consequently, HIF levels are kept low within
Somatic mutations in VHL gene have been normal cells under normoxic conditions through
found in 18–82% of sporadic CCRCC cases. the action of functional VHL. Under hypoxic con-
Loss of heterozygosity at the VHL locus has dition, however, HIF is not hydroxylated and can-
been reported in up to 98% of cases [10–12]. not be recognized by VHL, and therefore begins to
Hypermethylation of the VHL gene promoter accumulate. This in turn activates many down-
resulting in gene inactivation has been detected stream hypoxia-driven genes, including genes that
in 5–20% of patients without gene alteration. The promote angiogenesis [vascular endothelial growth

Fig. 2.2 Molecular pathways involving the VHL gene. multiple target genes and signal transduction pathways to
Under normoxic condition, VHL directs HIF for prote- control cell proliferation, survival, growth, and differenti-
olytic degradation. Under hypoxic condition or when ation. Several small molecule inhibitors can block various
VHL gene expression is inactivated by mutation or pro- critical steps in these pathways and are currently used to
moter hypermethylation, HIF accumulates and activates treat advanced stage disease
26 M. Zhou and H. He

factor (VEGF) and platelet-derived growth factor sule. Some tumors appear entirely necrotic and
b (PDGF-b)], cell growth or survival [transform- friable (Fig. 2.3a). PRCC is more likely to be bilat-
ing growth factor a (TGF-a)], anaerobic metabo- eral and multifocal than the other types of RCC.
lism (Glut-1), acid base balance (CA IX), and red Microscopically, PRCC is composed of vary-
cell production (erythropoietin). Along the way ing proportions of papillae, tubulopapillae, and
numerous intracellular signal transduction path- tubules. Occasionally it has tightly packed tubules
ways are activated, including PI3 kinase-Akt- or papillae and imparts a solid appearance. The
mTOR pathway and Ras-raf-erk-mek pathway, papillae characteristically contain delicate
which are involved in various cellular processes, fibrovascular cores infiltrated by foamy histio-
including cell proliferation, survival, and differen- cytes (Fig. 2.3b). Necrosis, hemorrhage, acute
tiation [12, 13]. These signal transduction path- and chronic inflammation, hemosiderin deposi-
ways serve a beneficial role by stimulating tion, and psammoma bodies are common.
angiogenesis and compensatory metabolic changes Two subtypes of PRCC are recognized based
in normal cells coping with hypoxia. When VHL on the histology [18]. Accounting for about two-
gene is inactivated by mutation or promoter hyper- thirds of PRCC, type I tumor contains papillae
methylation, no functional VHL is produced. The that are delicate and short, lined with single layer
end result is activation of the aforementioned cel- of tumor cells with scant cytoplasm and low-
lular processes which are no longer controlled by grade nuclei (Fig. 2.3b). In contrast, papillae in
normal physiological mechanisms and therefore type II PRCC are large and lined with cells hav-
contribute to the tumorigenesis and many of the ing abundant eosinophilic cytoplasm and large
clinical manifestations of CCRCC. Recent clinical pseudostratified nuclei with prominent nucleoli
trials have targeted the critical components of these (Fig. 2.3c). Patients with type I PRCC have a bet-
pathways in patients with advanced stage CCRCC, ter prognosis than those with type II tumor.
including VEGF using neutralizing antibody beva-
cizumab; VEGFR and PDGFR using small mole- Molecular Genetics
cule inhibitors of tyrosine kinase, such as sorafenib Trisomy or tetrasomy 7, trisomy 17, and loss of
and sunitinib; EGFR using erlotinib, and mTOR Y chromosome (in men) are the most common
using temsirolimus [14, 15] (Fig. 2.2). cytogenetic changes in PRCC [19]. Types I and
II PRCC have distinct genetic features, for
example, gain of 7p and 17p is more common in
Renal Cell Carcinoma, Papillary Type type I tumors [20]. Deletion of 9p is present in
(Papillary RCC) approximately 20% of PRCC and loss of
heterozygosity at 9p13, limited to type II tumors
Clinical Features in recent studies, has been linked to shorter sur-
Papillary RCC (PRCC) is the second most com- vival [21].
mon type of RCC and accounts for 10–15% of
RCCs. The gender and age distribution are simi-
lar to those of CCRCC. However, PRCC has a Renal Cell Carcinoma, Chromophobe
better prognosis with a 5-year survival approach- Type (Chromophobe RCC)
ing 90% [5]. The vast majority of tumors occur
sporadically, but some develop in members of Clinical Features
families with hereditary PRCC (HPRCC) [16] or Chromophobe RCC (ChRCC) accounts for
rarely in hereditary leiomyomatosis and renal approximately 5% of RCCs and is believed to
cell cancer (HLRCC) [17]. arise from the intercalated cells of the collecting
ducts [22]. ChRCC can occur in patients of wide
Pathology age range. Males and females are affected almost
Grossly, PRCC typically presents as a well-cir- equally. The prognosis is significantly better than
cumscribed mass enclosed within a pseudocap- that of CCRCC, with disease recurrence in <5%
2 Pathology of Renal Cell Carcinoma 27

Fig. 2.3 Papillary renal cell carcinoma has a thick tumor capsule and extensive necrosis (a). Type I tumors are com-
posed of papillae covered by a single layer of tumor cells with scant cytoplasm and low-grade nuclei. The fibrovascular
cores are expanded with foamy histiocytes (b). Type II tumor cells have abundant eosinophilic cytoplasm and large
pseudostratified nuclei with prominent nucleoli (c)

of patients [5]. Most cases arise sporadically, wrinkled with perinuclear haloes (Fig. 2.4b). Not
while some familial cases are associated with infrequently the tumor consists predominantly of
BHD syndrome [23, 24]. cells with intensely eosinophilic cytoplasm,
termed eosinophilic variant [25]. However, there
Pathology is no substantial difference in the clinical charac-
ChRCC is typically a solitary, well-circumscribed teristics between the two variants.
and nonencapsulated mass with homogenous light
brown solid cut surface (Fig. 2.4a). Hemorrhage Molecular Genetics
and/or necrosis are uncommon. A central stellate ChRCC harbors extensive chromosomal loss, most
scar can be seen in large tumors. commonly involving chromosomes Y, 1, 2, 6, 10,
Microscopically, the tumor cells are usually 13, 17, and 21 [26]. Occasionally, ChRCC occurs
arranged in solid sheets with some cases demon- in BHD syndrome, characterized by mutations in
strating areas of tubulocystic architecture. The Birt–Hogg–Dube gene (BHD) on 17p11.2, which
classic ChRCC tumor consists of large and encodes the protein folliculin [27]. However, BHD
polygonal cells with finely reticulated cytoplasm mutations are rarely found in sporadic ChRCC. It
due to numerous cytoplasmic microvesicles, and has been proposed that ChRCC may evolve from
prominent “plant cell like” cell membrane. The oncocytoma after acquiring additional cytogenetic
nuclei are typically irregular, hyperchromatic and abnormality [28].
28 M. Zhou and H. He

Fig. 2.4 Chromophobe renal cell carcinoma forms a circumscribed, nonencapsulated mass with a homogenous light
brown cut surface (a). The large and polygonal tumor cells have finely reticulated cytoplasm, prominent cell border, and
irregular nuclei with perinuclear clearing (b)

Other Uncommon Subtypes of Renal recently and were not included in the 2004 WHO
Cell Carcinoma classification. Several of these entities are
reviewed in Table 2.3 (Fig. 2.10).
Other subtypes of RCC are uncommon and col-
lectively account for <5% of RCC cases in the
kidney. However, they have clinical, pathologi- Renal Cell Carcinomas in Inherited
cal, and genetic characteristics distinct from the Cancer Syndromes
more common types discussed previously. The
clinical, pathological, and genetic features of Less than 5% of RCC occur in the setting of
these uncommon RCC subtypes are summarized inherited cancer syndromes, including von
in Table 2.2 (Figs. 2.5–2.9). Hippel–Lindau disease (VHLD), HPRCC, hered-
itary leiomyomatosis and renal cell cancer
(HLRCC), and BHD syndrome [6]. Each inher-
Renal Cell Carcinoma, Unclassified Type ited cancer syndrome predisposes patients to dis-
tinct subtypes of RCC which often occur at a
RCC, unclassified type, is a term for the designa- young age and have a higher incidence of bilater-
tion of RCC that does not fit into any of the ality and multifocality [56].
accepted categories. It is important to understand
that this is a diagnostic category rather than a true
biological entity. These tumors represent a het- von Hippel–Lindau Disease
erogeneous group of malignancies with poorly
defined clinical, morphological, or genetic fea- VHLD is an autosomal-dominant hereditary con-
tures and therefore cannot be classified using the dition with stigmata including CCRCCs, central
current criteria. Most unclassified tumors are nervous system hemangioblastomas, pheochro-
poorly differentiated and are associated with a mocytomas, pancreatic cysts and endolymphatic
poor prognosis. As our understanding of RCC sac tumors of the inner ear [13]. It is caused by
improves, this category is destined to diminish germline mutations in VHL gene. VHLD patients
and perhaps eventually disappear. There are sev- are born with a germline defect in one of the
eral other entities that were identified very alleles. Inactivation of the second allele results in
Table 2.2 Clinical, pathological, and genetic features of uncommon RCC subtypes included in the 2004 WHO classification of RCC
Pathology
RCC subtype Clinical features Grossly Microscopically Genetics Prognosis Reference
Multilocular cystic Variant of CCRCC (5% of CCRCC) Well-circumscribed, Variably sized cysts lined 3p deletion as observed in Favorable [29, 30]
RCC (Fig. 2.5) Mean age 51 years (range 20–76) entirely cystic mass; no with one or several layers CCRCC No local or distant
Male:female = 2–3:1 grossly visible nodules of flat or plump clear cells; metastasis after complete
expanding the septa; no expansile cellular nodules; surgical removal
necrosis is absent low grade nuclei (Fuhrman
nuclear grade 1 or 2)
Carcinoma of the <1% of all renal tumors; arising in Poorly circumscribed; High-grade tumor cells Variable results Poor; 1/3 presenting with [31–34]
collecting ducts of the collecting ducts of Bellini usually centrally located; form complex tubulocystic LOH on chromosomes 1q, metastasis
Bellini (Fig. 2.6) Often seen in 4th to 7th decade cut surface usually gray, structures; prominent 6p, 8p,9p, 13q, 19q32 and 2/3 patients dead of
with mean age 55 years white and firm desmoplastic stroma 21q; c-erB2 amplification disease within 2 years of
Male:female = 2:1 associated with unfavorable diagnosis
outcome
Medullary carcinoma Exceedingly rare; almost More common in right High-grade tumor cells Not well defined Highly aggressive [35, 36]
(Fig. 2.7) exclusively in patients with sickle kidney; poorly circumscribed, with reticular, microcystic 95% presenting with
cell hemoglobinopathies or traits; centrally located; tan to gray, or solid pattern metastasis; often dead of
majority are African-Americans with varying degrees of Desmoplastic stroma; may disease within 6 months
Mean age 19 years (5–69) hemorrhage and necrosis have abundant neutrophils of diagnosis
Male:female = 2:1
Xp11.2 translocation Predominantly affecting children Usually circumscribed; Most distinctive features: Chromosomal translocation Present at advanced [37–43]
carcinoma (Fig. 2.8) and young adults; accounts for 40% may resemble PRCC papillary structures lined with involving TFE3 gene on stage, but with indolent
of RCCs in this age group; occurs clear cells (Fig. 2.8a) Xp11.2 resulting in clinical course in
post-chemotherapy in some cases Confirmatory test: positive overexpression of the TFE3 children; Adult patients
male = female also affects adult nuclear immunostain for protein; has several may pursue more
patients with a striking female TFE3 protein (Fig. 2.8b) Translocation partner genes aggressive course
predominance
Mucinous tubular Mean age 53 years (range 13–82) Sharply circumscribed; Elongated compressed tubules Not well defined Favorable; majority of [44–47]
spindle cell Affects predominantly female gray–white with myxoid and bland spindle cells Losses involving chromo- patients remain disease
carcinoma (Fig. 2.9) patients (male:female = 1:4) appearance; many have embedded in a lightly somes 1, 4, 6, 8, 9, 11, 13, free after surgical
incidental finding in most cases minimal hemorrhage and/or basophilic myxoid stroma 14, 15, 18, 22 reported; 3p resection
necrosis Low-grade nuclei alterations and gain of
chromosome 7, and 17 not
present
Post-neuroblastoma In long-term survivors of Same as CCRCC Limited data; many tumors Not well defined Similar to other common [48, 49]
renal cell carcinoma neuroblastoma; male = female are typical CCRCC; some Loss of multiple chromo- RCC subtypes
neuroblastoma diagnosis in the first tumors have cells with somal loci observed
2 years of life; mean age of RCC abundant granular cytoplasm
diagnosis and arranged in solid, nests or
13.5 years (range 2–35) in papillae
Fig. 2.5 Multilocular cystic renal cell carcinoma is a well-circumscribed entirely cystic mass (a). The cystic septa are
delicate without solid tumor nodules. The cysts are lined with one or several layers of tumor cells with clear cytoplasm
and uniformly small, dense and low grade nuclei (b)

Fig. 2.6 Collecting duct carcinoma consists of high-grade Fig. 2.7 Renal medullary carcinoma comprises high-
tumor cells forming complex tubules or tubulopapillary grade tumor cells arranged in irregular nests with micro-
structures embedded in a remarkably desmoplastic stroma cystic formation. The stroma is desmoplastic

Fig. 2.8 ASPL-TFE3 renal cell carcinoma with t(X;17) nuclei with prominent nucleoli. Psammomatous
(p11.2;q25) chromosomal translocation shows nests or calcification is also present (a). The tumor cells are posi-
pseudopapillary structures lined by cells with abundant tive for nuclear TFE3 protein by immunostaining (b)
clear, sometimes eosinophilic cytoplasm and vesicular
2 Pathology of Renal Cell Carcinoma 31

esis, cell motility, proliferation, and morphogenic

differentiation. The tyrosine kinase domain of
MET is a promising therapeutic target [58].

Hereditary Leiomyomatosis and Renal

Cell Cancer

HLRCC is an autosomal-dominant disease and

predisposes patients to cutaneous leiomyomas,
uterine leiomyomas in women, and PRCC of type
II histology. The renal tumors are often solitary,
unilateral, and more likely to be aggressive and
Fig. 2.9 Mucinous tubular and spindle cell carcinoma is
composed of elongated cords and collapsed tubules with
lethal. Only 20–35% of patients develop RCC.
slit-like spaces embedded in a lightly basophilic myxoid Germline mutations are identified in the fumarate
background. The tumor cells have low-grade nuclear hydratase (FH) gene on chromosome 1 (1q42.3–43)
features [59], which is an essential regulator of the Krebs
cycle. Inactivation of FH impairs the Krebs cycle,
uncontrolled cell growth and tumor formation. thereby activating anaerobic metabolism and
Renal lesions in VHLD are always CCRCC and upregulation of HIF and hypoxia-inducible
tend to be bilateral and multifocal. Dozens or genes.
even hundreds of microscopic tumor foci can be
identified in resected kidney specimens. VHLD-
related RCC develops early with a mean age of Birt–Hogg–Dube Syndrome
onset of 37 years as compared to 61 years for
sporadic CCRCC. Although metastasis typically RCC is also part of the BHD syndrome, an auto-
only occurs when tumors are greater than 3 cm, somal-dominant disorder characterized by benign
RCC is nevertheless the leading cause of death in skin tumors (fibrofolliculomas, trichodiscomas
this syndrome. However, VHLD patients with of hair follicles, and skin tag), renal epithelial
renal involvement have better 10-year survival neoplasms, lung cysts, and spontaneous pneu-
than their sporadic counterparts [6]. mothorax [24]. Renal neoplasms are often multi-
focal and bilateral, the most common being
hybrid oncocytic tumors (50%) with features of
Hereditary Papillary Renal Cell both ChRCC and oncocytoma [60]. Renal tumors
Carcinoma can also include ChRCC (33%), oncocytomas
(5%), and occasionally CCRCC or PRCC. BHD,
HPRCC is an inherited renal cancer characterized the gene implicated in the syndrome, is a poten-
by a predisposition to develop multiple bilateral tial tumor suppressor gene on 17p11.2 and
papillary renal tumors of type I histology. To date, encodes the protein folliculin.
kidney is the only organ to be affected in these
patients [16]. HPRCC is associated with a ger-
mline mutation in the tyrosine kinase domain of Common Benign Renal Tumors
the c-met proto-oncogene on chromosome 7q31.
c-met gene encodes a cell surface receptor protein Papillary Adenoma
for hepatocyte growth factor (HGF) and has
tyrosine kinase activity [57]. Gain-of-function By WHO definition, papillary adenoma constitutes
mutations result in activated cellular processes that epithelial neoplasms with papillary and/or tubular
contribute to carcinogenesis, including angiogen- architecture, <5 mm in size and low-grade nuclei.
 32

Table 2.3 Uncommon subtypes of renal cell carcinoma not included in 2004 WHO classification [4]
Pathology
RCC subtype Clinical features Grossly Microscopically Genetics Prognosis Reference
Tubulocystic Occurs in 5th and Usually solitary; Circumscribed collection Gain in chromosome 7 Not fully established; [50–52]
carcinoma 6th decades (range circumscribed and of tubules and cysts of and 17 in some cases; majority cases are have
30–94 years); male: unencapsulated; spongy varied sizes; separated by may be related to PRCC indolent clinical course;
female = 7:1 cut surface resembling fibrous stroma; no desmo- recurrence or metastasis
“bubble wrap” plastic reaction; the lining in a few cases
cells usually exhibit
high-grade nuclei and
eosinophilic cytoplasm
Clear cell Mean age 60 years; Small tumor with mean Branching tubules, acini Limited data; do not Low-grade and low-stage [53]
tubulopapillary male = female size of 2.4 cm; the and/or clear cell ribbons exhibit the genetic tumor; mostly biological
carcinoma majority are cystic and with low-grade nuclei; changes characteristic indolent tumors
have prominent fibrous positive for CK7 and of CCRCC and PRCC
capsule and stroma negative for CD10
Thyroid-like follicular Very rare; mean age Wide size range; tan Prominent pseudocapsule; Limited data Not well defined; [54]
carcinoma 45 years colored micro- and macrofollicles available cases are free
lined with low-grade cells; of disease after surgical
colloid-like material resection
present in >50% of
follicles; negative for
TTF-1 and thyroglobulin
Acquired cystic kidney 2–7% incidence in Frequently multicentric About 40% are classic Limited data; gains in Less aggressive than [55]
disease (ACKD)- ACKD patients; and bilateral; generally CCRCC, PRCC or chromosomes 1, 2, 6, sporadic RCC
associated RCC occur in relatively well circumscribed ChRCC; various architec- and 10
(Fig. 2.10) young patients; male tures; 80% of tumor cells
predominance show abundant intratumoral
calcium oxalate crystals
M. Zhou and H. He
2 Pathology of Renal Cell Carcinoma 33

Fig. 2.10 Acquired cystic disease-associated renal cell carcinoma forms a well-circumscribed mass with cysts and
solid nodules (a). The non-neoplastic kidney is atrophic with several cysts. The tumor exhibits tubulocystic architec-
tures and contains calcium oxalate crystals (b)

Clinical Features Molecular Genetics

Adenoma is the most common renal cell neo- Papillary adenomas share many genetic altera-
plasm, frequently presenting as incidental tions with PRCC; both have combined gains of
findings after nephrectomy or at autopsy. In one chromosomes 7 and 17 and loss of the Y chromo-
autopsy study, papillary adenomas were found in some in men. PRCCs acquire additional genetic
up to 40% of patients older than 70 years of age. alterations, including trisomy 12, 16, or 20. The
Its incidence increases with age and also in cytogenetic findings support the hypothesis that
patients on long-term dialysis. papillary adenoma is a precursor of PRCC [62].

Pathology
Papillary adenomas appear as small (<5 mm), Renal Oncocytoma
well circumscribed, yellow or white nodules in
the renal cortex. They have papillary, tubular, or Clinical Features
tubulopapillary architecture, similar to PRCC Renal oncocytoma accounts for 5% of surgically
[61]. The tumor cells have uniform small nuclei resected nonurothelial renal neoplasms. Patients
and inconspicuous nucleoli equivalent to Fuhrman vary greatly in age with a peak incidence in the
grade 1 or 2 nuclei (Fig. 2.11). seventh decade of life. The male-to-female ratio
34 M. Zhou and H. He

than 10% of cases have multifocal or bilateral

lesions.
Microscopically, oncocytoma is characterized
by bright eosinophilic cells, termed oncocytes,
arranged in nested, acinar or microcystic pattern
associated with a loose hypocellular and hyalinized
stroma (Fig. 2.12b). Extension of oncocytoma into
the perinephric fat, or rarely into vascular space,
can be found sometimes and does not adversely
affect the benign prognosis of the lesion.

Molecular Genetics
Most oncocytomas are composed of a mixed
Fig. 2.11 Papillary adenoma comprises collection of
papillae that are lined with cells with uniform small nuclei
population of cells with normal and abnormal
and inconspicuous nucleoli. The tumor size is less than karyotypes [63]. Combined loss of chromosomes
5 mm 1 and X/Y is the most frequent chromosome
abnormality. Translocations involving chromo-
some 11, with a breakpoint at 11q12-13, have
is 1.7:1. Most cases are sporadic, although famil- also been reported. Other rare chromosome rear-
ial cases have been reported in association with rangements have been reported, such as t(1;12)
BHD syndrome and familial renal oncocytoma (p36;q13), loss of chromosome 14 and gain of
syndrome. chromosome 12 [64]. Oncocytoma can be a man-
ifestation of BHD syndrome.
Pathology Whether oncocytoma and ChRCC are related
Oncocytoma is typically solitary, well circum- is still controversial. They not only have overlap-
scribed and has varying degrees of encapsulation ping morphological features but also share some
(Fig. 2.12a). The cut surface exhibits a character- cytogenetic changes, such as the loss of heterozy-
istic homogeneous mahogany-brown color. A gosity at chromosome 1 [65]. However, mono-
central stellate scar can be seen in one-third of somy of chromosomes 2, 10, 13, 17, and 21
the cases, more commonly in larger tumors. More occurred exclusively in ChRCC [66].

Fig. 2.12 Renal oncocytoma forms a solitary, well-cir- philic cells nested in a loose stroma. The tumor cells are
cumscribed, nonencapsulated mass with homogeneous uniform, round to polygonal with granular eosinophilic
dark-brown cut surface (a). It consists of bright eosino- cytoplasm and regular round nuclei (b)
2 Pathology of Renal Cell Carcinoma 35

is lost in multivariate models. One recent study

Pathological Prognosis Parameters demonstrated that only nucleolar prominence is
for Renal Cell Carcinoma significantly associated with survival in both uni-
variate and multivariate analyses [71]. Another
Fuhrman Nuclear Grading study showed that Fuhrman grade, not the nucle-
olar grade, is an independent prognostic factor
Currently, the four-tiered Fuhrman grading and should be used as the standard grading sys-
scheme, first described in 1982, remains the most tem for PRCC [72]. Only a few studies addressed
commonly used grading system for RCC [67]. the prognostic significance of Fuhrman grading
Fuhrman grade, based on the nuclear size and system for ChRCC using univariate analysis.
shape, chromatin and nucleolar prominence, is A recent study found that Fuhrman grading does
categorized into G1–4 (Table 2.4) (Fig. 2.13). not correlate with survival, therefore is not appro-
Most studies have confirmed that Fuhrman priate for ChRCC [73]. A new grading system
nuclear grade is an independent prognostic pre- was recently proposed for ChRCC based on the
dictor for CCRCC [68]. Simplified two-tiered assessment of geographic nuclear crowding and
(G1–2 vs. G3–4) or three-tiered (G1–2 vs. G3 vs. anaplasia. This grading scheme was shown to be
G4) Fuhrman systems have been proposed to an independent predictor of clinical outcomes for
improve interobserver agreement and still pre- ChRCC [74].
serve its prognostic significance [69]. Grade 1
and grade 2 may be grouped together as low
grade since the two are not prognostically differ- Sarcomatoid and Rhabdoid
ent in multivariate analysis. However, studies Differentiation
have shown that grade 3 and grade 4 tumors
should not be grouped together as grade 3 tumors Sarcomatoid differentiation is present in about
have better 5-year cancer-specific survival than 5% of RCCs and can be observed in any RCC
grade 4 tumors (45–65% in grade 3 cancers vs. subtype [75]. Therefore, sarcomatoid RCC is not
25–40% in grade 4 cancers). A recent study considered a distinct subtype of RCC by 2004
showed that the three-tiered Fuhrman grading WHO classification; rather, it is thought to repre-
system is an appropriate option for the prognosti- sent a high-grade and poorly differentiated
cation of CCRCC in both univariate analysis and component.
multivariate model setting [70]. The use of a RCC with sarcomatoid differentiation typi-
simplified Fuhrman nuclear grading system in cally has other adverse pathological features,
clinical practice requires further clarification and including large tumor size, extension into peri-
preferably a consensus between pathologists and nephric fat and vessels, and presence of hemor-
urologists. rhage and necrosis. It is also significantly
The prognostic value of Fuhrman grading for associated with an increased likelihood of distant
nonclear cell RCC, however, remains controver- metastasis and cancer-specific death. It is an
sial. For PRCC, it is significantly associated with adverse independent prognostic indicator in both
survival in univariate analysis but this significance univariate and multivariate analyses [76]. Any

Table 2.4 Fuhrman nuclear grading system [67]

Grade Nuclear size Nuclear shape Chromatin Nucleoli
1 <10 mm Round Dense Inconspicuous
2 15 mm Round Finely granular Small, not visible at 10× magnification
3 20 mm Round/oval Coarsely granular Prominent, visible at 10× magnification
4 >20 mm Pleomorphic, Open, hyperchromatic Macronucleoli
multilobated
36 M. Zhou and H. He

Fig. 2.13 Fuhrman grading system is based on the RCC, nuclei have open chromatin and prominent nucleoli
nuclear size, irregularity of the nuclear membrane and visible at low magnification (c). Grade 4 nuclei are mark-
nucleolar prominence. Grade I RCC has uniformly small edly pleomorphic, hyperchromatic with single or multiple
and dense nuclei (a). Grade 2 nuclei have smooth open macronucleoli (d)
chromatin but inconspicuous nucleoli (b). In grade 3

RCC with sarcomatoid differentiation is assigned Rhabdoid differentiation can be identified in

a Fuhrman grade 4. approximately 5% of RCCs with tumor cells hav-
Sarcomatoid components usually appear as ing large eccentric nuclei, macronucleoli and
bulging, lobulated areas with white to gray, firm prominent acidophilic globular cytoplasm
and fibrous cut surface within a tumor (Fig. 2.14). (Fig. 2.15). The presence of rhabdoid component
Histologically, the sarcomatoid component is also associated with high grade and high stage
ranges from malignant spindle cells to those with frequent extrarenal extension. The rhabdoid
resembling leiomyosarcoma, fibrosarcoma, foci may account for 5–90% of the tumor area. It
angiosarcoma, rhabdomyosarcoma, and other is a marker of high risk for metastasis and poor
sarcomas. The coexisting RCC component, prognosis even when the rhabdoid component is
including clear cell, papillary, chromophobe RCC limited [77].
and sometimes collecting duct RCC, can often to
be identified and is used to subtype the RCC with
sarcomatoid differentiation. However, such sub- Tumor Necrosis
typing may not be possible if the sarcomatoid
component overruns RCC epithelial components, For CCRCC, tumor necrosis, identified either
a rare occurrence. macroscopically or microscopically, is an adverse
2 Pathology of Renal Cell Carcinoma 37

Fig. 2.14 Renal cell carcinoma with sarcomatoid differ- tion has a fleshy appearance, suggestive of sarcomatoid
entiation. The upper portion of this renal tumor is golden differentiation (a). Microscopically the sarcomatoid com-
yellow, characteristic of clear cell RCC. The lower por- ponent shows the malignant spindle cells (b)

pathological factor and is associated with worse

clinical outcomes in both uni- and multivariate
analyses. Studies from Mayo Clinic clearly
showed that histological necrosis is associated
with twice the cancer-specific death rate com-
pared to those without necrosis [5]. The presence
and extent of histological necrosis in CCRCC are
independent predictors of survival in localized
but not metastatic cases, although one recent
study showed limited prognostic value [78]. Two
outcome prediction models, SSIGN from Mayo
Clinic, and the postoperative outcome nomogram
from MSKCC, both incorporate tumor necrosis
Fig. 2.15 Renal cell carcinoma with so-called “rhab-
doid” morphology contains large eccentric nuclei, macro- in their models [79, 80]. A few recent studies also
nucleoli and prominent acidophilic globular cytoplasm reported that the proportional extent of necrosis
38 M. Zhou and H. He

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2 Pathology of Renal Cell Carcinoma 41

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Microvascular invasion is an independent prognostic
 Familial Renal Cell Carcinoma
3
Simon P. Kim and Bradley C. Leibovich

tary familial cancer syndromes has distinct

Introduction clinical manifestations and treatment challenges.
Herewith, we will provide an overview of the
Recently our understanding of the biologic mech- genetics, clinical syndromes, and management of
anisms underlying the development of renal cell hereditary kidney cancer syndromes.
carcinoma (RCC) has undergone a remarkable
evolution. Extensive research on familial kidney
cancer has served as the basis for better under- Overview
standing of the pathology and molecular genetics
of this malignancy. This has in turn facilitated the In 2010, approximately 58,240 patients were
introduction of novel targeted therapeutic agents diagnosed with RCC, which remains one of the
that continue to change and refine the clinical most lethal of the common urologic malignancies
management for both familial and sporadic forms [1]. Although most patients diagnosed with RCC
of this malignancy. present with sporadic unilateral tumors, approxi-
RCC represents the prototypical example of a mately 3–4% of incident cases are due to familial
malignancy in which discoveries related to the kidney cancer syndromes [2]. At present, four
familial syndromic forms of this malignancy have hereditary RCC syndromes have been well char-
transformed treatment paradigms. It is therefore acterized with each having a clearly identified
paramount to have a critical understanding of the genetic abnormality responsible for the specific
genetic mechanisms in hereditary kidney cancer histologic subtype of RCC and unique clinical
given the high prevalence of these genetic abnor- manifestations (Table 3.1).
malities that have been identified in sporadic
cases. To date, four forms of familial kidney can-
cer have been well characterized: (1) von Hippel– von Hippel–Lindau Disease
Lindau (VHL); (2) hereditary papillary renal cell
carcinoma (HPRCC); (3) Birt–Hogg–Dubè VHL is an autosomal dominant hereditary RCC
(BHD); and (4) hereditary leiomyomatosis renal syndrome in which affected individuals develop
cell carcinoma (HLRCC). Each of these heredi- clear cell RCC. Though the prevalence of VHL
has been estimated to affect approximately 1 in
every 36,000 individuals, it is the most common
form of familial RCC [3]. The molecular genetics
S.P. Kim, MD, MPH • B.C. Leibovich, MD ()
of VHL has important implications in both the
Department of Urology, Mayo Clinic, 200 First Street
SW, Rochester, MN 55905, USA familial and sporadic forms of clear cell RCC
e-mail: [email protected] [4, 5]. VHL gene mutation has clinically relevant

S.C. Campbell and B.I. Rini (eds.), Renal Cell Carcinoma: Clinical Management, Current Clinical Urology, 43
DOI 10.1007/978-1-62703-062-5_3, © Springer Science+Business Media New York 2013
44 S.P. Kim and B.C. Leibovich

Table 3.1 Hereditary familial RCC syndromes

Genetic element Patterns of
Syndrome (location) Gene product inheritance Type of RCC and manifestation
von Hippel–Lindau VHL gene (3p25-26) pVHL Autosomal Clear cell RCC
dominant Solid and/or cystic
Multiple and bilateral
Hereditary papillary c-MET proto-oncogene MET Autosomal Type I papillary RCC
RCC (7q31) dominant Multiple and bilateral renal tumors
Birt–Hogg–Dubè BHD gene (17p12q11) Folliculin Autosomal Hybrid oncoctyic RCC
dominant Chromophobe RCC
Oncocytoma
Clear cell RCC
Familial leiomyatosis FLCN (1.q42.3-q43) Fumarate Autosomal Type II papillary RCC
RCC hydratase dominant Solitary and aggressive

implications in sporadic cases, as mutation has inactivation of the VHL gene leads to accumula-
been associated with improved survival compared tion of HIF-a, resulting in increased production
to cases without the VHL mutation [6–9]. It is also of downstream products, such as EGFR, GLUT-1,
noteworthy that the VHL mutation is specific to PDGF, and VEGF [18–20]. It is the dysregulation
clear cell RCC and has not been identified in the of this process that results in the angiogenesis and
remaining histologic subtypes [10–14]. tumorigenesis responsible for the development of
Through molecular genetic linkage analysis of clear cell RCC.
affected families, the gene mutation responsible The clinical criteria for the diagnosis of VHL
for the familial form of clear cell RCC has been syndrome are based on the presence of one or
identified as the VHL tumor suppressor gene more major manifestations and/or a family history
(Fig. 3.1). The VHL gene, which has been located of VHL disease (Table 3.2). The major manifesta-
at chromosome 3p.25-26, has been fully sequenced tions of VHL include clear cell RCC, pheochro-
and encodes a 213 amino acid protein. The VHL mocytoma, retinal angiomas, and central nervous
gene produces a protein that binds elongins B and system hemangioblastomas (brainstem, cerebel-
C and Cul2, forming a protein complex that facili- lum, or spinal cord). Evaluation of affected fami-
tates ubiquitin-mediated degradation of hypoxia- lies has demonstrated that two types of the VHL
inducible factors (HIF-1a and HIF-2a) [15–17]. syndrome exist and each has varying degrees of
HIFs function as critically important intracellular tumor risk in the CNS and visceral organs [21].
proteins in regulating the cellular response to Molecular differences in the type of mutation in
hypoxia and stress. Under conditions of hypoxia, the VHL gene contribute to the heterogeneity of
there is an accumulation of HIF proteins causing clinical findings and the varying degrees of expres-
an upregulation in the transcription of epidermal sion in the two types of VHL (Table 3.3) [22–26].
growth factor receptor (EGFR), glucose trans- In type 1 VHL, individuals carrying the gene
porter (GLUT-1), platelet-derived growth factor mutation have increased risks of clear cell RCC,
(PDGF), and vascular endothelial growth factors CNS hemangioblastomas, and pancreatic endo-
(VEGFs). All of these downstream mediators play crine tumors or cysts, but a low risk in the devel-
an adaptive role under hypoxic conditions. Under opment of pheochromocytoma. Type 1 is also the
normoxic conditions and a normal functioning most common form of VHL, accounting for 75%
VHL gene, HIF-1a and HIF-2a are hydroxylated of familial cases. Mutations for type 1 VHL are
through an oxygen-mediated process by HIF pro- due to partial or complete deletion and nonsense,
lyl hydroxlase (HPH). Hydroxylated HIFs are missense, and frame shift mutations, thereby
readily recognized and bound by the VHL protein altering the ability of the VHL to bind to elongin
complex and targeted for degradation. However, C and preventing HIF degradation [27].
3 Familial Renal Cell Carcinoma 45

Fig. 3.1 Molecular pathway and targeting VHL pathway hypoxia, HIF-1a accumulates and promotes downstream
in clear cell renal carcinoma. A mutation in the VHL gene production of vascular endothelial growth factors (VEGFs),
prevents binding to elongin B and C causing an intracellu- glucose transporters (GLUT-1), transforming growth factor
lar accumulation of hypoxia-inducible factors (HIF). Under (TGF-a), and platelet-derived growth factor (PDGF) [2]

Table 3.2 Clinical criteria for a diagnosis of familial types 2A and 2B also share a high risk for CNS
VHL disease hemangioblastomas, but differ in that VHL type
Patients with a family history of VHL and 2B carries a high risk of clear cell RCC while type
One major manifestation 2A does not. Type 2B is associated with a high risk
Central nervous system hemangioblastoma pancreatic endocrine tumors and cysts. Type 2C is
Retinal angiomas
Pheochromocytoma unique in that the only visceral organ at risk is the
Clear cell RCC adrenal gland (pheochromocytoma).
Patients without a family history and
Two major manifestations
Two or more central nervous system Hereditary Papillary Renal Cell
hemangioblastoma
One hemangioblastoma and pheochromocytoma
Carcinoma
or clear cell RCC
In 1994, HPRCC was described as another hered-
itary renal cancer syndrome, in which affected
Type 2 VHL has been further subdivided into families were reported to have an increased risk
three distinct phenotypic subtypes (2A, 2B, and of bilateral multifocal tumors with type I papil-
2C) based on the different clinical manifestations lary renal carcinoma histologic subtype [28].
and types of mutation resulting in HIF accumula- HPRCC is a rare autosomal dominant familial
tion. All three subgroups in type 2 VHL are caused kidney cancer with the only phenotypic manifes-
by missense mutations in the VHL gene and carry tation occurring in the kidney [23, 28]. The causal
a high predisposition of pheochromocytoma. VHL genetic mechanism of HPRCC has been identified
46 S.P. Kim and B.C. Leibovich

Table 3.3 Major manifestations by genotype–phenotype corre-

lations for VHL disease
VHL type Genotype Phenotype
Type I Deletion, High risk of clear cell RCC
truncation Low risk of pheochromocytoma
High risk of CNS hemangioblastoma
Pancreatic endocrine tumor or cyst
Type 2
2A Missense High risk of pheochromocytoma
Low risk of clear cell RCC
High risk of CNS hemangioblastoma
2B Missense High risk of pheochromocytoma
High risk of clear cell RCC
Pancreatic endocrine tumor and cyst
2C Missense High risk of pheochromocytoma

as a proto-oncogene, the MET gene, located on lence of 1 in every 200,000 individuals. Although
the chromosome 7q31.3 [29–31]. BHD was first described based on the classic der-
The function of the protein encoded by the matologic presentation of fibrofolliculomas in
MET gene has been defined as a transmembrane 1977, it was later documented that these individ-
tyrosine kinase receptor with hepatocyte growth uals were also at increased risk for developing
factor, also located on chromosome 7, identified multiple renal tumors and pulmonary cysts,
as the ligand for activation [32]. Activation of the which manifest as a spontaneous pneumothorax
tyrosine kinase receptor by a gain-of-function [35–38]. The risk of renal tumors varies among
mutation in the MET gene leads to unregulated families with BHD. Investigators have docu-
proliferation and growth. It is this molecular mented that 25–35% of affected individuals will
mechanism that results in familial HPRC and a ultimately develop renal tumors [36, 38–40]. The
small subset (approximately 10%) of sporadic pathologic features of renal tumors in individuals
type 1 papillary RCC. Mutations in the MET with BHD have been shown to have several dif-
gene also lead to upregulation of HIFa, although ferent types of histologic features. Pavlovich and
HIF-a promotion in this instance is due to a VHL colleagues documented that a majority of renal
independent pathway. tumors in BHD consist of an oncocytic-hybrid,
In the clinical manifestations for HPRCC, the which was initially described as a chromophobe-
MET gene mutation causes a high propensity for oncocytoma renal carcinoma (50%), followed by
bilateral, multifocal type I papillary renal carci- chromophobe renal carcinoma (34%), clear cell
noma in young adulthood [33]. Of all the heredi- carcinoma (9%), oncocytoma (5%), and papillary
tary kidney cancer syndromes, HPRCC has the renal carcinoma (2%).
highest degree of penetration, such that 90% of The folliculin (FLCN) gene on the short arm
affected individuals develop multiple tumors with of chromosome 17p11.2 is now established as the
type I papillary RCC histology over the course of germline mutation responsible for BHD [41, 42].
a lifetime [30]. It has been shown that HPRCC The FLCN gene contains 14 exons and encodes
patients will go onto develop an average of 3,400 the folliculin protein that has been hypothesized
microscopic papillary tumors per kidney [34]. to function as a tumor suppressor gene. However,
its function in the pathogenesis of BHD has yet to
be fully elucidated. Baba and colleagues identified
Birt–Hogg–Dubè Syndrome folliculin-interacting protein1 (FNIP1) that facil-
itates phosphorylation of folliculin and interacts
BHD is a rare autosomal dominant inherited with 5¢ AMP-activated protein kinase (AMPK).
familial RCC syndrome with an estimated preva- This pathway serves to functions as a negative
3 Familial Renal Cell Carcinoma 47

regulator of the mTOR pathway [43]. mTOR (Fig. 3.2), one of which is histologically
appears to modulate folliculin since blockade of confirmed; or a pathogenic FCLN mutation. The
AMPK or MTOR will inhibit folliculin phospho- minor criteria may be one or more of the follow-
rylation by FNIP1. These findings suggest that ing: multiple lung cysts that are located at the
mTOR inhibitors may have efficacy in the treat- base of each lung bilaterally; early multifocal or
ment of renal carcinoma in patients with BHD. bilateral renal carcinoma of early age onset or
Given the various organ systems affected and renal carcinoma with a histology consistent of
differing degrees of phenotypic expression within mixed chromophobe renal carcinoma and onco-
each organ system, a validated and accepted diag- cytoma; or a first-degree relative with BHD.
nostic criteria system for BHD would facilitate Pulmonary cysts will present with spontane-
ease of diagnosis and a uniform measure of dis- ous pneumothorax and are the most commonly
ease severity. While a formal clinical criteria for observed clinical feature in BHD. Approximately
identifying individuals considered to be likely 80% of BHD individuals will have pulmonary
carriers of BHD has yet to be established or vali- cysts on CT of the chest. While spontaneous
dated, Menko and colleagues recently proposed a pneumothorax has been traditionally described in
clinical classification to further facilitate recogni- apical pulmonary cysts, BHD individuals have a
tion and diagnosis of this uncommon hereditary 50 times higher rate of pneumothorax due to large
kidney cancer syndrome (Table 3.4) [39]. The basal pulmonary cysts [36]. Toro and colleagues
diagnostic criteria have two components—major have estimated that the prevalence of pneumotho-
and minor criteria. In the major criteria, an indi- rax in BHD is 24% with a median age of presen-
vidual will have at least five fibrofolliculomas tation of 38 years [39, 45]. The clinical appearance
of the pulmonary cysts has been characterized
histologically as emphysematous changes [46, 47].
Table 3.4 Major and minor diagnostic criteria for BHD
Individuals suspected to have BHD, even
Major criteria those who have unclear clinical presentations,
Five or more fibrofolliculomas
Pathogenic FCLN germline mutation
should undergo genetic testing for the FCLN
Minor criteria (folliculin mutation) or referral to a medical
Multiple bilateral lung cysts located at the base geneticist. Detection of an FCLN mutation is
Renal cell carcinoma with early age onset (<50 years) pathognomonic and confirmatory in the diagno-
First-degree relative with BHD syndrome sis of BHD. Moreover, genetic testing is essential

Fig. 3.2 Cutaneous lesions and histology of fibrofolliculomas in Birt–Hogg–Dubè syndrome [44]
48 S.P. Kim and B.C. Leibovich

given the clinical variability of BHD and the need analysis among 11 affected family members [49].
to test family members due to the autosomal It was later determined that the genetic aberration
dominant transmission. in HPRCC resulted in loss of function of the
fumarate hydratase (FH) gene, located on the
chromosome 1q42. -q43 [50].
Hereditary Leiomyomatosis Renal Cell FH is a Krebs cycle enzyme and is typical for
Carcinoma genetic mutations in RCC in that it affects meta-
bolic pathways. Mutation of FH leads to a VHL
HLRCC is a familial kidney cancer syndrome dis- independent accumulation of HIF-a and its asso-
tinctly different from others in that the associated ciated downstream products. FH mutations have
renal tumors typically behave aggressively, with a been established as the major molecular pathway
propensity for early metastasis from small solitary responsible for HPRCC, since this mutation has
renal tumors. In this syndrome, affected individu- been identified in more than 90% of clinically
als have an increased risk of developing cutaneous affected individuals. Under normal conditions,
and uterine leiomyomas and type II papillary renal HIF-a is degraded by HPH and fumarate is con-
carcinoma. HLRCC was initially described as verted to malate by FH. However, fumarate and
multiple cutaneous and uterine syndrome, or reed HIF-a directly compete for the same binding site
syndrome in 1972 [48]. In the original description, of HPH, and a mutation in FH causes fumarate to
the clinical findings of uterine and cutaneous leio- accumulate and bind to HPH, thereby preventing
myomas were the only manifestations initially hydroxylation and subsequent degradation of
reported. In 2001, however, Launonen and col- HIF (Fig. 3.3). As a result, mutations in FH cre-
leagues demonstrated that Reed Syndrome was ate a pseudohypoxic environment, where accu-
also associated with type II papillary renal carci- mulation of intracellular HIF leads to the same
noma and further localized the genetic mutation as downstream products from VHL, although
a loss of chromosome 1q through genetic linkage through an independent pathway [52].

Fig. 3.3 Molecular pathway in HLRCC. Mutations in intracellular HIF and downstream transcription of vascu-
fumurate hydratase (FH), a critical enzyme in the Kreb lar endothelial growth factor (VEGF), glucose transporter
cycle, cause an accumulation of fumurate and compete (GLUT-1), platelet-derived growth factor (PDGF), and
with HIF for HIF prolyl hydroxlase (HPH), thereby creat- transforming growth factor (TGF-a) [51]
ing a pseudohypoxic state. This causes an increase in
3 Familial Renal Cell Carcinoma 49

In HPRCC, the phenotypic expression involves Nephron-sparing surgery remains the mainstay
cutaneous and uterine leiomyomas and type II in the urologic management of patients with renal
papillary renal carcinoma. Historically, the clas- cancer syndromes for multiple reasons. Patients
sic presentation is that of young female who may with inherited syndromes resulting in renal
undergo hysterectomy for multiple large leiomy- tumors tend to present early in life and most will
omas. It is also noteworthy that uterine leiomyo- have multiple renal tumors over their lifetime.
mas due to HPRCC have low malignant potential For example, patients with VHL are at risk for
for leiomyosarcoma [49, 53, 54]. Leiomyomas developing over 1,000 cysts and 600 tumors per
also present as a dermatologic manifestation. kidney, while patients with HPRCC may have up
Cutaneous leiomyomas are often painful and to 3,000 renal tumors per kidney [34, 58, 59].
located on the torso or extremities in a grouped, While patients undergoing kidney surgery for
segmental, or disseminated and segmental pat- renal carcinoma have other competing risks of
tern, affecting 80% of individuals with HPRCC cancer and chronic renal insufficiency from sur-
[55]. While HPRCC has been shown to have a gical extirpation, there is increasing evidence to
high prevalence in the phenotypic expression of suggest that nephron-sparing surgery may reduce
uterine and cutaneous leiomyomas, the degree of the risk of chronic renal insufficiency and mortal-
penetration of renal tumors with type II papillary ity [60–65]. Although existing studies in the sur-
renal carcinoma is lower. It has been estimated gical management of familial kidney cancer are
that approximately 15% of affected individuals limited to single institution, retrospective series,
will develop type II papillary renal carcinoma in Herring and colleagues reported that a large pro-
HLRCC [49, 53–55]. portion of patients with VHL, HPRCC, or BHD
Management of renal masses in HLRCC is avoided stage V chronic kidney disease and dial-
unique from the other familial renal cancer syn- ysis by undergoing multiple parenchymal-sparing
dromes due to the highly aggressive nature of the surgeries [57, 66, 67].
solitary small renal tumors with type II papillary With patients likely to require multiple surger-
RCC histology and predilection for early metas- ies over a lifetime, minimally invasive treatment
tasis [56]. As a result, immediate aggressive sur- with ablation also has been evaluated in individu-
gical intervention is recommended for renal als with hereditary renal cancer syndromes in
tumors in patients with HLRCC. order to reduce morbidity and complications asso-
ciated with open surgery. Though a large prospec-
tive study evaluating the effectiveness of ablation
Management of renal tumors among individuals with familial
kidney cancer syndromes has yet to be undertaken,
Surgical Treatment several smaller cohort studies suggest that percuta-
neous radio frequency ablation can be performed
Current recommendations in the management of safely and offers some efficacy following short-
renal masses in familial kidney cancer syndromes term and intermediate follow-up with limited
(with the exception of HLRCC) are based on the complications [68, 69]. Further studies with longer
observation that these tumors have little meta- follow-up are needed to determine the long-term
static potential when under 3 cm in size [57]. effectiveness of ablation in patients with heredi-
Consequently, patients should be observed with tary forms of RCC (with exception to HLRCC).
serial imaging until one or more tumors approach Although delaying surgical intervention until
a size threshold of 3 cm to initiate surgical inter- the size threshold of 3 cm and nephron-sparing
vention, or rapid increases in renal tumor size are surgery is the current recommended treatment for
noted on interval imaging. Delaying intervention most familial kidney cancer syndromes, the sur-
until renal tumors reach the size threshold mini- gical treatment for HLRCC differs given the
mizes the frequency of surgery and treatment highly aggressive nature of the associated renal
related morbidity. tumors and early risk of metastasis [56]. These
50 S.P. Kim and B.C. Leibovich

patients should have early and aggressive surgi- 3. Maher ER, Iselius L, Yates JR, et al. Von Hippel–
cal resection. Although the clinical benefit of a Lindau disease: a genetic study. J Med Genet.
1991;28(7):443–7.
lymph node dissection is debatable for patients 4. Latif F, Tory K, Gnarra J, et al. Identification of the
diagnosed with HLRCC, most of these patients von Hippel–Lindau disease tumor suppressor gene.
should undergo a radical nephrectomy at a mini- Science. 1993;260(5112):1317–20.
mum given the highly aggressive nature of these 5. Stolle C, Glenn G, Zbar B, et al. Improved detection of
germline mutations in the von Hippel–Lindau disease
associated renal tumors. tumor suppressor gene. Hum Mutat. 1998;12(6):417–23.
6. Yao M, Yoshida M, Kishida T, et al. VHL tumor sup-
pressor gene alterations associated with good progno-
Conclusion sis in sporadic clear-cell renal carcinoma. J Natl
Cancer Inst. 2002;94(20):1569–75.
7. Kim HL, Seligson D, Liu X, et al. Using tumor mark-
Although familial kidney cancer syndromes occur ers to predict the survival of patients with metastatic
infrequently, our understanding of the molecular renal cell carcinoma. J Urol. 2005;173(5):1496–501.
mechanism responsible for the clinical manifesta- 8. Patard JJ, Rioux-Leclercq N, Masson D, et al. Absence
of VHL gene alteration and high VEGF expression
tions has led to advances in novel targeted agents are associated with tumour aggressiveness and poor
and altered the management of metastatic disease survival of renal-cell carcinoma. Br J Cancer.
for all patients. It is also important to understand 2009;101(8):1417–24.
the unique clinical challenges and differences in 9. Patard JJ, Fergelot P, Karakiewicz PI, et al. Low CAIX
expression and absence of VHL gene mutation are
the surgical management of renal masses among associated with tumor aggressiveness and poor sur-
individuals with familial kidney cancer. Since vival of clear cell renal cell carcinoma. Int J Cancer.
there remains a significant risk of recurrent multi- 2008;123(2):395–400.
focal renal tumors, expectant management with 10. Maher ER, Yates JR. Familial renal cell carcinoma:
clinical and molecular genetic aspects. Br J Cancer.
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in size and nephron-sparing surgery are the key 11. Gnarra JR, Tory K, Weng Y, et al. Mutations of the
features in the surgical management for most VHL tumour suppressor gene in renal carcinoma. Nat
familial kidney cancer syndromes with exception Genet. 1994;7(1):85–90.
12. Shuin T, Kondo K, Torigoe S, et al. Frequent somatic
to HLRCC-associated tumors. Given the highly mutations and loss of heterozygosity of the von Hippel–
aggressive nature of renal tumors associated with Lindau tumor suppressor gene in primary human renal
HLRCC, early surgical intervention with a radical cell carcinomas. Cancer Res. 1994;54(11):2852–5.
nephrectomy and lymph node dissection is recom- 13. Neumann HP, Bender BU, Berger DP, et al. Prevalence,
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play an important role in reducing renal recur- renal cell carcinoma. J Urol. 1998;160(4):1248–54.
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taken at institutions with a high volume of clinical transcription elongation by the VHL tumor suppres-
experience using a multidisciplinary approach sor protein. Science. 1995;269(5229):1402–6.
16. Kibel A, Iliopoulos O, DeCaprio JA, Kaelin Jr WG.
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geneticists. protein to Elongin B and C. Science. 1995;269(5229):
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 Imaging of Renal Cell Carcinoma
4
Andrei S. Purysko, Erick M. Remer, and Brian R. Herts

contemporaneous development of a number of

Introduction surgical and ablative therapies to treat renal
tumors. These include partial nephrectomy, lap-
With the expanded use of imaging in recent aroscopic total or partial nephrectomy, and per-
decades, there has been an increase in the detec- cutaneous ablative procedures. These newer
tion of asymptomatic, incidental renal cell tumors techniques are typically used for patients with
[1–7]. While most incidentally detected lesions smaller size, lower stage tumors. The radiologi-
are benign cysts, solid renal tumors are predomi- cal imperatives for these patients include not only
nantly renal cell carcinomas (RCCs). Occasionally, accurate staging, but also a more sophisticated
though, solid masses are other benign renal neo- anatomical analysis than was needed when radi-
plasms [8, 9]. When malignant, these incidentally cal nephrectomy was the standard of care.
discovered tumors are more frequently lower This chapter will discuss imaging of RCC as it
stage and lower grade tumors, with a better prog- relates to the detection of RCC and its character-
nosis than tumors in patients who present with ization and the differential diagnoses of renal
hematuria or flank pain [10–13]. masses. We will briefly summarize the current
The introduction of thin slice, multidetector status of ultrasound (US), CT, and MR for detec-
computed tomography (MDCT) and advanced tion and staging of RCC, including presurgical
magnetic resonance (MR) imaging hardware and planning, and will also compare their strengths
software have helped radiologists confidently and weaknesses. The imaging features of differ-
characterize masses as enhancing and, therefore, ent histologies of RCC and other solid renal
solid tumors rather than cysts [14]. While imag- masses will then be discussed. Finally, we will
ing technology has advanced, there has been a review postprocedural imaging, including imag-
ing after partial nephrectomy, tumor ablation,
and targeted antiangiogenic therapy.
A.S. Purysko, MD
Section of Abdominal Imaging, Imaging Institute,
Cleveland Clinic, 9500 Euclid Avenue-A21, Cleveland, Imaging Methods for the Detection
OH 44195, USA
of Renal Cell Carcinoma
E.M. Remer, MD () • B. R. Herts, MD
Section of Abdominal Imaging, Imaging Institute,
Detection of renal lesions on US is dependent
Cleveland Clinic, 9500 Euclid Avenue-A21, Cleveland,
OH 44195, USA upon either a contour abnormality or a difference
in echogenicity between the lesion and normal
Glickman Urological and Kidney Institute, Cleveland
Clinic, Cleveland, OH 44195, USA parenchyma. Detection of renal lesions on CT
e-mail: [email protected] and MR is possible because of a difference in

S.C. Campbell and B.I. Rini (eds.), Renal Cell Carcinoma: Clinical Management, Current Clinical Urology, 53
DOI 10.1007/978-1-62703-062-5_4, © Springer Science+Business Media New York 2013
54 A.S. Purysko et al.

density or signal intensity from the normal renal to detect. Also, the ability to detect fat within a
parenchyma. This occurs not only because the lesion and, therefore, identify an angiomyoli-
kidneys filter contrast, but also because contrast poma (AML) is less robust with US than other
is concentrated within the collecting tubules as cross-sectional imaging methods. Renal tumors
water is reabsorbed. Normal renal parenchyma that are large, contour-deforming, or partially
becomes denser on CT and has higher signal cystic, however, can be detected sonographically
intensity on T1-weighted MR as contrast is con- (Fig. 4.1). On ultrasound, RCC can be less echo-
centrated. The degree of contrast concentration is genic, equally echogenic or more echogenic than
dependent upon the relative function of nephrons normal renal parenchyma. Advantages of renal
and the volume and concentration of contrast ultrasound include its noninvasive nature, no
given [15]. Neither cysts nor renal tumors will need for potentially nephrotoxic iodinated con-
concentrate contrast. Therefore, the kidneys trast agents, and lack of radiation exposure.
should be imaged at peak concentration of con- Ultrasound is performed with a 3–6 MHz
trast with the highest contrast load to maximize transducer and images are obtained through each
detection of renal lesions. Unfortunately, for kidney in both the axial and longitudinal planes.
patients with impaired renal function the risk of Tissue harmonic imaging can be used to increase
contrast-induced nephropathy is increased while the sensitivity of US for renal masses. Cysts
detection and characterization of renal masses is appear as round or oval, anechoic structures with
diminished. thin or imperceptible walls and increased through
transmission. The sensitivity of US for the detec-
tion of RCC is dependent upon the size and loca-
Ultrasound tion of the lesion. In general, smaller isoechoic
intraparenchymal lesions are more difficult to
Ultrasound is ideal for distinguishing between detect, and some exophytic lesions can be
cystic and solid renal masses [16]. Ultrasound is obscured by bowel gas [17]. Ultrasound has also
not considered the best test for the detection and been investigated for screening for RCC in select
characterization of renal tumors because small patient populations, although the cost is problem-
renal tumors are often similar in echogenicity to atic and generalized screening is not recom-
normal parenchyma, making the lesions difficult mended in the USA [18, 19].

Fig. 4.1 Renal cell carcinoma on ultrasound. Partially exophytic lower renal pole solid mass (arrow), with slightly
increased and heterogeneous echogenicity
4 Imaging of Renal Cell Carcinoma 55

The use of Doppler ultrasound has been tenuating to normal parenchyma on unenhanced
accessed to improve the detection of renal masses. scans and lesion enhancement is key to the diag-
Kitamura et al. compared color flow Doppler nosis. The optimal time to image the kidney is
(CFD) US to contrast-enhanced CT for the detec- during the nephrographic or parenchymal phase of
tion of renal tumors [17]. In this study, approxi- enhancement when there is peak contrast concen-
mately 90% of clear cell carcinomas seen on CT tration. This occurs 90–150 s after the initiation of
were identifiable as hypervascular lesions on a bolus of 100–150 mL of iodinated contrast. Early
CFD US; however, there was no additional benefit imaging in the corticomedullary phase (CMP) is
gained by using CFD US. less sensitive for focal renal masses [25] and some
Microbubble ultrasound contrast agents are may even be obscured [26].
able to depict renal vessels and show enhance- After a standard dose of IV contrast, most
ment without the use of iodinated intravenous RCC enhance more than 120 HU on CT [27];
contrast material. These agents, therefore, may some tumors, such as papillary and chromophobe
be especially useful in the problematic situation carcinomas, are much less vascular and enhance
of a patient who has both a suspected renal mass less avidly [28]. In the era of conventional CT, a
and renal insufficiency. The sensitivity of US for change of 10 Hounsfield units (HU) between
the detection of renal tumors appears to be unenhanced and enhanced scans was deemed evi-
improved with the use of intravenous microbub- dence of enhancement. The introduction of heli-
ble contrast agents; in one study the sensitivity cal CT scanning has led to increasing image noise
was 97% compared to 70% for gray scale US leading some authors to suggest 15–20 HU as an
alone [20]. The accuracy of ultrasound intrave- appropriate threshold to determine enhancement,
nous microbubble contrast to predict benign vs. while others consider a 10–20 HU change as
malignant histology of renal masses is currently indeterminate and suggest other imaging such as
under investigation (http://clinicaltrials.gov/ct2/ MRI [29]. One caveat is that with the detection of
show/NCT00671411). Another use of ultrasound smaller lesions there is more variability in the
contrast agents is to improve characterization of HU density. This occurs because the thickness of
complex renal cysts. Strong enhancement of the small lesions may be similar to the thickness of
vascularity in septations and mural nodules the CT slice, and therefore, pixels from outside
improves lesion classification [21]. Finally, by the lesion may be included in attenuation mea-
depicting similar blood flow to normal renal surements (so-called partial volume averaging).
parenchyma, ultrasound contrast can be used to
exclude tumors in renal pseudotumors [21]. Multiphasic CT Technique
Ultrasound contrast agents are available for use A three-phase CT scan is considered the optimal
with Doppler US systems but are not in general technique for detecting and characterizing renal
usage and are not FDA approved for this indica- masses, as well as staging RCC. This includes an
tion in the USA. The use of contrast eliminates unenhanced scan, a vascular or CMP scan and a
ultrasound’s main advantage by making it mini- parenchymal or nephrographic phase (NP) scan
mally invasive instead of noninvasive [22–24]. (Fig. 4.2). Several studies have shown that the NP
is the most sensitive for the detection of renal
tumors, although in one study more lesions were
Computed Tomography seen when a combination of unenhanced, CMP
and NP scans were used [29–34].
Computed tomography is the gold standard for the The CMP is useful for assessing the renal vas-
detection and characterization of renal masses, culature, and enhancement seen in this phase can
with a sensitivity for the detection of RCC ranging also be useful for characterizing lesions [35–37].
from 88% to 100%. Dedicated renal CTs should When used alone, however, the CMP can result in
routinely include pre- and post-contrast imaging if missed lesions and false positive diagnoses of
possible, because renal tumors are generally isoat- medullary lesions [38, 39].
56 A.S. Purysko et al.

Fig. 4.2 Renal cell carcinoma (clear cell type) on multi- the corticomedullary phase. The renal parenchyma con-
phasic computed tomography. (a) Pre-contrast; (b) corti- centrates the contrast more homogenously and becomes
comedullary phase; (c) nephrographic phase. Large central hyperdense compared to the mass in nephrographic phase
renal mass extending into the renal sinus (arrow on b), (arrow on c), improving the tumor outlining (arrowheads
with intense and heterogeneous contrast enhancement in on c)

Pseudoenhancement less than 10 HU, most less than 8 HU [40].

However, some simple cysts can have a measur-
Pseudoenhancement refers to an artificial attenu- able increase of more than 10 HU after contrast
ation change in a lesion between unenhanced and administration. Pseudoenhancement occurs most
enhanced scans. It is thought to be due to the often when the cyst is surrounded by enhancing
image reconstruction algorithm used in helical renal parenchyma. Many are small (<2 cm) and
CT scanners. In one study, more than 95% of are completely intrarenal [29]. Therefore, one
cysts demonstrated a change in attenuation value needs to take the lesion size and location into
4 Imaging of Renal Cell Carcinoma 57

consideration when using change in attenuation Magnetic Resonance Imaging

value to characterize renal lesions [41, 42].
MR imaging can also be used to characterize and
Surgical Planning stage RCC and is the test of choice in patients
With the introduction of multidetector high-speed with contrast allergies and mild renal insufficiency.
CT scanners, high-resolution MR imaging and At clinical doses, gadolinium-based MR contrast
three-dimensional (3D) postprocessing imaging agents do not appear to have substantial nephro-
software, surgical planning can now be performed toxic effects [49]. Recently an association between
using CT and MRI [43–48]. While 2D multipla- gadolinium-based MR contrast agents and neph-
nar reformations can depict pertinent surgical rogenic systemic fibrosis (NSF) [34, 38, 50], a
anatomy, real-time volume rendered 3D repre- potentially crippling, life-threatening skin disor-
sentations provide spatial cues that help plan a der, has been described in patients with compro-
surgical approach, resection margins, and vascu- mised renal function. Further studies are necessary
lar control. 3D images from the corticomedullary to determine what the exact relationships are
or vascular phase scans provide a detailed depic- between gadolinium-containing contrast agents,
tion of the number, size and locations of all renal patient renal function and NSF. Currently, the
arteries and veins, major segmental arterial development of NSF is thought be linked to the
branches, the left adrenal vein, the gonadal veins, administration of relatively high doses (e.g.,
and any prominent lumbar veins (Fig. 4.3). The >0.2 mM/kg) and to agents in which the gado-
renal parenchymal phase (NP) is used to render linium is least strongly chelated. The Federal
the renal position, renal tumor location, depth of Drug Administration recommends that until fur-
extension and relationship of the tumor to the ther information is available, gadolinium contrast
pelvocalyceal system, and position of the adrenal agents should not be administered to patients with
gland (Fig. 4.4). either acute or significant chronic kidney disease

Fig. 4.3 Contrast-enhanced computed tomography (cor- considered for partial nephrectomy. Single left renal artery
ticomedullary or vascular phase) using 3D volume render- (black arrow) and single left renal vein (white arrow) with
ing reconstruction technique for anatomical evaluation of typical course anterior to the aorta are demonstrated
patient with left lower pole renal mass (arrowhead), being
58 A.S. Purysko et al.

Fig. 4.4 Computed tomography

(excretory phase) using 3D
volume rendering reconstruction
technique, demonstrating relation
of exophytic renal lesion (arrow)
with contrast-filled renal pelvis
(asterisk)

(estimated GFR <30 mL/min/1.73 m), recent agreed upon method to quantify enhancement on
liver or kidney transplant or hepatorenal syndrome, MRI. Signal intensity in MR images is based on
unless a risk-benefit assessment suggests that the a relative scale, not on absolute density, as is the
benefit of administration in the particular patient Hounsfield unit scale [37]. Therefore, most
clearly outweighs the potential risk(s) [38]. Since authors recommend a subtraction between pre-
the implementation of these guidelines, the inci- and post-contrast MR sequences to eliminate the
dence of NSF has abated considerably [51]. subjectivity of determining enhancement after
In addition to characterizing and staging renal contrast on MR. A threshold of 15% increase in
masses, MR imaging is used to attempt charac- signal intensity has also been advocated to iden-
terization of lesions that are indeterminate on CT. tify enhancement in renal tumors [53, 54].
MRI is more contrast-sensitive than CT, i.e., MRI Identification of calcium in renal masses on MRI
is better at detecting enhancement. Similar to CT, is limited because calcium appears as a signal void.
MR imaging must be performed before and after The sensitivity for the detection of RCC is
contrast. T1-weighted images (T1WI), usually reported to be as high as 88–100% for CT and
with a fat-suppressed breath-hold sequence, are 78–100% for MR [39, 55–57]. In direct compari-
obtained before contrast and after contrast during son studies, the sensitivity for detecting renal
several phases, in both axial and coronal planes tumors is similar between MR and CT, and both
[36, 52]. Before contrast, T2-weighted imaging are more sensitive than ultrasound [58, 59].
(T2WI) is performed to characterize cysts. Other
techniques (in- and out-of-phase imaging and
chemical selective fat suppression) are used to Renal Mass Detection
detect fat within lesions. MR is highly sensitive
for renal tumors, approaching 100%, and has Currently, more than 60% of RCCs are detected
some advantages over CT for the characterization incidentally at imaging [10, 11]. In the era when
of subcentimeter cysts. There is no universally most renal masses were found due to patient
4 Imaging of Renal Cell Carcinoma 59

symptoms, it was dogma that any solid renal There are only a few imaging features of solid
mass was an RCC until proven otherwise. Even lesions that have been found to suggest a benign
today, excluding infections and AMLs, most diagnosis. Solid masses that contain regions of
solid renal masses in adults are RCC [13]. macroscopic fat on imaging are benign AMLs.
However, with the detection of an increasing AML is a type of perivascular epitheloid cell tumor
number of renal lesions, recent pathological and is composed of a variable amount of vessels,
series have found a higher than previously known muscle, and adipose tissue. The fat content is seen
proportion of small, solid renal masses to be as low attenuation on CT (Fig. 4.5) and can be
benign [7, 8, 13, 60]. One series of 2,770 renal identified with fat suppression sequences on MRI
tumor resections [60] found a benign rate of (Fig. 4.6). Approximately 5% of AML have small
12.8%. It is noteworthy that the likelihood of the amounts of fat that are not detectable on imaging
solid renal mass being malignant was generally studies, and therefore mimic RCCs [62]. Identifying
proportional to its size: 25% for masses smaller small regions of fat with CT pixel analysis can
than 3 cm, 30% for masses smaller than 2 cm, help identify these AMLs, but is a relatively insen-
and 44% for masses smaller than 1 cm. sitive technique [63]. Masses that are high attenu-
ation before contrast and enhance homogeneously
may prove to be AMLs with minimal histological
Solid Masses lipid content [19, 64]. Oncocytoma is a benign
solid neoplasm that has a classic imaging features
The typical appearance of RCC is a heteroge- of a central, stellate scar (Fig. 4.7). This feature,
neous, enhancing solid mass following contrast unfortunately, is neither sensitive nor specific for
administration (Fig. 4.2) [61]. While the major- the diagnosis [65]. Therefore, in general, imaging
ity of RCC are solid, rounded, or ovoid mass cannot be used to differentiate benign from malig-
lesions, some RCC are infiltrating or complex nant solid masses. Short of resection of these
cystic mass lesions. Clear cell, papillary, and masses, diagnostic options are limited to observa-
chromophobe RCC subtypes are usually solid on tion and percutaneous biopsy. With the increasing
CT, US, and MRI. Unfortunately, both benign realization that small, hyperattenuating, homoge-
(e.g., oncocytoma, angiomyolipoma) and other neously enhancing renal masses are more fre-
malignant (e.g., some transitional cell carcinoma quently benign than other solid renal masses, there
and metastatic disease) lesions are also solid, is currently an emerging role of percutaneous
mass lesions. biopsy at some institutions [13].

Fig. 4.5 Angiomyolipoma. (a) Hyperechoic rounded renal lesion on ultrasound (arrow). (b) Same lesion on contrast-
enhanced CT demonstrating predominantly fat attenuation
60 A.S. Purysko et al.

Fig. 4.6 Angiomyolipoma on MRI. T1-weighted image “in-phase” showing partially exophytic renal lesion (arrow on
a) with fat content that is characterized by a low signal intensity rim (India ink artifact) surrounding the lesion on T1-weighted
imaging “out-of-phase” indicating a fat-soft tissue interface (arrow on b)

Cysts and Complex Cystic Renal Masses solid, soft tissue density in the lesion or enhance-
ment after intravenous contrast.
RCC can have a cystic growth pattern that can Category II cysts are minimally complicated
be unilocular, multilocular, or necrotic, and cysts either with high-density fluid due to a
RCC can develop within the wall of an other- increased protein content or hemorrhage within
wise benign cyst [66]. Renal epithelial cysts are the cysts (higher than 20 HU density, a “hyper-
common and contain simple serous fluid. Other dense” cyst), or are multilocular with a few septa
benign cysts can contain fluid with a high pro- (Fig. 4.8b) or thin peripheral calcifications.
tein content, hemorrhage, or infection, making Category II cysts do not demonstrate enhance-
the differentiation between a benign cyst and ment after intravenous contrast and are almost
cystic RCC difficult [67, 68]. Different imaging- always benign [73, 74]. Contrast is needed to dis-
based classification methods have been pro- tinguish between a hyperdense cyst and a homo-
posed to help predict the likelihood of a cystic geneous solid renal neoplasm. Both lesions may
lesion being malignant; one used by both radi- appear similar on pre- or post-contrast scans, but
ologists and urologists was originally described the hyperdense cyst will not enhance after con-
in 1986 by Bosniak and has since been modified. trast, whereas the homogeneous solid renal neo-
Bosniak originally proposed four categories, plasm will enhance. Hyperdense cysts tend to be
each predicting an increasing likelihood of higher in attenuation and more homogeneous
malignancy. This classification system has been than RCCs on unenhanced CT [75]. On nephro-
modified more recently to include a fifth cate- graphic phase contrast-enhanced CT scans, atten-
gory [69–72]. uation greater than 70 HU or moderate or marked
Category I cysts are simple unilocular cysts, internal heterogeneity favor a diagnosis of RCC
either round or oval, with a thin, noncalcified over a diagnosis of high-attenuation renal cyst
walls (Fig. 4.8a). These cysts contain simple [58]. Category II cysts have a less than 15%
serous fluid measuring less than 10–20 HU at CT change of malignancy and, therefore, may be fol-
and have MR signal characteristics of simple lowed to document stability over time.
fluid (low signal intensity on T1- and high signal Category IIF cysts are complex lesions that have
intensity on T2-weighted sequences). There is no multiple septa or calcifications that have a relatively
4 Imaging of Renal Cell Carcinoma 61

Fig. 4.7 Oncocytoma. Large right renal mass on con- white fibrous tissue in pathological specimen (black arrow
trast-enhanced CT corticomedullary (a) and nephro- on c). While this pattern is typical for oncocytoma, it is
graphic (b) phases, showing central stellate-shaped low not specific and can be seen in renal cell carcinomas
attenuation area (black arrow on a) which corresponds to

benign appearance (Fig. 4.8c). Calcifications, once [28, 76]. Typically, these lesions are surgically
felt to be a potential sign of malignancy, are now explored. While biopsy has been studied in these
considered less important [26]. Category IIF cysts patients [33, 77], finding a “definitive” diagnosis
are thought to be benign, but need interval follow- in 61–88% of lesions, these studies suffer from the
up to confirm their stability [59]. fact that negative results were supported by inter-
Category III cysts are complicated cystic lesions val follow-up rather than histopathology [13].
that have some features suggesting malignancy— Category IV cysts contain solid, soft tissue
multiple septa, thick or irregular rims—or hetero- enhancing elements seen either within the cyst or
geneity suggesting necrosis (Fig. 4.8d). Category as part of a complex cystic mass (Fig. 4.8e).
III cysts have an approximately 50–60% chance of These lesions are almost always cystic RCC and
being a cystic RCC according to published studies should be treated as such.
62 A.S. Purysko et al.

Fig. 4.8 Spectrum of cystic renal lesions. (a) Thin-walled calcifications (arrow)—Bosniak IIF; (d) exophytic cystic
simple cyst (arrow) with homogenous low attenuation renal lesion with multiple thick (>1 mm) enhancing septa
content—Bosniak I; (b) cystic lesion with thin (<−1 mm) (arrow)—Bosniak III; (e) cystic renal lesion with solid
partially calcified internal septum (arrow)—Bosniak II; enhancing mural nodule (arrow)—Bosniak IV
(c) slightly thicker wall cystic lesion with peripheral
4 Imaging of Renal Cell Carcinoma 63

While one typically expects Bosniak III or IV characterized as Bosniak III lesions and 70% of
lesions to represent cystic clear cell carcinomas, 10 MEST had enhancing solid elements [78].
there are a number of benign cystic neoplasms These tumors are much more commonly seen in
that mimic this diagnosis. These include cystic women or men receiving exogenous hormones
nephroma (CN) (Fig. 4.9) and mixed epithelial and are frequently symptomatic [58].
and stromal tumor (MEST) of the kidney Management guidelines for complex renal
(Fig. 4.10). In one series, 70% of 22 CN were cysts are based on this classification scheme. In
general, category I lesions do not need further
evaluation; category II lesions, if larger than 3 cm
or irregular, and category IIF lesions should be
followed for interval growth or change, which
suggest malignancy; category III lesions should
be explored or resected; and category IV lesions
appropriately treated as presumed RCC. Biopsy
of indeterminate cystic renal masses can also be
considered, although concerns about tumor spill-
age and false negative results persist. It is impor-
tant to note that the Bosniak criteria are guidelines
for describing and managing cystic renal masses.
Other factors, including risk factors for RCC, a
genetic disorder that predisposes the individual to
cystic renal tumors, age, and comorbid conditions
should influence any management decision.

Fig. 4.9 Cystic nephroma. Large cystic renal mass with Infiltrative Renal Masses
multiple enhancing septa (arrowheads) insinuating into
the renal sinus, consistent with a Bosniak III lesion
While most renal tumors exhibit radial growth
patterns with a space-occupying mass and may
occasionally have a cystic growth pattern, RCC
can also infiltrate within the renal parenchyma
along the interstitium [79]. In these instances, the
renal contour is maintained but the involved por-
tion of the kidney is typically enlarged. Infiltrating
tumors encase rather than displace the vasculature
and renal collecting structures. On CT, infiltrating
lesions are poorly marginated areas of relatively
decreased enhancement reflecting the disruption
of the normal tubular concentration of contrast
(Fig. 4.11). On ultrasound, these are often similar
in echogenicity to normal parenchyma, making
their detection and definition by sonography
difficult. Only occasionally are infiltrating renal
lesions slightly hypoechoic or hyperechoic com-
pared to normal renal parenchyma.
Several tumors other than RCC demonstrate an
Fig. 4.10 Mixed epithelia and stromal tumor (MEST).
Coronal T2-weighted image showing complex cystic infiltrating pattern on imaging [40]. Transitional
lesion with peripheral solid nodular component (arrow) cell carcinoma (TCC) comprises 90% of urothelial
64 A.S. Purysko et al.

Fig. 4.11 Infiltrative renal cell carcinoma (medullary associated with confluent retroperitoneal lymphadenopa-
type). Contrast-enhanced CT shows ill-defined infiltrative thy encasing the renal veins (black arrow on a) and aorta
hypoenhancing right renal mass (white arrow on a and b), (black arrow on b)

tumors and when it involves renal parenchyma is hilar lymph nodes. Extranodal lymphoma is more
characteristically infiltrative in its growth pattern. common with Hodgkin’s disease than with NHL.
While typically a slow-growing papillary tumor, Perinephric confluent tissue is more suggestive of
TCC of the kidney is occasionally high grade and NHL than RCC (Fig. 4.12a). In general, however,
infiltrating. A key to the imaging diagnosis is its renal involvement in lymphoma is associated
central location in the kidney or in the renal sinus with systemic disease. On CT and MR, renal
and lack of visualization or displacement of renal lymphoma is typically hypovascular with multi-
collecting structures. ple solid or infiltrating masses (Fig. 4.12b) [80].
Primary renal non-Hodgkin’s lymphoma Leukemia is always infiltrating in its growth
(NHL) can arise in the renal parenchyma or renal pattern, typically causing renal enlargement [81].
4 Imaging of Renal Cell Carcinoma 65

Fig. 4.12 Lymphoma. (a) Enhancing tissue rind surrounding the left kidney on contrast-enhanced T1-weighted MR
image (arrow). (b) Multiple bilateral low attenuation renal nodules (black arrows) on contrast-enhanced CT

Metastatic disease to the kidneys is seen as mul- appearance should be distinguished from tumor
tiple, bilateral, poorly marginated solid lesions infiltration, especially with a history of fever,
that can occasionally demonstrate an infiltrative flank pain, and pyuria.
pattern [82, 83].
Some nonmalignant conditions can demon-
strate an infiltrating pattern on imaging, and it is Imaging Features of Renal Carcinoma
vitally important to recognize these entities. Subtypes
Acute pyelonephritis is seen as wedge-shaped
areas of decreased enhancement that extend from Renal cell neoplasms can be classified as clear
the papilla to the cortex. Differential enhance- cell, chromophobe, papillary, collecting duct,
ment of infected and uninfected parenchyma medullary, mixed cell types or as adenocarci-
occurs from tubular obstruction from inflammatory noma not specified; or as small cell carcinoma,
debris, interstitial edema, and vasospasm. This juxtaglomerular tumor or carcinoid [84–86].
66 A.S. Purysko et al.

Since prognosis differs among the different types Papillary Renal Cell Carcinoma
of RCC, it is worth reviewing the more common Papillary renal cell carcinoma (PRCC) comprises
features of each on imaging studies. 10–15% of RCC [92, 93]. Most studies suggest
that it has a greater tendency to lower stage and
better prognosis than clear cell RCC. On CT,
Clear Cell Renal Cell Carcinoma papillary RCC is typically a hypovascular, homo-
geneous solid mass [52, 94]. A tumor that
Clear cell carcinoma, the most common type of enhances less than 25% of the attenuation value
RCC, originates from the proximal convoluted (Hounsfield units) of normal parenchyma in the
tubule and accounts for 70–80% of all RCC. CMP and NP is significantly more likely to be a
Clear cell carcinomas are typically hypervascular PRCC. Conversely, tumors that enhance more
after contrast administration on CT, with more than 25% of the enhancement of the normal renal
avid enhancement than that displayed by other parenchyma are rarely papillary RCC [52].
RCC subtypes (Fig. 4.2) [51, 87, 88]. A hyper- Papillary RCC rarely invades the collecting sys-
vascular pattern is present in nearly 50% of clear tem, and locally invasive behavior is less com-
cell carcinomas, compared to approximately 15% mon [84]. On MR, PRCC can be hemorrhagic,
of papillary and 4% of chromophobe RCCs. The leading to heterogeneous signal intensity on
degree of enhancement is significantly different T1-weighted images and a decreased signal
among the clear cell, papillary and chromophobe intensity on T2-weighted images compared to
subtypes in the corticomedullary and excretory normal renal parenchyma (Fig. 4.14) [83].
phases as well [82]. The chromophobe subtype Enhancement is lower and delayed in papillary
shows homogeneous enhancement in 75% of RCC compared to clear cell RCC [95].
cases in comparison with 45% and 65% of clear An important feature of papillary RCC is that
cell and papillary subtypes. Clear cell carcinoma is more commonly bilateral and multifocal than
also has heterogeneous peripheral enhancement other RCC subtypes [96]. Papillary RCC is often
more frequently than papillary and chromophobe smaller in size than clear cell carcinoma [97].
RCC [81]. There are histologic descriptions of two different
On MRI, clear cell RCC is typically isointense types of papillary RCC: those with small baso-
on T1-weighted images and isointense to hyper- philic cells (Type 1) and those with eosinophilic
intense on T2-weighted images compared to nor- cells (Type 2) [98]. Survival is worse for type 2
mal renal parenchyma (Fig. 4.13) [89]. Clear cell and one small series that found that type 2 tumors
carcinomas are commonly more aggressive have less distinct margins, are more heteroge-
tumors than other cell types and they may directly neous, generally present at more advanced stages,
involve and invade the renal collecting system [90]. and frequently grow centripetally [99].
Cystic degeneration is also more common PRCC that are more than 3 cm in diameter
(15%) in the clear cell subtype than in the other may have heterogeneous attenuation and areas of
subtypes irrespective of tumor size. Tumor necro- necrosis and hemorrhage. PRCC may occasion-
sis can also cause a cystic appearance on imag- ally show cystic growth that can be from necro-
ing, but this feature confers a worse prognosis sis, but such changes are much less common than
than a true cystic clear cell carcinoma [91]. in clear cell RCC.
Calcification occurs in 21–25% of each of the
clear cell, papillary and chromophobe subtypes.
Overall, enhancement is the most valuable Chromophobe Renal Cell Carcinoma
parameter used to differentiate the subtypes of
RCC. The degree of enhancement, presence or The chromophobe subtype accounts for only a
absence of cystic degeneration, vascularity and small percentage of RCC [100]. Chromophobe
enhancement patterns can serve a supplemental RCC is typically hypovascular at CT, similar to
role in differentiating RCC subtypes. papillary RCC [81]. In one study of 11 patients
Fig. 4.13 Renal cell carcinoma (clear cell type). (a) slightly hypointense compared to the surrounding renal
Central right renal mass with slightly heterogeneous sig- parenchyma (arrow). (c, d) The lesion demonstrates
nal on T2-weighted image, and small focus of hyperin- intense contrast enhancement in the corticomedullary
tense signal (arrow), consistent with areas of cystic phase (arrow on c), and becomes slightly hypointense in
degeneration. (b) On T1-weighted image the lesion is the nephrographic phase (arrow on d)

Fig. 4.14 Papillary renal cell carcinoma. Left interpolar renal mass with low T2-weighted signal intensity (arrow on a),
demonstrating poor enhancement on T1-weighted post-contrast image (arrow on b), typical features of papillary RCC
68 A.S. Purysko et al.

with the chromophobe cell type, there was a Medullary Carcinoma

spoke-like enhancement pattern with a central Medullary carcinoma is often considered a
stellate form [101]. This can be seen with chro- distinct entity, but may be an aggressive form of
mophobe RCC and oncocytoma and is, therefore, CDRCC that occurs in children and young adults.
not specific for either tumor. Hale’s colloidal iron Medullary renal carcinoma has been associated
stain has been used to differentiate between the with sickle cell trait, but not sickle cell disease.
two pathologically. As with CDRCC, medullary RCC is typically
infiltrating and aggressive with centrally located
tumors. Large size, venous and lymphatic inva-
Collecting/Bellini Duct Carcinoma sion and regional lymph node metastases are usu-
ally present at presentation (Fig. 4.11). Medullary
Collecting duct (Bellini duct) carcinomas are carcinoma can demonstrate necrosis and hemor-
uncommon, comprising 1–2% of all RCC. rhage [40, 98].
Histologically, these tumors are characterized by
a tubular or tubulopapillary infiltrative growth
pattern, which is reflected in the CT appearance. Other Primary and Secondary Renal
Collecting duct RCC (CDRCC) are medullary Neoplasms
and infiltrating in the central sinus and only
rarely reported in the renal cortex [102–105]. Oncocytoma
Metastases are more common at presentation
than other types of RCC, occurring in 35–40% Stellate central scars (Fig. 4.7) on CT and MR
of patients [94, 97]. When bone metastases and spoke-wheel enhancement on angiography
occur, they are frequently osteoblastic, unlike have both been described as imaging features
metastases from clear cell RCC, which are oste- suggestive of renal oncocytoma. Oncocytoma is
olytic [94]. On CT and angiography, CDRCC are hypervascular, similar to clear cell carcinoma,
hypovascular tumors [97]. and homogeneous in attenuation [65]. Although
In one study reporting 11 cases of CDRCC, these imaging features can be used to raise suspi-
the vast majority of CDRCC were hyperechoic cion for oncocytoma, none is sufficiently diag-
on ultrasound and hyperintense on T2WI on nostic and a tissue diagnosis is needed [109]. The
MRI. The differential diagnosis of CDRCC histopathologic features of oncocytoma allowing
includes sarcomatoid variants of RCC, high grade differentiation from RCC on biopsy have only
infiltrating TCC or squamous cell carcinoma of recently been described [110, 111].
the renal pelvis, and NHL [106].

Cystic Nephroma/Mixed Epithelial and

Sarcomatoid Renal Cell Carcinoma Stromal Tumor

Sarcomatoid RCC is a highly aggressive variant CN or multilocular CN is a tumor characterized

of other histological subtypes and typically has by varying sized cysts, thin septa, and no solid
an infiltrating appearance on imaging. The vast elements. MEST is a biphasic tumor with com-
majority are symptomatic at presentation [107]. plex stromal and epithelial elements. They share
Renal sarcoma and sarcomatoid RCC should be pathological similarities and are grouped together
considered when there is an extensively infiltrating as mixed mesenchymal and epithelial tumor in
tumor with spread into the perinephric space and the 2004 World Health Organization of renal
adjacent organs. The differential diagnosis of sar- neoplasms [112]. CN have a complex cystic
comatoid RCC includes other infiltrating tumors appearance with multiple septa without soft tis-
such as TCC, NHL, fibrosarcoma, and leiomyo- sue components (Fig. 4.9). They characteristi-
sarcoma [108]. cally project or herniate into the renal sinus and
4 Imaging of Renal Cell Carcinoma 69

may extend into the renal pelvis. Patients have a ated with the lipomatous elements and can,
bimodal distribution, with CN often occurring in therefore, be diagnosed on imaging (Figs. 4.5 and
younger males or middle-aged females. MEST 4.6). About 5% of AML, however, have small
have similar features to CN on imaging, but also amounts of fat that cannot be identified preopera-
have solid, enhancing elements (Fig. 4.10) [78]. tively at CT. AML with minimal fat is radio-
Their imaging features have been described in graphically similar to RCC on CT. It may be
small series to date [78, 113]. higher in attenuation than normal renal paren-
chyma on unenhanced CT [117], a finding that is
atypical for RCC. Kim et al. described prolonged
Metastatic Disease enhancement and homogeneous enhancement in
AML with minimal fat as opposed to heteroge-
Metastatic disease to the kidneys is particularly neous, transient enhancement in clear cell RCC.
common with lung and breast carcinoma, mela- Both findings together have a 91% positive pre-
noma, and lymphoma [44, 114]. Lesions are usu- dictive value (PPV) for AML [118]. When
ally multiple and bilateral. When there is a history calcification is seen in a lesion with no or mini-
of a nonrenal primary tumor, as many as 50–85% mal fat, it is most likely an RCC and not an AML
of solitary renal masses are metastatic disease [119, 120]. On ultrasound, AML are generally
[43, 115]. Conversely, nearly 90% of patients smaller and are frequently hyperechoic; shadow-
with pathologically proven metastatic disease to ing from a renal lesion is also more suggestive of
the kidney have a history of a primary malig- an AML than an RCC. On MRI, the diagnosis of
nancy [44]. AML can be made when macroscopic fat can be
discerned with fat suppression techniques.
Minimal fat AMLs tend to have low signal inten-
Renal Lymphoma sity on T2WI, a finding also seen in PRCC, but
not clear cell carcinoma. More avid enhancement
Renal lymphoma can be primary, involving the after contrast is typical of AML, unlike papillary
renal or perirenal lymphatics, or secondary with RCC which tends to enhance only minimally.
associated lymphadenopathy. On CT and MRI, An exophytic AML can usually be differenti-
lymphoma can be seen as either a focal mass or ated from a retroperitoneal or renal capsular
have an infiltrative appearance (Fig. 4.12) [41, 116]. liposarcoma by the presence of a renal paren-
Lymphoma is typically homogeneous and chyma defect, large blood vessels feeding the
enhances less than normal renal parenchyma. mass, and aneurysms or varices [121, 122].
Renal lymphoma should be considered when
there is splenomegaly, bulky retroperitoneal or
mesenteric lymphadenopathy, and organ involve- Staging of Renal Cell Carcinoma
ment, such as bowel, that is not typical of RCC. by CT and MRI
Biopsy should be considered to differentiate renal
lymphoma from RCC when there are other imag- Accuracy of Imaging for Staging
ing findings suggesting lymphoma or the patient
has a history of lymphoma. The TNM system is now primarily used for stag-
ing RCC [123–128]. Overall, the accuracy for CT
and MR for staging RCC appears to be similar
Angiomyolipoma and Other [129–134]. The accuracy of contrast-enhanced
Fat-Containing Renal Tumors CT for RCC staging ranges from 72% to 91%
[133, 135] and the accuracy of MRI ranges from
AML is a benign renal hamartoma containing 78% to 98% [59, 76, 136]. In one study, there was
lipomatous, smooth muscle, and vascular ele- no difference between overall CT and MR accu-
ments. Most AML have macroscopic fat associ- racy [76], but in another MRI showed higher
70 A.S. Purysko et al.

accuracy than CT [59]. MRI was better than CT Tumor Size

for stage 2 disease and worse than CT for stage 4 Final pathological tumor size is an important
disease [137]. prognostic staging criterion in the current TNM
The major limitation of imaging for staging is staging system. Several studies have compared
identifying tumors that have spread beyond the CT tumor size with pathologic size [132–134]. In
renal capsule which increases the tumor stage general, there has been excellent correlation
from T1 or T2 to T3a by the TNM system. between CT size and pathological size with cor-
Criteria such as a discrete nodule or thickening relation coefficients ranging from 0.90 to 0.95
of a septum, either greater than 3 mm, in the [143, 144]. The size of smaller tumors tends to be
perinephric space are neither sensitive nor overestimated by CT [132]. Clear cell tumors
specific for spread beyond the renal capsule. have also been shown to be overestimated by CT.
Most studies demonstrate understaging by CT In one study of 30 tumors larger than 4 cm, 22
[138]. This understaging by CT, however, does clear cell RCC were overestimated by more than
not appear to affect patient’s overall prognosis. 1 cm [145]. This discrepancy may be explained
A study that compared patients with clinical by shrinkage of the pathological specimen in
stage T1 disease and pathologic stage T1 disease comparison with in vivo imaging due to lack of
to patients with clinical stage T1 disease and vascular perfusion. This also may account for the
pathologic stage T3 disease found no statisti- larger discrepancy that has been found between
cally significant difference in 5-year survival CT size and pathological size for the more vascu-
between the groups [139]. The lack of peri- lar clear cell RCC compared to hypovascular
nephric fat infiltration on MRI has been shown RCC. Another factor that might create a differ-
to have a high negative predictive value for ext- ence between measured CT and pathologic sizes
racapsular tumor invasion [140]. is that the tumors may have been measured only
Ultrasound is not generally recommended for in the axial plane when some tumors had the lon-
RCC staging. Ultrasound is inferior to CT and gest dimension in another plane.
MR in large part because of poor lymph node vis-
ibility [128]. Ultrasound may be accurate for Pelvic and Chest CT
assessing renal vein involvement and can be used Pelvic CT may not be needed for the initial stag-
as an adjunct to CT or MR if equivocal or limited ing evaluation of RCC. Most studies have shown
in any way. that there are few significant findings on pelvic
CT for most patients with renal tumors [146,
Renal Central Sinus Invasion 147]. For expected low-stage disease with small
and Urothelial Invasion primary tumors, a normal chest X-ray will likely
Invasion of the central sinus fat may have significant suffice for pulmonary staging [148]; for larger
prognostic implications in patients with RCC, tumors and patients with extensive regional dis-
similar to extension outside the renal capsule ease or pulmonary symptoms, chest CT is
[141]. Now staged as T3a in the 2010 TNM stag- indicated.
ing system, sinus invasion can be difficult to accu-
rately detect on CT [142]. It is considered the most Lymphadenopathy
common site for extrarenal extension of RCC. Both CT and MR are highly sensitive for meta-
Some authors have suggested that urothelial inva- static lymphadenopathy using a criterion of 1 cm
sion should be an added criterion for staging short-axis diameter. Computed tomography sen-
because it was associated with a worse prognosis sitivity for lymph node involvement is 89–100%
in one series [84]. In this study patients with patho- [59, 122]. The imaging features of lymph node
logically determined T2 tumors with urothelial metastases often mimic that of the primary tumor.
invasion did worse than patients with T2 tumors For example, lymph node metastases from clear
without urothelial invasion. cell RCC are frequently hypervascular.
4 Imaging of Renal Cell Carcinoma 71

Adrenal Metastases
Adrenal gland involvement by RCC is uncom-
mon, particularly so in the modern era with ear-
lier detection, smaller and lower grade tumors,
and asymptomatic, incidental presentation [149].
In one series, adrenal gland involvement ranged
from less than 1% in early, low-stage disease to
8% in advanced disease [150]. Computed tomog-
raphy has a reported 94–100% negative predic-
tive value for adrenal involvement [138, 151,
152]. Therefore, when the CT demonstrates a
normal ipsilateral adrenal gland, the gland is
almost certainly not involved. Moreover, when
the adrenal is not seen or the renal tumor obscures
visualization of the adrenal, the adrenal is still
only involved in a small percentage of cases
[141]. PPV of standard enhanced CT for adrenal
metastasis is low, only 11–26%. This is likely due
to the high prevalence of benign adrenal ade-
nomas. When an adrenal nodule coexists with a
renal tumor, unenhanced CT or MR with in- and Fig. 4.15 Contrast-enhanced computed tomography
showing large left upper pole renal mass (M), with enhanc-
out-of-phase imaging can be used to distinguish ing tumor-thrombus invading the left renal vein (arrow).
between lipid-rich adenomas and metastatic dis- Dashed lines demarcate different levels of invasion (see
ease; performing a bolus and delayed phase scan text for full description). L level, RA right atrium
at 10–15 min and calculating washout can further
increase the sensitivity for adrenal adenomas by involvement: 90–100% [158–162]. Earlier reports
identifying lipid-poor adenomas [153, 154]. noted that CT was not as sensitive as MR [59,
122, 147, 150]; however, with the use of state-of-
Renal Vein and Inferior Vena Cava Tumor the-art MDCT with multiphase and multiplanar
The identification of renal vein or inferior vena imaging, CT at 87% is essentially equivalent to
cava (IVC) tumor thrombus and its precise local- MR sensitivity [123, 149].
ization are critical for proper staging [144]. Level Ultrasound can also be used to assess renal
I tumor thrombus extends only within the renal vein and IVC involvement, but is frequently tech-
vein (Fig. 4.15), or into the renal vein and IVC nically inadequate [149]. Ultrasound with CFD
within 2 cm of the renal vein ostia; level II extends in experienced hands nearly matches the sensitiv-
within the IVC more than 2 cm from the renal ity of CT, but is not recommended for staging for
vein ostia but not into the intrahepatic IVC; level the reasons described earlier.
III extends into the intrahepatic IVC but not
above the hepatic veins; and level IV extends Metastatic Disease
above the hepatic veins including into the right Up to 30% of patients with a new diagnosis of
atrium. The presence of renal vein invasion not RCC can have metastasis at presentation [163].
only increases the stage of what may otherwise RCC can metastasize to almost any organ
have been a stage I or II tumor to stage III, but it (Fig. 4.16), but lung, brain, and bone are the most
also directly affects surgical management [155– common sites. The appearance of the metastasis,
157]. The level of extension of tumor thrombus whether hypervascular, hypovascular, or cystic,
within the IVC can be evaluated by transesopha- typically resembles the primary lesion. Lung
geal echo, ultrasound, MR, and CT. MR has metastases appear at chest X-ray or CT as multi-
excellent sensitivity and specificity for renal vein ple round pulmonary nodules of varying size and
72 A.S. Purysko et al.

Fig. 4.16 Renal cell carcinoma metastases. (a) Large atic metastases (arrowheads); (c) hypervascular mediasti-
hypervascular right adrenal metastasis (black arrow) nal and right hilar metastatic adenopathy (arrow), with
invading the inferior vena cava (asterisk). Normal left areas of central necrosis (asterisk); (d) numerous pulmo-
adrenal gland (white arrow); (b) hyperenhancing pancre- nary metastases (arrows)

are from hematogenous spread [137]. Mediastinal

lymphadenopathy is more common with more
extensive pulmonary metastatic disease.
Bone metastases tend to be expansile and
osteolytic. Patients with metastatic RCC may
have spread to the liver, adrenal glands, and soft
tissue. Pancreas metastases are more commonly
recognized due to improvements in scanning
techniques [164, 165].

Postoperative Imaging

Patients who have had partial nephrectomy

Fig. 4.17 Partial nephrectomy. Contrast-enhanced CT
undergo routine initial follow-up at 4–6 weeks
showing typical appearance after partial nephrectomy of
with serum creatinine and an excretory urogram the left lower renal pole (black arrow) with expected mild
to evaluate the reconstructed kidney (Fig. 4.17) adjacent retroperitoneal fat stranding (white arrowhead)
4 Imaging of Renal Cell Carcinoma 73

[166]. Earlier imaging is performed in patients nephrectomy, conventional postsurgical imaging

who have clinical findings such as fever or ele- algorithms are not used. A number of surveil-
vated white blood cell count, decreasing hemat- lance protocols have been reported. Some rely
ocrit, or increased output from surgical drains. predominantly on pathologic tumor stage [171,
These patients are imaged to assess for abscess, 172] and others are more complex, integrating
hematoma, or urinary leak [167, 168]. Generally, other factors such as tumor size, tumor grade, and
CT scan with intravenous contrast is utilized, degree of tumor necrosis.
although if a urine leak is the main consideration, One study evaluated 327 patients with sporadic
then excretory urography is an appropriate alter- RCC who underwent open nephron-sparing surgery
native. Urine leaks appear as contrast-filled col- [171]. The incidences of local recurrence and meta-
lections that may extend outside the renal contour static disease based on initial pathological staging
or be confined to it. Hematomas are heteroge- were: 0 and 4.4% for stage T1, 2.0 and 5.3% for
neous, soft tissue attenuation collections. stage T2, 8.2 and 11.5% for stage T3a, and 10.6 and
Abscesses may have an enhancing wall or con- 14.9% for stage T3b. Including all the patients in the
tain internal gas foci. Patients who present with study, local recurrence in the remaining renal rem-
hematuria may have an uncommon but significant nant occurred in 4% of patients with a peak time
complication: a pseudoaneursym (Fig. 4.18). interval of 6–24 months. One or more metastatic
Pseudoaneurysms are seen after <1% of open lesions were seen without local recurrence in 7.6%
partial nephrectomies [169] and <2% of laparo- of patients, with a peak time interval of longer than
scopic partial nephrectomies [170]. 48 months. Another study showed that patients who
Strategies to assess for recurrent tumor and had pathological T1 tumors that recur had symp-
metastases depend on metastatic or recurrent dis- toms and/or thoracic metastases 81% of the time
ease risk. Because tumors that are treated with suggesting that clinical follow-up and chest radio-
nephron-sparing surgery tend to be smaller and graphs are the most important components in the
lower stage than those that are treated by radical surveillance process [172].

Fig. 4.18 Pseudoaneurysm. (a) Contrast-enhanced CT parenchyma (black arrow). (b) Renal arteriography
of a patient status post-right partial nephrectomy with confirms the presence of small rounded areas of contrast
extensive retroperitoneal hematoma (asterisks). Small opacification (arrows), diagnostic of pseudoaneurysms
areas of contrast extravasation are noted in the renal
74 A.S. Purysko et al.

Taken together, this data suggests that postop- site in the residual kidney or nephrectomy bed. In
erative surveillance for recurrent disease can be the immediate postoperative period, operative
tailored based upon the initial pathological stage changes are significant after both partial nephrec-
of the tumor and the clinical status of the patient tomy and tumor ablation and should not be
[166]. All patients should be evaluated annually confused for residual disease. These include peri-
with a history and physical examination and blood nephric fluid or scarring and a defect at the
tests including serum calcium, alkaline phos- operative site. Residual hemostatic agents such
phatase, liver function tests, BUN, serum creati- as oxidized cellulose (Surgicel, Johnson and
nine, and electrolytes. Patients with T1 tumors Johnson, Arlington, TX) may be present [176].
based on the 1997 TNM classification (pT1 < 2.5 cm After ablation, the mass undergoes progressive
and organ confined) do not require postoperative decrease in size over time (Fig. 4.19) [177, 178].
imaging due to very low risk of recurrent malig- This involution is more evident after cryoablation
nancy. A yearly chest radiograph is recommended than radiofrequency ablation [179–182]. A nor-
for T2 or T3 tumors because the lung is the most mal postablation CT or MRI should show no
common site of metastasis. Patients with T2 tumors residual enhancement of the tumor with a rim of
should also have abdominal and pelvic CT every 2 nonenhancing ablated normal renal parenchyma
years. Patients with T3 tumors have a higher risk of (Fig. 4.20). Incomplete ablation manifests as
developing local recurrence, shorter time to recur- residual enhancing tumor [169, 170]. New areas
rence, and more commonly recur within the abdo- of enhancement or mass-like contour change sug-
men; they should have a CT every 6 months for 2 gest recurrent disease (Fig. 4.21).
years then at 2-year intervals.
The strategy discussed above is only one
example of a post-therapy algorithm. Many oth- Imaging After Targeted Antiangiogenic
ers have been published, some including more Therapies
variables. Frank et al. showed that metastases in
the abdomen, lung, bone, and brain can be pre- Antiangiogenic agents have been shown to be
dicted by independent variables such as TNM more effective than conventional therapies for
stage, tumor size, tumor grade, and degree of metastatic RCC [183]. Assessment of therapeutic
tumor necrosis [173]. Similarly, the group from response is most often based on tumor size and
the University of California, Los Angeles, pro- response evaluation criteria in solid tumors
posed a surveillance protocol based on prognos- (RECISTs). However, despite the substantial
tic categories that combine TNM stage, Fuhrman improvement in survival obtained with angiogen-
grade and ECOG performance status [174]. esis inhibitors, the RECIST response rate is rela-
Postprocedural imaging is less standardized tively low. This primarily results from RECIST
after renal tumor ablation. Typically, the first fol- reliance on tumor size change to indicate
low-up is obtained at 1 month and additional fol- response. Response to antiangiogenic therapy
low-up occurs at 6 months, 1 year and then yearly. has been shown to lead to necrosis with only
CT is the test of choice to search for tumor modest size change in other tumors such as GI
recurrence in the postoperative period [175]. stromal tumor. Criteria were developed to gauge
Contrast enhancement is important in detecting the treatment response of GIST that are based on
visceral organ metastases and local recurrence. quantification of change in both tumor size and
However, the risk of nephrotoxicity from iodi- density on CT. A similar approach has recently
nated CT contrast is higher in the patients who been taken for RCC [184, 185]. In one series, a
have surgery for RCC and may have compro- favorable response according to newly developed
mised renal function. In these patients MRI is criteria had a sensitivity of 86% and specificity of
often a reasonable alternative to CT. 100% in identifying patients with a good clinical
Local recurrence after resection or ablation outcome (i.e., progression-free survival of >250
manifests as an enhancing mass at the resection days) compared to 17% sensitivity and 100%
4 Imaging of Renal Cell Carcinoma 75

Fig. 4.19 Post cryoablation changes. Pre- and post-contrast follow-up CT scan before (c) and after (d) contrast adminis-
images (a and b, respectively) 24-h after cryoablation of tration. The ablation zone has decreased in size (tumor invo-
renal mass. The cryoablation zone (arrow) encompass the lution) and in attenuation. There is no enhancement to
mass entirely and part of the normal renal parenchyma suggest residual or recurrent disease. The perinephric hema-
(arrowhead) with no contrast enhancement. Small peri- toma has nearly resolved. There is a characteristic perinephric
nephric hematoma is observed (asterisks). Three months halo (arrowhead on d) demarcating the ablation zone

specificity for the RECIST category of partial complications or disease progression. Because of
response. developments in both imaging technology and
therapies for patients with RCC, imaging is used
in new ways, in particular to plan and guide ther-
Summary apy by depicting precise anatomical details. While
there has been an increased recognition that small
With modern computed tomography and MRI, renal masses can be benign, the majority of solid
imaging serves as an accurate means to character- renal masses are RCC. Imaging can distinguish
ize, stage, and plan therapy for patients with renal some of the subtypes of RCC. Clear cell RCC,
tumors, and to evaluate patients after therapy for oncocytoma, and AML are the most vascular of
76 A.S. Purysko et al.

Fig. 4.20 CT-guided percutaneous cryoablation. (a) Axial (arrowheads). (b) Contrast-enhanced CT image on coronal
CT scan obtained with the patient in the left lateral decubi- plane, obtained 24-h post procedure demonstrating expected
tus position during cryoablation procedure showing the lack of enhancement of the ablation zone (arrowhead ),
cryoprobe (black arrow) and early ice ball formation with hyperdense areas related to hemorrhage (white arrow)

Fig. 4.21 Renal cell carcinoma recurrence post cryoabla- no enhancing lesion within the ablation zone (arrowheads).
tion. (a) Sagittal plane contrast-enhanced CT image demon- (c) Sagittal contrast-enhanced MR image over 2 years post-
strating a left lower renal pole enhancing lesion (arrow). (b) ablation revealing enhancing tumor at the inner margin of the
Sagittal contrast-enhanced MR image postablation showing ablation zone (arrow) consistent with recurrence
4 Imaging of Renal Cell Carcinoma 77

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 Prognostic Factors for Localized
Renal Cell Carcinoma 5
Brian R. Lane

2010 [5–7]. The pressing need for more effective

Introduction systemic therapies has led to the development of
multiple targeted treatments for metastatic RCC
Renal cell carcinoma (RCC) responds modestly to that are now available for clinical use [8]. The
conventional systemic therapies, and when not Food and Drug Administration-approved agents
completely removed surgically, remains the most fall into two main categories: multi-tyrosine kinase
lethal of the common genitourinary cancers [1]. inhibitors that target the vascular endothelial
Cancer-specific survival correlates strongly with growth factor (VEGF) pathway and those that tar-
tumor stage, although several other factors have get the mammalian target of rapamycin (mTOR)
been shown to be independent predictive factors as pathway [8]. These agents can provide a modest
well [2–4]. Long-term survival exceeds 90% in extension of survival for patients with metastatic
patients with RCC up to 7 cm in size and contained RCC and are now being investigated in adjuvant
within the kidney (pathologic stage T1), but is less trials for high-risk patients after complete surgical
than 5% in patients with metastatic RCC [3]. resection. However, targeted agents are very
Although surgical treatment is curative for local- expensive and can be associated with substantial
ized disease, 25% of patients present with locally side effects.
advanced or disseminated disease, and 20–30% of Therefore, it is important to identify postsur-
those with localized disease at presentation will gical patients at greatest risk for recurrence, for
recur systemically [1]. Unfortunately, the incidence consideration for these and future adjuvant trials,
of all stages of RCC continues to increase by about and such information can also guide the intensity
2.5% per year and RCC was responsible for more of surveillance. Determination of the risk of
than 13,000 cancer-related deaths in the USA in recurrence in patients without evidence of metas-
tasis has traditionally been based on several pre-
dictive models that integrate known clinical and
B.R. Lane MD, PhD () pathologic risk factors for disease recurrence
Urology Division, Spectrum Health Medical Group,
4069 Lake Drive, Suite 313, Grand Rapids, [2, 9–20]. Some studies suggest that the addition
MI 49546, USA of molecular markers to clinical risk factors may
Michigan State University College of Human Medicine, improve the predictive ability of these models
Grand Rapids, MI, USA [18, 21]. This chapter will highlight the predictive
Van Andel Institute, Grand Rapids, MI, USA factors and algorithms for risk stratification for
e-mail: [email protected] patients with localized RCC.

S.C. Campbell and B.I. Rini (eds.), Renal Cell Carcinoma: Clinical Management, Current Clinical Urology, 83
DOI 10.1007/978-1-62703-062-5_5, © Springer Science+Business Media New York 2013
84 B.R. Lane

Table 5.1 Impact of pathologic findings and TNM stage on 5-year cancer-specific survival for patients with renal cell
carcinoma
Stage
Tumor characteristics Robson TNM (2002) TNM (2010) 5-Year survival (%)
Organ confined (overall) I T1-2 N0 M0 T1-2 N0 M0 70–90
£4.0 cm I T1a N0 M0 T1a N0 M0 90–100
>4.0–7.0 cm I T1b N0 M0 T1b N0 M0 80–90
>7.0–10.0 cm I T2 N0 M0 T2a N0 M0 65–80
>10.0 cm I T2 N0 M0 T2b N0 M0 50–70
Invasion of perinephric or renal sinus fat II T3a N0 M0 T3a N0 M0 50–70
Extension of tumor into renal vein or III-A T3b N0 M0 T3a N0 M0 40–60
branches grossly
Extension of tumor into IVC below III-A T3c N0 M0 T3b N0 M0 30–50
diaphragm
Extension of tumor into IVC above III-A T3c N0 M0 T3c N0 M0 20–40
diaphragm or invasion of IVC wall
Direct adrenal involvement II T3a N0 M0 T4 N0 M0 0–30
Locally advanced (invasion beyond IV-A T4 N0 M0 T4 N0 M0 0–20
Gerota’s fascia)
Lymphatic involvement III-B Tany N1-2 M0 Tany N1 M0 0–20
Systemic metastases IV-B Tany Nany M1 Tany Nany M1 0–10

Modified from AJCC Cancer Staging Manual, 7th ed. New York: Springer-Verlag, 2009. References: [2, 12, 13, 22–46]

TNM Staging System TNM stage remains the single best prognostic
indicator for RCC, it may be better viewed as an
In the latter half of the twentieth century, Robson’s algorithm that combines several factors, each of
radical nephrectomy and modification of the which provides information about the risk of
staging system proposed by Flocks and Kadesky progression.
provided the most reliable prognostic informa- T stage, which is a composite of tumor size
tion for clinicians caring for patients with RCC and local extension or invasion, is the foundation
[3]. RCC was often detected at advanced stage of the TNM system, representing a powerful and
and patients had a correspondingly poor progno- independent prognostic factor for RCC in virtu-
sis even with such “radical” surgical intervention. ally all series. Cancer-specific survival for RCC
The most common system in current use was at 5 years ranges from 90% to 100% for pT1a to
built upon this foundation by the Union 0–20% for pT4 (Table 5.1) [22, 23, 47, 49].
International Contre le Cancer (UICC) and the Organ-confined cancers (pT1–2) are subclassified
American Joint Committee on Cancer (AJCC) according to tumor size: pT1a (£4.0 cm), pT1b
(Table 5.1) [47, 48]. This TNM classification has (4.1–7.0 cm), pT2a (7.1–10.0 cm), and pT2b
undergone several modifications in an effort to (>10.0 cm). Tumor size is an independent prog-
more accurately reflect tumor biology and prog- nostic factor for both organ-confined and invasive
nosis and to guide clinical management. The RCC [2, 9, 16, 24, 25, 50, 51]. A review of 1,771
2002 modification demonstrated better prognostic patients with organ-confined RCC showed
ability than the 1997 staging system [14, 49], and 10-year cancer-specific survival rates of 90–95%,
the 2010 staging system appears likely to provide 80–85%, and 75% for patients with pT1a, pT1b,
further improvement [22, 23, 47, 49]. Although and pT2 tumors, respectively [13]. Larger tumors
5 Prognostic Factors for Localized Renal Cell Carcinoma 85

are more likely to exhibit clear cell histology and [22, 69–76]. Patients with microscopic venous
high nuclear grade, and both of these factors cor- invasion may also have a reduced prognosis, but
relate with lower survival rates [52–54]. Many this has not been incorporated into TNM staging
other studies have shown a particularly favorable at present [77–79]. The most recent version of the
prognosis for the unilateral pT1a tumors that are TNM system advocates capturing all such adverse
now being discovered with increased frequency. features during the staging process, but does not
In series from the Cleveland Clinic and the Mayo allow for formal integration of such features,
Clinic, such tumors were associated with greater which is a potential disadvantage of this system
than 95% 5-year cancer-specific survival rates, when compared with other predictive tools.
whether they were managed with nephron- The prognostic significance of the cephalad
sparing surgery or radical nephrectomy [26, 27, extent of tumor thrombus has been controversial
50, 55–57]. in part because the presence or absence of nodal
Several studies have documented a 15% or and/or distant metastases has been variably
greater reduction in survival associated with RCC recorded. In several series, the incidence of
invasion through the renal capsule and into the advanced locoregional or systemic disease
perinephric fat [2, 22, 24]. Renal sinus involve- increased with the cephalad extent of the tumor
ment is now classified along with perinephric fat thrombus, accounting for the reduced survival
invasion as T3a, and several studies suggest that associated with tumor thrombus extending into or
these patients are at even higher risk for metasta- above the level of the hepatic veins [22, 69–76].
sis related to increased access to the venous sys- On the other hand, other series suggest that the
tem [28–31, 58, 59]. Collecting system invasion cephalad extent of tumor thrombus is not of prog-
has also been shown to confer poorer prognosis nostic significance as long as the tumor is other-
in otherwise organ-confined RCC, but is not a wise confined [61, 63, 73, 80, 81]. Independent
component of the current TNM staging system of the level of tumor thrombus, direct invasion of
[58, 60]. the wall of the vein is clearly an adverse predictor
and is now classified as pT3c [82, 73].
The major drop in prognosis comes in patients
Vascular Involvement whose tumor extends beyond the Gerota fascia to
involve contiguous organs (stage T4) or has
Although venous involvement was previously spread to lymph nodes or distant sites [2, 4, 23].
thought to be a very poor prognostic finding, sev- Many reports have shown that most patients with
eral reports demonstrate that many patients with direct or metastatic ipsilateral adrenal involve-
tumor thrombi can be cured with an aggressive ment, which is found in 1–2% of patients, eventu-
surgical approach. These studies document ally succumb to systemic disease progression
45–69% 5-year survival rates for patients with [33–37, 84]. Although previously staged as T3a,
venous tumor thrombi as long as the tumor is oth- direct extension into the ipsilateral adrenal
erwise confined to the kidney [4, 22, 32, 61–68]. involvement is now classified as T4 and meta-
Gross tumor thrombus into the inferior vena cava static involvement of either adrenal gland as M1
(IVC) above the diaphragm is pT3c, below the to reflect the likely pattern of dissemination and
diaphragm is pT3b, and involvement of the renal similarly poor outcomes [23, 33, 47, 48].
vein or major branches has been down-staged to Lymph node metastases portend a poor prog-
pT3a to reflect its relatively favorable prognosis nosis, with cancer-specific survival rates of
[22, 23, 47, 69]. Patients with venous tumor 5–30% and 0–5% at 5 and 10 years, respectively
thrombi and concomitant lymph node or [3, 38, 85]. Distant metastases to lung, bone, and
systemic metastases have markedly decreased other sites are associated with survival rates of
survival, and those with tumor extending into the 50%, 5–15%, and 0–5% at 1, 5, and 10 years,
perinephric fat have intermediate survival respectively [3, 39, 86, 87]. Factors predicting
86 B.R. Lane

poorer outcomes in patients with metastatic dis- Table 5.2 Prognostic factors for renal cell carcinoma
ease include synchronous metastases, reduced Anatomic Clinical
performance status, larger burden of metastatic Tumor size Performance status
disease, bone, brain, and/or liver metastases, Venous involvement (Karnofsky, ECOG)
anemia, hypercalcemia, elevated alkaline phos- Extension into contiguous Systemic symptoms
organs (cachexia, loss of greater
phatase or lactate dehydrogenase levels, throm- Adrenal involvement than 10% of body weight)
bocytosis, and sarcomatoid histology [3, 39, (direct or metastatic) Symptomatic vs. incidental
86–96]. These factors have been used to effec- Lymph node metastases presentation
tively categorize patients with metastatic RCC as Distant metastases Anemia
Metastatic burden of Hypercalcemia
low, intermediate, and poor risk [3, 39, 86–91], disease Elevated LDH
which provide important information for deter- Elevated erythrocyte
mining the likelihood of benefit a patient may sedimentation rate
expect to receive after cytoreductive nephrec- Elevated C-reactive protein
(pre- and post-nephrectomy)
tomy and/or resection of other metastatic disease Thrombocytosis
and are discussed further in a subsequent Elevated alkaline
chapter. phosphatase

Histologic Molecular
Nuclear grade Hypoxia-inducible factors:
Patient-Related Factors Histological subtype CA-IX, IGF-1, VEGF,
Presence of sarcomatoid VEGFRs, CA-XII, CXCR3,
Although TNM staging facilitates communica- features CXCR4, HIF
Presence of histologic Co-stimulatory immune
tion about groups of cancer patients, it does not
necrosis regulators: B7-H1, B7-H3
take into account a number of other significant Microscopic vascular (tumor cell/vascular),
predictive factors that contribute to significant invasion B7-H4, PD-1
heterogeneity among patients within each Invasion of perinephric or Cell cycle regulators: PTEN,
renal sinus fat p53, Bcl-2, Cyclin A, p27,
classification [2, 22, 23, 47, 49]. This has led
Collecting system invasion Skp2
investigators to explore various prognostic fac- Surgical margin status Adhesion molecules:
tors to determine whether they can add value to EpCAM, EMA, E-Cad,
tumor stage alone (Table 5.2) [2, 97]. Patient alpha-catenin, Cad-6
Other factors: Ki-67, XIAP,
characteristics have a significant impact on over-
Survivin, EphA2, Smac/
all survival, with age and medical comorbidities DIABLO, PCNA,
playing a dominant role in the survival of patients Caveolin-1, AR, CD44,
with localized disease [98–100]. Hollingsworth Annexin II, Gelsolin,
Vimentin, CA-125), aberrant
et al. demonstrated that competing cause mortal-
DNA methylation, Na-K
ity was far greater than cancer-specific mortality ATPase a1 subunit, vitamin
for many patients with localized RCC [98]. This D receptor, retinoid X
indicates that reduction of the impact of surgery receptor
on renal functional outcomes may have as much Modified from Lane BR and Kattan MW. Prognostic
or greater impact on overall survival as cancer models and algorithms in renal cell carcinoma. Urol Clin
treatment. Patient factors should be given pri- N Am 2008;35:613–625
mary consideration during treatment planning for
patients with localized RCC [98–100]. In fact,
strong retrospective data demonstrated that surgi- prognosis then those with incidentally detected
cal intervention will not lengthen survival for tumors [9, 11–13]. Overall health is commonly
those with limited life expectancy [101]. assessed using either the Karnofsky scale
Patient characteristics at presentation also (0–100% function) or Eastern Cooperative
impact cancer-specific survival. Those who pres- Oncology Group (ECOG) performance status
ent with systemic symptoms have a worse [102]. The presence of symptoms of cachexia,
5 Prognostic Factors for Localized Renal Cell Carcinoma 87

including weight loss (exceeding 10% of body inflammatory or immunomodulatory factors by

weight), anorexia, or malaise, or a reduction in the tumor is believed to be responsible for the
overall health at diagnosis, confers a poor prog- development of constitutional symptoms such as
nosis in both localized and metastatic RCC weight loss, fever, and anemia as well as some of
[9, 10, 103, 104]. These symptoms may be related the distinct paraneoplastic syndromes, thereby
to circulating factors released by aggressive negatively impacting cancer-free survival [105].
tumors and/or micrometastatic disease that is not
clinically evident.
Laboratory-Related Factors

Paraneoplastic Syndromes Several abnormal laboratory values, even without

associated signs and symptoms, have been asso-
Paraneoplastic signs or symptoms have been ciated with poorer outcomes in RCC patients,
correlated with poor outcomes for patients with including anemia (hemoglobin <10 g/dL for
RCC. Under normal circumstances, the kidney females or <12 g/dL for males), thrombocytosis,
produces 1,25-dihydroxycholecalciferol, renin, hypercalcemia, albuminuria, and elevated serum
erythropoietin, and various prostaglandins. RCC alkaline phosphatase, C-reactive protein, lactate
may produce pathologic amounts of these sub- dehydrogenase, or erythrocyte sedimentation rate
stances, which are normally tightly regulated. (>30 mm/h) [103, 104, 110, 115–120]. Some of
These include the substances above, as well as these abnormalities, including hypercalcemia,
parathyroid hormone-like peptides, lupus-type anemia, and elevated erythrocyte sedimentation
anticoagulant, human chorionic gonadotropin, rate, are independent predictors of cancer-specific
insulin, and various cytokines and inflammatory mortality in patients with localized clear cell RCC
mediators [105–109]. Hypercalcemia has been [110]. Each is present more commonly in patients
reported in up to 13% of patients with RCC and with advanced RCC and some are predictive in
can be due to either paraneoplastic phenomena or this population as well. The most promising of
osteolytic metastatic involvement of the bone these laboratory values appears to be C-reactive
[106, 107, 110–112]. The expression of parathy- protein, which is predictive of metastasis when
roid hormone-like peptides is suppressed by the obtained preoperatively and during surveillance
wild-type VHL protein, and these peptides may after nephrectomy [105, 117, 121–123].
act as potent growth factors for RCC [113]. This
may account in part for the observation that
patients with RCC who present with hypercalce- Histopathologic Factors
mia have a compromised prognosis, with a rela-
tive risk of death from cancer progression of 1.78 Other tumor features that are routinely captured
compared with patients with normal serum cal- at histopathologic analysis are strong predictors
cium levels [110]. Polycythemia, due to erythro- of cancer-related outcomes and provide indepen-
poietin production by the tumor, and hypertension dent and additional predictive ability when com-
secondary to increased production of renin bined with TNM stage. Several factors have been
directly by the tumor; compression or encase- studied; the most critical being nuclear grade,
ment of the renal artery or its branches; or presence of sarcomatoid features, and histologic
arteriovenous fistula within the tumor are also subtype.
commonly found in patients with RCC [114]. In
general, treatment of paraneoplastic syndromes
associated with RCC has required surgical exci- Nuclear Grade
sion or systemic therapy and, except for hyper-
calcemia, medical therapies have not proved Several grading systems for RCC have been
helpful. Pathologic expression of these and other proposed on the basis of nuclear size, nuclear
88 B.R. Lane

configuration, and presence of nucleoli. Although Sarcomatoid Differentiation

interobserver variability is common in the assign-
ment of nuclear grade, almost all proposed grad- RCC displaying sarcomatoid differentiation is
ing systems have provided independent prognostic characterized by spindle cell histology, positive
information when subjected to multivariable staining for vimentin, infiltrative growth pattern,
analysis [2, 9, 17, 124–126]. In Fuhrman and aggressive local and metastatic behavior, and
colleagues’ original report (1982), the 5-year poor prognosis [137–141]. Sarcomatoid differen-
survival rates for grades 1–4 were 64%, 34%, tiation is found in 1–5% of RCCs, most com-
31%, and 10%, respectively [127]. Nuclear grade monly in association with clear cell RCC or
also proved to be the most significant prognostic chromophobe RCC, but variants of most other
factor for organ-confined tumors in this study subtypes of RCC have been described [130,
[127]. Fuhrman’s classification scheme remains 142–147]. Sarcomatoid lesions almost certainly
the most commonly used system and subsequent represent poorly differentiated regions of other
reports have demonstrated correlations between histologic subtypes of RCC rather than indepen-
Fuhrman’s nuclear grade and tumor stage, tumor dently derived tumors. Thorough examination of
size, venous tumor thrombi, and lymph node and a predominantly sarcomatoid tumor almost
systemic metastases [124, 125, 128, 129]. always yields some epithelial-derived compo-
Significant differences have been consistently nents [144]. For this reason, this entity is no lon-
observed between low-grade (grades 1/2) and ger recognized as a distinct histologic subtype of
high-grade (grade 3/4) tumors, leading some to RCC [145]. Invasion of adjacent organs is com-
suggest a two-tier grading system [124]. Other mon, and median survival has been less than
investigators have proposed a three-tier system 1 year in most series [137, 138, 140, 148–151].
because of interobserver variability and the Optimal management of patients with resected
difficulty distinguishing the intermediate grades, sarcomatoid RCC remains controversial, but
but this has not gained wide support [124, 130]. multimodal approaches should be considered if
In addition, although significant differences the patient’s overall health allows based on the
according to nuclear grade have been reported in extremely poor prognosis with surgery alone.
series of patients with clear cell RCC alone or Selected reports have demonstrated modestly
RCC of all subtypes combined, the value of improved response rates in patients receiving
Fuhrman grade in other subtypes of RCC is not IL-2-based immunotherapy, chemotherapy, or
entirely clear. Subclassification of papillary RCC targeted molecular therapy after nephrectomy
into type 1 and type 2 takes nuclear features into [8, 140, 162, 153].
account, and appears to better stratify patients
into higher-risk and low-risk groups than does
nuclear grade [131–133]. Chromophobe RCC is Other Histopathologic Factors
a generally indolent tumor that is now recognized
to be more similar genetically to hybrid oncocytic Invasion of the renal sinus is now established as
tumors and oncocytomas than to other RCC sub- an adverse feature, with similar (or potentially
types [134–136]. Only chromophobe with aggres- worse) outcome compared with perinephric fat
sive histologic features such as sarcomatoid invasion [28–31, 58, 59]. Likewise, collecting
differentiation and/or advanced pathologic stage system invasion is a poor prognostic feature, at
portend poorer outcomes [135, 136]. Therefore, least for low-stage tumors [58, 60]. Histologic
papillary RCC may be better subgrouped into tumor necrosis has been shown to be a negative
type 1 and type 2, and oncocytic neoplasms may prognostic indicator for clear cell RCC [17, 121,
be better classified as chromophobe RCC, hybrid 154, 155] and has been incorporated into some
oncocytic tumors, and oncocytomas, without ref- algorithms. There is controversy, however,
erence to nuclear grade, but this requires further regarding the value of macroscopic (vs. micro-
investigation [137]. scopic) tumor necrosis and the importance of the
5 Prognostic Factors for Localized Renal Cell Carcinoma 89

amount of necrosis as prognostic factors. Further been implicated in VHL disease, a condition in
research may clarify this debate, but the lack of which patients often develop multiple, bilateral
uniform coding will likely limit its universal clear cell RCC. Mutations in the VHL gene or
applicability as a predictive factor. Although the hypermethylation of the VHL gene promoter
presence of multiple renal tumors may compli- region have been identified in 57–70% of patients
cate surgical management, multifocality has been with sporadic RCC [184]. More recent work indi-
demonstrated to confer either a neutral or posi- cates, however, that the presence of a detectable
tive influence on cancer-specific outcomes, which VHL mutation does not affect survival in patients
appear to be driven by the tumor of highest with localized clear cell RCC [185]. Moreover, a
T stage [156–161]. gene dysregulated in 30% of sporadic RCC has
now been identified and may play a role down-
stream of VHL [186]. Dysregulation of hypoxia-
Histologic Subtype inducible factors (HIFs) by alterations in VHL
creates a vasculogenic environment favoring
RCC is now known to be a heterogeneous malig- tumor growth. Genes linked to the development
nancy with several subtypes that exhibit distinct of RCC have also been identified in individuals
clinical and pathological features [162, 163]. with hereditary papillary RCC syndrome, Birt–
Several histologic subtypes of RCC have been Hogg–Dubé syndrome, and hereditary leiomyo-
described, which most experts believe have their matosis and RCC syndrome [183]. However,
origins from distinct portions of the nephron. The only 4% of patients with RCC develop the disease
three most common RCC subtypes are clear cell within the context of these familial syndromes,
RCC, papillary RCC, and chromophobe RCC. suggesting that there are many other genes and
Several studies now suggest that clear cell RCC pathways yet to be implicated in the pathogenesis
may have a worse prognosis on average compared of RCC. A number of molecular factors have
with papillary RCC and chromophobe RCC, been found to further subclassify RCC and, in
although there are clearly poorly differentiated some cases, to serve as independent prognostic
tumors in each of these subcategories that can be factors for RCC [187].
lethal [2, 9, 128, 162–172]. Papillary RCC and
chromophobe RCC account for about 15–25% of
RCC, and patients with these subtypes generally Molecular Factors
present at lower stage and have a better long-term
disease-free survival than those with clear cell A large number of genes that may have prognos-
RCC [9, 121, 162–165, 167]. Several less common tic and therapeutic significance in RCC have been
subtypes denote poor prognosis, including collect- identified using high-throughput technologies
ing duct carcinoma, renal medullary carcinoma, (Table 5.2) [188–196]. The list includes hypoxia-
and the unclassified RCC histologic subtype [130, induced factors, co-stimulatory immunoregula-
147, 148, 150, 151, 173–179]. Finally, several sub- tory molecules, cell cycle regulators, adhesion
types of RCC are predictably indolent, including molecules, and other factors that play a variety of
multiloculated cystic clear cell RCC and mucinous known and/or unknown functions in the cancer
tubular and spindle cell carcinoma [180–182]. microenvironment. Several studies demonstrate
Consistent clinical behavior is not observed that each histologic subtype of RCC can be dif-
within each of the major subtypes, suggesting ferentiated by gene expression profiling of renal
that genetic heterogeneity exists within each tumors [188–200]. Correlation of changes in gene
RCC subtype. The unique molecular defects that expression with location of their gene products
are pathognomonic for familial and sporadic can be analyzed using immunohistochemical
occurrences of each subtype are becoming staining of individual tissue samples. Construction
defined [183]. For example, the von Hippel– of tissue microarrays can facilitate the screening
Lindau (VHL) gene on chromosome 3p25 has of a larger number of pathologic samples, but
90 B.R. Lane

interpretation of results from these and other high- factors. Proof-of-principle has been illustrated by
throughput analyses can be difficult [201, 202]. groups at UCLA and Mayo Clinic, which demon-
The two molecules that have been most rigor- strated that a clinical and molecular model can
ously evaluated at present are carbonic anhydrase outperform models that rely only on clinical pre-
IX (CA-IX), the hypoxia-induced protein prod- dictors [18, 21, 201]. Kim and colleagues demon-
uct of MN-9 gene, and the co-stimulatory mole- strated that the addition of expression data from
cule B7-H1. Although initial studies indicated five markers, including CA-IX, Ki-67, gelsolin,
that decreased CA-IX expression is indepen- vimentin, and p53 improved the discriminating
dently associated with poor survival in patients ability of the UISS for localized RCC [201].
with advanced clear cell RCC [21, 203], the same A second integrative tool was developed by
may not be true in patients with localized disease Parker and colleagues based on expression of
[204]. CA-IX is expressed in the vast majority of B7-H1, survivin, and Ki-67 [18]. The BioScore
clear cell RCC (97%) and only rarely in other provided improvements in predictive accuracy
histologic subtypes, making it an attractive above UISS and SSIGN score, particularly in
marker for diagnostic evaluation of renal masses patients at intermediate-to-high risk for recur-
[204, 205]. In addition, CA-IX may serve as a rence [18]. The authors hypothesized that
marker for response to systemic therapy, making BioScore could therefore play a role selectively
CA-IX immunostaining potentially of value in in these subsets of patients [18].
advanced RCC as well. One study reported that Prior to the incorporation of any new marker
all complete responders to immunotherapy with into routine use, molecular or otherwise, it must
IL-2 had high CA-IX expression [206]. Some cli- be evaluated after considering the contribution of
nicians have advocated using CA-IX expression established clinical and pathologic factors. In
and other histopathologic information to select other words, a new marker should improve the
patients with characteristics predicting the high- ability to predict a given outcome beyond what
est chance of benefit from high-dose IL-2 [207, can already be achieved with existing markers.
208]. However, a recent clinical trial testing this For example, the initial finding that high Ki-67
hypothesis was negative. In addition, other recent expression predicted for disease recurrence was
trials indicate that CA-IX expression does not called into question by data indicating that it was
appear to reliably predict for response to suni- simply a surrogate for histologic necrosis [155].
tinib or temsirolimus [209, 210]. More recent evidence seems to indicate that
B7-H1 expression in clear cell RCC was ini- Ki-67 and necrosis have independent prognostic
tially found to be associated with a 4.5-fold information [215]. In order to validate the cost of
greater risk of cancer-specific mortality [211]. obtaining molecular data in the current clinical
This finding has been internally validated [212], landscape, studies must evaluate the predictive
with the additional finding that high Survivin and ability of a new marker in this manner. A new
B7-H1 expression together were associated with marker that merely replaces an existing marker is
a 2.8-fold higher risk of cancer-specific death not particularly helpful and certainly not cost
[213]. In addition to serving as a tumor marker effective [97].
for progression, B7-H1 is an attractive therapeu-
tic target in patients with advanced RCC. Since
B7-H1 may function as an inhibitor of T-cell- Integrative Predictive Tools
mediated antitumoral immunity, blockade of its
activity with a humanized neutralizing antibody As discussed above, there are several factors that
has been postulated to facilitate immunothera- are independently associated with various out-
peutic responses in patients with clear cell RCC comes, such as cancer-specific and overall
and clinical trials are anticipated [214]. survival. The value of any individual predictor is
Many experts believe that the best prognostic established by its ability to improve the predic-
tools will incorporate both clinical and molecular tive ability beyond other known predictors.
5 Prognostic Factors for Localized Renal Cell Carcinoma 91

The most helpful tools are those that integrate the operative renal function have also been evaluated
most important factors into a single prediction for [53, 216, 217]. Paper versions can provide a
each individual patient. Several predictive algo- visual aid to clinicians for use during patient
rithms, or nomograms, have been developed for counseling. Online versions of many of these are
patients with localized RCC (Table 5.3). Most available, and most have been compiled at a web-
predict cancer-specific survival, but likelihood of site organized by Fox Chase Cancer Center (labs.
malignancy, competing-cause survival and post- fcc.edu/nomograms).

Table 5.3 Integrated predictive tools for renal cell carcinoma

Institution, Tumor Prognostic
author Year Setting subtype Prognostic indicators information Format
Preoperative
Cleveland 2008 Localized, All Tumor size, symptoms, Histology Nomogram
Clinic, Lane amenable gender, age, smoking
to PN
MSK/Mayo 2008 Localized All Tumor size, symptoms, Recurrence Nomogram
Clinic, Raj gender, lymphadenopathy,
necrosis on imaging
Keio (Japan), 2009 Localized, All TNM stage Survival Nomogram
Kanao, metastatic
Postoperative
MSK, Kattan 2001 Localized All TNM stage, tumor size, Recurrence Nomogram
histology, symptoms
UCLA, 2001 Localized All TNM stage, nuclear grade, Survival Algorithm,
Zisman performance status decision boxes
UCLA, 2002 Localized, All TNM stage, nuclear grade, Survival Algorithm,
Zisman metastatic performance status, decision boxes
metastasis (UISS)
Mayo Clinic, 2002 Localized, Clear cell TNM stage, tumor size, Survival Algorithm
Frank metastatic nuclear grade, histological
necrosis (SSIGN)
Mayo Clinic, 2003 Localized Clear cell TN stage, tumor size, nuclear Recurrence Algorithm
Leibovich grade, histological necrosis
UCLA, Kim 2004 Localized, All TNM stage, performance Survival Nomogram
metastatic status, metastasis, expression
of p53, vimentin, CA-IX in
metastatic patients
MSK, 2005 Localized Clear cell TNM stage, tumor size, Recurrence Nomogram
Sorbellini nuclear grade, histological
necrosis, microvascular
invasion, symptoms
Multi- 2007 Localized All TNM stage, tumor size, Survival Nomogram
institutional, nuclear grade, histologic
Karakiewicz subtype, local symptoms,
age, gender
Mayo Clinic, 2009 Localized Clear cell Expression of B7-H1, Survival Algorithm
Parker survivin, Ki-67 (BioScore)
UCLA, Klatte 2009 Localized Clear cell Expression of Ki-67, p53, Survival Nomogram
endothelial VEGFR-1,
epithelial VEGFR-1,
epithelial VEGF-D
(continued)
92 B.R. Lane

Table 5.3 (continued)

Institution, Tumor Prognostic
author Year Setting subtype Prognostic indicators information Format
Other (renal function / competing cause mortality)
MSK, 2006 Localized, All Preoperative creatinine, age, Renal Nomogram
Sorbellini metastatic gender, ASA score, percent insufficiency
change in kidney volume
Fox Chase, 2010 Localized, All Tumor size, age, gender, race Survival Nomogram
Kutikov metastatic (Non-cancer,
kidney
cancer, other
cancer)
MSK Memorial Sloan Kettering Cancer Center, Keio Keio University School of Medicine, Tokyo, Japan

Preoperative Nomograms is more useful in the postoperative setting, when

for Suspected Renal Malignancy this information might affect subsequent deci-
sion-making (e.g., surveillance protocol, adjuvant
Prior to intervention for a suspected RCC, clini- treatment). If additional information is needed
cal and radiographic features can be used to prior to a decision regarding treatment, molecular
determine the likelihood of benign or malignant characterization by either renal mass biopsy or
pathology and cancer-specific survival. Based on advanced imaging techniques can be performed
pathologic data obtained during 862 partial neph- [205, 224]. Certainly, the ultimate utility of such
rectomies in patients with a single enhancing an approach is as yet to be fully realized.
renal neoplasm amenable to partial nephrectomy,
the predicted probability of benign disease ranged
from 5% to 50% [53]. Overall, 20% of suspected Postoperative Prognostic
renal malignancies had benign histology and the Algorithms for Localized RCC
likelihood for a given patient was based on read-
ily identifiable preoperative factors (tumor size, Using pathologic information obtained at nephre-
age, gender, symptoms at presentation, and smok- ctomy, several groups have developed postopera-
ing history). This information may be particularly tive prognostic algorithms. In 2001, Memorial
applicable when active surveillance or tumor Sloan-Kettering Cancer Center (MSKCC)
ablation is being considered for smaller tumors in researchers proposed a nomogram for patients
more infirm patients; especially given recent evi- with localized clear cell, papillary, or chromo-
dence that active treatment may not increase life phobe RCC [9]. Predictive factors included tumor
expectancy in such individuals [101, 218]. stage, tumor size, histologic subtype, and symp-
Several additional preoperative nomograms toms at presentation [9]. Subsequently, the same
for recurrence-free survival have been developed group produced a second nomogram for patients
[219–223], but none perform as well as algo- with clear cell RCC based on tumor stage, tumor
rithms that incorporate data obtained during size, nuclear grade, necrosis, vascular invasion,
nephrectomy [15]. Using the nomogram devel- and symptoms at presentation [9].
oped by Raj et al., the 12-year recurrence free Researchers at other institutions also pub-
survival for an incidentally detected 3, 5, or 7 cm lished postoperative prognostic systems
RCC is about 95%, 88%, or 75%, respectively. incorporating a slightly different set of predic-
This information may be particularly useful in tors. The UCLA integrated staging system (UISS)
counseling patients in whom non-extirpative as proposed in 2001 initially divided patients into
options are being considered. However, for other five groups shown to have statistically significant
patients, we feel that estimation of this endpoint differences in disease-specific survival [10].
5 Prognostic Factors for Localized Renal Cell Carcinoma 93

Although the UCLA group evaluated many statistical rigor. First, and most importantly, any
potential prognostic parameters, the UISS was tool to be used in clinical practice should be sub-
reduced to include only tumor stage, nuclear jected to external validation. Second, because the
grade, and ECOG performance status for c-index is a measure of the ranking of outcomes
simplification [10]. In a subsequent report, the and does not address the absolute predictive
UISS was modified to identify patients with accuracy, calibration of a particular predicted
nonmetastatic or metastatic disease at low, inter- probability should also be performed. This is
mediate, or high risk of disease progression [225]. usually accomplished by plotting predicted vs.
This modified UISS has been validated in larger actual probabilities. Third, predictive accuracy
series of patients both internally and externally, cannot be compared directly across datasets, so a
but was found to be out-performed by other conclusion about the “best” nomogram cannot be
nomograms (each of which included tumor size) made by comparing c-index values in two reports
[225, 226]. One significant drawback of the UISS using two distinct patient populations. Far more
(and the TNM staging system) is that it does not accurate information is obtained from head-to-
predict a probability of failure for an individual head comparisons on the same dataset.
patient, and instead places individuals into low, Several examples of such work now exist,
intermediate, and high risk groups that have het- including a comparison of the 1997 and 2002
erogeneous outcomes. TNM staging systems and two reports that
In 2002, the group at the Mayo Clinic devised directly compared prognostic algorithms using
the SSIGN score, in which patients with clear cell the same dataset [15, 19, 49, 125]. Benefiting
RCC are assigned a score based on tumor stage, from earlier work, Karakiewicz and colleagues
tumor size, nuclear grade, and the presence of his- developed a nomogram for use in RCC patients
tologic necrosis [17]. The estimated cancer- of any histology and TNM stage using data from
specific survival for an individual patient at 2,530 patients with median follow-up of
1–10 years is then provided based on the total of 39 months [19]. The reduced model included
the SSIGN score. The SSIGN score was devel- T stage, N stage, M stage, tumor size, Fuhrman
oped based on data from over 1,800 patients and grade, and symptom classification (none, local,
has been validated internally and externally against systemic) and was externally validated using
additional datasets [17, 125, 126, 227, 228]. 1,422 patients’ data from other institutions
Many statistical methods can be employed in (Fig. 5.1) [19]. The model was found to outper-
order to evaluate predictive models [97]. The form the UISS, with a c-index of 86.7% vs.
concordance index (c-index) is a measure of the 83.9% for predicting survival at 5 years (p = 0.02)
predictive accuracy of prognostic algorithms, in [19]. While direct comparison with the other
which the algorithm is asked to predict which of nomograms mentioned above has not been per-
two patients will experience clinical failure first. formed, this nomogram benefits from relying
Comparison with the actual outcome in a large solely on the strongest and commonly available
series of patient pairs determines the c-index. predictors (stage, size, and grade) and omitting
Perfect predictive accuracy yields a highest pos- histopathologic features that can be variably col-
sible value of 1.0 (100%), while random chance lected across institutions (vascular invasion and
provides a baseline value of 0.5 (50%). Although necrosis). In addition, the use of symptom
the predictive accuracy of these integrative algo- classification which has been shown previously
rithms improves upon individual factors, such as to improve accuracy over TNM stage alone also
tumor size and nuclear grade and TNM stage, improves predictive accuracy in the published
each has been reported to have a c-index substan- model [12, 13, 19]. Further studies comparing
tially less than1.0, indicating further room for each of the prognostic models on the same data-
improvement. sets will help to identify the most practical and
Comparative evaluation of prognostic accurate nomograms for use in patients with
algorithms should be performed with care and localized RCC.
94 B.R. Lane

Fig. 5.1 Nomogram predicting RCC-specific survival at tion. Reprinted with permission from Karakiewicz et al.: J
1, 2, 5, and 10 years after nephrectomy. T T stage, N N Clin Oncol 2007;25(11):1316–1322. © 2008 American
stage, M M stage, S classification symptoms at presenta- Society of Clinical Oncology. All rights reserved

Other Predictive Algorithms preserves renal function and a nomogram pre-

dicting renal function after either approach can
Additional nomograms have been developed to facilitate discussions about surgical options [216,
predict outcomes that impact the overall survival 230].
of patients with localized RCC, including non-
RCC-related mortality and renal function after
surgery [216, 217]. Based on review of over Conclusions
30,000 cases of localized RCC contained within
the SEER database, Kutikov and colleagues cal- Patients should be provided with the most accu-
culated 5-year probabilities of kidney cancer rate information about their likely individual dis-
death, other cancer death, and non-cancer death ease course currently available to expert clinicians.
to be 4%, 7%, and 11%, respectively [217]. This Many patient and tumor characteristics have been
tool may be particularly helpful in elderly patients associated with cancer outcomes for those with
because quantifying the risk of death unrelated to localized RCC. Combination of these predictors
RCC may greatly impact treatment selection. into integrated predictive tools provides more
Based on the excellent recurrence-free survival accurate assessments than any single predictor
outcomes following surgical treatment of organ- alone. A preoperative nomogram can predict the
confined RCC, renal functional outcomes also likelihood that a suspected malignancy is a can-
contribute to overall survival, as chronic kidney cer and estimate survival after definitive treat-
disease has been associated with increased car- ment. At least five postoperative predictive
diovascular morbidity [229]. Compared with algorithms exist for localized RCC, each of which
radical nephrectomy, partial nephrectomy better improves upon predictions based on the TNM
5 Prognostic Factors for Localized Renal Cell Carcinoma 95

staging system. Refinement of the existing tools, 14. Ficarra V, Schips L, Guille F, et al. Multiinstitutional
with corresponding increases in accuracy, allows European validation of the 2002 TNM staging sys-
tem in conventional and papillary localized renal cell
physicians to better counsel patients regarding carcinoma. Cancer. 2005;104(5):968–74.
their likely clinical course, assists in the planning 15. Cindolo L, Patard JJ, Chiodini P, et al. Comparison
and tailoring of follow-up, and identifies patients of predictive accuracy of four prognostic models for
who are more likely to benefit from additional nonmetastatic renal cell carcinoma after nephrec-
tomy. Cancer. 2005;104(7):1362–71.
treatments. Future algorithms predicting disease 16. Sorbellini M, Kattan MW, Snyder ME, et al. A post-
outcomes or response to treatment will likely operative prognostic nomogram predicting recur-
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to provide information of even greater quality. cell carcinoma. J Urol. 2005;173(1):48–51.
17. Frank I, Blute ML, Cheville JC, Lohse CM, Weaver
AL, Zincke H. An outcome prediction model for
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 Part II
Management of Localized RCC
 Assessment of Oncologic Risk
for Clinical Stage T1 Renal Tumors 6
and the Emerging Role of Renal
Mass Biopsy

Matthew N. Simmons and Steven C. Campbell

oncologic causes, some of which may be treat-

Introduction ment related. One potential cause of non-oncologic
mortality in these patients is postoperative chronic
The incidence of RCC has been rising steadily kidney disease (CKD) and its harmful sequelae.
over the past several decades, and aggressive sur- Specific subsets of patients including the elderly
gical treatment of RCC has increased in parallel. and those with baseline CKD are at elevated risk
However RCC mortality rates have not declined for non-oncologic mortality after kidney surgery
and some studies show an increase in mortality in [6, 7]. These patient subsets comprise up to 35%
patients with localized disease [1–3]. This alarm- of all RCC patients and this percentage is expected
ing trend has prompted reexamination of long- to increase [8]. More intelligent and selective uti-
held beliefs regarding aggressive treatment of lization of surgery has the potential to significantly
localized RCC, particularly the overutilization of reduce non-oncologic mortality in these patients.
radical nephrectomy. Prior to the CT era most Individualized treatment of patients with cT1
patients presented with symptomatic high-grade tumors depends on the ability to accurately assess
tumors. Since the 1980s there has been a steady the relative contributions of oncologic and non-
downward stage migration due to an increased oncologic risk. Non-oncologic risk assessment is
rate of incidental tumor detection, such that currently feasible and relatively straightforward.
50–70% of patients currently present with asymp- Factors such as general health status and baseline
tomatic stage T1 (cT1) tumors [4, 5]. One would kidney function can be objectified using Charlson
expect RCC mortality rates to decrease as a result comorbidity score, ECOG performance score,
of early detection and the increased proportion of and the K/DOQI CKD classification system.
low-risk tumors, yet this has not happened. Oncological risk analysis is more of a challenge,
Survival in patients who undergo surgery for especially for cT1 tumors. Emerging data
RCC is impacted by two major factors, namely demonstrate that the majority of cT1 tumors are
cancer-related death and death due to non- at low risk for metastatic progression. The role of
renal mass biopsy (RMB) to evaluate cT1 tumors
is evolving to allow for improved oncologic risk
M.N. Simmons MD, PhD • S.C. Campbell MD, PhD () stratification. This chapter will focus on recent
Center for Urologic Oncology, advances in RMB biopsy and ongoing efforts to
Glickman Urological and Kidney Institute,
Cleveland Clinic, 9500 Euclid Avenue, Suite Q10-1,
provide a more rational and balanced approach
Cleveland, OH 44195, USA to the management of patients with clinical T1
e-mail: [email protected] renal tumors.

S.C. Campbell and B.I. Rini (eds.), Renal Cell Carcinoma: Clinical Management, Current Clinical Urology, 105
DOI 10.1007/978-1-62703-062-5_6, © Springer Science+Business Media New York 2013
106 M.N. Simmons and S.C. Campbell

Table 6.1 Contemporary SRM pathology data

Percent Percent Percent Percent Aggressiveness
Author n benign (%) indolent (%) aggressive (%) metastatic criteria
Frank et al. [9] 947 23 64 13 NA FG ³3
Remzi et al. [54] 287 20 58 22 5% Stage ³T3a or
metastatic
Schlomer et al. [55] 206 23 52 25 NA FG ³3
Pahernik et al. [56] 663 17 70 13 3% FG ³3, stage ³T3a
or metastatic
Lane et al. [10] 862 20 56 24 NA FG ³3 or stage ³T3a
Mean values 20 60 20
FG Fuhrman grade, NA not available

Fig. 6.1 Pathologic

distribution of cT1 tumors.
Large contemporary
pathology studies have
revealed that for contrast-
enhancing solid cT1
kidney tumors, 20% are
benign, 60% are RCC with
low-risk features, and 20%
are RCC with high-risk
features

of invasion into sinus fat or vascular structures

Pathologic Features of T1 Tumors (pT3 disease); and presence of extrarenal
extension.
Contemporary pathological studies of solid con- There are several issues with pathology stud-
trast-enhancing cT1 tumors are summarized in ies that limit their clinical relevance. Definitions
Table 6.1. Two of the largest independent stud- of high-risk criteria are not standardized among
ies reviewed cT1 tumor pathology in nearly studies, and as a result there is variability in the
2,000 patients [9, 10]. In general it was found reported percentages of high-risk tumor rates
that approximately 20% of incidental cT1 ranging from 13% to 25%. Pathological studies
tumors were benign, 50–60% were RCC tumors are also limited because they cannot definitively
with low-risk features, and only 20–25% were assess the relationship between tumor risk fea-
RCC tumors with high-risk features (Fig. 6.1). tures and clinical behavior. It is assumed that
High-risk features in contemporary pathology RCC tumors with low-risk features follow an
studies include Fuhrman nuclear grade ³3 pat- indolent clinical course, but this has not been
tern, presence of type II papillary, medullary, proven in controlled prospective studies.
sarcomatoid or collecting duct histology; presence Nonetheless, pathologic data illustrate the
6 Assessment of Oncologic Risk for Clinical Stage T1 Renal Tumors and the Emerging Role… 107

Table 6.2 SRM active surveillance and natural history

Mean cm Mean cm/year Mean months Metastatic
Author N tumor size growth rate follow-up progression (%)
Kato et al. [57] 18 2 0.42 26.9 0
Lamb et al. [13] 36 7.2 0.39 27.7 1 (2.8%)
Volpe and Jewett [58] 32 2.48 0.1 38.9 0
Wehle et al. [59] 29 1.83 0.12 32 0
Abouassaly et al. [60] 110 2.5a 0.26 24a 0
Kouba et al. [61] 46 2.92 0.7 35.8 0
Kunkle et al. [11] 106 2.0a 0.19a 29a 1 (1.1%)
Youssif et al. [62] 41 2.2 0.21 47.6 2 (5.7%)
Crispen et al. [63] 173 2.45 0.29 31 2 (1.3%)
Rosales et al. [26] 223 2.8a 0.34a 35a 4 (1.9%)
Mean values 2.7 0.31 33 1.2%
a
Median values

important concept that approximately 80% of growth rates in 53 patients and found that the pro-
cT1 tumors pose relatively low oncologic risk. portion of clear cell RCC was 31% in the 1st
quartile growth rate group versus 62% in the 4th
quartile growth rate group [12]. This study also
Natural History of cT1 Tumors compared specific tumor types under observa-
tion, finding no significant difference in growth
Investigation of the natural history of untreated rates, and there was a wide range of growth rates
cT1 tumors is an area of active research. within each histological group. Similarly, Kato
Observational studies provide a basis for risk et al. examined 18 cT1a tumors and also found no
assessment in patients who have elected to difference in the proportion of RCC in fast- ver-
undergo AS. Contemporary AS studies have sus slow-growing tumors. However this study did
established parameters that define “normal” and find that tumors with faster growth rate were
“abnormal” cT1 tumor growth rates, and they more likely to have higher Fuhrman nuclear grade
have characterized cT1 tumor metastatic progres- (FG). Tumors with FG 3/4 grew at an average
sion rates. A data summary of contemporary rate of 9 mm/year compared to 3 mm/year for
studies is presented in Table 6.2. tumors with FG 1/2. Larger prospective studies
AS studies show that cT1 tumors grow slowly are required to validate the data obtained from
at an average rate of 3 mm/year with a low risk of these more limited cohorts.
metastatic progression. There is a general assump- In addition to analysis of growth rates, AS
tion that tumors with faster growth pose higher studies have examined cT1 tumor metastatic
risk for malignancy and metastatic progression progression rates. Mean incidence of de novo
but these relationships remain incompletely char- metastasis over a 2- to 3-year period in these
acterized. For example, Kunkle et al. performed a studies has ranged from 0% to 5% [13–16]. For
systematic pathologic study in 106 cT1a tumors instance, Haramis et al. reported clinical behav-
that were observed over a median of 12 months ior of 51 cT1 tumors followed for >5 years [17].
[11]. Zero net growth was observed in 33% of RMB was conducted in 39% of patients, and
tumors while growth was observed in the remain- RCC was identified in 100% of those biopsies.
der. There was no difference in the percentage of Tumor growth rate for the biopsied specimens
tumors with malignant pathology in fast- versus was 2.5 mm/year, and none of the patients with
slow-growing tumors. Zhang et al. examined biopsy required treatment during the study period.
108 M.N. Simmons and S.C. Campbell

No patients exhibited metastatic progression Patient Demographic Factors

or died from RCC. A report by Zini et al.
examined cancer-specific mortality (CSM) rates Patient factors of primary importance in
of surgically treated (n = 9,858) versus untreated determining oncologic risk include presence of
(n = 433) T1a RCC tumors. CSM in the surgically symptoms, baseline performance status, and
treated group at 1, 2, and 5 years was 1%, 1.6%, comorbidity score. Local and systemic symptoms
and 3%, respectively. In comparison the CSM at are more common in patients with large tumors,
1, 2, and 5 years in the untreated group was 6%, but their presence in the context of cT1 tumors is
8%, and 12%, respectively. Age and tumor size associated with increased malignancy rates and
were independently associated with CSM. poorer outcomes. Lee et al. reported oncologic
AS study data imply that cT1 tumors pose low outcomes according to symptomatology in 633
risk for metastasis; however, the studies are lim- patients who underwent nephrectomy for RCC
ited and the data may not be generalized to all [18]. In this study 23% of stage cT1 tumors were
cT1 tumors. A major issue with these studies is symptomatic and this subgroup exhibited an
selection bias. Assignment of patients to AS pro- increased incidence of clear cell histology and
tocols was predicated on small tumor size, high Fuhrman nuclear grade.
absence of adverse radiologic features and slow Comorbidity and performance status have
growth rate. In this regard the data represent only been established as independent predictors of
this highly selected low risk subset of cT1 tumors. disease-specific survival, and as such are integral
In addition, in most studies only a small percent- components of two widely used oncologic risk
age of patients underwent biopsy at the initiation prediction nomograms [19, 20]. These features
of the observation period, therefore the ability to are unique in that they are important for assess-
correlate pathologic findings with clinical behav- ment of both oncologic and non-oncologic risk.
ior remains limited. In terms of oncologic risk, studies have shown
that there is an association of ECOG performance
status with presence of tumor necrosis and
Contemporary cT1 Risk Assessment decreased cancer-specific survival [21]. There is
no definitive data to support a causal relationship
Preoperative oncologic risk assessment of kidney between the two, but it is reasonable to suspect
tumors is currently based primarily on radiologic that patients with major comorbidities and poor
tumor size, morphology, and staging. There is a performance status are more likely to have higher
clear gradation of risk among tumors of different risk tumors.
stage. However, comparison of oncologic risk for Epidemiologic data suggest that specific
tumors of a single stage is considerably more demographic factors such as age and gender are
difficult, particularly for cT1 tumors. In these associated with malignancy rates. Benign tumors
patients analysis must rely on additional nuanced tend to be more commonly encountered in
risk features. Demographic factors that may aug- younger women <50 years of age. In this demo-
ment oncologic risk analysis include age, perfor- graphic the rate of malignancy is on the order of
mance status, comorbidity status, and presence of 50%, because a variety of benign histological
tumor-related symptomatology. Radiologic fea- subtypes such as atypical angiomyolipoma and
tures that impact risk analysis include size, mor- metanephric adenoma are more common in this
phology, contrast enhancement, and growth population, suggesting an important role of the
pattern. In isolation these adjunct features have hormonal milieu [10]. DeRoche et al. reported
low diagnostic and prognostic sensitivity and that males have a 12% higher likelihood of malig-
specificity and are not relied upon to guide nancy than females for all age groups [22]. They
clinical management. However, when considered also found that in patients <68 years of age with
collectively they may enhance standard risk tumors £3.5 cm malignancy was present in 87%
analysis. of males versus 69% of females. Verhoest et al.
6 Assessment of Oncologic Risk for Clinical Stage T1 Renal Tumors and the Emerging Role… 109

examined pathologic features as they relate to relates to aggressiveness within a narrower range,
patient age in 4,774 patients [23]. They found particularly 1–4 cm, has only recently been
that patients £40 years of age were more likely to characterized. For T1 tumors every 1 cm increase
have papillary or chromophobe RCC than clear in tumor diameter is associated with a 16–17%
cell RCC. These demographic and clinical cor- increase in the odds of malignancy [9, 24]. In two
relates associate with likelihood of malignancy, major studies 38–46% of tumors measuring
but in a nonspecific manner. Use of patient £1 cm were benign compared to 6–7% of tumors
demographics in risk assessment can augment ³7 cm. The risk of high nuclear grade (i.e.,
tumor evaluation but should not be relied upon Fuhrman nuclear grade ³3) disease was also
independently to guide clinical management. related to tumor size. Each 1 cm increase in tumor
In a small subset of patients there exist specific size increased the odds of high-grade disease by
tumor presentations that are nearly pathogno- 32% in clear cell stage T1 RCC [24].
monic for certain malignancies. Patients who These data ideally would answer the question
present with small, multifocal bilateral kidney of what size is “safe” for AS. One group has
tumors should be suspected to have a heritable described surveillance outcomes in patients with
syndrome such as Von Hippel–Lindau (VHL). T1a versus T1b–T2 masses [17, 25]. Failure of
VHL tumors measuring <3 cm pose low risk for surveillance was defined as progression to meta-
metastasis, and routine observation of these static disease or conversion from surveillance to
tumors is accepted practice. Medullary RCC, delayed treatment. Of 41 patients with pT1a
while very rare, occurs primarily in young African tumors, only one failed surveillance (2%), and
males with sickle cell trait. Medullary RCC is an none progressed to metastasis. In contrast, of 42
aggressive tumor; therefore, it is advisable to patients with T1b–T2 tumors 14% failed surveil-
manage incidentally detected SRMs in this demo- lance and 6% progressed to metastasis disease. No
graphic aggressively. study has adequately assessed risk differential
across a 0–4 cm size range; however, associations
between tumor size and failure of surveillance
Radiologic Risk Assessment have been reported. Rosales et al. observed 223
tumors over a median time period of 35 months
The majority of information pertaining to tumor [26]. Failure of surveillance defined as metastatic
risk analysis is obtained from cross-sectional CT progression or requirement for intervention
and MRI imaging. Key anatomical features occurred in 9% of patients. Median tumor size of
include tumor size, location, and appearance. In tumors in the failed group was 3.6 cm compared to
patients who have had serial imaging studies 2.6 cm in the success group. Final tumor size at
measurement of tumor growth rate may also be the end of the surveillance period in failed and
possible. As discussed previously, tumor size and success groups was 5.2 cm versus 3.6 cm, respec-
tumor growth rate are potential indicators of tively. These data suggest that tumors £3 cm are
oncological risk. In order to assess risk differen- less likely to behave aggressively. Large system-
tial among tumors with similar size and growth atic studies are required to validate these findings.
rate we must rely on more subtle features.

Contrast Enhancement
Tumor Size
A critical radiologic feature of RCC is the pres-
At present the best indicator of tumor malignancy ence of contrast enhancement, defined as an
and high nuclear grade is tumor size [9, 24]. Most increase of 15–20 Hounsfield units (HU).
data pertaining to this relationship compared Presence of contrast enhancement has a positive
tumors of different stages over a wide size range predictive value for detection of malignancy of
from stage T1a through T2. How tumor size approximately 80–90%. Several studies have
110 M.N. Simmons and S.C. Campbell

examined the relationships between the magni- the tumor in terms of the uniformity of its
tude of contrast enhancement and pathology. In peripheral edge. Birnbaum correlated CT findings
general, contrast enhancement is relatively higher with pathologic features in 100 surgically resected
in clear cell carcinomas and lower in papillary clear cell RCC tumors [32]. They found that well
RCC. This is an important distinction in that clear circumscribed spherical tumors were more likely
cell RCC has a greater tendency to metastasize to have Fuhrman grades 1–2 compared to tumors
than papillary RCC. One caveat to this is type II with irregular borders. Soyer et al. reported data
papillary RCC which comprises 20–40% of all from a similar study in 35 clear cell RCC tumors
papillary tumors. Type II papillary RCC can and found that radiographically apparent com-
behave aggressively with 5-year CSM rates dou- plete encapsulation of the tumor was observed in
ble that of type I papillary RCC [27]. Alshumrani 40% of tumors with Fuhrman grades 1–2, but in
et al. examined 46 cT1 tumors and found that the no tumors with Fuhrman grades 3–4 [33]. Tumor
degree of contrast enhancement in clear cell growth pattern can be classified as expansive or
RCC, oncocytoma, and papillary RCC tumors infiltrative. Expansive tumors are typically well
was 65, 80, and 16 HU, respectively [28]. Herts circumscribed and appear to displace adjacent
et al. reported that low tumor-to-aorta and tumor- tissues. In contrast, infiltrative tumors have indis-
to-parenchyma enhancement ratios correlated tinct edges and appear to replace adjacent tissue.
with papillary RCC [29]. These enhancement An infiltrative appearance is strongly associated
characteristics can also be observed with MRI with high grade or sarcomatoid differentiation
imaging. Sun et al. examined 122 patients and and poor prognosis [32]. Similarly, the internal
found a >200% increase in signal intensity in organization of tumors can also provide an
clear cell RCC versus a 32–96% increase for pap- indication of the degree of tumor differentiation.
illary RCC [30]. However, the sensitivity and A homogeneous appearance suggests
specificity of enhancement features are low, and preservation of tissue organization, uniform his-
findings must be interpreted with caution. tology, and ordered vascularity. Heterogeneous
A recently reported MRI imaging parameter organization suggests poor differentiation, loss of
termed apparent diffusion coefficient (ADC) has organization, central necrosis, and aberrant vas-
also shown potential to distinguish low versus cularization. Zhang et al. examined 193 tumors
high Fuhrman grade [31]. Measurements con- and found that 79–88% of tumors with heteroge-
ducted in 57 clear cell RCC tumors demonstrated neous enhancement patterns had clear cell RCC
a significantly lower ADC in high-grade tumors pathology [34]. In contrast papillary and chromo-
compared to low-grade ones. Two different ADC phobe tumors tended to have more homogenous
mapping protocols were capable of 89% sensitiv- appearance. As with other radiologic tumor fea-
ity and 96% specificity to detect high-grade tures, these findings are nonspecific and must be
pathology. These performance characteristics interpreted with caution.
were determined by correlating preoperative MRI
study data to surgical pathology. These data illus-
trate the potential for cross-sectional imaging to Renal Mass Biopsy
extend beyond gross evaluation into the micro-
scopic realm. Tumor biopsy forms the foundation for diagnosis
and management of many cancer types. Breast
and prostate tissues are relatively easy to sample,
Specialized Tumor Features and protocols for biopsy in these tissues are
firmly established. RBM has not been routinely
Specialized tumor features that can gauge onco- utilized due to several key obstacles. First, these
logic risk include morphology, growth pattern, tumors are deep within the body and often adja-
location, and internal organization. Tumor cent to large blood vessels or major organs. Safe
morphology refers to the overall appearance of and accurate guidance of biopsy needle to these
6 Assessment of Oncologic Risk for Clinical Stage T1 Renal Tumors and the Emerging Role… 111

tumors relies heavily upon high-resolution image RMB Techniques

guidance and technical expertise. Second, sam-
pling of tumor tissue is complicated by the pres- Techniques for percutaneous RMB include core
ence of tumor heterogeneity, regions of focal needle biopsy and fine needle aspiration (FNA).
necrosis, and shared eosinophilic histological Core biopsy involves sampling of the tumor with
features of certain benign and malignant tumors. an 18-guage core biopsy needle. Core specimens
The historical noninformative rate of RMB was can be preserved, sectioned, stained, and evalu-
on the order of 20–40%, and its accuracy to ated using standard surgical pathology protocols.
obtain the correct pathologic diagnosis ranged FNA is conducted by using multiple passes
from 70% to 80% [35–37]. Over the past decade through the tissue of interest using a small bore
the accuracy and informative rate of RMB has needle under negative pressure. This collection
increased significantly due to advances in CT and method results in the collection of cellular aspi-
US technology that have enabled high-resolution rates which are best suited for cytology, immuno-
tumor imaging and precise stereotactic needle histology, flow cytometry, and fluorescence in situ
placement [38]. Additional improvements include hybridization (FISH). The technique of FNA may
optimization of sampling techniques and stan- be better suited to situations in which the biopsy
dardization of pathologic analysis and interpreta- tract must traverse bowel or adjacent organs.
tion. As a result the contemporary noninformative A summary of contemporary core and FNA
rate has decreased to approximately 10–15%, biopsy data is presented in Table 6.3. Core biopsy
and accuracy to distinguish between benign and is equivalent to FNA in terms of informative rate,
malignant disease has increased to 97% for infor- and superior in terms of diagnostic accuracy.
mative biopsies [39–43]. The informative rate for both biopsy techniques

Table 6.3 Contemporary renal mass biopsy data summary

Informative Benign/malignant Histological Nuclear grade Complication
Author n rate (%) accuracy (%) accuracy accuracy rate
FNA studies
Lechevallier et al. [49] 63 79 97 89% 79% 0%
Neuzillet et al. [43] 88 91 92 92% 70% 0%
Schmidbauer et al. [41] 44 91 83 86% 28% 1%
Masoom et al. [64] 31 100 97 97% NA NA
Veltri et al. [65] 26 92 88 NA NA 3%
Mean values 91 91 91% 59% 1%
Core biopsy studies
Lebret et al. [66] 119 79 92 86% 46% 0%
Maturen et al. [67] 152 96 97 NA NA 2%
Somani et al. [68] 70 87 100 100% NA 1%
Schmidbauer et al. [41] 78 97 96 98% 76% 1%
Shannon et al. [42] 235 78 100 98% 98% 1%
Volpe et al. [46] 100 84 100 93% 68% 3%
Wang et al. [69] 110 91 100 NA NA 7%
Blumenfeld et al. [40] 81 98 97 88% 43% NA
Veltri et al. [65] 45 92 91 93% NA 6%
Mean values 89 97 94% 66% 3%
Informative rate refers to percent of biopsies providing diagnostic information; accuracy refers to percent correlation of
biopsy with definitive surgical pathology results for informative biopsies; complication rate includes both minor and
major events
NA not available
112 M.N. Simmons and S.C. Campbell

is 89–91% on average. The accuracy of core biopsies include those that report oncocytic tumor
RMB to correctly distinguish malignant versus features. These features reflecting an eosinophilic
benign pathology is 97% for informative biop- staining pattern can be observed in oncocytoma,
sies, and accuracy to correctly diagnose histology eosinophilic variants of conventional RCC,
and nuclear grade are 94% and 66%, respectively. chromophobe RCC, papillary RCC, and even
FNA is heavily dependent on consistency of cyto- epithelioid AML tumors. At one extreme, Liu
logical preparation and pathologic analysis. As a et al. reported detection of oncocytic features in
result there can be considerable variability of ten biopsies (56%) from 18 patients [47]. On final
results among institutions. Current data demon- pathology of these oncocytic neoplasms, eight
strate that FNA has an average informative rate of proved to be benign oncocytomas, while the
91%. Mean accuracies of FNA to properly diag- remaining two were chromophobe RCC and
nose malignancy, histology, and Fuhrman nuclear eosinophilic papillary RCC. In cases where the
grade were 91%, 91%, and 59%, respectively first biopsy renders noninformative results, a sec-
[41, 43–45]. ond biopsy has been advocated, and has a reported
Several groups have reported improved results success rate of 75–100% [48].
using a combination of both FNA and core biopsy. Informative rates are influenced by sampling
In one of the earliest studies, Wood et al. reported technique and tumor size. Sampling error is
sensitivity and specificity of combined FNA and affected by two major variables—accuracy of
core biopsy to be 95% and 93%, respectively. stereotactic needle placement and adequate sam-
Volpe et al. showed that the combination of FNA pling of tumor subcomponents. Noninformative
and core biopsy resulted in a 22% increase in biopsy rates have been reported to be higher for
informative rate [46]. A recent side-by-side eval- tumors <3 cm on average (37% versus 9%,
uation of core versus FNA versus combined core P = 0.006) [49]. This is likely because it is more
+ FNA biopsy accuracy has been reported by difficult to guide biopsy needles to these small
Veltri et al. The histological diagnostic accura- tumors, and also because the sampling tract for
cies of FNA and core biopsy were 76% and 93%, small masses is short. In smaller pT1a tumors
respectively. The combination of core biopsy and 1–3 biopsies from central and peripheral regions
FNA resulted in a 23% increase in histological should be obtained [44]. In larger tumors, ade-
diagnostic accuracy. quate sampling can be hindered by the presence
of central tumor necrosis. In larger pT1b tumors
it is recommended that two or three cores from
RMB Limitations the periphery of the tumor be acquired due to the
high prevalence of central necrosis. A recent
In the past noninformative RMBs were often study published by Rybickowski et al. illustrates
classified as false-negative results; however, this these effects of tumor size on informative rates.
was misleading. By definition, a false-negative In this study noninformative rates were higher for
biopsy occurs when benign disease is diagnosed masses <3 and >6 cm (60% and 44%, respectively)
in the biopsy specimen and malignant disease is versus those between 4 and 6 cm (NPV of 89%)
subsequently confirmed. Fortunately this event [50]. As protocols and imaging technologies
occurs rarely at an incidence of approximately improve, sampling error will become less preva-
1%. The term “noninformative” refers to several lent, and the limitations of RMB will diminish.
scenarios and is encountered in 10–15% of cases.
“Failed” noninformative biopsies refer to cases in
which insufficient tissue was obtained for analy- Complications of RMB
sis. “Indeterminant” noninformative biopsies
refer to cases in which tumor tissue was obtained Potential complications of RMB include
but a definitive pathological diagnosis could not hemorrhage, pseudoaneurysm formation, infec-
be made. Commonly encountered indeterminant tion, adjacent organ injury, pneumothorax, and
6 Assessment of Oncologic Risk for Clinical Stage T1 Renal Tumors and the Emerging Role… 113

tract seeding. Average minor and major compli- specific RCC subtypes. Study is ongoing to assess
cation rates in contemporary studies are 5% and the association between specific signatures and
1%, respectively. Hemorrhage is a primary con- clinical behavior and response to targeted ther-
cern given the highly vascular nature of the kid- apy. One of the most comprehensive array studies
ney. Bleeding complications are typically conducted to date was conducted by Rini
managed with conservative measures including et al. [52]. In this study expression of 732 genes
bed rest and transfusion. Angioembolization or were examined in samples from 931 patients who
surgery is rarely necessary. It is important that were followed for a median duration of 5.6 years.
patients stop coumadin, aspirin, or IIa/IIIb inhibi- Ultimately 16 genes were identified that were
tors 7–10 days prior to biopsy to allow for nor- associated with recurrence after definitive treat-
malization of coagulation parameters. Cessation ment. Development of rapid and cost-effective
of the medications and bridging with short-acting genome-wide expression analysis has the poten-
agents such as heparin or eptifibadtide may be tial to replace histopathology as the primary
necessary in some cases, and coordination of this means by which tumors are characterized.
process should be made in conjunction with the Pan-genomic mutational analysis has been a
patient’s cardiologist or vascular medicine primary focus of active investigation. Array-
specialist. In patients who do not require bridg- based comparative genomic hybridization (CGH)
ing, the risk of cessation of anticoagulation medi- allows for detection of microdeletions and copy
cations must be balanced by the potential benefit number changes at a resolution of 5–10 kilobases.
of the proposed biopsy. Tumor seeding of the One of the most comprehensive CGH studies to
biopsy tract appears to occur very rarely such that date was published by Beroukhim et al. in which
incidents have been documented only in isolated 90 clear cell RCC specimens were analyzed [53].
case report studies. Current practice is to conduct The study identified specific regions of the
RMB via a coaxial dilator to minimize the risk of genome that were commonly mutated and
needle tract seeding. allowed for classification of sporadic clear cell
RCC tumors into those with or without biallelic
VHL inactivation. The study has identified new
Evolving Role for RMB categorization criteria that may have significant
clinical implications in terms of prognosis and
At present RMB yields histological information response to targeted therapy.
including RCC subtype and Fuhrman nuclear Basic science studies are rapidly identifying
grade. These phenotypic descriptions of cancers key molecules and processes involved in RCC
cells are limited indicators of the pathobiology of tumorigenesis. Translational studies are in great
the tumor. Large pan-genomic studies have shown demand in order to define the relationships
that clear cell RCC tumors with indistinguishable between these biomarkers and clinical tumor
histology have substantial genotypic heterogene- behavior. It is likely that surgical intervention
ity [51]. Molecular analysis is able to character- will remain the mainstay for high stage RCC
ize tumor pathobiology at a level of resolution tumors. However, for lower risk cT1 tumors the
that is orders of magnitude greater than standard use of RMB-based molecular analysis may dic-
histological analysis. In this regard molecular tate management. If molecular analysis revealed
analysis may facilitate a shift to routine use of indolent RCC pathology, then surveillance or
RMB to diagnose and evaluate kidney tumors. minimally invasive ablative therapies may be
The emergence of technologies that allow for validated as safe options. Molecular analysis may
genome-wide and proteome-wide analysis are also allow for assessment of sensitivity to tar-
allowing for comprehensive characterization of geted therapy. In this manner appropriate combi-
mutation patterns that occur in RCC tumors. nations of targeted therapy and surgery can be
Genetic “signatures” have been identified for initiated to optimally treat these tumors.
114 M.N. Simmons and S.C. Campbell

Fig. 6.2 Stage T1 RCC management options. Management in patients with high-risk tumors, partial nephrectomy is the
of patients with cT1 RCC tumors should factor in patient reference standard. In poor surgical candidates or in patients
and radiologic tumor features and should include a bal- with tumors suspected to pose low risk, renal mass biopsy
anced discussion of oncologic risk versus procedural may alter management and improve survival rates by avert-
benefit. In healthy patients with normal kidney function and ing low-risk patients away from surgical management

prise the primary treatment modalities for cT1

Contemporary Management of the tumors, but we are now recognizing that in select
cT1 Kidney Tumor patients survival may actually be decreased as a
result of intervention, particularly for radical
The management of patients with cT1 tumors nephrectomy. In 2009 the AUA convened a panel
involves assessment of oncologic risk, technical to establish recommendations regarding manage-
feasibility of surgery, baseline patient health sta- ment of T1 renal masses, and one of the main take
tus, and baseline kidney functional status. An out- home points of this document related to a strong
line for cT1 RCC management options is shown preference for nephron-sparing modalities when-
in Fig. 6.2. Radical and partial nephrectomy com- ever feasible [36]. Key elements of preoperative
6 Assessment of Oncologic Risk for Clinical Stage T1 Renal Tumors and the Emerging Role… 115

evaluation include age, performance status, and an emerging role for RMB in patients who are at
presence of major comorbidities including ath- elevated operative risk, who have limited life
erosclerosis, hypertension, diabetes, and cardiac expectancy, or in those who are at high risk of
disease. Other important considerations include developing CKD as a result of intervention. An
smoking history, level of daily activity, and esti- example would be an active 74-year-old man
mation of physical ability needed for recovery. with a 2.5 cm exophytic, contrast-enhancing
Key laboratory factors include presence of anemia renal tumor with a baseline estimated glomerular
of chronic disease as well as serum creatinine. filtration rate of 48 ml/min/1.73 m [2], and
Radiologic evaluation should consist of a high- comorbidities including diabetes and a history of
resolution CT or MRI with and without contrast coronary artery disease. In this patient PN, abla-
to assess tumor anatomy and enhancement fea- tion or surveillance would all be reasonable
tures. Key aspects of radiologic evaluation include options, and RMB can stratify oncologist risk
tumor size, location, and morphology, amenabil- and guide counseling and management. For
ity to partial nephrectomy, and feasibility of lap- instance if RMB indicated a potentially high-
aroscopic intervention. grade clear cell RCC, PN would be considered,
Counseling of patients should consist of a bal- while RMB suggesting an oncocytic tumor might
anced discussion regarding the risks and benefits prompt more conservative management. A shift
of treatment. Available management options in practice toward use of this approach has the
include partial nephrectomy, radical nephrectomy, potential to significantly improve survival in this
thermal ablation, and AS. Each of these interven- subset of patients. With the development of reli-
tions will be discussed in detail in the upcoming able molecular diagnostics, we may eventually
chapters. Each management type is unique in be able to predict clinical tumor behavior with a
terms of oncological efficacy, functional preser- much higher degree of accuracy. In this event we
vation, and treatment-related morbidity, and mor- would expect that the role for RMB-based analy-
tality. In general, PN is now defined as the sis would be extended to all kidney tumors.
reference standard for T1 tumors, and RN should
be reserved as an alternate standard of care when
tumor anatomy precludes a nephron-sparing Conclusions
approach, a situation that is now relatively uncom-
mon. RN is associated with the highest degree of Contemporary data indicate that only about
functional decline, and should be avoided if pos- 20–30% of stage cT1 kidney tumors exhibit
sible. Thermal ablation is a less invasive treatment aggressive clinical behavior, therefore surgery
option compared to PN and RN and poses a rela- for all tumors, particularly smaller ones, may
tively lower risk for post-treatment renal func- constitute overtreatment. Demographics of
tional decline. However, TA is associated with patients with stage cT1 tumors are trending
decreased oncologic efficacy, and as such is pri- toward increasing age and decreasing preopera-
marily reserved for high operative risk patients tive kidney function, and traditional surgery can
who desire proactive treatment. Percutaneous be associated with significant increases in mor-
RMB should be performed in all patients under- bidity and risk for non-oncologic mortality in
going ablation therapy to define histology. AS is these vulnerable patients. This is especially true
currently reserved as an option primarily for for radical nephrectomy, which should be avoided
patients with limited life expectancy. whenever feasible. There has been renewed inter-
The current absolute indications for RMB are est in the use of RMB to differentiate patients
for assessment of tumors which are suspicious with indolent versus aggressive disease prior to
for lymphoma, abscess or metastatic involvement surgery. In this manner, patients with indolent
of the kidney. RMB should also be conducted if it disease could be identified and observed, or man-
is anticipated that the results may alter clinical aged less aggressively. Advances in imaging
management, a utility-based approach. There is resolution and ability to reliably sample tumor
116 M.N. Simmons and S.C. Campbell

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 Radical Nephrectomy for Localized
Renal Tumors: Optimum 7
Oncological and Renal Functional
Considerations

Paul Russo

ordered to evaluate nonspecific abdominal and

Introduction musculoskeletal complaints or during unrelated
cancer care, has changed the profile of the typical
There will be an estimated 58,240 new cases and renal tumor patient from one with a massive,
13,040 deaths from kidney cancer in the USA in symptomatic tumor at presentation to one with a
2010 [1]. Compared to 1971, this represents a small, asymptomatic, renal mass (<4 cm) inciden-
fivefold increase in the incidence and twofold tally discovered in 70% of the cases [4]. A sur-
increase in the mortality of renal cancer. vival rate of 90% or greater, depending on the
Associated risk factors for kidney cancer include tumor histology, is expected for these small
hypertension, obesity, and African American tumors if partial (PN) or radical nephrectomy
race. Epidemiological evidence suggests an (RN) is performed.
increase in all stages of renal cancer, including RN was once considered the “gold standard”
the advanced and metastatic cases. It is now and utilized to treat all tumors, small and large,
understood that renal cortical tumors are a family and even to solve diagnostic dilemmas when an
of distinct tumors with variable histology, cyto- uncertain renal mass was encountered. PN was
genetic defects, and metastatic potential [2]. only utilized in restricted conditions such as
Approximately 90% of the tumors that metasta- tumor in a solitary kidney or in patients with con-
size are the conventional clear cell carcinoma ditions which compromised renal function. New
[3]; however, they account for only 54% of the concerns that RN could cause or worsen preexist-
total number of resected tumors. Approximately ing chronic kidney disease (CKD) has lead to
30–40% of renal tumor patients will either pres- recommendations for more restricted use of RN,
ent with or later develop metastatic disease. whether performed by open or minimally inva-
The widespread use of the modern abdominal sive techniques, for the resection of large renal
imaging techniques (CT, MRI, and abdominal tumors, including those which destroy the major-
ultrasound) over the last two decades, usually ity of the kidney, invade the renal sinus, invade
branched or main renal veins or extend into the
inferior vena cava, and/or are associated with
regional adenopathy or metastatic disease. The
P. Russo MD, FACS () increased treatment and cure of small, inciden-
Department of Surgery, Urology Service,
tally discovered renal tumors, most of which are
Memorial Sloan Kettering Cancer Center,
New York, NY, 10021, USA nonlethal in nature, does not appear to offset the
increased mortality caused by the advanced and
Weill Medical College, Cornell University,
1275 York Avenue, New York, NY, 10021, USA metastatic tumors. This “treatment disconnect”
e-mail: [email protected] may result from unaccounted etiological factors

S.C. Campbell and B.I. Rini (eds.), Renal Cell Carcinoma: Clinical Management, Current Clinical Urology, 119
DOI 10.1007/978-1-62703-062-5_7, © Springer Science+Business Media New York 2013
120 P. Russo

increasing the incidence of all renal cortical questions in kidney tumor surgery were not yet
tumors and their virulence. In this chapter, the realized. Although a subsequent report with lon-
optimum contemporary utilization of RN in the ger follow-up from Robson in 1982 projected
management of localized renal tumors and its declining long-term survival rates in the range of
impact on renal function will be discussed. 40% [14], there was no doubt that the surgical
techniques associated with the safe removal of
large renal tumors were established, well
Radical Nephrectomy: Historical described, and reproducible making RN the only
Considerations effective treatment for renal cortical tumors.
Today, at major centers with a commitment to
Successful attempts to surgically cure renal tumors renal tumor surgery, despite the above-described
were reported widely after World War 2 with sur- imaging-induced stage and tumor size migration,
gical strategies designed to address the renal cap- RN is still required in approximately 20–30% of
sular and perinephric fat infiltration observed in patients with renal tumors not amenable to kid-
up to 70% of the tumors [5]. Using a thoracoab- ney sparing approaches (Fig. 7.1).
dominal incision, Mortensen [6] reported the first
radical nephrectomy, an operation that removed
all of the contents of Gerota’s fascia. Radical Radical Nephrectomy: Patient
nephrectomy was popularized in the 1960s by Selection and Preoperative Evaluation
Robson who described this operation as the peri-
fascial resection of the tumor-bearing kidney and To a large extent, the modern imaging studies of
perirenal fat, regional lymph nodes, and ipsilat- CT, ultrasound, and MRI that have been so
eral adrenal gland [7]. In 1969 Robson reported effective in creating the era of the “incidenta-
RN results in a series of 88 patients and described loma” and the associated tumor size and stage
a 65% survival for tumors confined within Gerota’s migration also provide the surgeon with an
fascia (Robson stages 1 and 2), but the finding of accurate description of the extent of disease
regional nodal metastases led to less than 30% prior to operation. At MSKCC, tumors routinely
5-year survival rate [8]. selected for RN include those large and cen-
En bloc RN, ipsilateral adrenalectomy, and trally localized tumors that have effectively
extensive regional lymphadenectomy, usually replaced the majority of the normal renal paren-
through large abdominal or transthoracic inci- chyma, often associated with regional adenopa-
sions, became the standard approach to the renal thy, inferior vena cava, or right atrial extension,
tumors for the next 20 years as major centers none of which are amenable to a PN [15]. In
began reporting favorable results [9, 10]. In this addition, RN is performed on patients with
era, the imaging studies used to diagnose a metastatic disease referred by medical oncol-
patient, who was generally symptomatic with a ogy for cytoreductive nephrectomy prior to the
large renal tumor, was intravenous urograms, ret- initiation of systemic therapy [16–18]. Patients
rograde pyelograms, and arteriograms. These with extensive metastatic disease and a poor
techniques were unable to detect small tumors Karnofsky performance status are advised to
and the incidental tumor detection rate was <5%. undergo percutaneous needle biopsy of the pri-
Despite this acceptance of RN by urologic sur- mary tumor or a metastatic site and subsequently
geons, convincing data did not exist establishing referred for systemic therapy. Patients with
the therapeutic impact of the component parts of small incidentally discovered or exophytic
the operation (i.e., the need for adrenalectomy tumors amenable to PN are asked to also sign
[11] or the need for and extent of lymph node dis- consent for radical nephrectomy if operative
section [12, 13]). Historical series were subjected findings or technical problems arise making PN
to selection biases, and the virtues of randomized unsafe or unwise. Over the last 3 years at our
trials in clinical investigation to address the many center, 1,030 surgical nephrectomies have been
7 Radical Nephrectomy for Localized Renal Tumors: Oncological and Renal Functional Considerations 121

Fig. 7.1 CT of the abdomen of a 44-year-old male with left radical nephrectomy, regional lymph node
massive left renal tumor (21 cm × 15 cm × 12 cm) com- dissection,and ipsilateral adrenalectomy
pletely replacing the kidney. He subsequently underwent

performed with 21% RN and 79% PN, reflecting Open Radical Nephrectomy: Surgical
our center’s commitment to kidney sparing Anatomy, Choice of Incisions, and
approaches whenever possible. Operative Considerations
Prior to operation, routine serum chemistries,
coagulation profile, type and cross match (or autol- The kidneys are retroperitoneal organs located in
ogous blood donation), and chest X-ray are the lumbar fossa. They are covered with a vari-
obtained. Routine brain imaging and bone able amount of perinephric fat and Gerota’s fas-
scanning are not performed unless site-specific cia and lay in proximity to the psoas major and
abnormalities in the history, physical, or routine quadratus lumborum muscles, and diaphragm.
preoperative laboratory examination are discov- The right kidney abuts the right adrenal gland;
ered. For patients with significant comorbid liver, hepatic flexure of the colon, and second
conditions, particularly cardiac and pulmonary portion of the duodenum cover the renal hilum.
related, appropriate consultations are obtained The left kidney is in proximity to the left adrenal
with an effort made to optimize patients for whose main vein drains into the left renal vein,
operation whenever possible. Patients with pancreatic tail, and spleen superiorly and the left
significant coronary or carotid artery disease may colon medially. Depending on the surgeon’s pref-
require revascularization prior to RN. For patients erence, relating mainly to patient’s body habitus,
with compromised pulmonary status, consulta- the tumor size and location, the RN can be per-
tion with anesthesiology is requested for consid- formed through an eleventh rib flank incision, a
eration of epidural postoperative analgesia. transperitoneal midline or subcostal incision, or
122 P. Russo

a transthoracic incision or a miniflank supra medially provides clear exposure of the inferior
eleventh rib incision rib miniflank incision [15]. vena cava and renal hilum. Peritoneal attach-
The “miniflank incision” (Fig. 7.2) has the advan- ments to the liver and ligamentous attachments to
tage of speedy entry into the retroperitoneum and the spleen are carefully divided with care taken
avoidance of the rib resection with a decreased not to tear liver and splenic capsules. Inferiorly,
likelihood (<5%) of subsequent atony of the flank the ureter is identified, ligated, and divided. The
muscles and bulge [19]. For large tumors with any gonadal vessels are identified coursing through
question of liver, pancreatic, splenic, or IVC the retroperitoneal soft tissues entering either the
extension optimum exposure with bilateral sub- left renal vein or inferior vena cava on the right
costal (chevron) or thoracoabdominal incision is where it is ligated and divided. Split and roll
preferred and leaves options open for gaining techniques are used along the ipsilateral great
control over the renal hilum particularly when vessel until the renal vein is identified. All lym-
there is regional adenopathy and parasitic veins to phatic attachments overlying the renal vein are
contend with. In the retroperitoneal approach carefully divided. On the left side, the adrenal
to RN, the peritoneum and pleura are dissected and gonadal veins are identified as they drain into
off Gerota’s fascia exposing the kidney and ipsi- the renal vein, ligated and divided. Using blunt
lateral great vessel. dissection, a vessel loop is placed around the
During transabdominal RN, the colon is renal vein allowing for upward traction and
reflected medially along the white line of Toldt. identification of the renal artery. Care is taken not
We commonly employ self-retaining retractors to tear a posterior lumbar vein which often also
to provide maximum exposure with care taken to drains into the renal vein. The renal vein should
pad organs prone to iatrogenic injury such as the be palpated and inspected to exclude the possi-
spleen, liver, and pancreas. On the right side, bility of a tumor thrombus. As soon as is possible,
mobilization of the duodenum (Kocher maneuver) the renal artery is identified beneath the renal

Fig. 7.2 Miniflank surgical incision is a quick and effective approach to the retroperitoneum and kidney and can be
utilized both for partial and radical nephrectomy [19]
7 Radical Nephrectomy for Localized Renal Tumors: Oncological and Renal Functional Considerations 123

vein at its aortic ostium, ligated, suture ligated,

and divided. The arterial decompression that Minimally Invasive Radical
ensues renders the kidney more mobile and Nephrectomy
deflates the many fragile and distended parasitic
vessels along the surface of the kidney that often Following its introduction in 1991 by Clayman
bleed during this mobilization process. Lack of et al. [22], laparoscopic radical nephrectomy
renal vein decompression indicates an accessory (LRN) offered a minimally invasive alternative to
renal artery often emanating from the aorta either the classical open RN with dividends of less
superior or inferior to the level of the renal vein. wound pain and morbidity, decreased analgesic
The surgeon should avoid the renal vein ligation requirement, decreased hospitalization, more
prior to complete arterial decompression which rapid convalescence, and faster return to normal
will cause marked venous congestion and hemor- activities. Survival rates were directly compara-
rhage from the tumor and parasitic vessels. ble to those achieved with open RN [23–28].
It is our practice to perform ipsilateral adrena- At the time of its introduction, RN in general was
lectomy and regional node dissection to maxi- the preferred treatment for all renal masses and
mize local tumor control, decrease the chance of PN was largely reserved for only essential cases
local recurrence if these tissues are harboring where RN would put a patient at risk for dialysis.
micrometastatic disease, and provide maximum The choice of which procedure to offer the patient
pathological staging to allow entry into ongoing with the small renal tumor, LRN or open PN,
adjuvant clinical trials. Little evidence currently posed a dilemma for surgical groups possessing
exists that the resection of tumor-bearing lymph both capabilities as the literature in each respec-
nodes or ipsilateral adrenal gland provides a tive field developed in parallel over the last
therapeutic effect [20]. Care is taken not to trau- decade. A 9-year experience compared LRN
matize the tail of the pancreas or the splenic (N = 61) to open RN (N = 33) for suspected renal
vein during this portion of the dissection. cancer [23] and found advantages for the laparo-
Dissection continues along the aorta clipping scopic operation which included less estimated
and ligating arterial and venous supply to the blood loss (172 ml vs.451 ml), shorter hospital
adrenal. Following removal of the kidney and stay (3.4 days vs. 5.2 days), and quicker return to
surrounding perinephric soft tissues and adrenal, normal activity (3.6 weeks vs.8.1 weeks), but dis-
the operative bed is thoroughly irrigated and advantages for the laparoscopic operation were
inspected for any bleeding vessels. The spleen longer operating time (5.5 h vs. 2.8 h) and greater
and pancreas are thoroughly inspected. Drains costs ($15,816 vs. $13,672.45). Interestingly,
are not used unless a laceration of the pancreas is 23% of patients in the LRN group had benign
suspected or documented. disease versus 9% for the ORN group perhaps
Once the tumor resection is accomplished, indicating a willingness of both surgeon and
postoperative nomograms are available that patient to accept a minimally invasive solution to
incorporate clinical presentation, tumor histo- a renal mass of uncertain nature.
logical subtype, size, and stage to provide and Other centers also described their initial expe-
provide a clinical prognosis. Results for our riences in similar terms and readily concluded
center indicate 5-year survival rates following that LRN should supplant ORN particularly in
resection of non-metastatic tumors ranging from cases with small renal tumors which remained
30% to 98% depending on the above-mentioned well within the technical capabilities of the early
clinical and pathological features. These post- laparoscopic surgeons [24, 25]. Many of the
operative nomograms have been extremely use- initial laparoscopic studies described renal corti-
ful in patient counseling, tailoring cost-effective cal tumors in a historical context as a single tumor
follow-up strategies, and designing clinical type (renal cell carcinoma) with a single meta-
trials [3, 21]. static potential and did not utilize the 1997
124 P. Russo

Heidelberg classification of renal tumors [2], did kidney and a serum creatinine <1.5 mg/dl. Tumors
not discuss the uncertainties of preoperative treated by LPN were smaller than LRN (2.4 cm
radiological diagnosis, and did not discuss the vs. 5.4 cm), whereas age, BMI, serum creatinine,
deleterious impact of RN (by whatever means) gender, and tumor location were similar between
on renal function. Often patients who underwent the two groups. The mean 6-month serum creati-
LRN and were found to have benign conditions nine was greater in the LRN group vs. the LPN
were not included in the outcomes analysis. group (1.4 mg/dl vs. 1.0 mg/dl) and 36% of the
These articles argued strongly that LRN should LRN developed renal insufficiency (defined as
be the new “gold standard” for all small, T1 renal serum creatinine >1.5 mg/dl) vs. 0% of the
tumors. patients undergoing LPN [29].
A study comparing open PN (N = 82) and LRN Considerable effort was spent in the urology
(N = 35) for small T1a renal tumors (<4 cm) dis- literature introducing and evaluating laparo-
cussed similar advantages of LRN described in scopic techniques for RN and comparing these
other papers but noted a deleterious impact on approaches to historical surgical approaches (i.e.,
renal function in the patients undergoing LRN thoracoabdominal, chevron, or rib resecting flank
[26]. In this study too, 20% of the patients in each incisions from the 1960s and 1970s) but not to
treatment group had lesions that were not renal the recently described min-flank surgical inci-
cell carcinoma. The question beginning to face sions which do not require rib resection and can
the urology community was this; was the price of be widely adopted and practiced without elabo-
a future of renal insufficiency for a speedy recov- rate laparoscopic training [19]. Not discussed in
ery, lesser surgical incisions, and faster return to the laparoscopic literature was the role of adrena-
normal activities after LRN potentially too great? lectomy and regional node dissections or issues
Evidence for intra-institutional differences in related to training or learning curves. Laparoscopic
the treatment of small renal masses since the studies focused on comparing oncological out-
availability of laparoscopy was reported in a comes to open RN (no apparent differences),
series of 194 patients Cornell Medical Center. Of length of stay (LOS) in the hospital, analgesic
the operations performed, 63 (33%, mean tumor requirements, time to return to work and normal
size 3.6 cm) were open partial nephrectomies, 51 activities (better than open RN), and complica-
(26%, mean tumor size 7.6 cm) were ORN, and tions. At the same time, improvements in periop-
80 (41%, mean tumor size 4.6 cm) were LRN. erative care and the use of clinical pathways were
When analyzed over time, in the latter half of reducing LOS for all urological procedures,
2000, 89% of the LRN were performed on tumors including open and laparoscopic kidney surgery.
of 4 cm or less. In 2002, the number of LRN Other reports detailing technical concerns such as
performed for tumors 4 cm or less had decreased surgical approach (transperitoneal vs. retroperito-
to 42%. The experience with OPN during the neal vs. hand assisted) [30], intact tumor extrac-
same time frame was more consistent; 30% for tion vs. morcellation [31], the impact of prior
tumors of 4 cm or greater from 1997 to 2000 and operations [32], and concerns for LRN in obese
26% from 2000 to 2002. For OPN tumors of 4 cm and comorbidly ill patients were published [33].
or less, 70% from the years 1997–2000 and 73% It would appear that morcellation procedures are
from 2000 to 2002 were performed. During the rarely done today due to loss of pathological clar-
same period, the number of ORN performed for ity and concerns for intra-abdominal contamina-
tumors of 4 cm or less continued to decrease to tion during the morcellation process. Descriptions
2.9% in 2001 and 0% in 2002 [28]. A recent of laparoscopic extraction incisions would indicate
study demonstrated the negative impact of LRN that they did not adversely affect LOS and patient
vs. LPN on renal function. The investigators recovery. These extraction incisions were in the
compared 93 patients undergoing an LPN to 171 range of 7 cm, not much smaller than the described
patients undergoing an LRN for a unilateral, miniflank incisions (8–10 cm), raising the ques-
sporadic renal tumor with a normal contra lateral tion, as in other laparoscopic procedures such as
7 Radical Nephrectomy for Localized Renal Tumors: Oncological and Renal Functional Considerations 125

cholecystectomy, whether patient expectations from individual centers and are more likely to
play a significant role in many of the laparoscopic occur earlier in a center’s experience (initial 50
outcomes. Surgeons have also used robotic- cases). In one series, when the initial 50 LRN
assisted techniques to perform RN, and the recent cases are compared to the subsequent 50 cases,
literature has compared outcomes to classical lap- surgical time decreased from 2.9 to 2.7 h while
aroscopic techniques with similar perioperative the mean tumor size increased from 4.8 to 5.4 cm.
outcomes such as EBL and complications but not Major complications were 14%, minor complica-
surprisingly, at the front end of any new approach, tions were 11%, and two patients required open
operating time and costs were significantly greater conversion in one series [27]. Intra-operative
in the robotic-assisted cases [34]. events occur in approximately 4% of cases and
include adjacent organ injury (spleen, bowel),
vascular stapler malfunction with open conver-
Complications of Radical sion occurring in approximately 1–2% of cases
Nephrectomy [36–41]. Minimally invasive surgical (MIS) train-
ing has gradually been integrated into more resi-
In a review of 688 RN from 1995 to 2002, 112 dency training programs, and, despite this, a
patients (16%) experienced a perioperative com- stable complication rate over the last 5 years in
plication [35]. Complications were graded using centers with a major commitment to MIS has
a five-tiered scale based on the severity of impact been observed which is attributed by some to the
or the intensity of treatment required to address passage of more relatively inexperienced surgeons
the complication. There were 21 (3%) complica- through the learning curve [23].
tions that were directly attributed to the procedure
(procedure related) including three patients with
acute renal failure, one patient with a retroperito- Radical Nephrectomy: Adverse Renal
neal hemorrhage, seven patients with an adjacent Medical Impact
organ injury, four patients with a bowel obstruc-
tion, and six patients with a pneumothorax. Four A historical misconception exists that RN can
patients required surgical re-exploration, three for cause a permanent rise in serum creatinine due to
decompression of bowel obstruction, and one for the sacrifice of normal renal parenchyma not
delayed splenic rupture (grade 4, N = 3). There involved by tumor but will not cause serious
were three postoperative deaths (grade 5), two long-term side effects as long as the patient has a
due to myocardial infarction, and one due to pul- normal contralateral kidney. The renal transplant
monary embolism. The remainder of the compli- literature is cited as the clinical evidence to
cations was grade 1–3 and was managed by oral support this view since patients undergoing donor
medication or bedside care (grade 1, N = 78), nephrectomy have not been reported to have
intravenous therapy or thoracostomy tube (grade higher rates of kidney failure requiring dialysis or
2, N = 43), or intubation, interventional radiology, death [42]. However, distinct differences between
endoscopy, or reoperation (grade 3, N = 11). The kidney donors and kidney tumor patients exist.
grading scale employed correlated with mean Donors tend to be carefully screened for medical
hospital LOS as follows: no complications, 5.2 comorbidities and are generally young (age 45 or
days; grade 1 complications, 6.8 days; grade 2 less) [43, 44]. In contrast, renal tumor patients
complications, 7.4 days; and grades 3–5 compli- are not screened, are older (mean age 61 years),
cations, 9.3 days. Grading complications provide and many have significant comorbidities affect-
an effective means of describing the severity of ing baseline kidney function including metabolic
complications although its current use in the syndrome, hypertension, coronary artery disease,
literature is limited. obesity, vascular disease, and diabetes. In addi-
Complications unique to LRN in particular tion, as patients age, particularly beyond 60 years,
and laparoscopy in general have been reported nephrons atrophy and glomerular filtration rate
126 P. Russo

progressively decreases [45]. A study of 110 interventions to treat cardiovascular disease

nephrectomy specimens in which the non- than those with normal renal function. The low
tumor-bearing kidney was examined demon- prevalence of patients with stage 4 or 5 CKD is
strated extensive and unsuspected underlying attributable to their 5-year survival rates of only
renal disease including vascular sclerosis, dia- 30% [56].
betic nephropathy, glomerular hypertrophy, A concern that the overzealous use of RN,
mesangial expansion, and diffuse glomeruloscle- particularly in patients with small renal masses
rosis [46]. Only 10% of patients had completely and common comorbidities that can affect renal
normal renal tissue adjacent to the tumor. function, could be causing or worsening preexist-
Evidence that RN could cause a significant ing CKD became a focus of intense research.
rise in the serum creatinine when compared to MSKCC investigators used a widely available
PN in patients with renal cortical tumors of 4 cm formula, the Modification in Diet and Renal
or less was published by investigators from Disease (MDRD) equation [57] (http://www.
Mayo Clinic and MSKCC in 2000 and 2002, nephron.com/MDRD_GFR.cgi), to estimate the
respectively. RN patients were more likely to have glomerular filtration rate (eGFR) in a retrospec-
elevated serum creatinine levels to >2.0 ng/ml tive cohort study of 662 patients with a normal
and proteinuria (Mayo Study) [47], a persistent serum creatinine and two healthy kidneys that
finding even when study patients were carefully underwent either elective PN or RN for an RCT
matched for associated risk factors (MSKCC 4 cm or less in diameter. To their surprise, 171
study) including diabetes, smoking history, pre- patients (26%) had preexisting CKD (GFR <60)
operative serum creatinine, and ASA score [48]. prior to operation. Data were analyzed using two
In both studies, oncological outcomes were threshold definitions of CKD, a GFR < 60 ml/
highly favorable (>90% survival rates) whether min/1.73 m2 or a GFR < 45 ml/min/1.73 m2. After
PN or RN was done. surgery, the 3-year probability of freedom from
CKD, defined as an estimated glomerular new onset of GFR < 60 was 80% after PN but
filtration rate (eGFR) of less than 60 min/ only 35% after RN. Corresponding values for
min/1.73 m2, is increasingly viewed as a major 3-year probability of freedom from a GFR < 45, a
public health problem in the USA and since 2003 more severe level of CKD, was 95% for PN and
is considered an independent cardiovascular risk 64% for RN. Multivariable analysis indicated
factor [49–53]. An estimated 19 million adults in that RN was an independent risk factor for the
the USA have CKD, and by the year 2030, two development of new onset CKD (Fig. 7.3 ) [58].
million will be in need of chronic dialysis or renal Mayo Clinic investigators identified 648 patients
transplantation [54]. Traditional risk factors for from 1989 to 2003 treated with RN or PN for a
CKD include age greater than 60, hypertension, solitary renal tumor less than or equal to 4 cm
diabetes, cardiovascular disease, and family his- with a normal contralateral kidney. In 327 patients
tory of renal disease, factors also common in the younger than 65, it was found that RN was
population of patients that develop renal cortical significantly associated with an increased risk of
tumors. A study involving 1,120,295 patients death which persisted after adjusting for year of
demonstrated a direct correlation between surgery, diabetes, Charlson–Romano index, and
CKD and rates of hospitalization, cardiovascu- tumor histology [59]. Using the surveillance, epi-
lar events, and death, which occurred before demiology and end results (SEER) cancer regis-
overt renal failure requiring dialysis or renal try data linked with Medicare claims, MSKCC
transplantation [55]. As kidney function deterio- investigators studied 2,991 patients older than 65
rated, the percentage of patients with two asso- years for resected renal tumors of 4 cm or less
ciated cardiovascular risk factors increased from from 1995 to 2002. A total of 254 patients (81%)
34.7% (stages 1 and 2 CKD) to 83.6% (for stage underwent RN and 556 patients underwent PN.
3) to 100% for stages 4 and 5 subjects. Patients During a median follow-up of 4 years, 609
with CKD are more likely to require medical patients experienced a cardiovascular event and
7 Radical Nephrectomy for Localized Renal Tumors: Oncological and Renal Functional Considerations 127

Fig. 7.3 Impact of radical vs. partial nephrectomy on of only 35% (vs. 80% after PN) and a 3-year probability
renal function after management of T1a renal tumors. of freedom from a GFR <45 ml/min/1.73 m2, a more
Radical nephrectomy is associated with a 3-year probabil- severe level of CKD, of 64% (vs. 95% for PN) [58]
ity of freedom from new onset of GFR <60 ml/min/1.73 m2

Fig. 7.4 Data from the SEER linked to Medicare data- times greater number of cardiovascular events when com-
base indicates that radical nephrectomy is associated with paredto partial nephrectomy [60]
a 1.38 times increased risk of overall mortality and a 1.4

892 patients died. After adjusting for preoperative cause mortality compared to those undergoing RN
demographic and comorbidity variables, RN was (HR 0.54), whereas no significant difference was
associated with a 1.38 times increased risk of noted in kidney cancer-specific survival [61].
overall mortality and a 1.4 times greater number A recent pooled analysis of 51 studies involving
of cardiovascular events (Fig. 7.4 ) [60]. Tan and 31,728 patients from the world’s literature was
colleagues recently confirmed these findings in an published by Kim and colleagues. The authors
updated report which utilized the same SEER reported that PN was associated with a 19% risk
linked with Medicare data between 1992 and 2007 reduction in all cause mortality, a 29% risk reduc-
in 7,138 patients of whom 1,925 (27%) patients tion in cancer-specific mortality, and a 61% risk
underwent PN and 5,213 (73%) underwent RN for reduction in severe CKD. Despite these findings,
T1a renal tumors. In this study, patients undergo- the authors pointed out that the data obtained were
ing PN had a significantly decreased risk of all observational and subject to selection biases and
128 P. Russo

statistical heterogeneity [62]. Similar results were over the more challenging PN, must now be
reported in patients undergoing laparoscopic RN tempered by these new concerns regarding CKD
and PN [63]. and overall survival. The most recent AUA guide-
Confusing matters to some extent was a lines for the management of the small renal tumor
recently published randomized clinical trial from emphasize these points and strongly support the
Europe comparing PN (N = 268) to RN (N = 273) use of PN whenever technically feasible [66].
for tumors of 5 cm or less (T1a, T1b) operated
upon from 1992 to 2003. After a median follow-
up of 9.3 years, oncologic events were uncom- Radical Nephrectomy Is Overutilized
mon with only 12 of 117 deaths due to RCC (8 in
the PN group, 4 in the RN group). Tumor pro- Despite the above well-described oncological
gression was also uncommon (12 in the PN and medical arguments in the contemporary lit-
group, 9 in the RN group). In this study the PN erature supporting PN as an ideal treatment for
patients did not experience better overall survival such small renal masses, the urological oncology
(76% vs. 81% in the RN group). The most com- community continues to use RN as the predomi-
mon cause of death was cardiovascular, but again nant treatment of the T1a renal mass. A cross-
there was no advantage for PN (25 cardiovascular sectional view of clinical practice using the
deaths in the PN group vs. 20 in the RN group). Nationwide Inpatient Sample revealed that only
This study had significant limitations, including 7.5% of kidney tumor operations in the USA
accrual difficulties leading to premature closure, from 1988 to 2002 were PN [67]. Using the SEER
inclusion of some tumors >4 cm, the fact that database, investigators from the University of
some patients (10.2%) switched treatment groups Michigan reported from 2001, only 20% of all
after randomization, the fact that the trial was renal cortical tumors between 2 and 4 cm were
conducted at many centers and occurred during a treated by PN [68] and using the SEER database
treatment era when elective PN was not common, linked with Medicare claims, Huang and col-
and the oncological efficacy was questioned by leagues from MSKCC reported a utilization rate
many. Despite these factors, the study was ran- of only 19% for T1a tumors (4 cm or less) [58].
domized and raises the possibility that within the Interestingly and for uncertain reasons, women
contemporary pool of patients undergoing PN or and elderly patients are more likely to be treated
RN for T1 renal tumors, other preexisting medi- with RN [69]. Many urologists believe that a
cal factors, including those that could adversely “quick” RN in an elderly patient would expose
affect renal function such as diabetes and hyper- the patient to fewer postoperative complications
tension, could be to some extent responsible for than would a PN. However, MSKCC investiga-
the apparent advantage to PN in the more vulner- tors evaluated age and type of procedure per-
able patient, whereas patients with excellent formed in 1,712 patients with kidney tumors
baseline renal function my not suffer the same ill found the interactive term was not significant
consequence of RN despite a reduced eGFR. indicating a lack of statistical evidence that the
Also unknown is to what degree the solitary risk of complications associated with PN increased
healthy kidney can recover and compensate with advancing age. Furthermore, no evidence
follow RN. Further investigation to clarify this was reported linking age with estimated blood
important issue is ongoing [64]. The effect of loss or operative time. Given the advantages of
these reports has made urologists increasingly renal functional preservation, the authors con-
aware that preexisting CKD can be significantly cluded that elderly patients should be perfectly
worsened by the liberal use of RN for the treat- eligible for PN [70].
ment of the small renal mass [65]. Short-term end Although the urology literature has many great
points, including length of hospital stay, analge- articles written concerning the use of laparo-
sic requirements, and cosmetic elements viewed scopic techniques to resect kidney tumors, the
by many as the reason to elect laparoscopic RN penetrence of laparoscopic RN according to the
7 Radical Nephrectomy for Localized Renal Tumors: Oncological and Renal Functional Considerations 129

National Inpatient Sample from 1991 to 2003 with the causation or worsening of preexisting
was only 4.6% with a peak incidence of 16% in CKD which may cause an increased likelihood of
2003. These data indicate that the bulk of “kidney cardiovascular morbidity and mortality. Despite a
wasting operations” are being done by traditional wealth of evidence supporting the more restricted
open surgical approaches [71]. In England, a sim- indications for RN, strong evidence exists that it
ilar under-utilization of PN was reported in 2002 remains overutilized in the USA. Widespread
with only 108 (4%) PN out of 2,671 nephrecto- education and training in kidney preserving sur-
mies performed [72]. Investigators at MSKCC gical strategies is essential going forward.
tracked nephrectomy use in 1,533 patients
between 2000 and 2007 excluding patients with
bilateral tumors and tumors in a solitary kidney References
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 Nephron-Sparing Surgery
for Renal Cancer 8
Alon Z. Weizer, Jeffery S. Montgomery,
and Khaled S. Hafez

indications for PN and suggested that this proce-

History of Nephron-Sparing Surgery dure could be performed, even in the presence of
a normal contralateral kidney. Vermooten sug-
Renal cell carcinoma (RCC) is a relatively rare gested that peripheral encapsulated renal
tumor that accounts for approximately 3% of neoplasms could be excised locally while leaving
adult malignancies. In 2010 approximately a margin of normal parenchyma around the tumor
58,240 new cases developed, with close to 13,000 [6]. In the early 1960s, however, Robson et al.,
patients dying of the disease [1]. Over the last established radical nephrectomy (RN) as the
century the incidence and mortality of RCC has treatment of choice for localized RCC, reporting
increased for both clinical T1 and T2 disease [2]. a 66% and 64% overall survival for stage I and II
Although radical surgery remains the mainstay of tumors, respectively [7]. These results repre-
treatment for locally advanced disease, recent sented a significant improvement in survival rates
guidelines encourage the use of nephron-sparing when compared with patients treated with simple
approaches for T1 disease whenever feasible [3]. nephrectomy, and this therapy became the treat-
The first partial nephrectomy (PN) was per- ment of choice for localized RCC.
formed in 1884 by Wells for removal of a perire- Over the last two decades, advances in renal
nal fibrolipoma [4]. In 1887, Czerny was the first imaging, renal and vascular surgery (such as
to use PN for excision of a renal neoplasm when improved methods for prevention of ischemic
he successfully removed an angiosarcoma from renal damage), and the significant increase in the
the upper third of the right kidney of a gardener rate of incidentally discovered small renal masses
[5]. At this time, however, PN was associated have all driven the renewed enthusiasm for
with significant complications, including renal nephron-sparing surgery (NSS). The fact that
bleeding, urinary fistula, and death as compared NSS can be performed safely with low morbidity,
with total nephrectomy, which had a lower opera- good preservation of renal function and sound
tive morbidity and satisfactory long-term results. oncologic outcomes is not debated, however,
In 1950, Vermooten published his techniques and recent data suggests that NSS continues to be
underutilized [8, 9]. This is largely driven by sur-
geon practice pattern; competing approaches,
A.Z. Weizer, MD, MS • J.S. Montgomery, MD, MHSA such as laparoscopic RN, are often favored
• K.S. Hafez, MD () because of decreased morbidity and lower
Division of Urologic Oncology, technical complexity. This chapter outlines the
Department of Urology, University of Michigan,
3875 Taubman Center SPC 5330, 1500 East Medical
indications, techniques, and outcomes that sup-
Center Drive, Ann Arbor, MI, 48109, USA port NSS as the treatment of choice for localized
e-mail: [email protected] renal masses.

S.C. Campbell and B.I. Rini (eds.), Renal Cell Carcinoma: Clinical Management, Current Clinical Urology, 133
DOI 10.1007/978-1-62703-062-5_8, © Springer Science+Business Media New York 2013
134 A.Z. Weizer et al.

kidney disease (CKD) when the initial procedure

Indications for Nephron-Sparing results in a renal remnant of borderline size or
Surgery function.

NSS is the preferred treatment for localized renal

masses, particularly in patients at risk of renal dys- Unilateral Renal Mass with Impaired
function. Potential indications for this approach or Absent Contralateral Kidney or
include: Concomitant Disease Processes that
(a) Bilateral synchronous renal masses Can Adversely Affect Renal Function
(b) Mass in an anatomically or functionally soli-
tary kidney Renal tumors in a functionally or anatomically
(c) Unilateral mass with a functioning contralat- solitary kidney also necessitate a nephron-
eral kidney and any concomitant condition sparing approach. In these circumstances, it is
with the potential to adversely impact renal crucial to counsel patients that temporary or per-
function manent renal replacement therapy may be neces-
(d) Renal masses in familial and hereditary sary postoperatively. Generally, a renal remnant
disease with the function of at least 20% is necessary to
(e) Unilateral mass <7 cm with a normal contral- avoid permanent renal failure. A report from the
ateral kidney Cleveland Clinic that represents the largest pub-
(f) Advanced renal cancer lished experience of renal tumors in solitary kid-
neys showed that in 323/400 total patients (81%)
the absent kidney had been surgically removed
Bilateral Renal Masses and 77 (19%) had a congenitally solitary kidney.
In 46% of these patients, evidence of renal
Early experience with PN was gained in patients insufficiency was present at baseline. Renal hilar
with bilateral, synchronous RCC, where the need clamping was used in 96% of the cases, with a
for preservation of at least a portion of one kid- mean tumor size of 4.18 cm. Interestingly, 36%
ney was obvious [10]. Bilateral renal tumors are of these patients had multifocal disease and 92%
reported in 1–5% of patients [11]. In a study from of the tumors were malignant. Postoperatively,
Memorial Sloan-Kettering Cancer Center 95% had satisfactory long-term renal function
(MSKCC), investigators identified 46 patients [13]. Authors from the same institution com-
with bilateral tumors (4%) of which 33 (72%) pared outcomes of laparoscopic (n = 30) and
were synchronous and 13 (28%) were asynchro- open PN (n = 169) in solitary kidneys and
nous. The second tumor in the asynchronous reported that the laparoscopic cases required lon-
group occurred at a median time of 84.5 (28–240) ger ischemia times, a greater need for postopera-
months after diagnosis of the incident tumor. The tive dialysis, and experienced twice the
histological concordance rate was 76% between complication rate than the open approach. They
tumors [12]. In these patients, it is crucial to pre- concluded that open PN is safer in these patients
serve as much functioning renal tissue as possi- at high risk of CKD [14].
ble. This entails performing bilateral partial The presence of a unilateral renal tumor with
nephrectomies whenever possible, usually as a functionally impaired contralateral kidney is
staged procedures beginning with the kidney that another common indication for NSS. Contralateral
seems most amenable to PN. When a large tumor functional impairment may be due to a variety of
on one side precludes PN, the operative sequence systemic or urologic diseases, including diabetes
is usually to perform the PN first, thereby obviat- mellitus, nephrosclerosis, renal artery stenosis,
ing the need for temporary dialysis in the imme- hydronephrosis, chronic pyelonephritis, and vesi-
diate postoperative period if acute renal injury coureteral reflux. The clinical and operative
occurs. Occasionally a partial rather than RN on considerations in these patients are similar to
the second side is necessary to avoid chronic those with true solitary kidneys.
8 Nephron-Sparing Surgery for Renal Cancer 135

Unrecognized medical renal disease is another tumor exceeds 3 cm in diameter, after which
challenge in renal cancer patients. A study from point there is a risk for developing metastatic dis-
the Harvard Medical School examined the non- ease [19].
tumor-bearing kidney of patients undergoing sur-
gery for renal tumors, and reported that only 10%
of patients had completely normal tissue adjacent Unilateral Renal Cell Carcinoma
to the tumor, and 90% were found to have vascu- with Normal Contralateral Kidney
lar sclerotic changes, diabetic nephropathy, glom-
erular hypertrophy, and diffuse glomerulosclerosis Refinements in imaging techniques have enhanced
[15]. In these patients, it is crucial to evaluate pre- the detection of early stage, incidental renal
operative renal function not solely based on serum masses and have contributed to an increasing role
creatinine but also instead with the measurement of NSS in patients with localized disease and a
of urine albumin and estimated glomerular contralateral normal kidney [20, 21]. Extended
filtration rate (GFR) using equations based on the experience has established that NSS can be per-
level of serum creatinine, age, sex and race [16]. formed safely with minimal morbidity, preserva-
Another indication for NSS is in patients with tion of renal function, and long-term survival in
unilateral tumors and a normally functioning patients with small, incidental renal masses [22].
contralateral kidney but with a condition that Multiple reports have shown that PN results in
might threaten future renal function. This includes survival rates equivalent to those achieved after
renal calculi, diabetes mellitus, hypertension, or RN for T1 disease [23, 24].
renal artery disease. The decision to perform a The more recent expansion of the indications
partial rather than an RN in these patients depends for NSS includes patients with renal masses
on the feasibility of partial resection. However, 4–7 cm in diameter in anatomically favorable
current guidelines indicate that PN is the default locations. A recently published study which com-
approach whenever feasible. bined patients from the Mayo Clinic and MSKCC
evaluated 1,159 patients with renal tumors 4–7 cm
in size. There was no significant difference in sur-
Renal Masses in Familial/ vival between patients treated with RN or NSS.
Hereditary Disease A more recent study from MSKCC reported on
the use of NSS in tumors >7 cm in diameter with
Multifocal and bilateral tumors are common in favorable outcomes. This study confirmed that
hereditary and familial tumor syndromes such as tumor size should not restrict the use of NSS, but
von Hippel–Lindau (VHL) disease, hereditary rather tumor location, careful case selection, and
papillary renal cancer, and the Birt–Hogg–Dube tumor biology are more critical factors [25]. In
syndrome, and can account for 3–5% of all renal addition, the amount of remaining functional
cancers [17]. RCC occurs in approximately 45% renal tissue should guide the use of NSS in
of patients with VHL [18]. The rationale for a patients with renal masses greater than 7 cm.
nephron-sparing approach in patients with this
disease is based on a younger average age of pre-
sentation than sporadic RCC and the propensity Advanced Renal Cell Carcinoma
for renal tumors in VHL to be multifocal, bilat-
eral, and recurrent. However, because of the mul- The use of PN in the setting of advanced RCC has
tifocal nature of renal tumors in VHL, these not been extensively addressed. Angermeier et al.
patients are at increased risk for developing reported on nine patients who underwent PN for
local recurrences over the long term. In the era RCC with venous involvement in a solitary func-
of advanced abdominal imaging and genetic tioning kidney. Complete tumor resection and
screening, most patients are diagnosed with preservation of renal function was achieved in all
small, asymptomatic renal tumors. Intervention cases, although recurrence rates were significantly
is generally recommended before an individual higher than for low-stage disease [26]. Currently,
136 A.Z. Weizer et al.

surgical resection after systemic therapy (e.g., though, has been hindered by competition from
mTOR and tyrosine kinase inhibitors) can be laparoscopic RN and ablative therapies as well as
considered as part of a multimodal approach. the increased technical expertise required for the
Cleveland Clinic researchers reported on 19 often complex intracorporeal reconstruction nec-
patients treated with systemic targeted therapies essary during laparoscopic PN [30]. Recent data
(sunitinib, bevacizumab/interleukin-2) followed suggests that robotic assistance may lower this
by surgical resection in cases of stable disease or barrier, making laparoscopic management of
a partial clinical response. In the subset of patients small renal masses more accessible to urologists
who subsequently underwent PN after tumor and their patients [31]. However, a solid laparo-
downsizing, no substantial complications were scopic foundation is important to the adoption of
encountered despite the potential impact of these robotic-assisted PN. Surgeons must determine
agents on wound healing and vascular integrity which approach to PN in their hands will provide
[27]. These clinical scenarios will be encountered the best oncologic and functional outcomes for
more frequently as the use of systemic therapy in their patients based on the preoperative patient
locally advanced disease expands. and tumor characteristics. Surgeons with experi-
ence performing both open and minimally inva-
sive NSS can select the best approach for
Techniques of Nephron-Sparing individual patients and tumors on a case-by-case
Surgery for Renal Cell Carcinoma basis. Surgeons with a greater comfort level with
one approach over another must consider whether
Although RN is considered optimum curative their skills match the needs of their patient.
therapy for patients with locally advanced RCC,
PN is the treatment of choice for T1 carcinomas. Patient Characteristics
In such patients, PN allows complete surgical In our experience, minimally invasive NSS (e.g.,
excision of the primary tumor while preserving laparoscopic or robotic PN) is the default approach
sufficient renal parenchyma to avoid future renal for most patients. However, there are important
dysfunction. A variety of surgical techniques are factors to consider as possible contraindications
available for performing PN in patients with for minimally invasive approaches:
RCC. All of these techniques require adherence • Prior open renal surgery such as open stone
to basic principles of early vascular control, surgery, upper tract reconstructive procedures
avoidance of ischemic renal damage, complete or prior open PN.
tumor excision with negative margins, precise • Prior minimally invasive NSS or ablative pro-
closure of the collecting system, careful hemosta- cedures (laparoscopic or percutaneous).
sis, and bolstering of the renal defect with adja- • Inability to tolerate insufflation due to
cent fat, peritoneum, or hemostatic agents. At its chronic obstructive pulmonary disease or other
origin, laparoscopic PN was developed to repli- conditions.
cate the open surgical approach, so as a result • Limitations on access or instrumentation due to
these techniques share several similarities. We patient body habitus, although multiple reports
describe the common characteristics below. describe safe and effective minimally invasive
NSS in patients with morbid obesity who may
benefit most by avoiding a flank incision [32].
Selection of Open Versus Minimally • Prior extensive intra-abdominal surgery,
Invasive Nephron-Sparing Surgery although a retroperitoneal approach can be
utilized in many circumstances as long as the
The first report of laparoscopic PN for malignancy retroperitoneal space can be developed safely.
was only 2 years after the original description of • Patients with advanced CKD particularly
laparoscopic nephrectomy by Clayman [28, 29]. those with complex tumors requiring pro-
Widespread adoption of minimally invasive PN, longed renal ischemia time during resection.
8 Nephron-Sparing Surgery for Renal Cancer 137

Tumor Characteristics Upper pole tumors are challenging to access via

The majority of patients with sporadic small renal an RP approach in our experience. An RP
masses <4 cm in diameter and select patients with approach is contraindicated if the RP space has
tumors <7 cm should be considered for robotic- been violated by previous surgery, such as prior
assisted or laparoscopic PN. In patients with soli- kidney surgery, some vascular procedures, and
tary kidney (anatomically or functionally) and colectomy. A hand-assisted laparoscopic
those with impaired renal function, the surgeon approach can be considered for patients with
must determine whether a minimally invasive extensive intra-abdominal adhesions and tumors
approach will expose the patient’s kidney to involving the upper pole. The hand port incision
undue additional ischemia time that would be (usually 6–8 inches in length) can be used for ini-
minimized by the open surgical approach and use tial lysis of adhesions until additional laparo-
of cold ischemia. While a significant number of scopic ports can be placed safely to then complete
methods have been described to cool the kidney the remainder of the adhesiolysis laparoscopi-
during minimally invasive NSS, none have been cally. Alternatively, the surgeon can elect to per-
widely adopted due to the lack of obvious benefit form the procedure via an open flank incision.
or cumbersome application [33]. The patient may Body habitus can also limit minimally inva-
derive greater long-term benefit from an open PN, sive NSS approaches. While there is no estab-
promoting the preservation of renal function lished body mass index (BMI) limit in choosing a
instead of shorter incision length and short-term transperitoneal or RP approach, it is crucial to
convalescence advantages. When minimally inva- assess the location and distribution of body fat
sive NSS is considered for endophytic tumors, it preoperatively to determine the best approach.
is crucial that the surgeon has access to and is Review of the three-dimensional axial imaging is
proficient in performing laparoscopic ultrasound. also important to determine the distribution of
At our institution where the majority of sur- body fat. A significant amount of cutaneous and
geons offer both minimally invasive and open RP body fat can make a retroperitoneal laparo-
NSS, we review all complex cases and offer a scopic approach difficult because of limitations
consensus opinion regarding proper approach. If of space and instrument mobility.
the patient’s initial surgeon does not offer a par- For most patients, the proper approach rests
ticular approach, the patient is referred to another with the location of the tumor and its proximity
surgeon in our group who is capable of offering to the renal hilum. Historically, we used a hand-
the approach to the patient. assisted laparoscopic approach to manage upper
pole tumors. Our current preference is to use a
robotic-assisted approach to manage these tumors
Selecting Approach to Laparoscopic to avoid the small yet real risk of port site hernia
and Robotic Assisted Partial associated with hand ports (3.5%) [35]. In addi-
Nephrectomy tion, we also prefer to use a robotic-assisted
approach for anterior and posterior hilar tumors
The best approach to minimally invasive NSS because of the greater flexibility in dissecting and
depends on patient and tumor characteristics. We suturing with the robot. The remainder of the
have previously published our approach algo- anterior and posterior kidney can be
rithm and herein present a modification based on approached via either a robotic-assisted or lap-
the flexibility of NSS using the robotic platform aroscopic approach, with posterior tumors
[34]. The patient characteristics that most affect accessed retroperitoneally.
surgical approach are prior abdominal surgery Several recent publications have proposed
and body habitus. In patients with extensive pre- more specific methods to describe the location
vious intra-abdominal surgery, a retroperitoneal and complexity of a renal tumor such as the
(RP) approach can be used if the tumor is poste- R.E.N.A.L. Nephrometry Score, PADUA
rior or anterior in the lower or interpolar region. classification, and C-Index [36–38]. This can be
138 A.Z. Weizer et al.

used as another variable in the surgical approach The basic surgical principles of a PN include:
selection equation. We currently utilize an algo- (a) Mobilization of the kidney with early vascu-
rithm to guide the decision to clamp the renal lar control
hilum and suture the renal defect after minimally (b) Preservation of renal function by limiting
invasive NSS based on tumor depth of penetra- hilar clamping
tion and proximity to the renal sinus. This tech- (c) Complete tumor excision with negative sur-
nique has performed well when compared to gical margins
R.E.N.A.L. Nephrometry Score in avoiding (d) Hemostasis
adverse perioperative outcomes [36, 39]. (e) Watertight closure of the collecting system
Patients referred for a renal mass have often (f) Closure of the renal defect
already undergone cross-sectional imaging with The retroperitoneal approach avoids entry of the
CT or MRI. If the patient is diagnosed based on peritoneal cavity which limits morbidity should a
ultrasound or the renal anatomy is not adequately postoperative hemorrhage or urine leak develop.
defined on the initial imaging, a renal mass pro- In addition, postoperative recovery is often has-
tocol study should be obtained. To minimize tened as early return of bowel function is the
blood loss and ischemic damage to adjacent norm. All approaches to NSS follow similar prin-
parenchyma, knowledge of the number and loca- ciples. The only difference between robotic-
tion of renal vessels is crucial. There are impor- assisted, laparoscopic, and open surgery is the
tant distinctions between the arterial and venous tools used to accomplish the same goals; the goals
blood supply of the kidney that must be kept in of the surgery are the same no matter the approach.
mind when performing these operations. All seg- The surgeon must pick the right set of tools in
mental renal arteries are end-arteries with no col- their hands to accomplish the procedure to the
lateral circulation; therefore, all branches benefit of the patient.
supplying tumor-free parenchyma must be pre-
served to avoid devitalizing functioning renal tis-
sue. In contrast, intrarenal venous branches Kidney Mobilization and Vascular
communicate among the various renal segments. Control
Ligation of a branch of the renal vein, therefore,
will not result in segmental congestion because Open Approach
collateral veins will provide adequate drainage. After the incision has been made, the retroperito-
Tumors in the renal hilum therefore can be neal space is entered, the psoas muscle is exposed
accessed by ligating and dividing small, adjacent and the peritoneum is mobilized medially. The
or overlying venous branches as needed. Major kidney is then mobilized outside of Gerota’s fas-
venous branches can then be mobilized com- cia, first freeing the upper pole of the kidney, dis-
pletely and retracted freely to expose the tumor secting the medial upper pole from the adrenal
with no vascular compromise of uninvolved gland. The lower pole is then mobilized, identify-
parenchyma. ing the ureter with a vessel loop as needed. The
In addition, given the low yet real risk of gonadal vein can then be followed cephalad to
metastasis in patients with tumors <4 cm in diam- the renal vein on the left side and inferior vena
eter (3%) [40], additional preoperative staging cava on the right side. Once the renal vein is iso-
studies needed include a chest radiograph, com- lated, further mobilization of the kidney posteri-
plete blood count, and comprehensive metabolic orly is often necessary to identify the renal artery.
panel with estimation of GFR. The utility and Alternatively, the renal artery can be identified by
need of nuclear medicine bone scan and other freeing the upper pole completely and lifting it
imaging, such as head CT, depends on the laterally. Kidney mobilization should be sufficient
patient’s symptoms or the finding of elevated to clamp the renal hilum if necessary, resect the
serum alkaline phosphatase or calcium levels on renal mass with negative margins, and reconstruct
initial laboratory evaluations. the kidney (Fig. 8.1).
8 Nephron-Sparing Surgery for Renal Cancer 139

Fig. 8.1 Open partial nephrectomy in a 48-year-old man with closure of defect over a bolster. No evidence of
with a symptomatic 9.2 cm mass. (a) Coronal computed bleeding after hilar clamp was released. (d) Excised renal
tomography image demonstrates an exophytic right upper mass. Final pathology was classic clear cell renal carci-
pole renal mass. (b) Exposure of the renal mass via an noma, Fuhrman grade 2/4 with negative margins
open flank incision. (c) Surgical resection of renal mass

Minimally Invasive Transperitoneal assistant port provides lift. The medial dissection
Approach is carried cephalad following the gonadal vein to
Whether using a conventional, hand-assisted or identify the renal vein. If exposure is not ideal,
robotic-assisted laparoscopic approach, we take the upper pole of the kidney can be mobilized,
the same approach for kidney mobilization. For further releasing attachments of the pancreas,
left-sided tumors, the colon is mobilized medi- spleen, and colon. In general, even if we do not
ally and the lower pole of the kidney is identified. intend to clamp the hilum, we isolate the renal
The ureter and gonadal vein are identified, and vein and artery to be able to clamp the hilum en
the lower pole of the kidney is bluntly mobilized bloc, artery only, or artery and vein separately.
off of the psoas muscle, and the lower pole of the For hilar tumors, further dissection of more distal
kidney and ureters are lifted anteriorly. For the branches of the artery and vein can be carried out
robotic-assisted approach, the third robotic arm is to allow for clamping of segmental branches or
useful at this point to maintain anterior elevation ligation of individual vessels entering the tumor
of the kidney. For the hand-assisted and conven- (Fig. 8.2).
tional laparoscopic approaches, a laparoscopic For right-sided tumors, we begin the dissec-
kitner or suction/irrigator device through an tion by incising the peritoneum over the right
140 A.Z. Weizer et al.

Fig. 8.2 Robotic-assisted partial nephrectomy in a 59-year- renal hilum. (d) Tumor exposed. (e) Resection bed.
old woman with biopsy-proven renal cell carcinoma. (a) (f) Repaired defect using nitrocellulose bolster. (g) Closure
Computed tomography image demonstrates an endophytic of Gerota’s fascia over defect using clips. (h) Resected
left lower pole renal mass. (b) Postoperative CT demon- tumor ready for removal. Final pathology was clear cell renal
strating good perfusion and complete excision. (c) Exposed carcinoma, Fuhrman grade 3/4 with negative margins
8 Nephron-Sparing Surgery for Renal Cancer 141

kidney and mobilizing to medially until the duo- tion of the hilum so that the perinephric fat will
denum is identified. The duodenum is then not obscure the hilum during dissection. We enter
Kocherized and further dissection is carried Gerota’s fascia at a point away from the tumor
cephalad so that the peritoneum between the and identify the capsule of the normal kidney
upper pole of the kidney and liver is incised. first. Ideally, Gerota’s is mobilized in such a way
From that point, the dissection progresses as that flaps of perinephric fat remain intact to re-
described for the left-sided procedure. approximate over the site of resection at the con-
Further dissection depends on the location of clusion of the case. The fat covering the tumor is
the tumor. For upper pole tumors it is often nec- left in place to send with the specimen to pathol-
essary to mobilize the entire kidney so that the ogy, but it is important to expose the kidney cap-
upper pole can be lifted anteriorly. The surgeon sule circumferentially around the tumor in
must judge whether this mobilization is best preparation for the renorrhaphy after the tumor is
performed with Gerota’s fascia intact or within excised.
Gerota’s. Several reports have established intraoperative
The assistant role in aiding exposure is critical ultrasonography (US) as a useful adjunct when
in both the laparoscopic and robotic-assisted performing PN. Intraoperative US is particularly
approaches. One advantage of the robotic useful for patients with intrarenal tumors that are
approach is that once the lower pole and ureter not visible or palpable even after the perinephric
are mobilized and elevated by the third arm, the fat has been removed. The topographical infor-
console surgeon is less reliant on retraction from mation obtained from intraoperative US is also
the bedside assistant. useful in patients with tumors that extend deep
into the kidney [41, 42]. In such instances US is
Minimally Invasive Retroperitoneal useful for defining the appropriate margins of
Approach resection and for allowing preservation of as
As initial access to the kidney is posterior and much uninvolved parenchyma as possible while
interpolar in this approach, the renal hilum is still obtaining negative surgical margins.
mobilized and isolated first. The hilum is typi- Ultrasound is also useful for locating multicentric
cally in line with the port placed at the costover- tumors, venous extension, and the presence of
tebral angle. If the thoracolumbar fascia has not other renal lesions. Advances in laparoscopic US
been incised when obtaining access, the hilum have greatly aided the management of increas-
may be obscured. It is useful to identify the ure- ingly complex tumors through a minimally inva-
ter, gonadal vein, and psoas muscle to maintain sive approach. We advocate its use on every NSS
proper orientation. For most cases, the renal to provide “real time” information about tumor
artery is encountered first when dissecting the dimensions to assist in surgical dissection and to
renal hilum. The vein, which is usually behind improve the surgeon’s US skill for assessing and
the artery in this approach, can also be isolated if managing more complex tumors. The incorpora-
the surgeon intends to clamp it as well. tion of ultrasound for robotic NSS has been
greatly aided by TilePro, which allows the con-
sole surgeon to visualize the operative field and
Tumor Localization US image at the same time [43].

High quality preoperative cross-sectional imag-

ing is crucial as a guide to tumor location. For Prevention of Ischemic Injury
open PN, the tumor may be identified and iso-
lated early in the dissection if mobilization is per- A number of steps can be taken to minimize isch-
formed within Gerota’s fascia. However, for emic injury during PN. Some of these options are
minimally invasive approaches, Gerota’s is available to both the open and minimally invasive
entered and the tumor is isolated after mobiliza- surgeon and depend largely on the depth of
142 A.Z. Weizer et al.

the tumor, proximity to the renal sinus, location method for renal cooling. A wide variety of alter-
of the tumor in the kidney and its blood supply. native approaches have been presented without
obvious advantage over ice slush. To date, there is
Depth of Tumor no compelling evidence that cold ischemia offers
For laparoscopic and robotic-assisted procedures, a significant advantage over warm ischemia as
we have created an algorithm to determine when long as hilar clamp time is minimized. A recent
it is advisable to clamp the renal hilum [31]. If the multi-institutional study of 660 patients with soli-
tumor has less than 5 mm of penetration into the tary kidneys undergoing PN demonstrated no
kidney and is greater than 5 mm from the renal significant difference in long-term renal function
sinus, it is often unnecessary to clamp the hilum, between warm and cold ischemia. The most criti-
although the hilum should still be isolated in the cal determinants of renal function were the qual-
event that the need to clamp arises during dissec- ity and quantity of the renal remnant [45]. Cold
tion. It is important to confirm the superficial ischemia allows up to 40–60 min of clamp time
nature of the tumor with intraoperative ultra- without permanent kidney damage. It is impor-
sound. Hemostasis can frequently be achieved tant to cover the entire kidney with ice for at least
with a combination of argon beam coagulation 5–10 min immediately after occluding the renal
and hemostatic agents. For those tumors with artery before beginning the PN. This allows the
>5 mm but <10 mm of penetration into the paren- kidney core temperature to reach 15–20°C, opti-
chyma, we typically clamp the hilum but unclamp mizing renal preservation. Administration of
once adequate hemostasis of the base of the intravenous mannitol (12.5 g) 15–30 min before
resection has been obtained, either with a running clamping the renal artery induces diereses,
absorbable suture or application of hemostatic reduces renal tubule swelling and protects against
agents. This is often referred to as “early unclamp- ischemic renal damage. Careful attention to peri-
ing” in the recent literature; however, this tech- operative fluid status is crucial, particularly for
nique has been practiced for some time and can patients with a solitary kidney.
be used in any approach.
Other Considerations Related to Ischemia
Proximity to Sinus We have found that it is valuable in all cases to be
For those tumors within 5 mm of the renal sinus/ prepared prior to tumor resection to clamp the
hilum, the hilum should be clamped. Again, if the renal hilum and suture the base of resection.
base of the tumor can be controlled with a run- There is considerable literature touting the resec-
ning absorbable suture, early hilar unclamping tion of renal masses without hilar clamping for
can minimize ischemia time. Early unclamping is minimally invasive approaches. The most com-
not recommended for large, central tumors where monly reported technique is to utilize a radiofre-
large segmental vessel can result in significant quency energy device such as the Habib. While
blood loss or result in the need for complex this has been demonstrated to be effective [46],
reconstruction. In this scenario, the use of cold our concern is that the tissue char created by the
ischemia may be more appropriate. device makes visualizing the resection margin
Segmental artery clamping can be used in any difficult, destroys surrounding benign paren-
approach. When the tumor is supplied by a dis- chyma, and can result in delayed bleeding or
tinct artery, ligation of this artery can provide urine leak. Other techniques described to limit
hemostasis without ischemia to the remainder of ischemia include pre-placement of hemostatic
the kidney. Not clamping the renal vein also helps sutures under the tumor with ultrasound guidance
to minimize ischemic injury [44]. [47] and relative hypotension [48]. While reduc-
If the anticipated renal hilum clamp time ing kidney ischemia is important, this must be
exceeds 20 min, additional protection from isch- balanced with sound oncologic principles. We
emic renal injury is necessary. Local hypothermia believe that cold resection in a bloodless field
currently offers the most effective means for this. achieved with renal artery clamping best
Ice slush packed around the kidney is a common achieves this.
8 Nephron-Sparing Surgery for Renal Cancer 143

A second related issue is the decision to clamp undisturbed to ensure en bloc removal of the
the renal artery alone, both the artery and vein, or malignancy. Patients with multifocal disease can
segmental arteries alone. The literature suggests be managed by PN if possible, but they are at
that clamping the artery alone is safe and likely increased risk for local recurrence after NSS [49].
limits renal damage [44]. However, if the tumor Regardless of the approach used, cold excision
is deep and/or central in location, it is often help- allows for optimal visualization to discern malig-
ful to clamp the renal artery and vein to achieve nant from benign renal tissue.
the best visualization. The choice of clamp (bull-
dog or Satinsky) depends on the anatomy of the Simple Enucleation
renal hilum and patient. Every effort should be Renal masses are often completely enveloped by
made to isolate the renal artery separately from a pseudocapsule of fibrous tissue that can allow
the renal vein, but in the case of a complex hilum relatively avascular tumor removal by enucleation.
with multiple renal vessels, using a Satinsky The technique of enucleation involves circumfer-
clamp across the entire hilum is often safer and entially incising of the parenchyma around the
more expedient. For minimally invasive tumor, identifying the plane between the pseudo-
approaches, laparoscopic bulldog or Satinsky capsule and adjacent uninvolved parenchyma,
clamps are available. Extra care must be taken and then gently mobilizing the lesion with a blunt
when using a laparoscopic Satinsky clamp with a instrument. During enucleation of peripheral
robotic approach as the robotic arms can clash tumors, it is generally unnecessary to occlude the
with the clamp externally and cause major vascu- renal artery, and the few transected blood vessels
lar injury. Segmental clamping with a bulldog at the base of the enucleation can simply be
clamp is appropriate when there is clearly a dis- ligated with suture. The argon beam coagulator
crete artery branch supplying the tumor. can be used to treat the resection base, fat or oxy-
Preoperative imaging can aid in defining the renal cel can be placed into the cavity, and the resec-
vasculature, but the ultimate decision on how to tion edges can be sutured together to further
proceed with hilar clamping is made intraopera- assure hemostasis.
tively once the hilum and tumor have been While enucleation has typically been reserved
exposed. Caution should be exercised in segmen- for patients with a peripheral, well-encapsulated
tal clamping of posterior polar tumors as these tumor or hereditary renal cancer syndromes,
tumors are often supplied by both the polar artery growing data suggests that oncologic outcomes of
and the posterior branch. It is important to pre- enucleation are similar to wedge resection.
pare the hilum to clamp the main renal artery and A retrospective cohort study of 982 patients under-
vein even when segmental clamping is employed going standard PN and 537 patients undergoing
in the event that vascular control is insufficient, enucleation showed no significant difference in
and the main artery and/or vein need to be progression-free or cancer-specific survival after
clamped during tumor excision. adjusting for other meaningful variables [50]. The
advantage of enucleation is maximal preservation
of renal function and improved hemostasis with-
Tumor Excision out apparent loss of oncologic efficacy. Ultimately,
the surgeon must judge whether enucleation is
Excision of the tumor with a conservative margin appropriate on a case-by-case basis.
(2–3 mm) of normal parenchyma is the preferred
technique for PN. This can best be accomplished
by wedge resection for centrally or peripherally Hemostasis
located tumors, or by transverse heminephrec-
tomy for large polar tumors. Frozen sections of Obtaining early vascular control and occluding
the base of resection to confirm negative surgical the renal artery when necessary are essential
margins can be obtained if needed. The peri- maneuvers to minimize intraoperative blood loss
nephric fat overlying the tumor should be left during NSS. Temporary occlusion of both the
144 A.Z. Weizer et al.

renal artery and vein also provides improved oper- needles is placed and secured in on position using
ative visualization which can be invaluable during Hem-O-Lok clips using a sliding renorrhaphy
challenging cases. The renal vein clamp is removed technique [51]. Additional sutures of 0-vicryl on
first and the parenchyma is carefully inspected CT 1 needles with a Hem-O-Lok pre-tied in place
during deep forced inspiration to identify addi- at the end can be used to further secure the bolster
tional bleeding sites that are not otherwise apparent. in place after tightening the suture with a second
For minimally invasive procedures, decreasing the Hem-O-Lok clip.
insufflation pressure to 5 mm Hg at the end of the
procedure helps to determine it adequate hemosta-
sis has been achieved. Closure of the Collecting System
When excising the tumor during an open sur-
gical approach, vessels can be suture ligated or Watertight closure of the collecting system is
clipped when they are encountered as they can essential to prevent urinary fistula formation.
retract into the parenchyma and become more Surgeons should look for entries into the collect-
difficult to control after the tumor is removed. ing system centrally as the renal tumor is excised.
Larger vessels tend to be located medially within If possible, the collecting system should be closed
or near the renal sinus. Residual bleeding vessels with absorbable suture before it has been com-
should be ligated with absorbable suture once the pletely transected. Calices and infundibula are
tumor is excised. The use of Argon beam coagu- often more difficult to locate if they have been
lator, fibrin glue, and other hemostatic agents allowed to retract into the parenchyma or peri-
is also helpful for obtaining hemostasis. sinus fat. For minimally invasive approaches,
Reapproximation of the capsule with absorbable entries into the collecting system can be closed
suture tied over a nitrocellulose bolster or peri- with a running absorbable suture which can
nephric fat aides in hemostasis, but this should be secured using Lapry-Ty clips to save ischemia
not be done until the parenchymal bleeding has time.
been adequately controlled. Other energy sources, The perspective regarding ureteral stenting at
such as radiofrequency devices or laser, have the time of PN has evolved as experience with
been described to aid in hemostasis. NSS has accumulated [22]. Initially, stents were
For minimally invasive approaches, we have placed whenever a significant opening in the col-
found that using a running suture at the base of lecting system was identified, regardless of the
the resection (2–0 absorbable suture) can improve location of the defect or the complexity of the
hemostasis and does not add significantly to the reconstruction. More recently, stents are placed
warm ischemia time. However, larger transected only when major reconstruction of the collecting
veins or arteries should be individually controlled system is required. With any entry into the col-
with absorbable suture first. Better visualization lecting system, a drain should be placed at the
in the case of venous bleeding can be achieved by conclusion of the case.
increasing the insufflation pressure to 20 mm Hg
for short periods of time without detrimental
effects on renal function. Outcomes of Nephron-Sparing
For tumors within 5 mm of the renal sinus or Surgery for Renal Cell Carcinoma
collecting system, our preference is to resect the
tumor with cold scissors while the hilum is Perhaps the best way to judge the various
clamped, close the renal sinus or collecting sys- approaches for extirpative management of small
tem with an absorbable suture, re-approximate renal masses is to directly compare their out-
the base of the resection bed with an absorbable comes. More robust, long-term data exit for
suture, and then unclamp the kidney. Following open PN than for the laparoscopic or robotic-
that, a bolster composed of rolled nitrocellulose assisted approaches. In addition, there is also
sheets with pre-attached 0-vicryl sutures on CT-1 appropriate selection bias among the approaches
8 Nephron-Sparing Surgery for Renal Cancer 145

making direct comparison difficult. The focus of advantage of avoiding an open flank incision. On
the following literature review is on contempo- average, though, the open surgical approach took
rary series. While we report the mean results less time than robotic or laparoscopic transperito-
here, they are not weighted by the number of neal approaches. There was variable reporting of
patients in the individual study included, and hilar clamp time, with the shortest ischemia times
therefore may not be representative of all reported for the robotic-assisted approach.
patients undergoing the various approaches. The Hospital stays were shortest for the laparoscopic
table references are included in the reference and robotic-assisted approaches; however, this is
section [34, 46, 52–95]. based on only a few series for the retroperitoneo-
scopic approach and may not reflect the true
advantage of the retroperitoneoscopic PN in
Demographic/Perioperative Factors terms of convalescence and recovery. We recently
reported our experience with robotic-assisted ret-
Table 8.1 summarizes general demographic infor- roperitoneal PN with a mean length of hospital
mation and perioperative outcomes of patients stay of 1 day [96]. Estimated blood loss was con-
undergoing NSS. Patient age was similar across sistently less for minimally invasive than the open
all series with a larger percentage of patients with approach.
solitary kidneys treated with an open surgical
approach. Only a small number series report
results for the retroperitoneal laparoscopic or Complications
robotic approaches. We did not include data for
the hand-assisted approach because of the small Table 8.2 summarizes the complications of NSS
number of cases reported in the literature. by approach. The literature is plagued by a lack
Mean tumor size was larger on average for the of standardization in defining and reporting com-
open surgical approach. The shortest operative plications. However, recent literature has adopted
times were reported for the retroperitoneoscopic more standardized complication reporting meth-
approach, reflecting the direct access to the renal ods, such as the National Cancer Institute
hilum and tumor with this approach and the Common Terminology Criteria for Adverse

Table 8.1 Demographic and perioperative outcomes by surgical approach [34, 46, 52–94]
Partial nephrectomy approach
Variable Laparoscopic Laparoscopic-RP Robotic Open
Na 11,505 255 1,055 9,947
Mean age (range) 59.4 (55–62.6) 60.4 (59–62) 60 (55–68) 60.4 (56–63)
% Solitary kidney (range) 0–5.9 Not reported Not reported 23 (11–30)
% Retroperitoneoscopic 0–63 – 18b –
Mean tumor size cm (range) 2.6 (2–3.9) 2.8 (2.4–3.5) 2.8 (2.5–3.5) 3.4 (2.5–4.1)
Operative time in 202 (85–293) 124 (84–200) 217 (140–373) 187 (150–266)
minutes(range)
% Unclamped 29 (0–100) Not reported 16b 20 (0–50)
Mean ischemia time in 28 (0–39) 24 (22–25) 18.6 (0–25.5) 28.9 (11–40)
minutes (range)
Mean length of hospital stay 3.1 (1–7) 5.5 (2.6–9) 3.3 (2.4–4.3) 5.7 (5–7)
in days (range)
Mean estimated blood loss in 237 (100–437) 227 (194–260) 200 (127–337) 358 (294–397)
cc (range)
a
Numbers may not represent mutually exclusive cases
b
Based on single series
146 A.Z. Weizer et al.

Table 8.2 Complications by surgical approach [34, 46, 52, 55–57, 59, 61, 62, 64, 66, 67, 70–77, 79–84, 86–93, 95]

Variable Partial nephrectomy approach

Mean % (range) Laparoscopic Laparoscopic-RP Robotic Open
N 11,505 255 1,055 9,947
Acute kidney injury 0.7 (0.6–0.9) Not reported 0 3.5 (0.5–13)
Death 0.3a Not reported 0 0.5a
Conversion to open partial 2.4 (0.6–5.4) 1.8a 1.6 (0–4) –
Nephrectomy 1.8 (0.5–4) Not reported 3.6 (1.6–7.7) 0
Clavien 3 or higher complication 11 (0–36) 4.5a 4.9 (0–8.2) 5 (4–6.7)
Pseudoaneurysm/embolization 1.7 (0.5–4) 0.9a 1.7 (1–2.6) 3a
Urine leak 3.4 (1–8) 0–1.8 3.9 (1–16.8)b 2.5 (0.6–5.5)
Hemorrhage 4.7 (0.8–11.1) 2.7–4.3 2.2 (0.7–4.8) 2 (0.9–4)
Blood transfusion 6.3 (1.6–12.5) 2.7–5.1 4.2 (0–7.1) 8.2 (5.1–11)
Cardiovascular 1.7 (0.8–2.5) Not reported 1.4 (0.5–3.7) 4.3a
Neuro 0a Not reported Not reported 2a
Infection 2.2 (1–5.3) 0.9a 3.2 (0.4–7.4) 2.1 (0.5–4)
Pulmonary 1.7 (0–2.7) 5.7a 0.7–2.4 2–5.5
Thromboembolic 1 (1–3) 0.9a 1.5–2.6 1.2–2
Hernia 3 (0.5–5) 0–3.6 Not reported Not reported
Readmission 11 (10.4–11.1)a Not reported 11.9a Not reported
a
Based on single series
b
Based on two series

Events (CTCAE) or the more surgically oriented and central tumor location [97]. Urine fistulas
Clavien Classification. The emphasis in this sec- often resolve spontaneously with conservative
tion will be the diagnosis, management, and clin- management. If urine fistulas persist, endoscopic
ical significance of the more common manipulation, including retrograde pyelography
complications of NSS. and placement of a temporary ureteral stent to
encourage the flow of urine down the ureter, may
Urinary Fistula Formation be necessary [22]. The surgical drain is left in
Urinary fistula formation is the most commonly place until the fistula resolves, and the drain fluid
reported complication of NSS. The mean rate for creatinine level should be reassessed before
most series we reviewed is 3–4%, with fewer removing the drain. If a normal pyelocalyceal sys-
patients experiencing urine leak with the open tem is identified on retrograde pyelogram yet drain
approach. There is significant variability in urine output persists, a renal papilla that was excluded
fistula rates for the laparoscopic and robotic- from the remaining collecting system during the
assisted approaches. This possibly reflects the rhenorraphy is the likely source. In this circum-
early experience of surgeons with these stance, it may take several months until that papilla
approaches and the more frequent use of energy no longer functions and the urine leak resolves.
sources to perform the tumor resection, poten- Alternatively, variable success has been reported
tially obscuring the renal anatomy. Urinary fistula with ureteroscopic division of suture obstructing
is defined as persistent (>7 days) drainage of fluid infundibula using the holmium laser [98].
(>50 cm3/day) with a drainage fluid to serum
creatinine ratio of greater than 2 mg/dl. Acute Kidney Injury
Risk factors for urinary fistula formation in Acute renal failure (ARF) requiring renal replace-
both the open and minimally invasive approaches ment therapy is the second most common
include large tumor size (>4.0 cm), the need for complication of NSS. The low rates of this com-
extensive reconstruction of the collecting system plication reported for minimally invasive
8 Nephron-Sparing Surgery for Renal Cancer 147

approaches suggest either under-reporting or that Other Complications

tumors managed by these approaches are consis- Other complications of NSS include postopera-
tently less complex than those managed with the tive hemorrhage, perinephric abscess formation,
open approach. Ischemic renal injury from hilar and renal vessel thrombosis. Hemorrhage is more
clamping and reduced parenchymal mass after frequently reported in laparoscopic series and
PN are the primary causes of ARF. Perinephric occurs at a similar rate in open and robotic-
urinoma and vascular thrombosis can also lead to assisted series (Table 8.2). Most studies defined
ARF after NSS [22]. The most significant predis- hemorrhage as intraoperative bleeding requiring
posing factor for the development of ARF in this resuscitation. Pseudoaneurysm or arteriovenous
series was the presence of a solitary kidney. fistula form when suture thrown in the base of the
Novick et al. found that ARF only occurred in tumor resection bed fuses arteries and veins,
2% patients with a normal contralateral kidney. resulting in direct communication between the
In contrast, ARF developed in 26% of patients two. This is more frequently reported in open sur-
with a solitary kidney. In the solitary kidney gical series, likely reflecting the greater complex-
cohort, additional risk factors for ARF included ity of these tumors. Delayed postoperative
large tumor size (>7 cm), greater than 50% paren- bleeding with perinephric hematoma can present
chymal excision, and greater than 60 min of cold with pain, gross hematuria, hypotension, flank
ischemia time. ARF rates after elective PN should mass, or bruising, and occurs more frequently
be relatively low as these patients have normal with the open than minimally invasive approaches.
contralateral kidneys which can maintain periop- After initial resuscitation and stabilization of the
erative renal function. The management of ARF patient, a CT scan of the abdomen and pelvis is
after NSS should include careful attention to vol- useful in making the diagnosis. Delayed bleeding
ume status, appropriate adjustment of medication can frequently be treated in interventional radiol-
doses, and dialysis as needed. More recently, the ogy with selective renal artery angiography and
same group evaluated factors that determine renal coil embolization. Avoiding deep passes with
function after PN in solitary kidneys. In multi- large needles into the renal sinus intraoperatively
variable analyses, increasing age, larger tumor diminishes the risk of this complication.
size, lower preoperative GFR, and longer isch- Although complications of NSS are not
emia time were associated with decreased post- uncommon, most can be managed conservatively
operative GFR (p < 0.05). On multivariable and associated morbidity is often minimal. The
analysis, the percentage of renal parenchyma rate of major complications (Clavien 3 or higher)
spared and the preoperative GFR proved to be the is approximately 5% for most approaches. For
primary determinants of ultimate renal function, the conventional laparoscopic approach, the rate
and time of intraoperative renal ischemia lost sta- is 11%, potentially reflecting its inherent techni-
tistical significance. Long-term renal function cal challenges, especially early in a surgeon’s
after PN was determined primarily by the quan- experience. Table 8.2 also summarizes complica-
tity and quality of renal parenchyma preserved tions by system. Complication rates in most series
[45]. It is important to emphasize that these are likely under-reported. Standardized reporting
results were obtained in a series notable for short of complications and meticulous patient follow-
warm ischemic times and liberal use of hypo- up is essential to better compare the approaches
thermia and will likely not apply to cases with for NSS. Mortality rates after NSS compare
longer warm ischemia. Indeed, when this was favorably with those for RN (1–2%).Taken
evaluated in a more homogenous group of patients together; these results suggest that NSS can be
with solitary kidneys managed only with warm performed safely and with minimal morbidity. Of
ischemia, the ischemic interval proved to be a course, individual outcomes depend greatly on
significant predictor of ARF, and when extended surgeon experience and tumor complexity.
beyond 25 min, it served as an independent pre- The rate of conversion to open PN is similar
dictor of new onset severe CKD. for the different minimally invasive approaches.
148 A.Z. Weizer et al.

Table 8.3 Oncologic and renal function outcomes [34, 46, 54–56, 58–62, 64–67, 69–73, 75–85, 87, 88, 93]

Variable Partial nephrectomy approach

Mean % (range) Laparoscopic Laparoscopic-RP Robotic Open
N 11,505 255 1,055 9,947
Positive margin 2.4 (0–12) 0–4.7 3.1 (0–7.7) 2.3 (0–7)
Recurrence 1.2 (0–4.2) 0–0.9 0.2–2.9 0.8–5.9
Mean follow-up (months) 26 (10–44) 15–23 7.8–26 25
Change in creatinine from 0.13 Not reported 0.13 0.16
baseline
Change GFR from baseline 6.3–18 22a 6.3–23 Not reported
Disease-specific survival 3 years: 99.3% Not reported Not reported 3 years: 99–100
5 years: 97.6% 5 years: 82–100
10 years: 77–100
a
Based on single series

Conversion to nephrectomy was reported more tion remained stable in 12 patients, whereas two
commonly with robotic-assisted NSS, reflecting developed end-stage renal failure. Nine patients
the early experience with this approach and issues developed proteinuria: low grade in four
with patient and tumor selection. (<750 mg/24 h) and moderate to severe in five
(930–6,740 mg/24 h). A statistically significant
inverse association was found between the degree
Functional and Oncologic Outcomes of proteinuria and amount of residual renal tis-
Following Nephron-Sparing Surgery sue. Renal biopsy performed in four patients with
moderate to severe proteinuria showed focal seg-
Preservation of Renal Function mental or global glomerulosclerosis [99].
Table 8.3 summarizes the renal function and These data suggest that patients with solitary
oncologic outcomes of NSS by approach. A fun- kidneys with more than a 50% reduction in renal
damental issue with such a comparison is the lack mass after PN are at increased risk for developing
of standardized methods or timeframe for report- a hyperfiltration injury, manifested by proteinuria,
ing renal function, as well as the absence of this glomerulopathy, and progressive azotemia. The
data in many series. Several series report the development of significant proteinuria usually
change in creatinine from baseline, but newer preceded detectable renal deterioration [99]. These
series more often report the change in GFR which observations suggest that patients with solitary
better assess the level of CKD and the need for kidneys who undergo PN should be followed with
renal replacement therapy. Most approaches serial 24-h urinary protein evaluations in addition
demonstrate similar renal function outcomes. It to serum creatinine levels and calculated GFR.
must be kept in mind, though, that most open A low-protein diet should be instituted in patients
series represent larger, more complex tumors. who develop proteinuria of >150 mg/24 h, and
The use of R.E.N.A.L. Nephrometry Score may treatment with angiotensin-converting enzyme
allow future series to compare results in patients inhibitors should be considered.
with similar tumor size and complexity.
Novick et al. reported on the long-term renal Oncologic Outcomes
function in 14 patients with solitary kidneys who As there is less robust, long-term data with some
underwent PN for localized tumors with no pre- of the newer minimally invasive approaches, sur-
operative clinical or histopathologic evidence of gical margin status is often used to assess onco-
primary renal disease. Postoperative renal func- logic efficacy. Recent reports, though, suggest
8 Nephron-Sparing Surgery for Renal Cancer 149

that focal positive margins have minimal adverse rence. The development of renal failure after PN
oncologic impact following PN [100]. Positive also has a significant impact on quality of life and
margin rates for most approaches are reported to mortality. The 1-, 2-, and 5-year survival rates for
be 2–3%. However, there is considerable vari- patients aged 55–64 years while on dialysis
ability in this rate, suggesting the impact of following RN for RCC in a solitary kidney are
surgeon experience. The rates of local recurrence, 84%, 67%, and 33%, respectively, and fall to
another short-term oncologic endpoint, are con- 73%, 51%, and 16% in patients older than
sistently low regardless of the approach, further 64 years [20]. Currently, these patients have to
strengthening the argument that focal positive survive disease free on dialysis for 12–24 months
margins likely have minimal oncologic impact. before renal transplantation is considered.
A recent report of a randomized controlled
trial of radical versus NSS demonstrated a 10-year
overall survival of 81.1% for RN and 75.7% for Patterns of Tumor Recurrence and
PN, with a statistically significant difference in Guidelines for Follow-Up After NSS
favor of RN (p = 0.03). When the authors limited
the analysis to patients with RCC only, there was The surveillance schedule after NSS for RCC
no significant difference found between these receives relatively little attention in the literature.
approaches. The fundamental limitation of this There is a higher risk of local tumor recurrence
multicenter randomized-controlled study was after NSS compared to RN, with larger studies
poor accrual which limits its power to detect a suggesting an incidence of up to 10% [22]. Data
difference between the approaches. Another concerning the occurrence of metastatic disease
major issue was the less than expected number of after NSS for RCC has also been lacking, although
events seen in the study, with only 12/117 patients it is presumed that rates are not markedly differ-
dying from RCC and 21 patients developing dis- ent from those observed after RN. The incidence
ease progression after a median follow-up of of both local and metastatic tumor recurrences
9.3 years [101]. after NSS for RCC varies according to the patho-
Several recent reports have documented long- logic tumor stage. In designing an appropriate
term disease-specific survival rates for most of strategy for postoperative surveillance after NSS
the surgical approaches to NSS. Ten-year disease- for RCC, a balance must be established between
specific survival for open PN ranges from 77% to detecting recurrent disease early and overly
100% in the series reporting this endpoint. While aggressive follow-up. The cost of postoperative
this data is not available for the robotic-assisted monitoring studies is an additional issue. The
approaches as of yet, a 5-year disease-specific available data indicates that surveillance after
survival of 97.6% has been reported for the con- NSS can be tailored according to the pathologic
ventional laparoscopic approach, suggesting that tumor stage and can perhaps be more limited than
in well-selected patients, it can offer comparable the current practice in many centers.
cancer control to the open approach (Table 8.3). The recommended postoperative surveillance
Reviewing the outcome of NSS in 216 patients scheme after NSS for sporadic localized RCC is
with sporadic RCC treated at the Cleveland Clinic as follows: all patients should be evaluated with a
Foundation, disease-specific survival was associ- medical history, physical examination and
ated with pathologic stage, tumor size, multiplic- selected blood studies, including serum calcium,
ity, unilaterality, and whether the tumor was alkaline phosphatase, liver function tests, blood
discovered incidentally or on the basis of clinical urea nitrogen, serum creatinine, and electrolytes
symptoms [102]. Another study reported the out- on a yearly basis. A 24-h urinary protein mea-
come of NSS in 241 patients. The mean disease- surement should also be obtained in patients
specific survival rate was 95% at 3 years, and with a solitary remnant kidney to screen for
there were only two cases of local tumor recur- hyperfiltration nephropathy [96]. The need
150 A.Z. Weizer et al.

Table 8.4 Surveillance regimen after partial nephrectomy for localized RCC
Intermediate risk High risk
(T1/grades 3–4; any (T3/grades 2–4, any
Risk category Low risk (T1/grades 1–2) T2; T3/grades 1) T4)
Return visit interval Every year to 5 years, then 6, 12, 18, 24 months, 6, 12, 18, 24 months,
every other year then annually then annually
History and physical Every visit Every visit Every visit
examination
Complete blood count Every visit Every visit Every visit
Comprehensive panel Every visit Every visit Every visit
Chest X-ray Every visit Every visit Every visit
Three-dimensional axial Years 1 and 3, then as needed Every other visit Every visit
abdominal imaging starting at 12 months

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 Thermal Ablation
9
Surena F. Matin and Kamran Ahrar

guidelines list ablative therapies as options for

Introduction the management of patients with small renal
masses [1].
With the increasing acceptance of partial nephre-
ctomy as the standard of care for small renal cell
carcinomas (RCCs), as well as its endorsement Cytotoxic Mechanisms
by groups such as the American Urological of Thermal Ablation
Association (AUA), nephron-sparing surgery
will be increasingly employed [1, 2]. Partial In RFA, friction of water molecules reacting to
nephrectomy has been shown to provide equiva- radiofrequencies generates heat which destroys
lent cancer control to that of radical nephrec- tumor tissue. Under light microscopy chromatin
tomy, but with the additional advantage of renal blurring, increased cytoplasmic eosinophilia, loss
preservation, which has important long-term of cell membrane integrity, and interstitial hem-
health benefits [1]. Nevertheless, there are some orrhage are the earliest changes seen in renal
patients with small RCCs, particularly elderly parenchyma [3]. Later, extensive coagulative
patients, those with severe renal dysfunction, and necrosis with early infiltration of fibroblasts and
those with competing comorbidities, who may acute inflammatory elements at the border of the
be poor candidates for surgical excision. Many RFA can be seen. Nuclear degeneration and acute
of these patients are good candidates for thermal inflammation becomes more pronounced after
ablation, either by radiofrequency ablation (RFA) 1 week. Cell death occurs within minutes of
or by cryoablation. Recently published AUA exposure to temperatures at or above 50°C.
Temperatures in the 50–100°C range are main-
tained homogeneously throughout the target area
S.F. Matin, MD, FACS () for optimal therapy [4]. High temperatures
Department of Urology, Minimally Invasive New
(greater than 100°C) can actually compromise
Technology in Oncologic Surgery (MINTOS),
The University of Texas MD Anderson Cancer Center, treatment because tissue carbonization occurs,
1515 Holcombe Boulevard, Unit 1373, which limits heat conduction and thus the efficacy
Houston, TX, 77030, USA of RFA.
e-mail: [email protected]
Cryoablation directly kills tumor cells by
K. Ahrar, MD causing osmotic dehydration that damages enzy-
Department of Diagnostic Radiology, Section of
matic pathways, organelles, and the cell mem-
Interventional Radiology, The University of Texas MD
Anderson Cancer Center, Houston, TX, USA brane and by causing intracellular ice formation
e-mail: [email protected] that supercools the cytoplasmic contents [5, 6].

S.C. Campbell and B.I. Rini (eds.), Renal Cell Carcinoma: Clinical Management, Current Clinical Urology, 155
DOI 10.1007/978-1-62703-062-5_9, © Springer Science+Business Media New York 2013
156 S.F. Matin and K. Ahrar

Small blood vessels are injured and in time

become thrombotic resulting in a hypoxic tumor Patient Selection and Preparation
microenvironment that adds to the cytotoxicity
[6, 7]. Four parameters determine the rate of The single most important requirement for the
cellular cytotoxicity: cooling rate, minimum appropriate selection of patients for ablative ther-
temperature reached, time maintained at the apy is the availability of good-quality imaging
minimum temperature, and thawing rate [5]. with a renal-protocol computed tomography (CT)
A temperature of −40°C must be achieved or magnetic resonance imaging (MRI) examina-
throughout the tumor; this typically occurs when tion. Thermal ablative treatments are all primarily
the ice ball extends 0.5–1 cm beyond the tumor guided by such imaging. The most ideal candi-
margins [8]. Faster cooling and slower thawing dates for ablative therapy are patients with small
also improve cytotoxicity. (<3.5 cm) renal masses that are relatively exo-
phytic and accessible percutaneously. In reality,
many patients have variations of anatomy that
The Role of Diagnostic Biopsy present less ideal situations. Examples include
in Patients Undergoing Thermal tumors larger than 3.5 cm, tumors that are deeper
Ablation and more central, and tumors in locations such as
the anterior upper pole, which may be difficult to
If a patient has a small renal mass suspected to be access percutaneously [16–18]. In particular,
RCC and is a candidate for ablative therapy, a larger tumors and deeper tumors have a lower suc-
biopsy is performed for histologic confirmation cess rate with ablative therapies, as has been shown
of malignancy. At our institution, we perform in multiple studies [17–19]. For example, Zagoria
these biopsies as a separate and preliminary step et al. showed that with each 1-cm increase in tumor
before deciding whether to pursue aggressive diameter over 3.6 cm, the likelihood of recurrence-
therapy, because a substantial number of tumors free survival decreased by a factor of 2.19 [18]. To
will prove to be benign and not require enhance the effectiveness of ablation for larger
treatment [9]. Thus, patients at high risk of tumors, some investigators have advocated embo-
complications with benign lesions are spared lization of the tumor prior to ablation [20]. Renal
unnecessary procedures and anesthetics, as these angiography and selective embolization of the
have an indolent behavior that is unlikely to cause tumor-feeding arteries can reduce perfusion-
morbidity or shorten survival. The argument to mediated cooling of the tissue (i.e., a heat-sink
not biopsy because of high non-diagnostic rates effect) during RFA, allowing a larger volume of
is no longer fully valid. The false-negative and tissue to attain a cytotoxic temperature.
non-diagnostic rates of percutaneous biopsy of Although tumor factors are important in deter-
renal masses have significantly improved in mining the adequacy of an ablative therapy
recent years as a result of improved techniques approach, patient-related factors are just as impor-
(such as core sampling in addition to fine-needle tant and sometimes trump less than ideal indica-
aspiration) and improved pathologic immunos- tions for ablation. For example, we now often see
taining panels [10–13]. Patients confirmed to patients who cannot be taken off anticoagulation
have RCC should be counseled about therapeutic agents, such as those with drug-eluting coronary
alternatives, such as the reference standard of stents; these patients have a very high risk of cor-
partial nephrectomy and the possible appropri- onary thrombosis if the anticoagulants are acutely
ateness of active surveillance. discontinued. Because ablative therapy minimizes
In addition to pretreatment biopsies, in some the time off such compounds, it may represent the
cases postablation biopsies may be needed, as best form of treatment for these patients, even if
evidence suggests that imaging by itself may not they have less favorable tumor factors such as a
be not sufficient to confirm treatment success in central location or large size. Table 9.1 outlines
all cases, as outlined below [14, 15]. our current indications for ablative therapy.
9 Thermal Ablation 157

Table 9.1 Factors considered when evaluating patients accessible percutaneously under CT or MRI
for ablative therapy guidance. On occasion repositioning the patient
Tumor factors in the prone or oblique-prone position will shift
Tumor size: <3.5 cm most ideal some of the structures such as the spleen or colon
Tumor depth: peripheral more favorable than central away from the zone of treatment, allowing percu-
Tumor location: determination for percutaneous or taneous therapy. Other adjunctive maneuvers,
laparoscopic access
described below, may also be performed to
Patient factors
mobilize or protect structures from heat injury.
Elderly physiologic age or health status unfit for major
surgery Tumors that remain in a difficult location or close
Major medical comorbidities or another primary to bowel or the ureter may require a laparoscopic
malignancy that requires active therapy approach, which allows mobilization of these
Enlargement of renal mass to 3 cm in size during structures away from the tumor and the intended
active surveillance zone of ablation. In the laparoscopic approach,
Need to minimize time off anticoagulation or initial electrode placement is performed under
antiplatelet compounds
laparoscopic ultrasound guidance.
Prior ipsilateral partial nephrectomy or other major
renal surgery Our RFA technique has been previously
Chronic kidney disease described [22, 23]. Briefly, percutaneous RFA is
performed with the patient under general anes-
thesia in prone position. RFA is delivered using a
The potential for complications still exists 200 W impedance-based device. One or more
despite the minimally invasive nature of thermal electrodes (depending on tumor size) are posi-
ablative therapies. Also, given the lack of knowl- tioned into the tumor under CT guidance, and
edge about the long-term results of these novel sequential overlapping ablations are then per-
treatments, strict imaging surveillance is impera- formed, depending on the size and location of the
tive for an indefinite period. Patients who are tumor, until it is completely ablated, along with a
unable to meet these follow-up criteria—imaging margin of surrounding normal tissue. Some inter-
surveillance and possible postablation biopsies— ventional radiologists withdraw the electrode into
should not, in our opinion, be considered for the subcutaneous tissues and ablate the tract,
ablative therapy. although it is not clear that this is required. In
Patients also must be medically cleared for cases in which the tumor may remain adjacent to
delivery of general anesthesia. Although some critical structures such as the intestine, nonionic
centers perform ablative therapy with moderate fluid (5% dextrose in water or sterile water) may
sedation [21], our philosophy is that the likeli- be injected and hydrodissection performed,
hood for a single successful treatment depends allowing displacement of the critical structures
on the ability to control respiratory excursion of away from the area of intense heat [24]. Additional
the kidney, resulting in better targeting, and on measures for protecting normal tissues from heat
allowing for treatment as long as is needed dur- injury include irrigating cooled saline in a
ing the case. These two factors are critical for retrograde fashion through a ureteral catheter to
complete tumor ablation in a single procedure. protect the collecting system, rotating the RFA
electrode to displace the kidney, and
strategically placing an angioplasty balloon
Techniques [25, 26]. Immediately after RFA treatment, con-
trast material is given intravenously to assess the
Radiofrequency Ablation ablation zone and confirm adequate treatment.
Contrast-enhanced CT images taken immediately
After a needle biopsy confirms malignant after ablation demonstrate a sharp boundary
histology, patients are referred to an interven- between the zone of ablation and the normal renal
tional radiologist to assess whether the tumor is parenchyma. Mild, diffuse enhancement within
158 S.F. Matin and K. Ahrar

landmarks, as there will be significant shrinkage

and distortion of anatomic landmarks during
treatment. The RFA electrode is then placed into
the tumor under ultrasound guidance until the tip
is at the deepest tumor margin. This initial target-
ing is absolutely critical because visualization of
this margin is most optimal before treatment.
After RFA starts, the resulting vaporization and
cavitation cause gas and microbubbles to form in
the parenchyma, significantly degrading the
ultrasound image and limiting accurate targeting.
Once the deep margin is treated, the electrode is
withdrawn partially and the process repeated. In
addition to facilitating visualization, this maneu-
ver actually achieves a vascular amputation of the
Fig. 9.1 Computed tomography scan 1 month after RFA
of a left renal mass showing an enhancing crescent shaped more superficial untreated levels, such that
area of unablated tumor (arrows). Repeat ablation was the overlapping superficial ablations proceed
guided by this imaging, specifically targeting these areas. more quickly. The electrode can also be reposi-
Copyright S.F. Matin 2011 tioned as necessary into the more peripheral
aspects of the zone of intended ablation, again
the zone of ablation is expected with delayed treating from deepest to more superficial levels,
images [27], but any nodular or crescent areas of until the entire tumor and margin are treated.
intense enhancement are considered unablated
(Fig. 9.1) [26]. Under these circumstances or
when the margin of ablation is close to the tumor Cryoablation
boundary, an RFA electrode can be placed directly
into the area of concern, and an overlapping abla- Cryoablation has been described using a variety
tion can be performed. With this strategy, most of access methods, including open, laparoscopic,
renal tumors can be completely ablated in a sin- and percutaneous. The open approach is now
gle session. largely historical, although there are occasional
Tumors that require laparoscopic RFA (such cases of multifocal disease in which open partial
as anterior or medial tumors or those close to the nephrectomy can be combined with thermal
renal hilum or ureter) are treated using a trans- ablation of additional lesions to minimize the
peritoneal laparoscopic approach. The patient is ischemic interval [28]. The most common
placed in modified flank position, and access is approach is laparoscopic, although an increasing
gained using a Veress needle. A standard three- number of publications report percutaneous route
port approach is performed; the colon is mobi- [29–31]. The laparoscopic approach is similar to
lized, as are other critical structures, such as the that described for RFA, with a notable exception:
ureter, as dictated by tumor location, and the area during cryoablation, laparoscopic ultrasound
around the tumor is exposed. The perinephric fat guidance is utilized throughout the entire treat-
is mobilized, except that overlying the tumor, ment process. The ice-ball edge is seen in excel-
which may either be left in place or sent for lent detail as an advancing hyperechoic rim with
pathologic evaluation to confirm the absence of postacoustic shadowing. This ability to monitor
fat invasion. Intraoperative ultrasonography is the treatment probably is cryoablation’s single
then performed to evaluate the location of the greatest advantage. However, such monitoring
tumor and its depth. At this point, small cautery requires significant mobilization of the kidney,
marks are placed on the renal capsule at the because the postacoustic shadowing prevents
margin of intended treatment to serve as visual visualization of the treatment edge opposite the
9 Thermal Ablation 159

ultrasound transducer. Therefore, the ultrasound adequate tumor cytotoxicity [32]. The recent
probe needs to be navigated around the kidney at availability of thinner probes allows placement of
multiple locations in order to circumferentially multiple probes for ablation of larger tumors [33].
visualize the advancing margin of treatment. This However, one concern is that the routine use of
amount of renal mobilization and perinephric multiple probes may increase the risk of ice-ball
dissection is probably also the reason why surgi- related fracture, a complication unique to cryoab-
cal salvage of laparoscopic cases is rendered so lation that can predispose to significant hemor-
difficult compared to salvage of percutaneous rhage during thawing [31]. In fact, in a recent
therapy, as discussed below. analysis by Vricella and colleagues, the only
Percutaneous cryoablation is also performed significant predictors of complications after
similarly to percutaneous RFA, as described cryoablation were the number of cryoprobes used
above. Percutaneous cryoprobes are now smaller and comorbidity index [34].
(17 gauge to 2.4 mm in diameter) than prior
generation probes. As such, percutaneous cryoab-
lation of most renal tumors requires strategic Follow-Up and Outcomes After
placement of more than one probe. A major Thermal Ablative Therapy
advantage of percutaneous cryoablation over
RFA is that growth of the ice ball can be carefully Patients are seen 4–6 weeks after treatment for a
monitored using CT or MRI, allowing for opti- renal-protocol CT or MRI examination, and if the
mal targeting. The ice ball appears as an area of initial imaging findings are favorable, patients
low density on CT images, so the interface of the return every 6 months for 2 years. After 2 years,
ice ball and the normal kidney is very well delin- depending on the findings of imaging and biopsy
eated. However, the boundary of the ice ball (if performed), semiannual, annual, or biannual
against the retroperitoneal fat, which also appears follow-up is recommended. This follow-up
as low density on CT images, is less well defined. schedule was recommended in a prior multi-
When percutaneous cryoablation is performed institutional study and consensus statement [35].
under MRI guidance, the ice ball can be imaged Confirmatory biopsies after ablation are gen-
in multiple planes. It appears as an area of mark- erally not performed in the first 6 months, as data
edly low signal intensity on all pulse sequences suggest that in some cases, particularly after
(T1 or T2 weighted). Careful monitoring of the RFA, tumor and cellular architecture is preserved,
ice ball allows for modulation of cryogenic gases possibly leading to false-positive biopsy findings
in different probes to prevent growth of the ice [3, 36]. A postablative biopsy is considered, how-
ball in one or more dimensions. This modulation ever, after 6 months, for any enlarging lesions or
provides an additional safety measure that is not when there is a concern regarding recurrence, as
possible with RFA. The inability to visualize discussed below.
beyond the advancing ice ball is the main reason
that using solely ultrasound monitoring during
percutaneous cryoablation cases is not recom- Defining “Success”
mended, as the medial (most inner) edges of the
advancing ice ball cannot be adequately seen. Treatment has traditionally been considered suc-
Whether cryoablation is done percutaneously cessful on the basis of two findings on imaging
or laparoscopically, two freeze/thaw cycles are studies, absence of enhancement and involution
performed, which optimizes tumor cytotoxicity. of the tumor. However, there can be confusion
A margin of normal tissue of at least 0.5 cm when thermally ablated lesions, in the absence of
beyond the tumor is treated; the ice-ball edge has enhancement, do not involute. This scenario,
been shown to represent a 0°C gradient, while which is common, complicates the traditional
0.5 cm within the ball the temperature is −20°C, definition of success. Matsumoto and colleagues
the minimum temperature required to achieve described the natural radiological history of
160 S.F. Matin and K. Ahrar

RFA-treated kidney tumors and showed that superior, and inferior margins of the ablation
many tumors retained an appearance similar to zone. Samples from different areas of the abla-
that of the original tumor, but with absence of tion zone are labeled accordingly and submitted
enhancement and involution [37]. There are separately for pathologic analysis.
reports showing viable cancer cells on percutane-
ous biopsies of ablated lesions in the absence of
contrast enhancement [15]. As well, we have Functional Outcomes
found that viable cancer cells are seen on biopsy
in the absence of enhancement and tumor involu- In general, ablative therapies appear to cause less
tion in approximately 8–10% of cases, at an aver- renal dysfunction than do partial nephrectomy
age time of 23 months after ablation [38]. These and radical nephrectomy, although the data are
cases essentially represent false-negative imag- likely subject to retrospective and selection
ing findings. biases. Lucas and colleagues compared renal
As well, the potential exists for false-positive function using estimated glomerular filtration
imaging findings, wherein there appears to be rates in patients who underwent RFA, partial
recurrence and progression of tumor as noted by nephrectomy, or radical nephrectomy [41]. The
new enhancement, enlargement, and infiltrative investigators found that patients who underwent
changes around the zone of ablation [14, 39]. RFA maintained greater kidney function and
Biopsies or resection in some of these cases have were less likely to develop stage 3 chronic kidney
shown inflammation but no viable tumor despite disease than those who underwent partial nephre-
extensive sampling [39, 40]. It is unknown what ctomy or radical nephrectomy. In addition,
causes these de novo massive inflammatory reac- Raman and colleagues evaluated patients with
tions that frequently, if observed over time, lead solitary kidneys and reported that those who
to significant involution of the ablation zone [40]. underwent open partial nephrectomy with cold
Undoubtedly, however, these false-positive imag- ischemia had a greater decline in kidney function
ing scenarios complicate the clinical picture and than those who underwent RFA [42]. Another
can lead to unnecessary interventions or patient report of patients with solitary kidneys by
anxiety about cancer recurrence. Weisbrod and colleagues showed a large cohort
Biopsy samples should be obtained from any treated by cryoablation with minimal change in
areas of nodular enhancement. In absence of any renal function [43]. Jacobsohn et al. and Hoffmann
abnormal enhancement in the zone of ablation, a et al., reporting on ablative therapy in patients
question arises as to the potential sampling bias with solitary kidneys, showed minimal reduction
of postablation biopsies. The zone of ablation is in kidney function in this high-risk cohort [23,
frequently larger initially than the original tumor 44]. While these retrospective reports may be
because of treatment of a normal margin and, in biased by selection factors such as tumor size and
some cases, tissue edema. Thus, needle biopsies, tumor location, the weight of the data to date sup-
if not thoughtfully considered, may easily miss ports ablative therapy as a viable nephron-sparing
small foci of recurrence. approach.
To address these concerns, our technique
includes obtaining multi-quadrant core biopsy
specimens (Fig. 9.2). A guide needle is inserted Oncological Outcomes
under CT or real-time CT fluoroscopic guidance
into the center of the tumor. An automated, side- It should be noted that there are significant differ-
cutting core biopsy needle is inserted in coaxial ences among various studies with respect to
fashion to obtain at least three biopsy samples. definitions of local recurrence and the quality of
When the zone of ablation is large enough (at least reporting, complicating comparative analysis of
2 cm), the guide needle is then repositioned to this literature. This variability results from a mul-
obtain biopsy samples from the medial, lateral, titude of limitations in the published literature.
9 Thermal Ablation 161

Fig. 9.2 (a–c) Figures showing multisite-directed CT-guided biopsy using an automated, side-cutting core biopsy
needle, in order to maximize sampling of the zone of ablation. Copyright S.F. Matin 2011

For example, diagnostic pretreatment biopsies recurrence within the zone of ablation, in a
were not performed in most studies; thus, as a separate area of the kidney that was not treated,
substantial portion of renal tumors prove to be and/or in an extrarenal site. These limitations in
benign, reports of survival and recurrence may be the literature were categorically described in the
skewed. Additionally, it appears that the natural recent meta-analysis conducted by the AUA
history of small RCCs is generally toward an guidelines panel [2].
indolent pattern of growth, thus the short follow- The AUA meta-analysis provides the most
up of these lesions after ablative therapy has little current summary of outcomes of various treat-
significance [45]. Many investigators describe ments for the small renal mass, including ablative
success as tumor eradication after a certain num- therapies. Cryoblation and RFA were associated
ber of planned or unplanned treatments, and the with significantly lower local recurrence-free
published reports may not include this informa- survival (local RFS) rates (87–91%) than were
tion. Variable definitions of success may also not surgical treatments (³98%) [2]. This difference is
clarify whether reported recurrences include made more pronounced by the fact that the
162 S.F. Matin and K. Ahrar

follow-up period after ablative therapies was

much shorter than that for open partial nephrec-
tomy and other surgical treatments (median
18.2–19.4 months vs. 46.9 months for partial
nephrectomy), suggesting that the local RFS rate
seen after ablation may be even lower with longer
follow-up. Metastatic RFS was high regardless of
approach, but this finding may reflect the indo-
lent nature of small renal tumors. This analysis
provides valuable information that should be
shared with patients during counseling.

Complications

Generally, complications related to ablation are Fig. 9.3 Computed tomography scan 6 months after RFA
secondary to local effects and less likely due to of a right renal mass showing a small amount of urine
extravasation into and around the zone of ablation. The
systemic adverse events [16, 22, 23, 46, 47]. Pain, patient was asymptomatic and observed. Copyright S.F.
paresthesia, neuromuscular complications, pneu- Matin 2011
mothorax, and other adverse events have been
reported [46, 48]. For example, Johnson et al.
documented morbidity rates in a multi-institu- vascularity is reestablished, sudden and significant
tional study from four centers involving 271 hemorrhage can occur.
patients [48]. Complications were reported in Hematuria and clot obstruction can occur with
11.1% of patients, with the overwhelming major- treatment of a more central tumor, and in cases of
ity of the complications classified as minor (9.2% solitary kidneys, this complication can result in
of patients), largely consisting of pain or par- acute renal failure, which may require stent place-
esthesia at the site of probe insertion [48]. ment [23]. Concerns have been expressed about
A recent meta-analysis of the published data treatment of the urinary collecting system and
reported major non-urological complication inci- formation of a urinary fistula, but animal and
dence rates in the 3–7% range and major urologi- clinical evidence suggests that as long as the col-
cal complication incidence rates in the 3–8% lecting system is not mechanically punctured,
range [2]. The rate of conversion to a more inva- this adverse event is unlikely to result in a clini-
sive or escalated procedure during cryoablation cally meaningful adverse event [26]. Rarely, we
(3.5%) was nearly twice as high as during RFA have incidentally seen wisps of urine tracking
(1.6%) [2]. within or just outside the ablation zone (Fig. 9.3).
Bleeding is generally uncommon after RFA These patients are monitored and treated conser-
relative to cryoablation. Small hematomas may vatively, with nearly every case showing resolu-
be seen during imaging but may not be clinically tion over time. Tract seeding of a tumor is
evident. Transfusion incidence rates are reported exceedingly rare and is generally avoided with
in the 1–5% range [2]. Higher rates are seen with careful technique.
cryoablation, however, which is associated with
the specific complication of ice-ball fracture as
discussed previously. This complication may be Ablation for Salvage of Previously
caused by inadvertent torquing of the probe while Treated Kidneys
the ice ball is formed, or possibly by the creation
of larger cryolesions. The fracture may be hair- Repeat surgery in patients who have had prior
line in size initially and not readily apparent dur- partial nephrectomy or other renal procedures is
ing the freeze cycle, but during thawing, as much more difficult. The retroperitoneal and
9 Thermal Ablation 163

perinephric desmoplastic reaction can add rence after thermal ablation, showing that cryoab-
significantly to the complexity of the case [49, lation in particular can lead to extensive
50]. Repeat partial nephrectomy is associated perinephric fibrosis, which can complicate or
with significant rates of blood loss and morbidity preclude attempted surgical salvage [54]. Of ten
and with a quantifiably higher mortality rate in patients in whom partial nephrectomy was
some series [49]. In this setting, percutaneous attempted, only two were able to have it done,
ablative therapy may offer a viable, less morbid and in most cases a laparoscopic approach was
alternative to repeat partial nephrectomy, prompt- not feasible. Kowalczyk and colleagues reported
ing some to recommend ablation as a primary their experience with partial nephrectomy in 13
option in those at high risk for reintervention, patients after RFA, with no cases converted to
such as patients with von Hippel–Lindau syn- radical nephrectomy [55]. The majority of
drome [51–53]. patients had significant fibrosis present in the
A significant proportion of reported patients operative field, however, and operative times
with a solitary kidney who are treated with abla- were long (7.8 h).
tive therapies had a prior partial nephrectomy. If one looks more critically at these studies, it
The results of such series indicate generally appears that cases involving initial laparoscopic
favorable outcomes despite the risks and chal- ablation, which were performed more frequently
lenges involved [23, 42–44]. For instance, Raman using cryoablation, are the ones in which the
and colleagues published a multi-institutional greatest difficulty is encountered and in which
study of patients with a solitary kidney treated adverse events are most likely to occur. Cases
with either partial nephrectomy or RFA; preser- treated percutaneously, which until recently were
vation of renal function favored RFA, possibly as reported more frequently using RFA, are much
a result of avoiding ischemic insults, although easier to salvage, as the area of desmoplastic reac-
patient selection may have also contributed [42]. tion is confined to the area of treatment and not
Similarly, Weisbrod and colleagues reported on throughout the entire perinephric space. To the
cryoablation in 31 patients with a solitary kid- point, when evaluating the data from Nguyen and
ney—the majority of whom had had prior ipsilat- colleagues, patients undergoing surgical salvage
eral renal procedures—and showed a 92% local after RFA procedures (which were nearly all done
tumor control rate, 1 day hospitalization, and a percutaneously) had no intraoperative or postop-
20% major complication rate. In comparison, one erative complications, minimal blood loss, and no
can evaluate outcomes after repeat partial neph- need for intraoperative blood transfusions [54].
rectomy to appreciate the context of these out-
comes. Liu and colleagues reported their
experience with 25 patients undergoing repeat The Future of Ablative Therapies
partial nephrectomy in a solitary kidney, showing
an average of 2,400 ml blood loss, 8.5 h mean Other Ablative Therapies
operative time, and a 52% major complication
rate, which included one (4%) death and a 12% Nearly every promising energy source has been
rate of renal loss requiring long-term hemodialy- investigated for invasive and noninvasive abla-
sis [49]. Although the groups from these separate tion of small renal tumors, including laser ther-
institutions likely have notable baseline differ- moablation [56, 57], photodynamic therapy [58],
ences, the dramatic difference in outcomes high- microwave thermotherapy [59, 60], high-inten-
lights the potentially important role of ablative sity focused ultrasound (HIFU) [61, 62], and
therapy in the salvage setting, particularly if it robotic four-dimensional radiotherapy [63]. To
can be delivered percutaneously. date, all these approaches have been associated
However, surgical salvage of recurrence in with either: (1) technical challenges limiting their
previously ablated kidneys may also represent a clinical application (e.g., laser, photodynamic
surgical challenge. Nguyen et al. reported their therapy, microwaves); (2) inferior clinical out-
experience with surgical salvage of RCC recur- comes (e.g., HIFU); or (3) only very preliminary
164 S.F. Matin and K. Ahrar

experience that represents inadequate assessment thetic, or anatomic situations in whom the lower
of clinical potential (e.g., radiotherapy). Laser efficacy rates are balanced by the reduced risk of
and microwave ablative therapy in particular have serious adverse events. Elderly patients with an
multiple parameters that have not been systemati- enlarging mass, with extensive comorbidities, or
cally studied, such as ideal wavelengths, power those with a recurrence after prior partial nephre-
outputs, duration of treatment, or applicator size ctomy represent situations where thermal abla-
and type. Cryoablation and RFA thus remain the tion therapies may have their best roles. While
two most studied and clinically applied thermal newer energy modalities and delivery devices
ablative technologies to date. continue to be investigated, RFA and cryoabla-
tion continue to have the largest clinical experi-
ence and available data.
Thermal Ablation as Part of an
Immunotherapeutic Strategy
References
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 Active Surveillance of the Small
Renal Mass 10
Marc C. Smaldone, Daniel Canter,
Alexander Kutikov, and Robert G. Uzzo

discovered [6]. Radiographic stage I small renal

Introduction masses (SRMs) represent a heterogenous entity,
with as many as 20% being benign [7] and an
Kidney cancer, predominantly renal cell carci- estimated 20–30% being potentially aggressive
noma (RCC), is among the most lethal of uro- [8, 9]. As the incidence of SRM diagnoses has
logic malignancies. In 2010, approximately risen, an increase in the median age at RCC diag-
58,240 men and women were diagnosed with nosis has also been observed, with the most
cancer of the kidney or renal pelvis, and 13,040 significant rise demonstrated in patients between
(22.4%) will ultimately succumb to their disease 70 and 90 years of age [10]. However, while the
[1]. Due to increased utilization of cross-sectional rates of renal surgery have risen in conjunction
abdominal imaging over the past several decades with increased tumor detection, mortality rates
[2, 3], a stage and size migration towards the have paradoxically risen as well [3]. These
detection of smaller localized renal tumors findings indicate that a proportion of SRMs rep-
(<4 cm) has been observed in large population- resent indolent disease that may not require sur-
based cohorts. Likewise, mean tumor size at gical excision and have led to the reassessment of
diagnosis has decreased over time, and in 2004 contemporary practice patterns for incidentally
tumors <3 cm represented 43.4% of all stage I diagnosed lesions.
tumors detected (Fig. 10.1) [4, 5]. As a result Traditionally, clinical stage I renal masses
incidental detection of asymptomatic lesions now have been treated with surgical excision, most
accounts for more than half of all renal masses commonly by radical nephrectomy [11]. However,
concern that radical nephrectomy may predispose
patients to the sequelae of chronic kidney disease
M.C. Smaldone (CKD) [12, 13], including increased cardiovas-
123 Winchester Road, Merion Station, PA 19066, USA
cular risk and shortened overall survival [14–16],
Division of Urologic Oncology, has led to the increased utilization of nephron
Department of Surgical Oncology,
Fox Chase Cancer Center, sparing procedures with the goal of preserving
333 Cottman Avenue, Philadelphia, PA 19111, USA long-term renal function without affecting cancer
e-mail: [email protected] control [17]. With technological advances, lap-
D. Canter • A. Kutikov • R.G. Uzzo () aroscopic [18] and robotic [19] platforms have
Division of Urologic Oncology, now become well established in the armamen-
Department of Surgical Oncology, tarium of nephron-sparing techniques, resulting
Fox Chase Cancer Center, 333 Cottman Avenue,
Philadelphia, PA 19111, USA in contemporary management of SRMs which is
e-mail: [email protected] substantially less radical and less invasive.

S.C. Campbell and B.I. Rini (eds.), Renal Cell Carcinoma: Clinical Management, Current Clinical Urology, 167
DOI 10.1007/978-1-62703-062-5_10, © Springer Science+Business Media New York 2013
168 M.C. Smaldone et al.

14,000
>3.0cm
≤3.0cm
12,069
12,000 11,650
11,403

10,248
10,000 9,513
Number of Cases

8,750
8,453

8,000 7,456
6,867
6,477
5,959
6,000 5,335

4,000

2,000

0
1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004
Year of Diagnosis

Fig. 10.1 Number of stage I renal cell carcinoma cases renal cell carcinoma: Analysis from the national cancer
by diagnosis year (1993–2004) stratified by tumor size database, 1993 to 2004. The Journal of Urology (2008);
(<3 cm or ³3 cm). (Reproduced with permission from 179(6):2132”; American Urological Association by
“Cooperberg et al. Decreasing size at diagnosis of stage 1 Elsevier, Inc.)

Beyond excision, tumor ablation has been broadly disease. This management strategy has evolved
applied, despite a lack of meaningful published and has been extended to younger and healthier
endpoints and short median follow-up periods, men with low-volume, low-risk prostate cancer.
thereby confounding treatment decisions [20, 21]. Coined “active surveillance (AS) with delayed
Whereas 5-year cancer-specific survival of curative intent,” immediate intervention is
surgically treated stage I SRMs remains in excess deferred to avoid the potential morbidities of
of 95% [20], the formidability of RCC tumor treatment. These men are closely followed with
biology has been questioned as no treatment data serial PSAs, physical exams, and repeat prostate
have been compared to lesions managed expec- biopsies at defined intervals with the intention of
tantly [22]. Moreover, there is a growing recogni- undergoing active treatment if there is evidence
tion that competing risks to longevity from for clinical progression of disease [25]. Although
comorbidities may outweigh the benefit of inter- this management strategy is still in the early
vention in elderly and infirmed patients [23]. phases of investigation in men with prostate can-
Over diagnosis of malignancy, along with cer [26], AS has recently been applied in select
receipt of unneeded treatment as well as its atten- patients with SRMs and significant competing
dant risks, is arguably the most important harm risks with intriguing results. Although limited by
associated with early cancer detection [24]. small cohorts and retrospective methodology, the
Conceptually, the practice of observing docu- current AS in SRM data represents perhaps the
mented malignancies has precedence in the uro- most comprehensive observational data for any
logic and oncologic communities. “Watchful solid organ malignancy to date. In this chapter
waiting” of elderly men with prostate cancer and we aim to define the malignant potential of
substantial comorbidity has become a standard the SRM based on preoperative radiographic
option, with definitive androgen deprivation characteristics, describe contemporary AS proto-
therapy held until documentation of metastatic cols, summarize the existing body of evidence
10 Active Surveillance of the Small Renal Mass 169

Fig. 10.2 Probability of A

high-grade disease vs.

0.5
tumor size in localized
renal cell carcinoma.

Probability of High Grade Disease

(Reproduced with
permission from “Rothman

0.4
et al. Histopathological
characteristics of localized
renal cell carcinoma
correlate with tumor size:
A SEER analysis. The

0.3
Journal of Urology (2009);
181(1):32”; American
Urological Association by
Elsevier, Inc.)

0.2
0.1

0 5 10 15 20
Tumor Size (cm)

investigating the natural history of SRMs under nuclear features [stratified by clear cell, OR 1.32
AS, and identify which clinical and radiographic (CI 1.27–1.37); p < 0.001 or papillary, OR 1.12
characteristics are associated with progression to (CI 1.06–1.19); p < 0.001; histology] [27]. In a
metastatic disease while under AS. smaller retrospective series comparing 168 renal
tumors £3 cm with 119 renal tumors >3–4 cm,
Remzi et al. reported decreased rates of local
Assessing the Malignant and extension (pT3a 19.1% vs. 35.7%, p < 0.05), high
Metastatic Potential of the Small grade (Fuhrman grades 3–4) disease (9.2% vs.
Renal Mass 25.5%, p < 0.05), and synchronous metastasis
(M + 2.4% vs. 8.4%, p = 0.05) in patients with
Considerable effort has been undertaken to iden- smaller lesions [9]. In a large single institution
tify preoperative radiographic characteristics of cohort of 2,675 renal tumors treated surgically,
renal masses associated with malignant potential Thompson et al. reported similar risks of malig-
and disease progression. Currently, the most nant pathology [OR 1.16 (CI 1.11–1.22);
reproducible imaging characteristic on cross- p < 0.001] and high-grade disease [OR 1.25 (CI
sectional imaging is tumor size, and recent large 1.21–1.30); p < 0.001]. In fact, in this subset the
series have demonstrated that as maximal linear incidence of high-grade lesions increased from
tumor diameter increases, there is increased risk 0% for tumors <1 cm to 59% for tumors
of malignant vs. benign pathology [27, 28], high- >7 cm [28]. Using data from SEER, Rothman
grade vs. low-grade disease [27–29], clear cell et al. investigated the relationship between pri-
vs. more indolent histology [28, 29], and pres- mary tumor size at presentation and histopatho-
ence of synchronous metastases [30–32]. In a logical features in 19,932 patients with localized
cohort of 2,770 patients with sporadic, unilateral, renal tumors. Findings of this study demonstrate
localized renal masses, Frank et al. reported that that for each 1 cm increase in size, the probability
increasing tumor diameter was associated with of a high-grade tumor increased by 13%
malignant pathology [OR 1.17 (CI 1.08–1.26); (OR 1.13, p < 0.001) [29] (Fig. 10.2). Interestingly,
p < 0.001], clear cell vs. papillary histology [OR while almost 85% of RCCs <4 cm were low
1.17 (CI 1.11–1.23); p < 0.001], and high-grade grade, 70% of lesions >7 cm were also low-grade
170 M.C. Smaldone et al.

lesions, suggesting that a large proportion of elderly or infirmed patients in which comorbid
localized renal tumors can grow quite large with- medical conditions compete with RCC malignant
out acquiring metastatic potential. potential as primary causes of death represents a
While it is clear from available data that a unique set of challenges. Most contemporary RCC
significant proportion of SRMs are more indolent predictive models combine pathologic characteris-
whereas only a small minority represent high- tics such as tumor grade, presence of tumor necro-
grade lesions, the biology of these lesions must be sis, vascular invasion, and, in some cases, molecular
distinguished from the infrequent case of a small markers in attempts to predict disease recurrence
renal mass with aggressive malignant characteris- following definitive therapy [34–43]. While these
tics and synchronous metastatic disease. Using existing models are useful to help guide postopera-
data from a single institution tumor registry, tive management, their utility is limited in the pre-
Kunkle et al. compared 110 patients with biopsy- operative setting as clinical metrics such as
proven synchronous metastatic disease at presen- comorbid indices or performance status [44] are
tation to 250 controls with clinically localized not incorporated. As a result, new tools are needed
RCC. Study findings revealed that tumors associ- to quantitate survival differences and improve
ated with synchronous metastasis were significantly effective decision-making in the preoperative set-
larger compared to clinically localized lesions ting. In an effort to predict disease recurrence fol-
(median 8.0 cm vs. 4.5 cm, p < 0.0001), and the lowing nephrectomy, Cindolo et al. included
odds of synchronous metastasis increased by 22% clinical presentation as well as tumor size on pre-
for each 1 cm increase in tumor size (p < 0.0001) operative imaging in an analysis of pooled multi-
[30]. Importantly, no patients with tumors 2 cm or institutional data of patients undergoing treatment
smaller presented with biopsy-proven metastatic for localized RCC. However, the utility of this
disease, and less than 5% of all systemic metasta- instrument for preoperative assessment is also lim-
ses occurred in patients with tumors <3 cm. ited by inclusion of pathologic features to deter-
Although a clear association between tumor size mine risk stratification [45]. Similarly, nomograms
and risk of metastasis has not been determined, purely based on preoperative clinical and imaging
most current reports utilize a 3 cm threshold that characteristics have been developed to predict dis-
has been extrapolated from clinical data in patients ease recurrence and metastasis , However, since
with von Hippel–Lindau syndrome [33]. Using these predictive models do not address competing
SEER data from 24,000 patients, Nguyen et al. health risks or survival, their clinical utility in the
estimated the risk of synchronous metastases to be pre operative setting is limited [46, 47].
<5% for patients with a primary tumor size £3 cm Recent reports have highlighted the discrep-
[31], thereby substantiating this threshold. ancy between cancer-specific risk of death and
Similarly, in a large single institution cohort of competing risk from comorbidity. Data from an
2,691 patients with sporadic renal tumors, EORTC trial comparing oncologic efficacy of rad-
Thompson et al. demonstrated an association ical and partial nephrectomy for localized tumors
between tumor size and metastasis-free survival £5 cm revealed that, of 117 deaths over a median
(HR 1.24, p < 0.001) and reported that only 1 in follow-up period of 9.3 years, 10.3% were a result
781 (0.1%) patients with tumors <3 cm presented of RCC compared to 89.7% from other cause [48].
with synchronous metastatic disease [32]. In an institutional series of 537 patient >75 years
of age with renal masses <7 cm, Lane et al. reported
that over a median follow-up period of 3.9 years,
Competing Risk Assessment in the most common cause of death was cardiovascu-
Patients with Localized Renal Masses lar (29%) compared to cancer progression (4%)
[49]. Two contemporary studies have attempted to
While surgical resection of SRMs in young, quantitate competing risks of death in patients
healthy patients is currently the accepted standard with RCC utilizing the Charlson comorbidity
of care [20], management of localized RCC in index (CCI). Santos Arrontes et al. reported the
10 Active Surveillance of the Small Renal Mass 171

results of a retrospective competing risk analysis ity estimates were generated for cancer-specific
in 192 patients with clear cell RCC. With a median and competing cause mortality [51]. Not surpris-
follow-up of less than 4 years, there were a total of ingly, they found that patients with the smallest
72 patient deaths, 45 of which (63%) were attrib- tumors had the lowest cancer-specific survival,
uted to RCC. Patients with clinically localized and that competing cause mortality increased with
RCC and a CCI >2 demonstrated significantly age. The authors reported that irrespective of tumor
reduced overall survival compared to patients with size, 5-year competing cause mortality was 28.2%
a CCI £2, whereas there were no significant differ- in patients ³70 years, and concluded that reevalua-
ences in survival between CCI stratified groups tion of initial management strategy was necessary
with locally advanced or metastatic RCC. in select patients with SRMs.
Interpreting these findings, the authors concluded In an effort to refine a clinical tool to stratify
that patients with CCI scores >2 do not gain a sur- the competing risks of comorbidity and tumor
vival advantage from the surgical treatment of malignant potential, Kutikov et al. developed a
localized RCC [50]. Using the SEER database, comprehensive nomogram to predict 5-year risk
Hollingsworth et al. performed a competing risks of kidney cancer death, death from other malig-
analysis in 26,618 patients undergoing surgical nancy, and noncancer death utilizing select pre-
treatment of RCC. Stratified into 20 groups by operative clinical and demographic variables
tumor size and age at presentation, 5-year mortal- (Fig. 10.3) [23]. In this large cohort of 30,000

Points
0 5 10 15 20 25 30 35 40 45 50 55 60 65 70 75 80 85 90 95 100
Non−cancer death points

Race
Other White Black
Sex
F M
Tumor size (cm)
20 15 10 5 0
Age
30 35 40 45 50 55 60 65 70 75 80 85 90 95

Kidney cancer death points

Race
Black White/Other
Sex
FM
Tumor size (cm)
0 1 2 3 4 5 6 7 8 10 12 14 16 18 20
Age
30 40 50 60 70 80 90 95

Other cancer death points

Race
Other White Black
Sex
FM
Tumor size (cm)
20 15 10 0
Age
30 35 40 45 50 55 60 65 70 80 90

Total points
0 10 20 30 40 50 60 70 80 90 100 110 120 130

Probability of
non–cancer death 0 0.01 0.01 0.02 0.02 0.03 0.05 0.07 0.1 0.14 0.2 0.27 0.37 0.49

Probability of
kidney cancer death 0 0 0.01 0.01 0.01 0.02 0.02 0.03 0.05 0.07 0.1 0.14 0.2 0.29

Probability of
other cancer death 0 0 0 0 0 0 0.01 0.01 0.01 0.02 0.03 0.04 0.06 0.08

Fig. 10.3 Nomogram evaluating 5-year competing risks with permission from “Kutikov et al. Evaluating Overall
of death in patients with localized renal cell carcinoma. Survival and Competing Risks of Death in Patients With
Total point values are independently calculated for each Localized Renal Cell Carcinoma Using a Comprehensive
cause of death and then applied to the corresponding Nomogram. The Journal of Clinical Oncology (2010);
probability scale at the bottom of the figure. (Reproduced 28(2):315”; American Society of Clinical Oncology.)
172 M.C. Smaldone et al.

patients with localized RCC identified from the restricted to percutaneous biopsy. Biopsy of the
SEER database, age (p < 0.001), race (p < 0.001), enhancing renal mass has been limited due to
gender (p < 0.002), and tumor size (p < 0.001) risks, sampling error and clinically irrelevant data
were associated with mortality, while histologic obtained and historically was reserved only for
subtype was not significantly associated with cases where lymphoma, infection, or a metastasis
mortality and was excluded from the model. For from another organ to the kidney was suspected
example, utilizing this nomogram, a 75-year-old [58]. Using pooled data from a large systematic
white male with a 4 cm tumor would have a review of the literature, Lane et al. reported that
5-year predicted disease specific mortality of 5% prior to 2001, renal biopsy exhibited an 81% accu-
vs. 4.5% from other malignancies and 14% from racy rate with four out of five biopsies correctly
noncancerous causes. Although externally vali- predicting the tumor’s pathology [58]. Recently,
dated in another large SEER cohort [52], specific the utility of percutaneous renal biopsy has been
comorbidity information was not available for reexamined in select patients, and modern series
inclusion in this initial analysis, thereby limiting utilizing 18 gauge core biopsies and improved
the nomogram’s clinical utility. In an effort to immunohistological characterization techniques
address these limitations, our institution is cur- have reported improved accuracy in differentiat-
rently working to enhance the nomogram by ing benign from malignant histologic types (>90%)
incorporating comorbidity data [53]. with minimal procedure-related complications
[59]. When a malignancy is found on biopsy, the
positive predictive value is reported to be over
Role of Percutaneous Biopsy, 95%, and reported risks of minor complications
Molecular Markers, and (<5%) or tumor seeding (<0.01%) are exceedingly
Non-extirpative Prediction low [58]. Meanwhile, negative predictive value
of Malignant Potential appears to be over 80% with most contemporary
series reporting false negative rates less than 5%
When an incidental renal mass is identified, a [59, 60]. Despite these improvements, small tumor
diagnosis of malignancy is presumed based on size has been associated with a “nondiagnostic”
enhancement with contrast on cross-sectional biopsy, with a recent series reporting presence of
imaging [20]. Preoperative counseling and treat- insufficient tissue for diagnosis in 37% of tumors
ment planning are often made in the context of <3 cm compared to only 9% of tumors ³3 cm [61].
this uncertainty despite the fact that 20–30% of While the accuracy of renal biopsy in determining
these lesions ultimately prove benign while less histologic subtype has substantially increased,
than 30% are found to be potentially aggressive most modern series do not assess tumor grade [58]
[7, 27]. The ability to match renal mass biology which has established prognostic implications for
with an appropriate treatment strategy remains an cancer-specific survival [62]. In fact, contempo-
elusive goal of modern urologic oncology [54]. rary series utilizing modern core biopsy techniques
While efforts have been made to predict malig- have reported distinction of tumor grading in only
nant potential using preoperative clinical and 62.7% of patients undergoing biopsy as part of an
radiographic variables [55, 56], to date the clini- active surveillance protocols [63], and underesti-
cal utility of non-extirpative diagnostic strategies mation of nuclear grade has been noted in more
including percutaneous biopsy and pathological than half (55%) of patients undergoing biopsy
predictive models remains limited [57]. prior to surgical resection [64].
While there is renewed interest in the utility of
percutaneous biopsy in the management of the
Percutaneous Biopsy SRM, its role remains controversial in the uro-
logic community [57]. In a recent national survey
Traditionally, non-extirpative assessment of of consultant urologists in the United Kingdom,
enhancing renal mass pathology has been largely 34% reported always using biopsy in the treatment
10 Active Surveillance of the Small Renal Mass 173

algorithm of small indeterminate renal masses; that is a marker of active cellular proliferation)
however, the majority of the sample reported [70, 71], p53 (marker of apoptosis) [72, 73],
either selectively (23%) or never using biopsy HER-2 (epidermal growth factor) [74], vascular
(43%) to inform their management decisions endothelial growth factor (VEGF) [75], bcl-2
[65]. What remains to be determined is what pre- (apoptotic inhibitor) [76], cyclin-D1 (cell-cycle
cise impact does information from a biopsy have regulatory molecule) [77], vimentin (epithelial
on treatment decisions, and does it justify associ- cell adhesion molecule) [78], C-reactive
ated procedural risks and costs? In an early retro- inflammatory protein [79], carbonic anhydrase
spective review of 79 image-guided renal mass IX (cell surface transmembrane enzyme upreg-
biopsies in 73 patients, clinical management was ulated by hypoxia-inducible factor in low oxy-
altered in 41% of cases managed nonoperatively gen environments) [80], among others [81].
[66]. In a contemporary series of 152 biopsies Unfortunately, although many show promise,
using 18 gauge core biopsy technique, Maturen few, if any, of these preliminary data can be
et al. reported highly accurate sensitivity (97.7%), considered robust enough to be relevant or even
specificity (100%), positive predictive value applicable in determining which patients with
(100%), and negative predictive values (100%) SRMs require immediate intervention and
for malignancy, stating that biopsy results which can be safely observed [54].
significantly impacted clinical management in For the purpose of this review, we focus on the
60.5% of cases [67]. Although these results are current body of evidence investigating biomarker
limited by selection bias, these findings have led activity in lesions initially managed with a period
some authors to change their practice to recom- of radiographic surveillance. In six localized and
mend a CT-guided biopsy of all SRMs before 12 metastatic (n = 12) tumors, Fujimoto et al. ana-
treatment to confirm malignancy, classify histo- lyzed argyrophilic nucleolar organizer regions
logic subtype, and establish tumor grade [68]. (AgNORs) and proliferating cell nuclear antigen
While use of biopsy has evolved and gained trac- (PCNA) activity, reporting that, in localized
tion, it has yet not been accepted as an alternative tumors, tumor doubling time was inversely pro-
to resection in young or otherwise healthy candi- portional to, and significantly correlated with,
dates for excision, and it is currently utilized on a AgNOR expression and PCNA activity [82]. In
selective basis in patients with absolute or rela- 18 patients with localized SRMs, Kato et al. mea-
tive indications, or specific circumstances such as sured cell proliferation and apoptosis using the
synchronous bilateral lesions [69]. marker Ki-67 and the transferase-mediated
dUTP-biotin nick (TUNEL) assay. They reported
that tumor growth rate was associated with a pos-
Molecular Markers itive TUNEL ratio, but not with degree of Ki-67
immunostaining [83]. In an early series investi-
Molecular biomarkers obtained from percuta- gating growth kinetics of SRMs under observa-
neous biopsy specimens that could accurately tion, Oda et al. observed that the growth rate of
predict aggressive RCC phenotypic features incidentally found RCCs varied and that the ini-
would be an ideal means of matching treatment tial clinical and pathological features did not pre-
strategy to tumor biology on an individual dict subsequent tumor growth [84]. To further
patient level [54]. Although a discussion of the characterize these lesions, the authors examined
many biomarkers currently being studied in cell proliferation, apoptosis, and angiogenesis in
RCC (primarily to predict disease recurrence 16 incidentally found cases of RCC, using the
following surgical resection) is beyond the Ki-67 labeling index (KI), apoptotic index (AI),
scope of this chapter, molecular markers of cel- and TUNEL technique. They found that while KI
lular proliferation and apoptosis currently under and AI were not associated with each other or
investigation include Ki-67 (a nuclear antigen tumor growth rates, the KI/AI ratio was
174 M.C. Smaldone et al.

strongly correlated with tumor growth rate from 32% to 100% and for staging ranging from
(r = 0.71; p = 0.01) [85]. Unfortunately, the role of 47% to 75% [87]. While a majority of these stud-
biomarkers in the selection and management of ies were performed prior to combination scan-
patients under AS is currently limited [54]. Until ning, reported false negative results are as high as
molecular markers specific for malignant or met- 68%, severely limiting the utility of 18F-FDG-
astatic potential are identified and validated, PET for the initial assessment of primary renal
alternative prognostic tools are required to help masses.
stratify risk in patients presenting with inciden- Alternative molecular agents reflecting aber-
tally diagnosed SRMs. rant cellular pathways such as cellular oxidative
metabolism, DNA synthesis, and tumor hypoxia
tracers are currently under development and are
Imaging Techniques in the early phases of investigation in RCC [88–
90]. However, antibody-based molecular imag-
Currently, multiphase contrast-enhanced imaging ing, or immuno-PET, appears to offer a more
(CT or MRI) scanning provides the best evalua- clinically relevant strategy to improve molecular/
tion of a renal mass, namely enhancement char- biologic imaging in RCC. Immuno-PET offers
acteristics, assessment of bilateral renal flow and the promise of highly selective binding to cancer-
function, and clinical (radiographic) staging data. specific antigens to provide radiographically rec-
Unfortunately, while contrast-based cross-sec- ognizable molecular targets, and enthusiasm for
tional imaging can distinguish most renal cystic this imaging technique parallels recent progress
lesions from solid masses, it provides minimal in the development of small molecule targeted
biological information to predict a tumor’s natu- therapy for RCC. In an early phase I pilot study
ral history. Existing imaging methods cannot imaging 26 patients with renal masses prior to
definitively distinguish between benign and surgery, immuno-PET using a monoclonal anti-
malignant solid tumors, RCC histologic subtypes, body to CA IX labeled with 124I (124I-G250-PET)
or indolent vs. aggressive tumor biology. was able to discriminate between ccRCC and
Molecular imaging, such as positron emission non-ccRCC with a high sensitivity (94%) and
tomography (PET), has the potential to character- specificity (100%) and no serious drug-related
ize biologic processes at the cellular and subcel- adverse events [91]. This has led to considerable
lular level noninvasively in addition to providing enthusiasm regarding the potential for the devel-
the macroscopic detail obtained from CT or MRI. opment of a first in class histologically specific
The use of 2-deoxy-2-[18F] fluoro-d-glucose (18F- imaging modality with the ability to offer relevant
FDG) to functionally image malignancies is preoperative biological data. In a multi-institu-
based on the anticipated altered glycolytic path- tional phase III study (REDECT trial) including
way in malignant cells. When used in combina- 202 patients, 124I-G250-PET/CT was able to dis-
tion with standard CT, 18F-FDG PET (PET-CT) criminate ccRCC from non-ccRCC with a much
provides both functional and anatomic tumor higher sensitivity (86%) and specificity (87%)
data thereby improving the diagnostic accuracy compared to conventional CT, with a 95% posi-
and tumor localization for a number of solid tive predictive value and no associated serious
malignancies vs. either modality alone [86]. adverse events [92]. In comparison with previous
While there was initial enthusiasm for the utiliza- efforts demonstrating only questionable or theo-
tion of 18F-FDG-PET to diagnose, stage, or retical utility of molecular imaging to guide clin-
restage renal lesions, there are significant limita- ical decision making, results from the REDECT
tions to its clinical applicability. Summarized by trial demonstrate that immuno-PET can be used
Lawrentschuk et al., these series are comprised of to provide important preoperative diagnostic
a number of small reports (samples ranging from information that may help guide optimal
4 to 66) with sensitivities for diagnosis ranging therapy.
10 Active Surveillance of the Small Renal Mass 175

Preoperative Non-extirpative between tumor histology groups with the exception

Assessment of Malignant Potential of the anterior/posterior (A) designation [99].
Papillary and chromophobe tumors had the low-
Algorithms have been developed with the aim of est scores in each attribute indicating that they
predicting the biological potential of SRMs prior tended to be small, exophytic tumors with a polar
to intervention. Using a large institutional cohort, distribution, resulting in low total Nephrometry
Lane et al. constructed a nomogram based on the Scores similar to benign lesions. Comparatively,
findings that gender, tumor size, and smoking clear cell carcinomas and uncommon yet more
history were predictive of malignant vs. benign aggressive histologic subtypes (collecting duct,
disease. However, the concordance index (CI) of sarcomatoid) tended to be large, endophytic,
this model was a modest 0.64. Furthermore, addi- interpolar lesions, thereby having higher total
tional efforts to differentiate indolent from Nephrometry Scores. Based on these data, pre-
aggressive cancers yielded a CI of 0.56, accuracy dictive nomograms integrating anatomic tumor
that is only slightly better than a flip of a coin [56]. attributes with patient’s age and gender were con-
Utilizing a multi-institutional dataset, Jeldres structed for preoperative prediction of tumor
et al. developed a tool with the aim of accurately malignant histology (AUC 0.76) and high-grade
predicting high-grade (Fuhrman grades 3–4) fea- features (AUC 0.73) [99]. This model represents
tures at nephrectomy using four covariates (age the most accurate predictive model to date, with
at diagnosis, gender, tumor size, and symptom accuracy rates (particularly for tumor grade) that
classification). Of these factors, only tumor size rival the results of contemporary percutaneous
was significantly associated with high-grade dis- core biopsy series [56].
ease on univariate analysis, and their most accu- It is our hope that ultimately, the quantifiable
rate multivariable model prediction of high-grade probabilities of harboring malignant and high-
disease resulted in an accuracy similar to Lane’s grade pathology based on preoperative cross-
model (58.3%) [55]. Given the lower than accept- sectional imaging can be objectively compared to
able accuracy of these early efforts to predict competing risks of comorbid medical conditions
biology using demographic data, further evalua- and the morbidity of treatment itself. For exam-
tion of additional characteristics to more accu- ple, using the Kutikov predictive model, an
rately predict pathologic features are necessary. 80-year-old male with an enhancing renal mass
There is increasing evidence to suggest a rela- with a Nephrometry Score of 1 + 3 + 1 + a + 2 = 7a
tionship may exist between renal mass anatomy has only a 26% chance of lesion malignancy. In
and pathology; however, only recently objective turn, if the mass is indeed malignant, his chance
measures of renal mass anatomy have been of the cancer being high grade is approximately
described [93–95]. The R.E.N.A.L. Nephrometry 30%. Overall, the patient has a 7.8% probability
Score is the first scoring system designed to (0.26 × 0.30 = 0.078) of harboring high-grade
assess reproducible and pertinent renal tumor malignancy. In contrast, an 80-year-old female
anatomical attributes as they relate to surgical with a Nephrometry Score 2 + 2 + 2 + a + 3h = 9ah
resectability [96], while alternative systems has a 92% chance of harboring a malignancy. If
including P.A.D.U.A. [97] and the C-Index [98] the tumor is malignant, the likelihood of high-
have been published. Using a large prospectively grade disease is 59%. Unlike the 80-year-old
maintained institutional cohort, Kutikov et al. male patient with “simple” tumor anatomy whose
evaluated the relationship between anatomical chance of having a high-grade malignancy is less
variables stratified by Nephrometry and malig- than 10%, this female patient with a higher com-
nant or high-grade pathologic features at the time plexity renal mass which has a 54.2% chance
of surgical resection. They found that total (0.92 × 0.59 = 0.542) of harboring high-grade dis-
Nephrometry Score and all individual anatomic ease. With further refinement, these and other
descriptor components significantly differed predictive models show significant potential for
176 M.C. Smaldone et al.

counseling patients newly diagnosed with SRMs, reduced estimated glomerular filtration rates
particularly elderly individuals with significant (GFRs) is associated with increased risks of
competing risks. death, cardiovascular events, and hospitalization
[14]. As part of the initial evaluation, it is our
practice to determine creatinine clearance and
Indications for Observation GFR to classify patient by CKD stage and refer
and Contemporary Active patients to nephrology for further evaluation prior
Surveillance Protocols to pursuing definitive therapy. For patients con-
sidering AS who are adequate surgical candi-
When evaluating patients with newly diagnosed dates, an informed discussion must be held fully
SRMs, it is helpful to stratify their risk status disclosing the current body of evidence as well as
prior to choosing a treatment strategy. In our the limitations regarding known growth kinetics
practice, each patient is categorized by absolute, of SRMs under observation and risk of disease
relative, and elective indication for AS. Absolute progression. Regardless of AS indication, when
indications include patients in whom surgery considering observation of an enhancing renal
poses an immediate and unacceptable risk of mass, both the patient and treating physician must
mortality due to competing medical risks. understand that surveillance entails inherent cal-
Relative indications for observation include other culated risk due to the heterogeneous and occa-
concomitant disease states such as second malig- sionally unpredictable behavior of RCC. In all
nancy, potential need for renal replacement ther- cases, the primary goal of AS is to balance the
apy, and significant but not overriding medical risks of treatment vs. the risks of disease progres-
comorbidities. Lastly, elective indications include sion and development of metastasis.
patients who choose to pursue AS despite being To date there are no consistent surveillance
low risk surgical candidates [100]. In our recent protocols, and there have been no comparisons of
systematic review of all contemporary series of the health care costs of active surveillance/
SRMs under AS, reason for AS was reported in delayed intervention with traditional surgical
eight studies (N = 312 patients), consisting of therapies or ablative techniques. Such compari-
elective (60.9%), relative (12.5%), and absolute sons are challenging, since patients must be
(26.6%) indications [101]. matched not only by clinicopathological vari-
When considering management options, it is ables related to the renal mass, but also by associ-
the treating physician’s responsibility to quantify ated comorbidities. Furthermore, costs of surgical
factors affecting life expectancy, including per- morbidity and mortality must be captured in such
formance status and operative risk, and compare datasets. In addition, surveillance of suspected
these factors to the morbidity and mortality of malignant lesions carries implicit risks and effec-
untreated localized RCC. Often, this requires a tive surveillance protocols mandate a high degree
team approach, including the patient’s urologist, of individual patient adherence. Current recom-
primary care provider, medical specialists (par- mendations state that imaging should be per-
ticularly cardiopulmonary and nephrology evalu- formed with a consistent modality at defined
ation), and anesthesiologist. The potential need intervals (3–6 months) [20]. The exact imaging
for postoperative renal replacement therapy must interval is based on a qualitative decision by the
be strongly considered, particularly in elderly treating physician, which is determined by clini-
patients with diabetes, hypertension, and other copathological risk factors specific to the renal
systemic diseases that predispose to CKD. While mass and the patient’s overall health status. In our
the relationship between end-stage renal disease practice, imaging is performed at 3- to 4-month
and adverse morbidity and mortality events is intervals following initiation of AS to establish
well recognized [102], recent large population- baseline SRM growth kinetics to guide the timing
based cohort data have demonstrated that mild or of additional imaging studies. In general, tumor
moderate renal insufficiency determined by size comparisons should be performed using
10 Active Surveillance of the Small Renal Mass 177

consistent lesion characteristics [e.g., maximum accurate and methodical measurements of tumor
tumor diameter (MTD) or estimated tumor vol- diameter, linear growth may not fully reflect the
ume (ETV)], while paying close attention to the overall change in tumor volume. Indeed, calcula-
cross-sectional cut from which the data is tion of volumetric growth, which may be easily
obtained across various radiographic studies determined on the basis of known cross-sectional
[100]. Most importantly, patients must be appro- dimensions, may better quantify biologic growth
priately counseled regarding management plans [116]. Tumor volume is calculated depending on
in the event that their tumor exhibits a rapid the available dimensions reported on imaging
growth rate, a new lesion appears, or the onset of data. If three dimensions are present, an ellipsoid
clinical symptoms occurs. volume formula (0.5326xyz) is utilized. If two
dimensions are present, the formula 0.532xy(x + y/2)
is used. If only one dimension is available, the
Natural History of Observed formula for the volume of a sphere (0.5326x3) is
Renal Masses employed [113]. Such volume measurements
may be more meaningful for solid lesions, as the
Recent attention has been directed towards growth rate in cystic lesions is confounded by the
describing the natural history, or growth kinetics, loss or accumulation of fluid that may not repre-
of SRMs under observation in an effort to identify sent a true change in tumor mass. Using mass
which lesions are safe to observe and which volume as a unit of measurement (mL or cm3),
require early definitive intervention. Since surgi- growth can then be expressed as change in ETV
cal excision has historically been performed soon per year or tumor doubling time [117]. Relative
after diagnosis, there are limited existing data proportional change in tumor diameter and vol-
regarding the growth history of SRMS. The ume can also be calculated and are expressed as
current body of evidence consists of small retro- percentage change in tumor size and volume per
spective accounts of SRMs undergoing a delay year [100].
prior to definitive treatment monitored with serial
abdominal imaging at unspecified intervals [82–
84, 103] and recent single institution series inves- Summary Data
tigating outcomes in select patients intentionally
managed with AS (all £level III evidence) [12, In an attempt to consolidate these individual
100, 104–115]. small experiences and identify growth trends in
SRMs, Chawla et al. performed a meta-analysis
of nine single institution retrospective series
Growth Kinetics including 234 masses followed for a mean dura-
tion of 34 months. Initial MTD was 2.6 cm (range
While there is considerable variation in the way 1.73–4.08), mean growth rate was 0.28 cm/year,
tumor characteristics are reported across studies, and pathologic confirmation was available in
the most reproducible method of reporting renal 46% (92% RCC or RCC variant) [118] (Fig. 10.4).
lesion growth is measurement of linear size We have recently updated these findings, per-
(MTD), which assumes that the tumor is spheri- forming a systematic literature review identifying
cal and that growth occurs uniformly in all direc- 18 studies that included 880 patients with 936
tions. The maximal cross-sectional diameter is SRMS (Table 10.1) [101]. Mean initial MTD was
measured with the growth rate expressed as the available in 14 studies (N = 586), ranging from
change in diameter per year (cm/year). When fol- 1.73 to 7.2 cm at the time of diagnosis [82, 83,
lowing a lesion with serial imaging it is essential 100, 103, 104, 106–110, 112–114, 119]. Initial
at each study to perform lesion measurements at ETV was included in six studies (N = 284), rang-
the same cross-sectional axial level for determi- ing from 6.0 to 83.5 cm3 at the time of diagnosis
nation and comparison of interval growth. Despite [100, 104, 107, 112, 113]. In comparison, MTD
178 M.C. Smaldone et al.

Fig. 10.4 Tumor size vs. Tumor Size Versus Time

time in published series 6
investigating small renal Sowery et al, N=22
masses under a period of
observation. Line slope
and length represent mean 5
growth rate and duration of
follow-up, respectively.
N represents the number of Chawla et al, N=61

Tumor size (cm)

renal lesions followed in
4
each individual series.
(Reproduced with Fujimoto et al, N=6
permission from “Chawla Kassouf et al, N=26
et al. The natural history of
3 Kato et al, N=18 Bosniak et al, N=40
observed enhancing renal
masses: Meta-analysis and
Volpe et al, N=32
review of the world
literature. The Journal of Wehle et al, N=32
Urology (2006); 2
175(2):427”; American
Urological Association by
Elsevier, Inc.)
1
0 15 30 45
Time (months)

(range 2.4–3.78 cm) and ETV (range 18.2– angiomyolipoma (1.6%) were most common. Of
116.4 cm3) at the conclusion of surveillance or malignant lesions, predominant histologic sub-
time of intervention were available in seven types included clear cell (67.2%) and papillary
(N = 139) [82, 83, 103, 107, 110, 119] and two (14.5%) disease, while chromophobe (1.1%) and
(N = 45) [107, 113] studies, respectively. Imaging collecting duct carcinoma (0.5%) were uncom-
characteristic data was available in 14 studies mon. Eighteen patients (2.1%) developed meta-
(N = 803) [82, 84, 100, 104–107, 109–113, 115, static disease over a mean period of observation
119]; the majority (88.2%) of lesions were solid of 40.2 months.
with 11.8% categorized as cystic. Multifocal dis- Representing perhaps the most robust data on
ease was reported in 10.1% of patients. Mean the natural growth history of solid untreated
change in maximal diameter per year was reported tumors to date, Smaldone et al. performed a
in 14 studies (N = 586), ranging from 0.1 to pooled analysis summarizing available individual
0.7 cm/year [82, 83, 100, 103, 104, 106–110, level data from 275 patients (299 SRMs) meeting
112–114, 119]. Change in ETV per year was final inclusion criteria [101]. This analysis
reported in seven studies (N = 389), ranging from revealed a mean age of 66.9 ± 12.3 years (median
2.7 to 26.8 cm3/year [100, 103, 104, 106, 107, 69; range 35–88) in 239 patients, while mean
112, 113]. Pathologic data were available for 248 maximal tumor diameter (n = 297) and ETV
patients across 17 studies [82, 83, 100, 103–106, (n = 297) at the time of diagnosis were 2.4 ± 1.4 cm
108–115, 119] (Table 10.2), which revealed pre- (median 2; range 0.2–12) and 17.8 ± 63.9 cm3
dominantly malignant disease (86.7%) of low- (median 4.3; range 0.004–903.7), respectively. In
grade (81%) nature. However, specific use of comparison, mean maximal tumor diameter
percutaneous biopsy was rarely reported. Of (n = 263) and ETV (n = 295) at the conclusion of
available data from six studies (N = 477) [105, observation were 3.2 ± 1.7 cm (median 2.8; range
106, 110, 111, 119], only 85 patients (17.8%) had 0.9–15) and 34.3 ± 115.9 cm3 (median 11.5; range
a biopsy performed as part of management plan- 0.27–1,765.1). With a mean duration of observa-
ning. Of benign lesions, oncocytoma (12%) and tion (n = 298) of 33.6 ± 23.1 months (median 27.1;
Table 10.1 Clinical and cross-sectional imaging characteristics of small renal masses managed with active surveillance
Mean
Mean Mean linear volumetric Mean
Mean age initial Mean initial Mean final Mean final growth rate growth rate follow-up
(years) Indication Imaging MTD (cm) ETV (cm3) MTD (cm) ETV (cm3) (cm/year) (cm3/year) (months) No.
N (no. (median; for AS characteristics (median; (median; (median; (median; (median; (median; (median; metastasis
Study SRMs) range) No. (%) No. (%) range) range) range) range) range) range) range) (%)
Fujimoto 6 (6) 59.7 (57; A—3 (50) Solid—6 (100) 2.47 (2.4, 3.78 (3.8; 0.57 (0.58; 29 (20.3; 0
et al. [82] 47–70) R—0 1.7–3.4) 2.8–4.7) 0.39–0.74) 9.7–71)
E –3 (50)
Bosniak 37 (40) 65.1 (65.5; Multifocal—9 (24) 1.73 (1.8; 3.11 (3; 0.4 (0.36; 5.26 (3.1; 43.9 (39, 0
et al. [103] 42–84) 0.2–3.5) 1.2–7) 0–1.1) 0–42.1) 21–102)
Oda et al. 16 (16) 54a (28–78) Solid—16 (100) 2a (1–4.5) 25a (12–72) 0
[84]
Volpe et al. 29 (32) 71a (27–84) Solid—25 (78) 2.48 (2.4; 10.06 (7.01; 18.2 (13.7; 0.1 3.8 (1.2; 35.3 (27.5; 0
[113] Cystic—7 (22) 0.9–3.9) 0.39–31.59) 0.3–63.7) 0–33.8) 5.3–143)
Multifocal—N/A
Wehle et al. 29 (29) 70.5 (N/A; 1.83 (N/A; 0.12 32 (N/A; 0
[114] 51–88) 0.4–3.5) 10–89)
Kato et al. 18 (18) 55.1 (56.5; E—18 (100) 1.98 (2; 2.81 (2.8; 0.42 (0.28; 27 (22.5; 0
[83] 37–71) 0.8–3.4) 1.4–4.4) .08–1.6) 12–63)
Sowery 22 (22) 77a (60–92) A—15 (68) Solid—15 (68) 4.08 (N/A; 62.4 (N/A; 0.86 24 (N/A) 26 (N/A) 1 (4.5)
et al. [112] E—7 (31.8) Cystic—7 (32) 2–8.8) 1.8–363)
Lamb et al. 36 (36) 76.1 (77, A—14 (39) Solid—36 (100) 7.2 (6; 0.39 (0; 27.7 (24; 1 (2.8)
[109] 56–91) R—17 (47) 3.5–20) 0–1.76) 3–136)
E—5 (14)
Kouba 43 (46) 67 (69, 2.92 (2.9; 0.7 (0.35, 35.8 (N/A) 0
et al. [108] N/A) N/A) N/A)
Abou 35 (44) 71.8 (74, Solid—38 (86) 2.2 (N/A; 6.1 (4.4; 0.21 (0.17; 2.7 (0.83; 47.6 (41; 3 (8.6)
Youssif 29–90) Cystic—6 (14) 0.5–4) 0.1–34.1) −0.3–1.9) −0.7–26.3) 6–160)
et al. [104] Multifocal—N/A
Fernando 13 (13) 80.4 (N/A, A—2 (15) Solid—13 (100) 5.02 (N/A; 83.5 (N/A; 5.57 (N/A, 116.4 (N/A; 0.17 11.97 38.4 (N/A; 1 (7.7)
et al. [107] 66–88) R—1 (8) 2–8.6) 4.2–338.8) 2–12.2) 4.2–618) (N/A) 19–105)
E—10 (77)
Matsuzaki 15 (15) 67 (N/A; A—5 (33) Solid—15 (100) 2.2 (N/A; 2.4 (N/A, 0.06 (N/A; 38 (N/A; 0
et al. [110] 44–87) E—10 (67) 1–3.9) 1–4.2) −0.09–0.28) 8–91)
(continued)
Table 10.1 (continued)
Mean
Mean Mean linear volumetric Mean
Mean age initial Mean initial Mean final Mean final growth rate growth rate follow-up
(years) Indication Imaging MTD (cm) ETV (cm3) MTD (cm) ETV (cm3) (cm/year) (cm3/year) (months) No.
N (no. (median; for AS characteristics (median; (median; (median; (median; (median; (median; (median; metastasis
Study SRMs) range) No. (%) No. (%) range) range) range) range) range) range) range) (%)
Wong et al. 1 (1) 78 A—1 (100) Solid—1 (100) 2.5 6 5.9 96 2.7 71.9 15 1 (100)
[115]b
Siu et al. 41 (47) 68 (N/A, A—25 (53) Solid—47 (100) 2 (N/A; 2.6 (N/A; 0.27 (N/A; 29.5 (23.7; 1 (2.4)
[119] 34–84) E—22 (47) Multifocal—N/A 0.8–5) 0.8–6.9) −0.13–1.5) N/A)
Abouassaly 110 81a (76–95) Solid—106 (96) 2.5a 0.26 (0.08; 24 (N/A) 0
et al. [105] Cystic—4 (4) (0.9–11.2) 0–3.3)
Multifocal—N/A
Beisland 63 (65) 76.6 (78.8; Solid—60 (92) 4.3 (3.5; 0.66 (0.31; 26.8 (3.5; 33 (37; 1–34) 2 (3.2)
et al. [106] 56–89) Cystic—3 (5) 1.3–11.1) −0.4–4.9) −4.8–277)
Multifocal—N/A
Crispen 154 69 (71; A—18 (12) Solid—147 (85) 2.45 (2; 20 (4.18; 0.29 (0.15; 17 (3; 31 (24; 3 (1.9)c
et al. [100] (173) 35–88) R—21 (13) Cystic—26 (15) 0.4–12) 0.3–904) −1.4–2.47) −20–431) 12–156)
E—115 (75) Multifocal—12 (8)
Rosales 212 71a (50–92) Solid—183 (86) 2.8a 3.7a 0.34a 35a (6–137) 4 (1.9)
et al. [111] (223) Cystic—40 (14) (0.5–13.1) (0.9–14.1) (0.29–2.3)
SRM small renal mass, AS active surveillance, MTD mean linear tumor diameter, ETV estimated tumor, A absolute, R relative, E elective
a
Median value
b
Case report of a single small renal mass progressing to metastasis under observation, which was excluded from summary data
c
Includes unpublished data
 10

Table 10.2 Pathologic characteristics of small renal masses managed with a period of observation
Study Pathologic grade Histologic subtype—malignant Histologic subtype—benign
No. with
pathologic No. High Low Clear Collecting Unable to
No. (%) data malignant grade grade cell Papillary Chromophobe duct characterize AML Oncocytoma Cyst
Fujimoto et al. [82] 6 6 (100) 1 (17) 5 (83) 6 (100)
Bosniak et al. [103] 26 22 (85) 0 22 (100) 4 (15)
Oda et al. [84] 16 16 (100) 1 (6) 15 (94)
Volpe et al. [113] 9 8 (89) 4 (50) 4 (50) 8 (89) 1 (11)
Wehle et al. [114] 4 3 (75) 0 3 (100) 1 (25)
Active Surveillance of the Small Renal Mass

Kato et al. [83] 18 18 (100) 3 (17) 15 (83) 15 (83) 3 (17)

Sowery et al. [112] 2 2 (100)
Lamb et al. [109] 24 23 (96) 1 (25) 3 (75) 18 (75) 1 (4) 1 (4)
Kouba et al. [108] 14 12 (86) 2 (17) 10 (83) 1 (8) 1 (8)
Abou Youssif et al. [104] 8 6 (75) 4 (50) 2 (25) 2 (25)
Matsuzaki et al. [110] 3 3 (100) 0 3 (100) 3 (100)
Wong et al. [115] 1 1 0 1 1 (100)
Siu et al. [119] 16 10 (63) 10 (63) 6 (37)
Abouassaly et al. [105] 4 2 1 (50) 1 (50) 1 (25) 1 (25) 1 (25) 1 (25)
Beisland et al. [106] 18 15 (83) 5 (50) 5 (50) 9 (60) 5 (33) 1 (7) 3 (17)
Crispen et al. [100] 68 57 (84) 12 (23) 40 (77) 39 (68) 15 (26) 2 (4) 1 (2) 4 (17) 2 (3) 7 (10)
Rosales et al. [111] 11 11 (100) 11 (100)
Total
248 215/248 30/157 127 /157 125/186 27/186 2/186 (1.1) 1/186 (0.5) 6/186 (3.2) 3/186 (1.6) 26/216 (12) 1/186
(86.7) (19) (81) (67.2) (14.5) (0.5)
AML angiomyolipoma
181
182 M.C. Smaldone et al.

range 5.3–156), calculated mean change in maxi- radiographic growth with low metastatic potential
mal diameter (linear growth rate; n = 263) and while under an initial period of observation.
ETV (volumetric growth rate; n = 295) per year However, early efforts to identify radiographic
were 0.33 ± 0.41 cm/year (median 0.26; range characteristics associated with rapid growth rate
−1.4 to 2.7) and 7.3 ± 27.9 cm3/year (median 1.9; or aggressive malignant potential have been elu-
range −20.0 to 430.7). sive, as no correlation or conflicting data has been
documented between tumor growth and patient
age [100, 108], initial MTD [57, 104, 105, 108,
Radiographic Predictors of Tumor 113], tumor size >4 cm [106, 112], development
Growth Rate and Malignant Potential of clinical symptoms vs. incidental detection
[112], multifocality [120], or solid/cystic appear-
These data confirm initial observations that a ance [112, 113] (Fig. 10.5a, b). In fact, while ini-
majority of localized renal tumors exhibit slow tially assumed that larger tumors at presentation

a
2.5

1.5
Growth Rate (cm/yr)

0.5

−0.5

−1

−1.5
0 2 4 6 8 10 12 14
Size on Presentation (cm)

b 0.3

0.25
Growth Rate (cm/yr)

0.2

0.15

0.1

0.05

0
1
e

tic

y
e
al

lid

l
ar
ca
al
m

ys
So

lit
M

o
Fe

tif

So
ul
M

Fig. 10.5 (a) Observed tumor growth rate vs. tumor size (Reproduced with permission from “Crispen et al.
at presentation (p > 0.05). (b) Observed tumor growth rate Predicting growth of solid renal masses under active sur-
comparing male vs. females, solid vs. cystic tumors, and veillance. Urologic Oncology: Seminars and Original
multifocal vs. solitary tumors (p > 0.05 for all comparisons). Investigations (2008); 26(5):556–7”; Elsevier, Inc.)
10 Active Surveillance of the Small Renal Mass 183

may demonstrate faster growth rates, Crispen et al. does not account for selection bias and may reflect
demonstrated in a large single institutional series a trend towards earlier intervention in patients
that when annual percent change in tumor size and with rapid growth rates [68]. On further subanaly-
volume is calculated, smaller tumors grow at pro- sis of 76 SRMs (9 oncocytomas, 67 RCC variants)
portionally faster rates compared to larger tumors with available pathologic and growth kinetic data,
[100]. This finding is suggestive of Gompertzian the authors reported that both initial MTD (2.0 cm
growth kinetics, which theorizes that a tumor’s vs. 2.2 cm; p = 0.59) and mean growth rate (0.1 cm/
growth rate is initially exponential and then year vs. 0.4 cm/year; p = 0.15) were comparable
decreases with increasing size [121]. Although between groups [118]. These data, supported by
there are emerging anecdotal data suggesting that positive growth rates documented in percutane-
cT1b and even cT2 tumors may be judiciously ously biopsied oncocytomas managed subse-
observed for short periods in select patients with quently with observation [123], suggest that a
significant medical comorbidity [122], the biology positive growth rate is not always indicative of
of these lesions must be distinguished from the malignant histology, and further assessment to
infrequent case of a localized mass with aggres- identify characteristics predictive of aggressive
sive malignant potential that develops metachro- malignant potential is necessary.
nous disease during a period of AS.
Additional efforts to characterize the malignant
potential of SRMs have also yielded conflicting SRMs Undergoing Delayed Intervention
results and are severely limited by lack of compete
pathologic assessment. In 18 patients who under- While consideration of preoperative indications
went surgical excision 12 or more months follow- for AS are important, it is equally important to
ing diagnosis, Kato et al. reported that grade 3 review characteristics of lesions progressing to
lesions grew at significantly faster rates than grade delayed intervention. In a large single institution
2 lesions (0.93 cm/year vs. 0.28 cm/year; p = 0.01); review of 87 SRMs followed for more than
however, these findings are limited by small sam- 12 months, Crispen et al. reported that definitive
ple size. In fact, in their dataset grade 1 lesions treatment was delayed for ³12 or 24 months in
grew faster than grade 2 lesions (0.37 cm/year vs. 69% and 33% of tumors, respectively. Of these,
0.28 cm/year) although this did not reach statisti- pathology assessment confirmed RCC in 84% of
cal significance (p = 0.47) [83]. From their retro- treated tumors, of which only 26% revealed
spective series of 47 SRMs under surveillance, Siu aggressive histologic features. Importantly,
et al. compared patients with proven RCC (n = 10) despite delay in therapy, 76% of patients under-
vs. oncocytoma (n = 6), reporting no differences in went nephron-sparing approaches and 60% were
tumor growth rate (0.71 cm/year vs. 0.52 cm/year; treated in a minimally invasive fashion. The
p = NS) between groups [119]. In one of the larg- authors concluded from these data that definitive
est single institution experiences to date (154 therapy may be cautiously delayed in select
patients, 173 SRMs followed for a minimum of patients without limiting available treatment
12 months), Crispen et al. reported that SRMs options or incurring a high risk of disease pro-
stratified by Fuhrman grade and presence of gression [124].
benign histologic features exhibited no differences From our systematic review (Table 10.3), 204
in growth rates [100]. In their original meta-analy- (23.2%) underwent delayed intervention after a
sis, when comparing pathologically confirmed mean period of observation [82–84, 100, 103–
RCCs with lesions managed with observation, 106, 108, 110–114, 119] ranging from 11.3 to
Chawla et al. reported that initial MTD was simi- 45.6 months (N = 151) [83, 100, 103, 106, 108,
lar between groups but the growth rate of proven 110, 113, 114]. Reason for progression to therapy
malignant lesions was significantly greater was available in 11 series (N = 138) [82, 100,
(0.4 cm/year vs. 0.2 cm/year, p = 0.001) compared 104–106, 110–114, 119] and consisted of patient
to strictly observed lesions [118]. However, this preference (46.4%), improved medical condition
 184

Table 10.3 Comparison of cross-sectional imaging characteristics and growth kinetics of small renal masses managed with observation alone and those who progressed to
delayed intervention
SRMs managed with observation alone SRMs progressing to delayed intervention
Mean linear Mean Mean volumetric Mean linear Mean volumetric
No. Mean initial growth rate initial ETV growth rate No. Mean initial growth rate Mean final growth rate (cm3/
Study SRMs MTD (cm) (cm/year) (cm3) (cm3/year) SRMs MTD (cm) (cm/year) ETV (cm3) year)
Fujimoto et al. [82] 1 1.8 0.55 5 2.6 0.58
Bosniak et al. [103] 14 1.91 0.29 3.13 26 1.63 0.46 6.41
Volpe et al. [113] 23 2.3 8.34 3.5 9 2.93 14.5 4.54
Kato et al. [83] 0 18 1.98 0.42
Kouba et al. [108]a 32 3.07 0.61 6.5 1.17 14 2.59 0.9
Abou Youssif et al. [104]a 17 2.1 0.15 8 1.9 0.5 4 5.5
Matsuzaki et al. [110] 12 2.18 0.08 3 2.17 0
Crispen et al. [100] 105 2.49 0.24 17.4 5.74 68 2.38 0.34 24 11.3
Rosales et al. [111]b 197 2.61 0.34 15 3.56 1.75
Total Total
Summary data (range) 204 1.8–3.07 0.08–0.61 6.5–17.4 1.17–5.74 151 1.63–3.56 0–1.75 4–24 4.54–11.3
Pooled analysis 155 2.4 0.25 15.7 5.6 129 2.2 0.39 22.9 9.7
SRM small renal mass, MTD maximum linear tumor diameter, ETV estimated tumor volume
a
Individual data unavailable and was not utilized in pooled analysis evaluation of growth kinetics
b
Only median values reported which were not included in final summary data
M.C. Smaldone et al.
10 Active Surveillance of the Small Renal Mass 185

(6.3%), tumor growth (45.7%), or other (1.6%; assessment revealed similar malignancy rates
retroperitoneal hematoma, concurrent surgical between groups (83% vs. 89%, p = 0.56), an
procedure). In our recent pooled analysis of indi- observation which has been confirmed in other
vidual level data, comparison of patients under- small series [103, 114]. Supporting this data, our
going delayed intervention (N = 129) and those recent systematic review reported that of 421
managed strictly with surveillance (N = 155) SRMs with available data, 29.5% exhibited zero
revealed similar initial MTD (2.4 cm vs. 2.2 cm; net growth over time, and there was no difference
p = 0.212) and initial ETV (16.4 cm3 vs. 16.03 cm3; in pathologic malignancy rate (84% vs. 93%,
p = 0.82) at the time of diagnosis. However, p = 1.0) between lesions exhibiting positive and
significantly increased linear (0.26 cm/year vs. zero growth [82, 83, 100, 103, 105, 107–110,
0.39 cm/year; p = 0.0001) and volumetric 113–115, 119]. Pooled analysis of available indi-
(5.5 cm3/year vs. 8.8 cm3/year; p = 0.001) growth vidual level data (220 exhibiting growth vs. 65
rates were observed in the patients undergoing patients exhibiting no growth) revealed no differ-
active treatment [101]. While intuitive that lesions ence in initial MTD (2.3 cm vs. 2.5 cm; p = 0.46)
with faster growth kinetics would self-select for between groups (Table 10.4) [101]. While these
treatment, these data are confounded by lack of data confirm that lack of interval radiographic
standardized criteria for intervention among con- growth does not correlate with benign histology,
temporary surveillance protocols. Furthermore, an important observation is that no lesion demon-
similar to clinical experiences with AS in pros- strating zero net growth while under surveillance
tate cancer [25], a large proportion of patients has progressed to metastatic disease.
(46% of those with available data) proceeded to
intervention despite the absence of predetermined
clinical or radiographic triggers. SRMs Progressing to Metastases
While Under Surveillance

SRMs Exhibiting “Zero Net Growth” Progression to metastatic disease in patients with
While Under Surveillance SRMs under AS is uncommon and poorly docu-
mented in the literature. Our recent systematic
Observed linear growth rates range from 0.06 to review identified 18 patients progressing to meta-
0.86 cm/year in contemporary individual series static disease from a cohort of 880 patients with
[82–84, 100, 103–114, 119], with summary data SRMs under AS (2.1%) [100, 104, 106, 107, 109,
consistently reporting overall growth rates rang- 111, 112, 115, 119, 126] (Table 10.5). Indications
ing from 0.28 to 0.32 cm/year [101, 118]. for active surveillance (n = 13) were absolute in
However, these data also reveal a subset of SRMs 61.5% and elective in 38.5%. Pathologic
that demonstrate no interval growth on serial confirmation of diagnosis was made in nine cases
imaging while under observation. In single insti- (50%); three with percutaneous biopsy [100, 111,
tution series of enhancing SRMs followed for 115], five at the time of surgical exploration [100,
more than 12 months (mean 29 months), Kunkle 104, 119], and one unknown [126]. Of the 11
et al. compared radiographic characteristics in 35 patients with available information, three (72.7%)
(33%) lesions exhibiting zero net growth and 70 were diagnosed with distant visceral or bony dis-
masses (67%) showing growth at 0.31 cm/year. ease with or without positive lymphadenopathy,
No differences were seen with respect to patient and three patients were diagnosed with patho-
age (p = 0.96), initial MTD (p = 0.41), solid/cystic logic lymph node involvement only (27.3%).
appearance (p = 1.0), or incidental detection rate Histologic subtypes were predominantly clear
(p = 0.38) [125]. Not surprisingly, there was a cell (66.7%) [100, 104, 109, 115, 119, 126] and
significantly increased rate of intervention in papillary (22.2%) [104, 111], with one lesion
lesions demonstrating positive growth rates (51% exhibiting mixed clear cell and papillary features
vs. 17%, p = 0.001). However, pathological (11.1%) [100]. Importantly, time to development
 186

Table 10.4 Comparison of growth kinetics and pathologic characteristics in small renal masses exhibiting zero growth and positive growth during a period of observation
SRMs with zero growth SRMs with positive growth
No. with zero Mean initial Pathologic No. with positive Mean initial Mean linear growth
Study growth MTD (cm) characteristics growth MTD (cm) rate (cm/year) Pathologic characteristics
Fujimoto et al. [82] 0 6 2.47 0.57 6—malignant (6—clear cell; 1 HG, 5 LG)
Bosniak et al. [103] 2 1.9 1—malignant 38 1.72 0.42 4—benign (oncocytoma)
(LG RCC) 21—malignant (21 LG RCC)
Volpe et al. [113] 7 2.82 25 1.98
Kato et al. [83] 0 18 1.98 0.42 18—malignant (15—clear cell,
3—papillary; 15—HG, 3—LG)
Matsuzaki et al. [110] 11 2.25 3—malignant 4 2 0.21
(3 clear cell)
Wong et al. [115]a 0 1 2.5 2.7 1—LG clear cell RCC
Siu et al. [119]b 21 1.9 2—malignant 26 2.1 0.5 8—malignant
6—benign (oncocytoma)
Abouassaly et al. 38 2.49 51 2.87 0.56 2—malignant (1 clear cell, 1 papillary)
[105]b 2—benign (1 oncocytoma, 1 atypical)
Crispen et al. [100] 45 2.5 8—malignant 128 2.4 0.41 44—malignant
1—benign 8—benign
(oncocytoma)
Total Total
Summary data (range) 124 1.9–2.82 Malignant (93) 297 1.72–2.87 0.21–0.57 Malignant (84)
Benign (7) Benign (16)
Pooled analysis 65 2.5 220 2.3 0.43
SRM small renal mass, MTD maximum linear tumor diameter, RCC renal cell carcinoma, HG high grade, LG low grade
a
Case report of a single small renal mass progressing to metastasis under observation, which was excluded from summary data
b
Individual data unavailable and was not utilized in pooled analysis of growth kinetics
M.C. Smaldone et al.
 10
Table 10.5 Clinical and radiographic characteristics of documented small renal masses progressing to metastasis under a period of observation
Linear
Age MTD at ETV at MTD at ETV at Time to growth Volumetric
Clinical (years); Indication diagnosis diagnosis metastasis metastasis metastasis Rate growth rate
series gender for AS (cm) (cm3) (cm) (cm3) (months) (cm/year) (cm3/year) Site of metastasis, pathologic data; outcome
Lamb 79 Electivea 132 Clear cell (FG 3)
et al. [109] Alive at 136 months
Sowery 74; M CHR 8.8 363 10.7 653 68 0.33 50.9 RPLAD, liver
et al. [112] Managed with angioembolization, mortality
at 70 months
Wong 78; F CHR 2.5 6 5.9 95.8 15 2.7 71.8 RP LAD, pulmonary; clear cell (FG 2)
et al. [115] Mortality at 20 months
Fernando NA; F 20 Pulmonary
et al. [107] Mortality at 22 months
Siu et al. NA; F CHR 3 14.4 6 115 78 0.46 15.5 RP LAD; clear cell
Active Surveillance of the Small Renal Mass

[119] Attempted pNx which was aborted due to

grossly positive lymphadenopathy. Patient
ultimately died from locally advanced disease
Abou NA Electivea 2.7 10.5 5.8 103.9 40 0.94 28.3 Spine
Youssif NA [104] Elective 2.7 10.5 4.5 48.5 29 0.75 15.8 Pulmonaryb; pT3aN0Mx; clear cell (FG 3)
et al. [104] Nx at 26 months, mortality at 35 months
NA [104] Elective 4.5 33.5 4.8 46.6 37 0.1 4.8 Pancreas, RP LADb; pT1bNxMx; papillary
Nx at 13 months, developed metastasis at
37 months from diagnosis
Biesland 81 CHR 6.2 126.9 Mortality at 9 months from diagnosis
et al. [106] 82 CHR 6.7 160.2
Crispen 84; M CHR 3 11 8 102.1 54 1.1 20.2 Pulmonary
et al. [100] Hospice, mortality
70; F CHR 3.2 16.6 4.8 51.1 63 0.3 6.6 RP LAD; pT1bN2Mx; mixed clear cell and
papillary (FG 4)
Partial Nx and lymph node dissection. No
adjuvant therapy, deceased
54; M CHR 2.7 6.5 80 38 RP LAD; pT3aN2Mx; clear cell (FG 2)
[100] Alive, no adjuvant therapy
(continued)
187
Table 10.5 (continued)
188

Linear
Age MTD at ETV at MTD at ETV at Time to growth Volumetric
Clinical (years); Indication diagnosis diagnosis metastasis metastasis metastasis Rate growth rate
series gender for AS (cm) (cm3) (cm) (cm3) (months) (cm/year) (cm3/year) Site of metastasis, pathologic data; outcome
Rosales NA 2 4.3 4.1 36.7 22c 1.2 18 papillary
et al. [111] NA 3.1 15.9 3.8 29.2 22c 0.4 7.4
NA 5.1 70.7 6.1 120.9 22c 0.6 27.9
NA 7.2 198.8 8.7 350.7 22c 0.83 84.4
Jewett 74; F Elective 2.7 8.3 3.1 13.4 12 0.4 5.1 Pulmonary; clear cell (FG 2)
et al. [126] Alive on tyrosine kinase inhibitors
Pooled analysis (n = 18)
75.1 4.3 70 5.9 132.1 40.2 0.77 27.4
AS active surveillance, MTD maximum linear tumor diameter, ETV estimated tumor volume, CHR competing health risk, LTF lost to follow up, Nx nephrectomy, pNx partial
nephrectomy, RP LAD retroperitoneal lymphadenopathy, FG Fuhrman grade
a
Patient lost to follow up for prolonged period, metastasis documented at time patient represented
b
Underwent nephrectomy prior to documentation of metastasis
c
Mean time to metastasis in this cohort was 22 months, individual data per patient not available
M.C. Smaldone et al.
10 Active Surveillance of the Small Renal Mass 189

of metastatic disease was a late event (mean 40.2, observations to consider are that metastasis was a
range 12–132 months). late event (>3 years following diagnosis), all
Comparing patients who progressed to meta- lesions that progressed were >3 cm at the time of
static disease in our systematic review (n = 18) metastasis, all demonstrated positive growth
with those who did not in our pooled cohort of rates, and no lesion exhibiting zero net growth
patients with individual level data (n = 281), the while under surveillance has developed metasta-
duration of observation was similar between ses while under observation [101]. Of available
groups (40.2 months vs. 33.3 months; p = 0.47), characteristics, a positive growth rate may be the
but there were significant differences in mean most accurate available predictor of potential for
patient age (75.1 years vs. 66.6 years; p = 0.03). disease progression among readily available met-
Trends in patients progressing to metastases rics and indicate the need for definitive interven-
included larger tumor size (4.1 cm vs. 2.3 cm; tion, while lesions demonstrating zero net growth
p < 0.0001) and ETV (66.4 cm3 vs. 15.1 cm3; may self-select for continued AS. There has been
p < 0.0001) at diagnosis as well as mean linear one reported case of a 73-year-old male with a
(0.80 cm/year vs. 0.30 cm/year; p = 0.0001) and 2.4 cm renal mass progressing to bony metasta-
volumetric growth rates (27.1 cm3/year vs. ses at 5 months with no increase in tumor size
6.2 cm3/year; p < 0.0001) [101]. [126]. It is unclear from available data whether
When considering patient selection for AS this represents true clinical progression or occult
protocols, the most important endpoint to con- undiagnosed systemic disease at the time of pre-
sider is metastatic disease progression. While sentation and for this reason was excluded from
findings of our review suggest that the proportion our progression cohort. However, this example
of lesions that progressed was low (2.1%), these highlights the need for close scrutiny of contem-
lesions demonstrated a rapid growth rate (0.8 cm/ porary surveillance protocols.
year) and were predominantly high-grade, clear
cell histology, and ³cT1b at the time of diagnosis
(38% >4 cm), perhaps reflecting poor initial case Conclusions
selection or substantive competing risk [101].
Supporting this theory, elderly patients with With the increased utilization of cross-sectional
absolute indications for surveillance were more abdominal imaging, there has been a significant
common in the progression cohort, implying that stage migration towards the incidental detection
they were not acceptable operative candidates at of small clinically localized renal masses <4 cm.
diagnosis despite concerning radiographic char- The gold standard for the management of enhanc-
acteristics. Furthermore, because this group ing renal lesions remains surgical excision.
included some individuals who were lost to fol- However, despite a concurrent increase in surgi-
low up it is conceivable that a proportion of these cal resection rates, cancer-specific mortality
patients would have undergone definitive treat- remains unchanged implying that a proportion of
ment if more closely followed. these SRMs may be indolent tumors that may not
There are significant limitations in the inter- require surgical intervention. Although the con-
pretation and application of existing AS data, temporary body of literature on the natural his-
including the quality of evidence (all £level III), tory of untreated SRMs is limited, recent pooled
significant selection bias, and lack of universal data demonstrate that the vast majority demon-
pathologic evaluation. These limitations are espe- strate slow growth kinetics with a very low rate of
cially important to consider when evaluating the progression to metastatic disease. Approximately
rate of progression to metastatic disease, as the 20–30% of SRMS exhibit zero net growth under
inclusion of benign disease and exclusion of rap- observation, and while malignancy rates are
idly growing lesions might falsely lower the equivalent when compared to lesions demonstrat-
observed rate of disease progression [127]. ing positive growth, to date no zero growth lesion
However, despite these limitations, important has progressed to metastatic disease nor has any
190 M.C. Smaldone et al.

SRM been <3 cm at the time of progression. 4. Cooperberg MR, Mallin K, Ritchey J, et al. Decreasing
Analysis of lesions that have progressed to metas- size at diagnosis of stage 1 renal cell carcinoma: anal-
ysis from the National Cancer Data Base, 1993 to
tases under observation reveals that these tumors 2004. J Urol. 2008;179(6):2131–5.
are more likely to be larger at diagnosis, high 5. Kane CJ, Mallin K, Ritchey J, et al. Renal cell cancer
nuclear grade, with significantly more rapid stage migration: analysis of the National Cancer Data
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ognizing more aggressive phenotypes at the time dipitously discovered renal cell carcinoma. Urology.
of presentation are needed, metastatic progres- 1998;51(2):203–5.
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event. Of available characteristics, linear growth Incidence of benign pathologic findings at partial
nephrectomy for solitary renal mass presumed to be
rate appears to be the most useful predictor of renal cell carcinoma on preoperative imaging.
metastatic potential, and it seems reasonable that Urology. 2006;68(4):737–40.
SRMs that demonstrate rapid growth kinetics 8. Crispen PL, Boorjian SA, Lohse CM, et al. Outcomes
should proceed to immediate definitive interven- following partial nephrectomy by tumor size. J Urol.
2008;180(5):1912–7.
tion while lesions exhibiting zero or minimal 9. Remzi M, Ozsoy M, Klingler HC, et al. Are small
growth self-select for continued AS. We antici- renal tumors harmless? Analysis of histopathological
pate that as contemporary investigations prog- features according to tumors 4 cm or less in diameter.
ress, improved imaging techniques, utilization of J Urol. 2006;176(3):896–9.
10. Jemal A, Siegel R, Ward E, et al. Cancer statistics,
percutaneous biopsy, and biomarker discovery 2008. CA Cancer J Clin. 2008;58(2):71–96.
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match treatment to individual tumor biology. In utilization trends of partial nephrectomy for renal cell
the interim, emphasis on preoperative nomo- carcinoma: a case of underutilization? Urology.
2006;67(2):254–9.
grams stratifying SRM malignant potential and 12. Huang WC, Levey AS, Serio AM, et al. Chronic kid-
competing medical risks will continue to grow as ney disease after nephrectomy in patients with renal
more practitioners embrace AS as a viable treat- cortical tumours: a retrospective cohort study. Lancet
ment strategy. While prospective trials would be Oncol. 2006;7(9):735–40.
13. McKiernan J, Simmons R, Katz J, et al. Natural his-
ideal, randomized comparisons with surgical tory of chronic renal insufficiency after partial and
excision and ablation are unlikely. In the absence radical nephrectomy. Urology. 2002;59(6):816–20.
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partial nephrectomy. J Urol. 2008;179(2):468–71
[discussion 72–3].
17. Gill IS, Kavoussi LR, Lane BR, et al. Comparison of
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 Part III
Locally Advanced Disease
 Locally Advanced Renal Cell
Carcinoma 11
Stephen H. Culp and Christopher G. Wood

distant disease using the surveillance epidemiology

Introduction and end result (SEER) database, Zini et al. found
that the 1-, 2-, 5-, and 10-year disease-specific
Renal cell carcinoma (RCC) accounts for 3% of survival for patients undergoing nephrectomy for
all adult malignancies and is the most lethal of locally advanced disease (n = 6,575) was 88.9%,
the common genitourinary cancers. Surgery 88.1%, 68.6%, and 57.5%, respectively [3]. For
remains the standard of care for patients with patients undergoing nonsurgical therapy (e.g.,
localized disease. Independent predictors of both observation, systemic therapy, etc.) (n = 282), the
progression-free and overall survival in patients corresponding numbers were 44.8%, 30.6%,
with non-metastatic RCC include tumor stage, 14.5%, and 10.6%. Nonsurgical therapy was
grade, and regional lymph node involvement associated with a 5.8-fold increased risk of
[1, 2]. Although patients with low-stage, low-grade death in patients with locally advanced but
tumors tend to do well, patients with locally non-metastatic RCC. In patients with locally
advanced RCC demonstrate a high risk for both advanced disease, staging modalities should
recurrence and progression of disease despite include a dedicated MRI or multiphase CT scan
surgical therapy. In this chapter, we review locally of the abdomen and chest. For patients with bone
advanced RCC, including venous involvement, pain or an elevated alkaline phosphatase, a bone
extracapsular extension, and involvement of adja- scan should also be obtained. For those with
cent lymph nodes or organs. symptoms attributed to central nervous system
Surgery is the mainstay of treatment for involvement, appropriate imaging of the brain
patients with locally advanced and non-metastatic and/or spine should also be obtained [4].
disease, providing improved cancer-specific sur-
vival (CSS) that cannot be achieved with other
modalities. In their study of patients with locally Lymph Node Disease
advanced disease (T3/T4, N0–2) but no evidence of
Historically, lymph node involvement was seen
S.H. Culp in 23–35% of RCC cases [5]. More recently,
Department of Urology, University of Virginia Health however, isolated lymph node involvement is
System, Box 800422, Charlottesville, VA 22908, USA observed in only 3–5% of patients without clini-
e-mail: [email protected]
cal evidence of visceral metastatic disease.
C.G. Wood () Obviously, the incidence of positive lymph nodes
Department of Urology, The University of Texas
depends on the extent of lymph node dissection
MD Anderson Cancer Center, 1515 Holcombe
Boulevard, Unit 1373, Houston, TX 77030, USA (LND) [6]. When only hilar and regional lymph
e-mail: [email protected] nodes are resected, the incidence of lymph node

S.C. Campbell and B.I. Rini (eds.), Renal Cell Carcinoma: Clinical Management, Current Clinical Urology, 197
DOI 10.1007/978-1-62703-062-5_11, © Springer Science+Business Media New York 2013
198 S.H. Culp and C.G. Wood

Table 11.1 2010a and 2002b AJCC classification of renal LND, Giuliani et al. found that when tumors were
cell carcinoma based on TNM staging confined to the kidney, only 6% of patients had
Primary tumor Lymph node Metastasis lymph node involvement. However, the incidence
Stage (T) (N) (M) of lymph node disease increased to 46.4%
I T1 N0 M0 with locally advanced disease and 61.0% when
II T2 N0 M0 distant metastases were present. When vascular
III T1/T2 N1 M0
infiltration and distant metastases were both
T3 N0/N1 M0
IV T4 Any N M0
present, the incidence of lymph node disease was
Any T N1a or N2b M0 66.6% [11]. In a later study, Zisman et al. exam-
Any T Any N M1 ined 661 patients without metastatic disease and
found that in patients with stage T2 or less disease
(based on 1997 UICC TNM scheme), 3% had
positive disease is 5–8%. However, the incidence lymph node positive disease whereas 20% of
of lymph node positivity can be as high as 38% patients with stage III/IV disease had lymph node
when an extensive LND is performed [6]. positivity [12].
Regardless, most patients with lymph node Lymph node involvement is also correlated
involvement will also have concurrent distant with Fuhrman nuclear grade. In patients with
metastatic disease. lymph node negative disease, Pantuck et al. found
Table 11.1 details the staging of RCC pertinent that 67% had low-grade disease (Fuhrman grade
to locally advanced disease, staged 3 and 4. I or II). However, 68% of patients with node
According to the historic Robson staging system, positive disease had high grade disease (Fuhrman
lymph node positive disease was stage IIIb because grade III or IV) [13]. In addition, Guiliani et al.
the prognosis of patients with lymph node involve- found that 81% of grade III patients but only
ment was significantly worse than those classified 25% of grade 1 tumors were node positive or
Robson stages I–IIIa [7]. In the 2002 TMN AJCC metastatic [14].
staging criteria, a single node corresponds to stage RCC tumor histology is another potential
IIIb or IIIc in the absence of metastatic disease and predictor of regional lymph node involvement.
whether the primary tumor (T) stage was I/II or III, In their study of 245 patients with non-metastatic
respectively. Two or more positive nodes corre- papillary RCC undergoing nephrectomy at
spond to stage IV in the 2002 TMN AJCC staging. MDACC, Margulis et al. found that 13% har-
However, in the most recent 2010 TMN AJCC bored lymph node metastasis, compared to 8% in
staging criteria, only N0 or N1 (not N2) is used to patients with clear cell histology (p < 0.02) [15].
determine stage III or IV disease in conjunction Of interest, lymph node metastases in patients
with T stage and metastatic status. with papillary RCC seemed to demonstrate a
Preoperative evaluation of lymph node involve- more indolent course in that these patients had a
ment has evolved over the past few decades with 65% disease-specific survival compared to 19%
the advancement of imaging. CT imaging is the for patients with regional lymph node disease and
standard modality, with a sensitivity greater than clear cell histology. In addition, in a subsequent
90% [8]. Sensitivity is decreased when only hilar study by Delacroix et al. examining 68 patients
lymph nodes are involved, with accuracies rang- with RCC and pathological nodal involvement
ing from 43% to 83% [9, 10]. The risk of a false but no distant metastasis, papillary histology was
positive reading is increased in the presence of an independent predictor of overall survival (HR
tumor thrombus or necrosis, because, when the 0.26; 95% CI 0.08, 0.85; p = 0.026) and patients
latter is present, lymph nodes as large as 2 cm with papillary RCC demonstrated a delayed time
may be reactive rather than involved by tumor. to recurrence (37.2 months) compared to patients
The risk of lymph node disease involvement with clear cell RCC (4.4 months) [16].
increases with tumor stage. In their study of 104 Multiple studies have shown that lymph
consecutive patients undergoing an extended node involvement is associated with decreased
11 Locally Advanced Renal Cell Carcinoma 199

Fig. 11.1 Cancer-specific survival of patients with A protocol for performing extended lymph node dissection
clear cell renal cell carcinoma treated with nephrectomy using primary tumor pathological features for patients
based on regional lymph node involvement (pN0/pNx treated with radical nephrectomy for clear cell renal cell
vs. pN1/pN2). Reprinted with permission from Blute carcinoma. The Journal of Urology 2004;172(2):
ML, Leibovich BC, Cheville JC, Lohse CM, Zincke H. 465–9

survival. In their study of 1,652 patients undergoing positive lymph nodes was an independent predictor
radical nephrectomy for unilateral non-metastatic of both decreased recurrence-free survival (HR
sporadic clear cell RCC between 1970 and 2000, 2.83; 95% CI 1.06, 7.61, p = 0.039) and overall
Blute et al. found that the 1-, 5-, and 10-year survival (HR 9.33; 95% CI 1.85, 47.09, p < 0.01)
disease-specific survival of patients with pN0/ [18]. The ratio of positive to total lymph nodes
pNx disease was 95.5%, 82.1%, and 72.5%, removed is also important in survival. In their
respectively. However, patients with pN1/pN2 study of 618 patients undergoing LND between
disease demonstrated a much decreased 1-, 5-, 1983 and 1999, Terrone et al. found that 14.2% of
and 10-year disease-specific survival of 52.2%, patients had positive lymph nodes with a 5-year
20.9%, and 11.4% (Fig. 11.1) [17]. In addition, disease-specific survival of 18%. There was no
Margulis et al. found that 5-year CSS for patients difference in survival based on pN1 and pN2 or,
with clear cell RCC and lymph node involvement as important, the number of lymph nodes
was only 19% [15]. removed. However, on multivariate analysis, poor
Potential predictors of survival in patients with prognostic factors included greater than four
lymph node disease and no evidence of metasta- lymph nodes removed (p = 0.02) and a lymph
sis include numbers of lymph nodes involved, node density greater than 60% (p = 0.01) [19].
lymph node density, and the presence of extran- Importantly, this study reported that the number
odal extension. In their study of 40 patients with of lymph nodes influenced the detection rate of
clinical regional node-positive non-metastatic metastasis. These authors reported that the inci-
disease who underwent an extended LND, dence of lymph node metastasis was 3.4% when
Canfield et al. found that survival was dependent 12 or fewer nodes were removed at the time of
on pathological node stage. Patients having pN1 nephrectomy; however, this increased to 10.5%
disease (30%) had a median survival of 37.5 when 13 or more lymph nodes were removed
months whereas in patients with pN2 disease [19]. For patients with localized disease, lymph
(70%), median survival was 14.5 months. In node positivity increased to 19.7% and 32.2%
addition, on multivariate analysis, two or more when <13 or ³13 lymph nodes were removed at
200 S.H. Culp and C.G. Wood

the time of surgery, respectively. These results patients. In addition, lymph node removal in
were corroborated by Joslyn et al., examining other GU malignancies (e.g., prostate, bladder,
data on 4,000 patients from the SEER registry, penile, and testicular germ cell tumors), initially
demonstrating that the incidence of lymph node only done for staging purposes, has been shown
detection significantly correlated with the number to demonstrate therapeutic benefit [9, 22, 23].
of lymph nodes removed at the time of nephrec- Therefore, in RCC, some could argue that it could
tomy [20]. Based on these studies, the sixth mean possible cure in patients with disease lim-
edition of the AJCC states that removal of eight ited to the retroperitoneum and that an LND
or more nodes at the time of LND is required for would ultimately decrease the risk of local recur-
adequate nodal staging in RCC [21]. rence of disease. In addition, in the era of tar-
The presence of extranodal extension of lymph geted systemic therapy, a LND would allow for
node disease is also important in patient survival. sufficient cytoreduction in patients with systemic
Dimashkieh et al., in their review of 2,076 patients disease in order for them to respond better to
without metastatic disease, found that, although adjuvant therapy. Nonetheless, there are potential
there was no difference in survival in patients risks of LND including bleeding, bowel injury,
based on pN1 vs. pN2 disease, patients with chylous ascites, and prolonged postoperative
extranodal extension were twice as likely to die recovery.
from their disease (5-year disease-specific sur-
vival of 18% vs. 35%) [21].
Types of LND

Lymph Node Dissection Initial studies of renal lymphatic drainage by

Alice Parker in 1939 on stillborn fetuses with
Based on multiple studies, it is apparent that not Prussian blue dye demonstrated that the normal
only are there differences in patient survival flow of renal lymphatics follows the arterial
based on lymph node involvement but also there system to eventually coalesce in the renal sinus
is variability in survival based on extent of lymph prior to draining into the regional lymphatics.
node disease. The question then becomes when Unfortunately, lymph node drainage in renal
to perform an LND and how extensive does the cancer is not always predictable [14, 24, 25].
dissection need to be? Studies to date are plagued Extensive neovascularization and collateral circu-
by major limitations. Most have been retrospec- lation induced by the primary kidney tumor may
tive, have included a small number of patients, alter lymph node drainage [26]. Furthermore,
and ultimately have shown a selection bias with lymphatic drainage of perinephric fat is not the
respect to the performance of an LND. In addi- same as the kidney, and therefore higher stage
tion, there is a lack of a standardized LND tem- tumors will show additional drainage patterns not
plate as well as a standardized pathologic seen in the “normal” kidney [27].
examination and defined postsurgical systemic According to Robson four decades ago, at a
treatment. time when adequate preoperative imaging did not
The benefits of LND undoubtedly include exist and up to 22.7% of patients undergoing
more accurate staging of the patient’s disease and radical nephrectomy had positive lymph nodes,
evaluation of prognosis. However, the therapeu- the standard treatment of RCC should include a
tic benefit remains controversial. Over the past radical nephrectomy as well as removal of “the
two decades, there have been significant develop- para-aortic and para-caval lymph nodes from
ments in other malignancies (breast, colon, and the bifurcation of the aorta to the crus of the
head and neck) demonstrating that removal of diaphragm” (Fig. 11.2) [28]. Traditionally, a hilar
potentially diseased lymph nodes at the time of LND would include resection of all lymph nodes
primary tumor surgery not only prolongs survival from the involved kidney to the inferior vena cava
but also results in cure in a select number of or the aorta for a right or left-sided tumor,
11 Locally Advanced Renal Cell Carcinoma 201

Fig. 11.2 Patient with renal cell carcinoma and bulky retroperitoneal lymphadenopathy before (left) and after (right)
radical nephrectomy and complete lymph node dissection

respectively (Fig. 11.3). A regional LND would include those by Herrlinger et al. in 1991 who
include resection of all hilar nodes as well as prospectively examined 511 patients with non-
additional lymph nodes along the inferior vena metastatic disease and compared survival based
cava or aorta for a right or left-sided tumor, on extended (n = 320) vs. facultative (nodes
respectively (Fig. 11.3). An extended LND for a resected for staging purposes only) (n = 191)
left-sided tumor would include all para-aortic LND. The authors found that there was a 26%
and interaortocaval lymph nodes from the aortic improvement in 5-year survival in patients with
bifurcation to the crus of the diaphragm. For a Stage I–II disease undergoing LND. Specifically,
right-sided tumor, an extended LND would patients undergoing an extended LND had a
include all paracaval as well as interaortocaval 5- and 10-year survival of 66% and 56.1%,
lymph nodes, the latter because 50% of positive respectively. Patients undergoing a facultative
lymph nodes in right-sided tumors will be within LND had a 5- and 10-year survival of 58% and
the interaortocaval region (Fig. 11.4) [29]. 40.9%, respectively. In interpreting these results,
Multiple retrospective studies have shown a one must consider stage migration to account for
potential therapeutic benefit for performing an the discrepancy between improvement in survival
LND at the time of nephrectomy. Peters and (26%) and incidence of positive lymph nodes
Brown, in 1980, found that in patients undergo- (8%) [6]. In their review of 200 consecutive
ing an extended LND, both 1-year and 5-year patients undergoing extended LND, of which
survival were better (87.5% and 43.8%) com- 25% had metastatic disease at the time of surgery,
pared to patients who did not undergo an LND Giuliani et al. found that patients with node-
(56.5% and 25.7%). The authors found an 18% positive, non-metastatic disease undergoing LND
improvement in 5-year survival in patients with had a survival statistically similar to those with
stage C disease who underwent an LND [30]. pT3N0M0 disease and better than patients with
However, this study lacked information regarding M1 disease (47.9% 5-year and 31.9% 10-year)
the number and extent of lymph node involve- [14]. In the largest retrospective study to date
ment. Furthermore, improved imaging over the examining 900 patients, Pantuck et al. found that
following decades would likely make these there was a 5-month increase in median survival in
results irrelevant. More recent and larger studies patients undergoing any type of LND compared
202 S.H. Culp and C.G. Wood

Fig. 11.3 Area of resection for hilar (top) and regional sion from Wood DP, Jr. Role of lymphadenectomy in
(bottom) lymph node dissection in renal cell carcinoma renal cell carcinoma. The Urologic Clinics of North
based on side of primary tumor. Reprinted with permis- America 1991;18(3):421–6

to those patients with clinically positive lymph with RCC, and this remains a very controversial
nodes left in situ. In addition, performing an LND topic. In their review of 554 patients diagnosed
was an independent predictor of survival on mul- with RCC at autopsy between 1958 and 1982,
tivariate analysis in patients with clinical evi- Johnsen and Hellsten found that only five (<1%)
dence of lymph node disease. Importantly, there patients had no metastatic disease and positive
was no measurable benefit in survival (overall or nodes limited to the retroperitoneum and therefore
progression-free) in patients with clinically nega- were amenable to potential cure with nephrectomy
tive lymph nodes undergoing LND [31]. and LND alone [32]. In addition, Minervini and
Multiple studies have also demonstrated no colleagues examined 167 patients without meta-
clear benefit for performing an LND in patients static disease from 1990 to 1997 [33]. Fifty-nine
11 Locally Advanced Renal Cell Carcinoma 203

Fig. 11.4 Area of resection for extended lymph node DP, Jr. Role of lymphadenectomy in renal cell carci-
dissection in renal cell carcinoma based on side of noma. The Urologic Clinics of North America
primary tumor. Reprinted with permission from Wood 1991;18(3):421–6

of these patients underwent radical nephrectomy patients had node-positive disease. Most patients
with regional LND, of which 49 of these had no had low-stage and low-grade disease and there-
clinical evidence of lymph node involvement. The fore, based on previous studies, had a low risk for
LND consisted of dissection limited to the ante- lymph node involvement. Furthermore, only 17%
rior, posterior, and lateral sides of the ipsilateral of patients progressed or died of RCC. Importantly,
great vessel from the level of the renal vessels though, this study did demonstrate that morbidity
down to the IMA. Only one (2%) patient had a from a standardized LND was low with few
positive node on final pathology. Five-year sur- complications.
vival was 79% and 78% for patients undergoing Various nomograms have been developed in
nephrectomy or nephrectomy with LND, respec- order to help identify factors that are important
tively. In a larger study, Schafhauser et al. exam- for predicting lymph node disease and therefore
ined 1,035 patients and estimated that only 4% provide better guidance on when to perform an
benefited from an extensive LND [34]. These stud- LND. These nomograms can provide better pre-
ies suggest that LND do not provide a survival operative surgical planning as well as counseling
advantage in patients with RCC, especially those to the patient. In addition, nomograms can poten-
without clinical evidence of lymph node disease. tially identify those patients who may be best
The only randomized trial examining the served with enrollment in neoadjuvant or adju-
influence of LND on survival of patients with vant therapy trials. Blute et al. examined their
RCC was the EORTC 30881 trial [35, 36]. Seven results from 955 patients with non-metastatic
hundred and seventy-two patients were random- clear cell RCC who underwent radical nephrec-
ized to undergo radical nephrectomy alone or tomy and LND from 1970 to 2000 [17]. Sixty-
radical nephrectomy with LND. The results eight (7.1%) patients had pN1 or pN2 disease. On
showed that there was no discernable difference multivariate analysis, significant independent
in CSS between the two groups. However, this predictors of lymph node involvement were
was an underpowered study in that only 3.3% of tumor size greater than 10 cm, pT3 or pT4
204 S.H. Culp and C.G. Wood

Side of Primary Tumor

Right Left

43% 0% 0% 76%
57% 20% 7% 62%

20% 14%

Fig. 11.5 Location of pathological positive lymph nodes PL, Breau RH, Allmer C, et al. Lymph node dissection at
based on side of primary tumor. Percentage represents the time of radical nephrectomy for high-risk clear cell
frequency of involved location in patients with lymph node renal cell carcinoma: indications and recommendations for
positive disease. Reprinted with permission from Crispen surgical templates. European Urology 59(1):18–23

disease, Fuhrman grade III or IV, and sarcoma- percentage of positive lymph nodes based on
toid de-differentiation. In addition, the presence anatomic location (Fig. 11.5) [37].
of necrosis on pathology, although not significant, A similar but more complex nomogram was
was included in their nomogram to identify developed based on results from 4,844 patients at
patients who would benefit from an LND at the MSKCC and the Mayo Clinic. Of these, 139
time of nephrectomy. Only six of 1,031 patients (2.9%) had lymph node positive disease. The
(0.6%) with 0 or 1 of the above features had posi- accuracy of this nomogram for predicting patho-
tive lymph nodes. However, 62 (10%) patients logic node-positive disease was 76.1%. Factors
with two or more features had lymph node dis- involved in this nomogram included symptoms at
ease. Overall, there was a fourfold increased risk presentation, history of hematuria, gender, ECOG
with two or more features and a 50% increase if performance status, comorbidity index, tumor
all five features were present. Therefore, the location, preoperative hemoglobin level, tumor
authors recommend an intraoperative risk assess- size, lymph nodes on imaging, and necrosis.
ment whereby the primary tumor would be sent In an effort to develop a nomogram based on
for frozen pathologic analysis. An LND should fewer factors, Hutterer et al. looked at 4,658
be performed if two or more of the above features patients from seven centers [38]. Of these, 2,522
are present in the primary tumor. Of course, some (54.1%) patients, of which 4.2% had positive
could argue that an LND could be performed in lymph nodes, were used for development of a
the time needed to wait for the results from the nomogram and 2,136 (45.9%) patients, of which
frozen analysis. A more recent study by Crispen 4.7% had lymph node disease, were used for
et al. validated these risk factors in patients with validation of the nomogram. Prediction of
high-risk clear cell RCC and demonstrated the lymph node involvement is based on tumor size,
11 Locally Advanced Renal Cell Carcinoma 205

symptom classification (no symptoms, local, or and above the diaphragm is pT3c. This most
systemic), and age. Based on their results, the recent change in staging of tumor thrombus was
AUC was 78.4% for the nomogram. supported by a large multi-institutional study of
1,215 patients reported by Martinez-Salamanca
et al. [44]. Traditionally, the Mayo Classification
Summary of Lymph Node Management of Tumor Thrombus [45] is as follows: level
0—thrombus in the renal vein only (detected
Lymph node involvement in RCC is associated clinically or during pathologic evaluation), level
with a higher grade and stage of disease and com- I—thrombus either at entry to renal vein or within
promised patient prognosis. Undoubtedly, LND at the IVC less than 2 cm from the confluence of the
the time of surgery does provide improved staging renal vein and IVC, level II—thrombus within
and better ascertainment of patient prognosis. IVC greater than 2 cm distal to renal vein but
However, there is controversy as to whether an below the hepatic veins, level III—thrombus
LND provides a therapeutic benefit. Patients with involving the intrahepatic IVC, and IV—thrombus
low-stage, organ-confined tumors are at a low risk extends above the diaphragm or into the right
to have lymph node disease and therefore an LND atrium of the heart (Fig. 11.6).
is not necessary in these patients. However, based
on studies that demonstrate that an LND can be
performed safely and with low morbidity, we Imaging
would recommend that an LND be performed in
patients with clinical or intraoperative evidence of Various imaging modalities may be used to iden-
nodal disease or locally invasive disease with tify and evaluate thrombus associated with RCC.
associated risk factors. Further studies are needed MRI has traditionally been used for this purpose;
to better define the role of LND in RCC, which however, newer CT modalities, specifically mul-
will likely evolve with the new therapeutic strate- tiplanar CT, can be as accurate as MRI, and CT is
gies used to treat metastatic disease. now the most commonly utilized modality for
imaging IVC thrombi. Nonetheless, MRI is still
preferred at many centers related to its accuracy
Tumor Thrombus for determining the true extent of tumor throm-
bus, the degree of IVC occlusion, and the exis-
Inferior vena caval involvement by tumor throm- tence of bland thrombus in the infrarenal IVC
bus occurs in 4–10% of patients with RCC [39, and any venous anomalies [46, 47]. During surgi-
40], with thrombus reaching the atrium in 1% of cal resection, transesophageal echocardiography
patients [41]. One-third of patients with tumor is frequently used to provide real-time imaging of
thrombus will have distant metastatic disease [42]. the thrombus [48].
Tumor thrombus may be detected incidentally as
with the primary tumor but if present, symptoms
may include lower extremity edema, right-sided Surgical Resection
varicocele, pulmonary embolus, and caput medusa
[43]. Additional findings may include proteinuria, The first RCC thrombus ever resected was done in
right atrial mass, or a non-functioning renal unit. 1919. Once considered a death sentence, the
thrombus was usually left in situ. The majority of
patients undergoing removal of the kidney alone
Staging survived less than a year [49]. Currently, the
surgical mortality from nephrectomy and high
According to the AJCC TMN 2009 staging sys- level IVC thrombectomy is 5–10% [50]. However,
tem, renal thrombus located within the renal vein mortality can be as high as 40% if the thrombus
is pT3a, in the IVC below the hepatic veins is pT3b, extends above the diaphragm [51–53]. Fortunately,
206 S.H. Culp and C.G. Wood

Fig. 11.6 Mayo classification of tumor thrombus based on level of inferior vena caval involvement in renal cell carcinoma.
Reprinted with permission from Kirkali Z, Van Poppel H. A critical analysis of surgery for kidney cancer with vena cava
invasion. European Urology 2007;52(3):658–62

45–70% of patients with non-metastatic disease Table 11.2 Five-year survival of patients with renal cell
carcinoma and inferior vena cava tumor thrombus and no
can be cured with complete surgical resection evidence of metastatic disease undergoing surgical resection
[54, 55]. Five-year survival of patients with IVC
Study Study year Patient number %Survival
thrombus ranges from 60% to 82% and 18% to
Swierzewski 1994 100 64
55% for patients without or with metastatic
Quek 2001 99 59
disease, respectively, who undergo surgical
Zisman 2003 100 72
resection [56, 57] (Table 11.2). Blute 2004 191 59
Careful surgical planning prior to resection is Skinner 1989 43 57
paramount and may require a multidisciplinary Glazer 1996 18 57
approach. Radical nephrectomy with IVC throm- Lubahn 2006 44 56
bectomy is a complex procedure with potential
for high morbidity [58] and a mortality rate of
10% [51–53]. Surgical management depends on whether the thrombus is infiltrating the wall of
the size of the tumor, the cranial extent of the the IVC [59]. Depending on the size of tumor
thrombus, baseline surgical risk factors, and and thrombus, there is potential for significant
11 Locally Advanced Renal Cell Carcinoma 207

surgical blood loss as well as pulmonary embolism If possible, this bland thrombus may be removed
during thrombectomy. at the time of removal of the tumor thrombus. If
The choice of incision depends on the size and not possible, then it may be necessary to ligate
location of tumor as well as thrombus extent but the infrarenal IVC to avoid postoperative embo-
may involve a midline, Chevron, subcostal, or lization of clot [71].
thoracoabdominal approach. For thrombi isolated Boorjian et al. examined the Mayo Clinic
to the renal vein or within 5 cm of the IVC/renal experience in more than 400 patients in terms of
vein ostium, a flank incision may also be appropri- complications from tumor thrombus resection
ate. Although we do not routinely perform it, pre- [72]. They found that the incidence of both early
operative embolization of the kidney may be done (<30 days) and late (≥30 days) complications
in order to decrease blood loss and to facilitate more correlated with the level of tumor thrombus. If
direct access to the renal hilum and vessels. In addi- the IVC thrombus is small or there is incomplete
tion, embolization may result in partial regression obstruction of the IVC with minimal collateral,
of the tumor thrombus and may decrease venous then vena caval clamping can result in profound
congestion in the primary tumor and thrombus hypotension and the need for a venous–venous
[58, 60, 61]. bypass in order to augment venous return. With a
Resection of a level I or II thrombus requires left-sided renal tumor and venous/IVC occlusion,
early control of the renal artery, ligation of any there are multiple methods of venous return
lumbar veins, and venous control both proximal (adrenal, inferior diaphragmatic, gonadal, ureteral,
and distal to the thrombus as well as the contral- and lumbar) [73].
ateral renal vein. If possible, the goal is to remove
the diseased kidney and thrombus en bloc [62].
After proper mobilization of the kidney, ligation Clinicopathological Features
of the renal artery and lumbar veins, and clamp-
ing of the IVC and contralateral renal vein, the Multiple studies have examined the association of
renal ostium is opened allowing removal of the clinicopathologic features with the presence and
diseased kidney and simultaneous extraction of level of tumor thrombus. The majority of renal
the IVC thrombus. The IVC is oversewn being tumors with associated thrombus are of clear cell
careful to avoid significant narrowing of the ves- histology with 5–28% of them having sarcomatoid
sel (Fig. 11.7). For a level III thrombus, mobiliza- de-differentiation [74–76]. In their study of 1,082
tion of the hepatic caudate lobe is required [63]. patients, Rabbani et al. reported that renal vein and
This allows access to IVC above the tumor throm- IVC extension of tumor thrombus were present in
bus and the ability to clamp below the intrahe- 5.4% and 2.8% of patients, respectively [77].
patic veins. Tumor thrombus above the hepatic Clear cell histology was significantly associated
veins may require complete liver mobilization with an increased risk for thrombus while histo-
[64], veno-venous bypass, Pringle maneuver, and logies such as oncocytoma and papillary RCC were
occlusion of select hepatic veins [65, 66]. Level significantly associated with a decreased risk [77].
IV thrombi may require circulatory arrest with Larger tumor thrombi are associated with higher
[67, 68] or without hypothermia [69, 70]. There Fuhrman nuclear grade and more advanced stage
is an increased risk for coagulopathy, cerebral [45]. In examining markers associated with tumor
vascular incident, and myocardial infarction thrombi, vascular endothelial growth factor expres-
[67, 68, 70]. For patients with a level III or IV sion was found not to be significantly associated
non-adherent thrombus, it may be possible to with the level of tumor thrombus [78]. However,
“milk” the thrombus back below the hepatic veins Ki67 expression was positively associated with the
therefore avoiding the need for clamping the presence and level of tumor thrombus [79]. Higher
suprahepatic IVC. level of thrombus is also associated with decreased
It is not uncommon to find complete thrombo- response to immunotherapy and increased periop-
sis of the IVC inferior to the tumor thrombus. erative morbidity and mortality [80].
208 S.H. Culp and C.G. Wood

Fig. 11.7 Illustration of surgical resection of infrahepatic thrombus (b). The renal vein and tumor thrombus are then
tumor thrombus from renal cell thrombus. Control of infe- separated from the IVC (c) and the IVC is oversewn (d).
rior vena cava (IVC) both proximal and distal to thrombus Reprinted with permission from Wszolek MF, Wotkowicz
as well as contralateral renal vein is performed (a). The C, Libertino JA. Surgical management of large renal
IVC is then opened to allow for mobilization of the tumor tumors. Nature Clinical Practice 2008;5(1):35–46

Patient Survival In addition, tumor thrombus level is associated

with likelihood of metastatic disease. In a study
Complete resection of tumor thrombus in patients of 56 patients, Ciancio et al. found that 10 of 49
with non-metastatic disease can result in a survival patients with levels I–III thrombus and four of
greater than 50%. However, survival is dependent seven patients with level IV thrombus had distant
on level of tumor thrombus with an IVC throm- metastasis [82].
bus extending above the diaphragm predicting a In a study of 118 patients with pT3b or pT3c
worse survival even after controlling for Fuhrman RCC from 1989 to 2006, Lambert et al. found
nuclear grade and ECOG performance status [81] . that the 5-year CSS was 60.3% and 10% for
11 Locally Advanced Renal Cell Carcinoma 209

patients without or with distant metastasis, lower extremity edema and a patch or interposition
respectively [83]. Importantly, the level of tumor graft should be considered, either a PTFE, peri-
thrombus was not an independent predictor of cardial [88], or autologous venous graft [89].
survival, only positive lymph node disease and Grafting techniques may be technically challeng-
tumor diameter greater than 7 cm. Another retro- ing and may therefore require the expertise of
spective study of 1,192 patients with pT3b or vascular surgery. Depending on which type of
pT3c disease from 13 European institutions graft used and location, there may be an increased
(1982–2003) found no difference in survival risk for infection [90], renal and/or hepatic fail-
based on IVC level of tumor thrombus. However, ure, ascites, and lower extremity edema. Invasion
there was a significant difference in median sur- of the wall of the inferior vena cava is a poor
vival of patients based on renal vein vs. IVC prognostic sign and is staged pT3c independent
thrombus below or above the diaphragm (52 vs. of the cephalad extent of the thrombus.
25.8 and 18 months, respectively) [84]. Zini et al. evaluated 32 patients undergoing
Unfortunately, based on the multi-institutional nephrectomy from 2000 to 2006 with IVC
nature of the study, there was no ability to control involvement and found that renal vein ostium
for difference in surgical techniques or the use of wall invasion was present in 13 (40.6%) patients
adjuvant therapy. In a study of 153 patients, [91]. RV ostium wall invasion was significantly
Moinzadeh and Libertino found that 5-year sur- associated with a higher recurrence rate, lower
vival was similar between renal vein only and CSS, and higher level of tumor thrombus. From
IVC tumor thrombus; however, 10-year overall this study, CT imaging with cutoffs of 1.8 cm of
survival was significantly different (66% vs. 29%, IVC AP diameter and 1.4 cm of renal vein ostium
respectively) [85]. diameter had a sensitivity of 90% for predicting
The impact of tumor thrombus level on sur- invasion.
vival depends on whether or not the patient has
distant disease. In a study of 101 patients with
pT3b disease between 1990 and 2006, Klaver Budd–Chiari Syndrome
et al. found that Mayo Clinic level of tumor
thrombus was an independent predictor of CSS in Although rare, some patients with RCC and IVC
patients with non-nodal, non-metastatic disease thrombus may have tumor involving the orifices
on multivariate analysis (median survival of 69, of the hepatic veins. This results in Budd–Chiari
26, and 21 months for levels I, II, and III tumor syndrome (BCS) with occlusion of hepatic
thrombus, respectively) [86]. However, in patients venous outflow, hepatic congestion, and potential
with either nodal or distant disease, tumor size progression to liver failure. Symptoms may
and histologic subtype (but not level of tumor include abdominal pain, hepatomegaly, ascites,
thrombus) were independent predictors of CSS. jaundice, lower extremity edema, bleeding, and
encephalopathy. Aggressive surgical manage-
ment is required to prevent liver failure and death.
Venous Wall Involvement Based on the anatomy and complexity of the sur-
gery, dedicated transplant and thoracic surgeons
It is rare for a tumor thrombus to invade the wall should be involved.
of the IVC. However, when extensive invasion or In their review of 12 cases of BCS caused by
caval adherence is present, partial or complete RCC thrombus, Kume et al. divided patients into
resection of the IVC may be required. When the two groups, mild/silent and severe, based on the
IVC is chronically obstructed, resection of the absence or presence of liver failure, respectively
cava with no replacement can be well tolerated [92]. Patients with mild/silent disease had minimal
with few sequelae [39, 87]. In the absence of ade- hepatic dysfunction likely secondary to gradual
quate collateral circulation, however, resection or incomplete occlusion resulting in sufficient
can result in significant IVC narrowing and/or time to develop collateral outflow. Patients with
210 S.H. Culp and C.G. Wood

severe disease, however, had sudden and complete resulted in a significant reduction in the median
occlusion resulting in significant liver failure and survival from 33 to 10 months [58]. Similar
disseminated intravascular coagulation. Based on findings were found by Fujita et al. in their retro-
their experience, patients who underwent spective review of 43 patients with pT3b disease
immediate thrombectomy for mild/silent disease [95]. Patients with tumor thrombus only (tumor
avoided fulminant hepatic failure and their prog- otherwise confined to the kidney) had a median
nosis was similar to patients with IVC thrombus CSS of 70.9 months, while patients with con-
only. Although there is increased risk in patients comitant perinephric fat invasion had a median
with severe disease based on the presence of liver CSS of 25 months. Based on similar findings
failure and consequent poor condition, manage- showing that perinephric fat invasion was not
ment should be made on a case-by-case basis as a only an independent prognostic factor for patients
successful thrombectomy may lead to resolution with tumor thrombus but also seemed to have a
of liver dysfunction. In the MDACC experience, greater impact on survival when present by
five of six patients with BCS due to RCC throm- itself, both Ficarra [96] and Thompson [97] and
bus have undergone complete thrombectomy and their associated colleagues proposed separate
two are alive with no evidence of disease at 37 reclassification schemes in the TMN staging to
months (MDACC, unpublished data). include perinephric fat invasion as a prognostic
factor and in an effort to more accurately stratify
patients with pT3 RCC with respect to risk of dis-
Extracapsular Extension ease recurrence. The scheme proposed by Ficarra
and associates stratifies perinephric fat invasion
Perinephric Fat Invasion or thrombus below the diaphragm as pT3a, peri-
nephric fat invasion and tumor thrombus below
Perinephric fat invasion has been shown by mul- diaphragm as pT3b, and adrenal gland involve-
tiple studies to be a poor prognostic indicator in ment or tumor outside Gerota’s fascia, or tumor
patients with RCC. There is controversy regard- thrombus above the diaphragm as pT4 disease
ing the significance of focal vs. extensive peri- [96]. The scheme proposed by Thompson and
nephric fat invasion. Roberts et al. evaluated 186 colleagues includes level 0 thrombus with no
patients with clinical T1 disease and found that perinephric fat invasion as pT3a, perinephric
57 (31%) were upgraded to pT3a disease based invasion only as pT3b, level 0 thrombus with
on focal perinephric fat invasion [93]. Five-year perinephric fat invasion or levels I–III thrombus
CSS was not different between the two groups of with no fat invasion as pT3c, levels I–III
patients (90.6% for pT1 and 97.5% for pT3a). thrombus with fat invasion or level IV thrombus
Jung et al. retrospectively reviewed 198 patients as pT3d, and extension beyond Gerota’s fascia
to determine the impact of focal vs. extensive as pT4 [97]. These proposals highlight the
perinephric fat invasion [94]. All patients were importance of capturing all adverse features
free of nodal and distant metastasis. Of these when staging patients with locally advanced renal
patients, 57 and 61 had minimal (£ 5mm) or cancer, because they allow for more refined risk
extensive (>5 mm) perinephric fat invasion with stratification.
5-year survival rates of 85% and 76%, respectively.
Therefore, based on this study, the prognosis of
perinephric fat invasion did not depend on extent Renal Sinus Invasion
of involvement.
The presence of perinephric fat invasion in The renal sinus is a fatty compartment located
combination with other factors also results in a within the central aspect of the kidney, adjacent
poorer outcome. In their review of 96 patients to the collecting system, and is composed of an
with pT3b RCC, Sweeney et al. found that the abundance of lymphatics and small veins [98].
concomitant presence of perinephric fat invasion This potentially lends it to be an ideal location for
11 Locally Advanced Renal Cell Carcinoma 211

propagation of tumor otherwise located within Klatte et al., in evaluation of 519 patients with
the renal capsule. Although, historically, renal intracapsular RCC, found that renal capsule and
sinus involvement was not routinely evaluated, collecting system involvement occurred in 21.6%
the 2002 AJCC TMN staging placed renal sinus and 7.5% of patients, respectively [103]. There
invasion as pT3a. The prognostic significance of was a significant association of collecting system
renal sinus involvement remains somewhat con- involvement and microvascular invasion, and col-
troversial. Bonsib et al. demonstrated in a pro- lecting system invasion was an independent pre-
spective study of 31 patients that tumors with dictor of progression-free survival (RR 3.78).
renal sinus involvement were more often larger, Further studies are undoubtedly needed to better
displayed higher Fuhrman nuclear grades, and elucidate the impact of collecting system inva-
more frequently involved the renal vein and cap- sion on disease recurrence and patient survival.
sule, all of which would increase the metastatic
potential of the tumor [99]. Thompson et al., in
their evaluation of 205 patients with pT3a RCC, Adjacent Organ Involvement
found that tumors with clear cell histology involv- (T4 Disease)
ing the renal sinus displayed higher aggressive-
ness compared to tumors invading the perinephric The incidence of adjacent organ involvement in
fat lateral to the kidney, demonstrating a higher RCC ranges from 5% to 15% [104]. Renal tumors
propensity for metastasis to lymph nodes, a are more likely to compress rather than invade
higher Fuhrman nuclear grade, and a greater pro- adjacent structures. Additionally, large renal
portion of sarcomatoid de-differentiation [100]. masses can frequently induce a significant degree
In addition, on multivariate analysis, renal sinus of reactive changes which may obliterate surgical
invasion remained an independent predictor of tissue planes and therefore mimic T4 disease
poor survival in patients with pT3a disease. [105]. The poor prognosis in patients with T4
However, in contrast to the above findings, other disease is compounded by the fact that a majority
authors have found similar patient survival rates of these patients also have nodal or distant metas-
between those with renal sinus involvement and tases, high-grade tumors, or sarcomatoid de-dif-
those with perinephric fat invasion [101]. ferentiation [97]. However, only 1% of patients
Specifically, Margulis et al., in their review of without distant disease undergoing nephrectomy
patients at MDACC, did not find a significant dif- have pT4 disease [106]. Organs at risk for tumor
ference in disease-specific survival between peri- invasion include the ipsilateral adrenal gland,
nephric fat and renal sinus invasion (54.1% and posterior abdominal wall, paraspinous muscles,
50.8%, respectively, p = 0.782). These differences diaphragm, liver, spleen, duodenum, pancreas,
in findings may reflect the higher number of and colon (Fig. 11.8). Patients may experience
patients and increased incidence of renal sinus significant pain when the tumor involves the
invasion (56% vs. 21%) in the series by Margulis paraspinous muscles and nerve roots. T4 disease
et al. [102]. is associated with a poor prognosis with a 5-year
survival of 5–18% [96, 97]. Unfortunately, com-
plete surgical excision of tumor and any involved
Collecting System Invasion organs represents the only chance for cure.
Incomplete resection of the primary tumor results
Renal tumor involvement of the urinary collect- in a dismal prognosis with greater than 90% of
ing system has not been extensively studied and patients dying within 1 year from disease pro-
its implications remain unclear. Terrone et al., in gression [107].
their study of 671 patients at two institutions, In one of the larger series of locally invasive
found that involvement of the collecting system disease, Karellas et al. evaluated 38 patients with
by tumor was low (8.8%) and was not an inde- pT3 or pT4 disease undergoing radical nephrectomy
pendent prognostic factor [103]. In contrast, with adjacent organ/structure resection [108].
212 S.H. Culp and C.G. Wood

Fig. 11.8 Preoperative imaging of renal cell carcinoma with adjacent organ involvement (pT4 disease): right primary
renal tumor invading liver (a), left primary renal tumor involving descending colon (b), and left primary renal tumor
invading spleen (c)

The liver was the most common organ involved nectomy is likely. The surgical approach can be
(ten cases), 68% of patients were pT4, clear cell tailored to fit the challenges of the situation on an
was the most common histology (95% of cases), individual basis. Preoperative embolization can
and 14 (37%) patients had a positive surgical mar- be considered selectively, particularly for tumor
gin. Median survival of patients was 11.7 months encasing the hilum, in an effort to facilitate dis-
after surgical resection and surgical margin status section in this area.
was the only significant factor predicting disease Ipsilateral adrenal invasion occurs in approxi-
recurrence and death. In a separate study at mately 6% of advanced RCC tumors [110, 111]
MDACC, Margulis et al. evaluated 30 patients and is found in 2.5% of nephrectomy specimens
with suspected T4 disease without distant metas- [112]. When adrenal invasion is present, the
tasis [109]. The colon, pancreas, and diaphragm 5-year CSS is 42%. Preoperative CT imaging has
were the most common adjacent organs involved. a sensitivity and specificity of 90% and 99%,
Compared to patients with pT3 or lower RCC, respectively, for detecting adrenal involvement
pT4 disease was an independent predictor on mul- by the renal tumor [104]. Ito et al. evaluated 30
tivariate analysis of decreased recurrence-free patients with ipsilateral adrenal involvement and
survival (10 months vs. 28 months) and decreased compared them to 926 control patients without
CSS (22 months vs. 65 months). Importantly, a adrenal involvement [113]. Independent predic-
significant number of these patients (60%) were tors for ipsilateral adrenal involvement on multi-
downstaged on final pathology and no tumor char- variate analysis were tumor size greater than
acteristic was predictive of pT4 disease. Therefore, 5.5 cm, distant disease separate from the adrenal
the authors concluded that prediction of pT4 dis- gland, retroperitoneal lymph node involvement,
ease cannot be adequately done by pre- or intra- and clinical stage T3 or higher. Based on their
operative findings. results, the authors conclude that the adrenal may
Preoperative planning is vitally important for be spared if the tumor size is less than 5.5 cm,
patients with locally advanced RCC. This there is no evidence of distant or lymph node dis-
requires careful imaging to define organs at risk, ease, clinical stage remains less than T3, and
and patients should be counseled about the prob- there is no evidence of adrenal involvement on
able need for en bloc resection of adjacent CT imaging. Surprisingly, upper pole involvement
organs. A formal bowel preparation should be by the renal tumor was not predictive of adrenal
instituted if hemicolectomy is planned, and vac- gland involvement. In a separate study examining
cination protocols should be considered if sple- when the adrenal gland can be spared, Paul et al.
11 Locally Advanced Renal Cell Carcinoma 213

examined 866 consecutive patients from 1983 to was much worse in those with venous involve-
1999 [114]. Of these, 27 (3.1%) had ipsilateral ment (12 months) compared to those without (24
adrenal gland involvement. Based on their study, months).
the authors concluded that the adrenal gland can
be spared if the primary tumor size is less than
8 cm, and there is no evidence of lymph node or Postoperative Surveillance
distant metastasis.
Another study by Tsui et al. evaluating 511 After surgical treatment, predictors of tumor
patients from 1986 to 1998 found that 29 (5.7%) recurrence include tumor histology, Fuhrman
patients had adrenal involvement, 58.6% of which nuclear grade, stage of tumor, margin status, and
were local extension of disease [115]. CT imag- the presence of lymph node involvement [114].
ing had a 99.4% negative predictive value for pre- Therefore, patients with locally advanced RCC
dicting adrenal gland involvement. There was no (³pT3 stage and/or LN + disease) have a higher
correlation between tumor size and adrenal gland risk of disease recurrence and progression despite
involvement. In contrast to other studies, an upper definitive surgical therapy. In their series examin-
pole tumor was prognostic for adrenal gland ing patients with pT3N0/Nx RCC undergoing
involvement. nephrectomy with curative intent, Levy et al.
There has been controversy regarding correct found that 39% of patients developed metastases
staging of ipsilateral adrenal gland involvement. with a median time to progression of 17 months
Before 1987, infiltration of the adrenal gland (range 2, 88) [117]. Likewise, Stephenson et al.,
was not considered as a prognostic factor. The in their study of 495 patients with pT1–T3 RCC,
2002 AJCC TMN staging listed adrenal gland 5-year disease-free survival and time to progres-
involvement as pT3a disease. However, multiple sion were 67% and 14 months for patients with
studies have shown that patients with direct pT3a tumors, respectively, and 57% and 9 months
invasion of the ipsilateral adrenal gland have a for patients with pT3b tumors [118]. Based on
worse prognosis compared to patients with peri- these results as well as other studies [119, 120],
nephric fat invasion (also pT3a). Because of recommended surveillance for patients with
this, the 2009 AJCC TMN staging now lists pT3N0 RCC after surgery includes physical exam,
direct involvement of the ipsilateral adrenal laboratory studies (chemistry, liver function tests,
gland as pT4 disease. alkaline phosphatase), and chest X-ray every
In a retrospective study of 1,087 patients, Han 6 months for 3 years and then annually thereafter.
et al. found that 187 had perinephric fat involve- An abdominal CT scan should be performed every
ment and 27 (2.5%) had direct adrenal invasion 6 months for the first 2 years then at year 3 and 5
[112]. The latter group was twice as likely to unless an abnormality is discovered. For patients
present with gross hematuria (59% vs. 33%) and with lymph node disease at the time of surgery
more likely to have lymph node involvement regardless of stage, Canfield et al. reported a 70%
(52% vs. 26%, p < 0.001). Median survival was progression rate with a median time to progres-
compromised in patients with adrenal gland inva- sion of 4.9 months [18]. In their study of 45
sion (12.5 months) compared to those with peri- patients with pTanyN + M0 RCC, Saidi et al.
nephric fat invasion (36 months). In addition, found that the progression rate was 64% with a
whereas 5-year survival of those with perinephric median time to progression of 9 months [121].
invasion alone was 36%, 5-year survival of those Most disease will progress within a year with
with adrenal gland invasion was 0%. >90% having progressed within 3 years of surgery.
The multi-institutional European study by Common sites of progression include the retro-
Ficarra et al. demonstrated that patients with peritoneal lymph nodes, lung, liver, bone, kidney
adrenal gland invasion should be classified into fossa, and brain. Based on these results and other
two subgroups based on venous involvement by studies [122], the surveillance recommended for
tumor thrombus [96]. Median survival of patients patients with lymph node positive disease includes
214 S.H. Culp and C.G. Wood

physical exam, laboratory studies (including liver

function tests), chest X-ray, and CT of the abdo-
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 Neoadjuvant Targeted Therapy
and Consolidative Surgery 12
Sean P. Stroup and Ithaar H. Derweesh

Introduction Rationale and Potential Limitations

of Primary Targeted Therapy for
Although great strides have been made in the Management of Locally Advanced
diagnosis and treatment of renal cell carcinoma, Renal Cell Carcinoma
approximately 30–40% of patients continue to
present with locally advanced or metastatic dis- Background
ease at initial diagnosis [1]. With improved
response rates and tolerability of targeted agents Important advances in the understanding of the
[2–4], the concept of primary targeted therapy molecular and genetic components of RCC have
followed by consolidative surgery has emerged ushered in a new era of targeted molecular therapy.
as a novel paradigm for the management of These treatments have primarily focused on block-
select patients with locally advanced RCC. ing signaling pathways associated with the von
Herein we discuss patient selection criteria for Hippel–Lindau tumor suppressor gene. Inactivation
this strategy, including the concept of response of this gene leads to elevated levels of hypoxia-
to therapy and consolidative nephrectomy, and inducible factor alpha (HIF-a) and overexpression
assess the quality of emerging data using primary of vascular endothelial growth factor (VEGF) [4].
systemic therapy in the treatment of patients Small molecule inhibitors of this pathway targeting
with locally advanced RCC. We will also the VEGF receptor tyrosine kinase and mammalian
highlight perioperative patient safety concerns target of rapamycin (mTOR) pathways have proven
and the arguments for and against utilization of efficacy. Landmark studies in the past decade helped
primary systemic targeted therapy. Finally, we pave the way for approval of sorafenib, sunitinib,
discuss current and future directions for investi- temsirolimus, everolimus, and recently pazopanib
gation regarding this topic. and axinitib. Other studies identified a role for beva-
cizumab in combination with interferon-alfa for
mRCC. These agents have demonstrated improved
survival outcomes over traditional immunothera-
peutic regimens with better tolerability [3, 4].
S.P. Stroup • I.H. Derweesh ()
Division of Urology, Department of Surgery,
Moores UCSD Cancer Center, University of California Rationale for Primary Targeted Therapy
San Diego School of Medicine, 3855 Health Sciences
Drive, Mail Code 0987, La Jolla, CA 92093-0987, USA
e-mail: [email protected]; [email protected]; Using these agents in the neoadjuvant setting for
[email protected] locally advanced renal cell carcinoma represents

S.C. Campbell and B.I. Rini (eds.), Renal Cell Carcinoma: Clinical Management, Current Clinical Urology, 219
DOI 10.1007/978-1-62703-062-5_12, © Springer Science+Business Media New York 2013
220 S.P. Stroup and I.H. Derweesh

a new and promising treatment paradigm. as part of a multimodal approach for management
Neoadjuvant targeted therapy offers the potential of mRCC. Neoadjuvant targeted therapy strate-
advantage of tumor downstaging which may gies may be primarily considered for patients
make surgical interventions possible in some with locally advanced disease with direct inva-
patients who would not otherwise be surgical sion into surrounding organs and in those with
candidates. Reduction of the primary tumor and large, bulky tumors for whom resection might be
metastatic disease may also make any surgical particularly challenging [5, 6]. In these cases, ini-
intervention less morbid, provided sufficient tial targeted therapy may reduce surgical morbid-
washout time is given to limit wound complica- ity by shrinking the tumor and minimizing
tions. Furthermore, as the biological understand- resection of neighboring organs or structures,
ing of RCC advances, tissue provided from initial although the degree of this response is variable
biopsy may provide a genetic tumor fingerprint and usually limited (see Fig. 12.1) [2, 7]. Patients
that would allow more individualized targeted with renal vein or inferior vena cava thrombi have
therapy with a chance for better patient selection also been selected for treatment with upfront tar-
and efficacy. geted therapy as a means to reduce the tumor
thrombus level, although the data supporting this
is largely anecdotal [8]. Patients with bulky cen-
Potential Limitations of Primary tral or hilar tumors in the setting of locally
Systemic Targeted Therapy advanced disease with imperative indication for
nephron-sparing surgery may also benefit from
Counterarguments to upfront TKI therapy iden- primary targeted therapy prior to planned
tify treatment-related presurgical morbidity and a nephron-sparing surgery (see Fig. 12.1). Level III
lack of high level evidence supporting the evidence exists in the form of several small
approach as concerns. Neoadjuvant TKI strate- series examining neoadjuvant (presurgical) targeted
gies may also complicate the surgical procedure, therapy before cytoreductive surgery which sug-
unnecessarily delay surgery, and/or increase the gest the approach appears safe [9–11].
risk of perioperative morbidity. Despite being
oral agents, these agents are associated with a
significant degree of toxicity. Postoperative Renal Mass Biopsy
wound healing, infection, spontaneous bowel
perforation, and cardiovascular morbidity with In recent years the accuracy and safety of renal
hypertension and declines in left ventricular ejec- mass biopsy have improved substantially due to
tion fraction are among the most feared compli- refinements in CT- and MRI-guided techniques.
cations in surgical patients. Theoretical concerns Pretreatment tumor biopsies to confirm histology
also exist about the risk of starting, stopping, and should be performed before embarking on neoad-
restarting TKIs. Selection of tumors resistant to juvant therapy. The diagnostic accuracy of renal
targeted therapy is a potential adverse outcome of mass biopsy for clinically confined renal tumors
this strategy. has improved from about 82% before 2001 to
more than 95% currently. Noninformative biop-
sies continue to be seen in 10–15% of cases,
Primary Targeted Therapy Followed while false negative rates now approach 1% and
by Planned Surgical Consolidation the incidence of symptomatic complications is
low with <2% requiring some form of interven-
Patient Selection tion. Needle tract seeding also appears to be
exceptionally low. The addition of fine needle
A number of factors are important in determining aspiration may complement the standard core
whether a patient is suitable for initial targeted biopsy and is particularly helpful when assessing
molecular therapy followed by consolidative surgery extrarenal metastatic lesions. Biopsy of locally
12 Neoadjuvant Targeted Therapy and Consolidative Surgery 221

Fig. 12.1 Representative neoadjuvant targeted treatment of sunitinib and radiation therapy to her clavicular and
scenarios. (a, b) A 68-year-old female with stage III CKD spinal mets, resulting in reduction of her thrombus and
presented with a 6.30 cm right renal mass and a high tumor to 7.4 cm, thereby enabling laparo-endoscopic sin-
R.E.N.A.L. score. The patient underwent biopsy which gle site left radical nephrectomy and renal vein thrombec-
confirmed CC-RCC, followed by two cycles of primary tomy. (e, f) A 56-year-old female with CKD and a solitary
sunitinib resulting in reduction of the mass to 3.25 cm, kidney presented with an 8 cm renal mass and pancreatic
thus facilitating nephron-sparing surgery. (c, d) A 51-year- metastases. After confirmatory biopsy for CC-RCC, the
old female presented with bone and lung mets and a patient underwent two cycles of sunitinib, resulting in
9.1 cm left renal mass with a renal vein thrombus. After reduction of the primary tumor to 6.7 cm and facilitating
confirming mCC-RCC, the patient underwent two cycles cytoreductive nephron-sparing surgery
222 S.P. Stroup and I.H. Derweesh

advanced RCC is more challenging, because response rates that have approximated those of
these tumors have a more broad differential diag- sunitinib [15].
nosis, potentially including adrenal neoplasms, In most cases, the clinical response to therapy
urothelial-based tumors, lymphoma, and a variety is assessed after two or three cycles. With this
of other malignancies. Tumor necrosis is also more strategy, clinicians can determine tumor progres-
common in this population, and multiple cores sion and offer alternative therapy. After two or
including peripherally based ones should be con- three cycles of sunitinib before planned nephrec-
sidered. Most studies suggest that clear cell tumors tomy most studies have reached a maximum clin-
tend to respond best to targeted therapies in ical benefit, and prolonging therapy beyond this
any setting, and biopsy may play a role in patient point is likely to be counterproductive. In the
selection and for guiding choice of therapy. multinational study from the UK and the
Although precise Fuhrman grading and tumor Netherlands, after two or three cycles, 73% had
subtype histology are not always accurately clinical benefit with a partial response in 6%.
determined, the addition of histopathologic and Ultimately 71% of this group went on to consoli-
molecular imaging techniques to renal mass dative nephrectomy [16].
biopsy represents an important potential advance.
Interphase fluorescence in situ hybridization
(FISH) has been used to identify abnormalities in Radiographic Response to Therapy
chromosomes 3, 7, 10, 13, 17, and 21 and the
locus 3p25–26 [12]. The technique improved the Tumor response to therapy is generally assessed
diagnostic accuracy in subtyping RCC from 87% by CT/MRI every two to three cycles of treat-
to 94%. Polymerase chain reaction has also been ment and defined according to the response eval-
used to amplify CA-IX from FNA specimens and uation criteria in solid tumors (RECISTs) v.1.1
results in enhanced sensitivity and specificity [12, [17]. The clinical response of the primary tumor
13]. Finally, newer techniques of molecular is classified as complete response, partial
profiling, gene expression, and proteomic analy- response, stable disease, or progressive disease.
sis applied to renal mass biopsy may further Progressive disease is defined as a greater than
refine the role of neoadjuvant systemic therapy 20% increase in sum of longest diameters from
prior to debulking nephrectomy by refinement of nadir or the appearance of new lesions. Partial
risk and outcome stratification. Such strategies responders are identified with greater than 30%
may eventually further decrease patient morbid- reduction in the sum of target lesion diameters,
ity and improve outcomes, but remain investiga- while stable disease is within these limits.
tional at present [14]. Level III evidence exists demonstrating a
moderate response to primary targeted therapy in
the setting of the primary tumor. Important work
Selection of Targeted Molecular by van der Velt and colleagues helped to establish
Therapy and Duration of Therapy tumor response parameters for neoadjuvant treat-
ment. They evaluated the effects of sunitinib on
A variety of agents have been used in the neoad- the primary tumor in 17 patients with initially
juvant setting before debulking nephrectomy. unresectable advanced RCC [2]. Partial response
Most experience has been gained using sunitinib, or stable disease was seen in 16 of 17 (94.1%)
as this agent has been associated with better patients by RECIST, while 13 (76.5%) had a vol-
response rates and more impressive downsizing. ume reduction of the primary tumor between
Alternative therapies may include interferon-alfa 18% and 64%. They also noted that the 31%
with bevacizumab in patients who can tolerate this median reduction in tumor volume was associated
regimen or temsirolimus in those with non-clear with increased areas of central necrosis. Three
cell histology. Pazopanib is also a promising (18%) patients eventually underwent nephrectomy
agent for tumor downsizing, given its impressive with good perioperative outcomes.
12 Neoadjuvant Targeted Therapy and Consolidative Surgery 223

Utilization of Primary Targeted 2–46%). At median follow-up of 6 months (range

Therapy Prior to Debulking 1–15), four patients (21%) had undergone neph-
Radical Nephrectomy rectomy and five died of disease progression. No
unexpected surgical morbidity was encountered.
Robert et al. reported on the first case of complete Viable tumor was present in all four specimens.
remission after neoadjuvant sunitinib. In a 78-year- Sorafenib has been evaluated in the presurgical
old woman with locally advanced RCC with vena setting by Cowey and colleagues from the
cava thrombus extension, 6 months of neoadjuvant University of North Carolina Group. In a prospec-
therapy led to sufficient downstaging and a com- tive nonrandomized study, the authors examined a
plete tumor response [18]. This and other case histologically heterogeneous RCC population
reports contributed to the initial excitement about (17 localized, 13 metastatic), noting a primary
the possibility of dramatic tumor downstaging reduction in 77% of patients with a mean diameter
with targeted therapy. Larger studies have helped reduction of 9.6% in the primary tumor [20].
to better quantify expected tumor shrinkage. These and other similar studies (Table 12.1)
The experience of Thomas and colleagues demonstrate that most tumors may experience a
from the Cleveland Clinic is informative, as they modest decrease in size, which can potentially
reported the response of advanced primary renal facilitate tumor resection in the setting of metastatic
tumors to treatment with neoadjuvant sunitinib and locally advanced disease. However, further
[19]. In their series, 19 patients with advanced investigation is necessary to provide more detailed
renal cell carcinoma deemed unsuitable for initial outcomes data and to refine selection criteria.
nephrectomy due to locally advanced disease or Development of central necrosis has also been
extensive metastatic burden were treated with noted as a unique tumor response to TKIs, but it
standard dosing sunitinib (50 mg daily for 4 is rare to see complete eradication of malignant
weeks followed by 2 weeks off therapy). No elements, and resection of residual masses is
patients experienced complete response. Primary strongly advocated if possible. In the van der Velt
tumor partial responses were noted in three study, treatment with sunitinib led to decreases in
patients (16%), stable disease in seven (37%), the median density of the solid component of the
and nine (47%) had disease progression in the renal tumors suggesting an increase in the degree
primary tumor. With a median of two cycles of of central necrosis, with an average reduction of
TKI therapy, primary tumor shrinkage was 16 HU (82–66). A multinational group from the
observed in eight patients (42%) with an average UK and the Netherlands also noted that necrosis
decrease in primary tumor size of 24% (range was a prominent feature at nephrectomy in 49%

Table 12.1 Primary targeted therapy for renal cell carcinoma

No. of patients with Amount of primary
Agent/type of study Patient population primary tumor shrinkage tumor shrinkage
Sunitinib (retrospective) [19] “Unresectable” RCC (n = 19) 42% 24% (range 2–46%)
Sunitinib (retrospective) [2] M+ patients with primary 76% 12% (range 2–33%)
tumor in place (n = 17)
Sunitinib (prospective, phase II) M+ patients with primary Not stated 12% (range 8–35%)
[21] tumor in place (n = 52)
Sorafenib (prospective) [20] ³T2 RCC; 17 localized; 13 77% 9.6% (range 1–40%)
M+ (n = 30)
Bevacizumab (±erlotinib) M+ patients with primary 52% (range 1–£30%)
(prospective) [22] tumor in place (n = 50)
Sunitinib (retrospective) [11] Localized (n = 7) and M+ 100% 21% (range
(n = 5); imperative NSS 4.7–46%)
(n = 12)
224 S.P. Stroup and I.H. Derweesh

of patients [21]; however, a pT0 response has selection limit our ability to extrapolate this
only rarely been reported [18]. experience to all patients with locally advanced
RCC. While Cost et al. represents the largest
reported experience with in situ caval tumor
Utilization of Primary Targeted Therapy thrombi treated with targeted therapy, there is
in the Setting of Tumor Thrombus insufficient statistical power to assess the useful-
ness of TMTs for tumor thrombus cytoreduction
Neoadjuvant targeted therapy has been investi- on a larger scale. A prospective study with more
gated in the setting of tumor thrombus to see formalized inclusion criteria may better answer
whether this approach could improve operative these questions.
characteristics and decrease perioperative morbid-
ity and mortality. Karakiewicz et al. reported on a
75-year-old woman who presented with an 11-cm Utilization of Primary Targeted Therapy
left renal mass, ECOG status 0, and extension of Prior to Nephron Sparing Surgery
tumor thrombus into the right atrium [23]. After
two cycles of sunitinib therapy, the tumor regressed Presurgical targeted therapy has been reported in
into the IVC below the hepatic veins. This an attempt to downsize tumors in patients with
significantly reduced the extent of the surgery. At imperative indications for partial nephrectomy,
this point, only Level III and IV evidence has been and in patients with tumors potentially amenable
reported to examine the outcomes in this setting. to staged nephron-sparing approaches. In one case
In one of the largest retrospective series, Cost report, 15 months after undergoing a left radical
et al. evaluated the cytoreductive effects of targeted nephrectomy for a pT3bN0M0 high-grade clear
molecular therapies on in situ level II or higher cell RCC, a 62-year-old woman was found to have
inferior vena cava tumor thrombi [8]. The main two enhancing renal masses in her remaining right
outcome measured was a change in the clinical kidney without evidence of other metastatic dis-
level of tumor thrombus following TMT. They ease [24]. Her performance status was excellent.
also measured radiographic responses in thrombus Neoadjuvant targeted therapy led to a 20% reduc-
size and location before and after TMT. Before tion in tumor size and stable disease over six
targeted therapy, thrombus level was II in 18 cycles. The authors contended that the course of
patients (72%), III in five patients (20%), and IV treatment allowed the lesions that were not previ-
in two patients (8%). Sunitinib was initial therapy ously amenable to nephron sparing surgery, to be
for 12 cases, while alternative targeted molecular resected successfully with negative margins while
treatments (TMTs) were administered in 13. avoiding the need for renal replacement therapy.
Following TMT, seven patients (28%) had a mea- Our group reported on the efficacy of neoadju-
surable increase in thrombus height, 7 (28%) had vant TKI therapy prior nephron-sparing surgery
no change, and 11 (44%) had a decrease. One in 12 patients with 14 tumors in the setting of
patient (4%) had an increase in thrombus-level locally advanced and/or metastatic disease and
classification, 21 (84%) had stable thrombi level, with imperative indication for nephron-sparing
and in three (12%) the thrombus level decreased. surgery; all patients had bulky local disease or
There was only one case (4%) where the surgical central lesions [11]. We observed a mean tumor
approach was potentially affected by tumor size reduction of 21.1%, and noted a partial
thrombus regression (levels IV–III). Statistically response in 4 of 14 (28.6%) tumors and stable
significant predictors of tumor thrombus response disease in the remaining ten (71.4%) tumors. All
to targeted therapy could not be identified. The attempted partial nephrectomies were successful
authors concluded that TMT had a minimal clini- with negative margins, and at a mean follow-up
cal effect on RCC tumor thrombi. of 24 months, 10 of 12 patients are alive, with
The retrospective design of these data and lack one dying from metastatic RCC. Three of the 14
of prospective, protocol-driven criteria for patient renal units developed delayed urinary leaks,
12 Neoadjuvant Targeted Therapy and Consolidative Surgery 225

which only occurred in those given postoperative safety profiles and encouraging results [5, 30].
sunitinib. These data demonstrate that in well Thomas et al. reported perioperative complica-
selected patients with imperative indications for tions in 16% of patients with fatigue (74%),
nephron-sparing surgery in the setting of locally abnormal taste (43%), diarrhea (31%), and hand–
advanced disease, primary TKI therapy results in foot syndrome (32%) being most common [19,
tumor response and may facilitate or enable chal- 31]. Margulis et al. found that patients treated
lenging partial nephrectomy. While all planned with preoperative targeted therapy experienced
renal units were successfully salvaged, patients marginally increased rates of wound related
who subsequently underwent further systemic complications, although this did not reach statis-
therapy were at high risk for developing a delayed tical significance. In multivariate analysis, the
urine leak, which is likely due to the potent anti- type of preoperative systemic therapy and its
angiogenic and antiproliferative effects of suni- duration and interval from discontinuation of
tinib, and is analogous to wound healing data systemic therapy to surgery were not associated
reported in other studies. with the development of perioperative morbidity.
Further study is requisite to determine the utility In addition, none of the surgical parameters such
of nephron-sparing surgery in this setting, partic- as EBL, rate of blood transfusion or operative
ularly in assessing the benefits of cancer control time were different between the studied patient
weighed against the risk of chronic kidney disease cohorts treated with or without TMT, suggesting
and cardiovascular death [22, 25]. that the procedural difficulty was not affected by
preoperative administration of TMT. However,
most of these consolidative surgical experiences
Safety, Toxicity, and Side Effects for RCC have been rather limited and further data
of Primary Targeted Therapy will be required.
Silberstein and colleagues described compli-
Perioperative Safety of cations of targeted therapy in the setting of partial
Neoadjuvant Therapy nephrectomy [11]. They found delayed urine
leaks in 3 of 14 renal units undergoing nephron-
Tyrosine kinase inhibitors and mTOR inhibitors sparing surgery after neoadjuvant sunitinib. It is
can have notable toxicities based upon their unique important to note that all had a bulky tumor bur-
and novel mechanisms action. Proangiogenic den that required extensive collecting-system
pathways have important roles in tissue healing reconstruction. All patients resumed sunitinib 4
and integrity. Hence, disturbance of these path- weeks after surgery. Conservative measures that
ways may lead to increased incidence of delayed included temporary discontinuation of sunitinib
wound healing, fascial disruption, and incisional and placement of ureteral and perirenal drains led
hernia [26, 27]. These agents will also block the to resolution of fistulae in all patients. Satisfactory
natural regeneration of the microvasculature and healing after partial nephrectomy, as observed in
might thus predispose the patient to postoperative the majority of patients this series, represents a
bleeding or thrombotic events [28–30]. strong indication that consolidative surgery can
Fatigue, nausea, diarrhea, hepatotoxicity, and be performed safely given appropriate surgical
myelosuppression are fairly common in patients expertise and a meticulous approach.
taking these agents and could impact quality of
life prior to surgery or delay consolidative sur-
gery [27]. TKI-associated hand–foot syndrome Wound Healing
may also be a factor at higher toxicity grades.
Most toxicities are reversible and manageable if a Concerns remain about perioperative morbidity,
sufficient washout period is allowed before sur- wound healing and long-term outcomes. Targeted
gery. Most series of primary TKI therapy before agents have a variety of half-lives; with temsirolimus
debulking nephrectomy have provided reassuring at 17 h, sorafenib at 1–2 days, sunitinib at 4 days,
226 S.P. Stroup and I.H. Derweesh

and the bevacizumab infusion at 17 days is the events and consideration should be given to
longest. To minimize the effect on wound heal- using low-dose aspirin or unfractionated or low-
ing, most series have advocated at least a 2-week molecular-weight heparin during the periopera-
washout period for most oral TKIs and at least 4 tive period to reduce the risk of these events.
weeks for bevacizumab. Despite these recom- Pooled data from five randomized controlled tri-
mendations, some have reported good outcomes als that included a total of 1,745 patients with
in patients who did not suspend therapy before metastatic colorectal, breast, or non-small-cell
surgery. In a paper by Margulis and colleagues, lung carcinoma treated with bevacizumab sup-
there appeared to be no difference in periopera- ports a concern in this area, particularly when
tive complications between those stopping TKIs targeted agents are used along with chemother-
1 day or 14 days before surgery [29]. In the apy [30]. Using Cox proportional hazards
Jonasch study, presurgical treatment of patients regression, treatment with bevacizumab and
with bevacizumab before surgery resulted in a chemotherapy, compared with chemotherapy
20.9% rate of delayed wound healing, vs. 2% for alone, was associated with increased risk for an
non-treated patients [26]. Further, these compli- arterial thromboembolic event (HR = 2.0, 95%
cations range from superficial to deep fascial and CI = 1.05–3.75; p = 0.031) but not for a venous
may significantly delay restarting targeted ther- thromboembolic event (HR = 0.89, 95%
apy. Bowel perforation is also a known, but rare CI = 0.66–1.20; p = 0.44). The absolute rate of
complication of treatment with TKIs and should developing an arterial thromboembolism was
be considered in the postoperative setting in 5.5 events per 100 person-years for those receiv-
patients with extensive lysis of adhesions, bowel ing combination therapy and 3.1 events per 100
manipulation, or resections [32, 33]. person-years for those receiving chemotherapy
alone (ratio = 1.8, 95% CI = 0.94–3.33;
P = 0.076). Therefore combination treatment
Cardiovascular Toxicity with bevacizumab and chemotherapy, compared
with chemotherapy alone, was associated with
Cardiovascular toxicity, hypertension, and venous an increased risk of arterial thromboembolism
thrombosis are also concerning side effects of suni- but not venous thromboembolism. Whether this
tinib and sorafenib that may complicate the periop- will apply to patients with RCC who do not
erative course [34]. VEGF inhibitors block the received conventional cytotoxic chemotherapy
natural regeneration of the microvessels and could or to TKIs that have a different mechanism of
potentially affect vascular and coronary integrity. action when compared to bevacizumab, is not
Sunitinib has the greater potential for inducing car- known.
diac toxicity with up to a 21% of patients experi-
encing a decline in left ventricular ejection fraction
below the lower limit of normal. Sunitinib has also Future Directions
been shown to increase the QTc interval and care
should be used when prescribing this regimen to Based on the limited data currently available,
patients with any history of ventricular arrhyth- neoadjuvant TKI therapy followed by consolida-
mias, or co-administering medications that also tive surgery appears to be a promising approach
prolong the OT interval [32]. Close measurement for select patients with locally advanced tumors
of electrolytes to prevent hypokalemia and hypo- or to facilitate or enable challenging partial neph-
magnesemia is also warranted. rectomies, but it is important to emphasize that
this approach is still experimental, and further
work is required.
Thromboembolic Complications While several randomized studies are aimed
at answering the question of utility and timing
Tyrosine kinase inhibitors may increase risk of of cytoreductive nephrectomy in the setting of
developing arterial and venous thromboembolic mRCC [34], currently no prospective randomized
12 Neoadjuvant Targeted Therapy and Consolidative Surgery 227

studies exist to evaluate utility of primary targeted

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metastatic clear cell renal cancer. Ann Oncol. 2011;22: 30. Scappaticci FA, Skillings JR, Holden SN, et al.
1041–7. Arterial thromboembolic events in patients with meta-
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 Part IV
Advanced Disease
 Biology of Renal Cell Carcinoma
(Vascular Endothelial Growth 13
Factor, Mammalian Target of
Rapamycin, Immune Aspects)

Alexandra Arreola and W. Kimryn Rathmell

gene as the primary genetic perturbation, thus

Introduction providing a valuable resource for understanding
this pivotal genetic event driving the development
Considering for a moment only clear cell renal of RCC [1].
cell carcinoma (ccRCC), we can focus on the
unique biology of this renal tumor subtype, which
accounts for the majority (>70%) of all cases of Molecules Mediating RCC
renal cell carcinoma (RCC). Although familial Pathophysiology
RCC occurs in fewer than 5% of cases of kidney
cancer, there is much that has been learned from von Hippel–Lindau
genetic studies from families with ccRCC. The
majority of familial ccRCC occurs in association Lessons from VHL Disease
with the familial von Hippel–Lindau (VHL) fam- To understand the pathways currently targeted
ily cancer syndrome, which is characterized by for therapy of RCC, we must first explore the les-
multifocal bilateral ccRCC in addition to pheo- sons that we have learned from the study of VHL
chromocytoma/peripheral neuroendocrine tumor disease. As alluded to above, the tumor suppres-
(PNET) and hemangioblastomas of the retina, sor gene VHL has been associated with a familial
cerebellum, and spine [1]. In 1994, it was recog- predisposition for various cancers including,
nized that the majority of sporadic ccRCC cases hemangioblastomas (central nervous tumors that
were also associated with inactivation of the VHL originate in the vascular system), pheochromocy-
tomas (adrenal gland tumors), as well as clear
cell renal carcinoma. Specifically, some families
bear increased risk for one or more of these clas-
sic three tumor manifestations. VHL disease has,
A. Arreola
Department of Genetics, Lineberger Comprehensive therefore, been classified according to these clini-
Cancer Center, University of North Carolina, cal manifestations as Type 1, 2A, 2B, and 2C [2].
450 West Drive, CB 7295, Chapel Hill, NC 27599, USA In this classification, VHL Type 1 disease is
W.K. Rathmell () highly associated with ccRCC and hemangio-
Department of Medicine, Lineberger Comprehensive blastoma, but poses no risk for the development
Cancer Center, University of North Carolina,
of the pheochromocytoma, whereas Types 2A,
450 West Drive, CB 7295, Chapel Hill, NC 27599, USA
2B, and 2C all present this risk. Within Type 2
Department of Genetics, Lineberger Comprehensive
disease, however, Type 2A presents some risk
Cancer Center, University of North Carolina,
450 West Drive, CB 7295, Chapel Hill, NC 27599, USA for ccRCC, Type 2B presents high risk for
e-mail: [email protected] ccRCC, and Type 2C patients exclusively develop

S.C. Campbell and B.I. Rini (eds.), Renal Cell Carcinoma: Clinical Management, Current Clinical Urology, 231
DOI 10.1007/978-1-62703-062-5_13, © Springer Science+Business Media New York 2013
232 A. Arreola and W.K. Rathmell

pheochromocytoma, this subtype having no The chromosomal deletions that are encountered
association with ccRCC [3]. are therefore thought to primarily represent loss
The identification of these RCC-associated of heterozygosity (LOH) events.
subtypes within the VHL disease spectrum gave pVHL partners with Elongin C, Elongin B,
way to a better understanding of the function of Ring Box Protein 1 (Rbx1/Roc1), and Cullin 2 to
VHL gene and its role in RCC [4]. A variety of form an E3 ubiquitin ligase complex known as
VHL mutations occur, including several higher VBC [10–14]. This E3-ubiquitin ligase complex
frequency hot spots, spread over virtually the resembles the canonical complex SCF in its struc-
entirety of the gene. All of the major structural ture and function, with pVHL performing the
mutations are associated with ccRCC, but not function of the F-box protein [15]. Its role, there-
risk for pheochromocytoma. Therefore, when a fore, is to provide the complex’s target specificity.
subset of families were found to carry structur- Several target proteins have been identified, but
ally intact missense mutations of VHL, which the most notable to date are the hypoxia-inducible
also shared association with ccRCC risk, it pro- factors HIF-1a and HIF-2a [16]. Representative
vided new insight into the specific tumor sup- hotspot missense mutations identified in VHL
pressive action of the protein. Among the occur in residues that produce mutant proteins
missense mutations, those associated with greater affecting the ability of pVHL to properly bind the
penetrance for RCC largely affected the portions VBC complex or reduce its affinity for detecting
of the VHL gene that encode for domains that HIF-1a and HIF-2a subunits. This work gave
either disrupt the participation of pVHL with its way to the investigation of differential affinity
known partners in the E3-ubiquitin ligase com- and thereby, regulation, of HIF-a subunits by
plex in which pVHL plays the role of the key pVHL and the VBC complex [17].
substrate recognition component or prevents
binding to a key family of substrates of that com- VHL: Regulation of HIF and the Cellular
plex, the hypoxia-inducible factors (HIFs), which Hypoxic Response
we will discuss below [5]. This classification and As the substrate recognition molecule in the
the identification of genotype/phenotype-linked E3-ubiquitin ligase complex VBC, under normal
VHL mutations provide an interesting starting oxygen conditions pVHL is responsible for
point for defining domains and functions of the recognizing and recruiting the HIF-a subunits
pVHL protein that are integral to the develop- to the VBC complex where they will undergo
ment of ccRCC. These relationships have given polyubiquitination, targeting them for subsequent
way to a genetic and molecular understanding of proteosomal degradation [18, 19]. Under condi-
VHL gene target regulation, primarily the regula- tions of oxygen deprivation (<4% Oxygen),
tion of the HIF pathway [6], which, as we shall pVHL fails to recognize HIF-a, and the proteins
see, has altered the paradigm for understanding are stabilized as a result of avoiding degradation.
and treating ccRCC. Because the HIF proteins are translated at a high
basal rate, stabilization of these proteins means
VHL Mutation in Sporadic RCC they can accumulate to high levels very rapidly,
While patients with sporadic RCC commonly in a matter of minutes.
have a deletion of a portion of chromosome 3p that The essence of this oxygen dependency comes
encompasses the VHL gene, most of the VHL from a post-translational modification that occurs
mutations also associated with sporadic RCC are in the presence of molecular oxygen. HIF-a fac-
missense mutations that result in inactivation of the tors contain an oxygen-dependent domain which
VHL protein (pVHL) either completely or partially. hosts proline residues that are hydroxylated by an
VHL functions as a classical tumor suppressor gene, iron and oxygen-dependent family of enzymes
such that disruption of VHL tumor suppressor called the HIF prolyl hydroxylases (PHD). pVHL
activity requires biallelic inactivation in accor- specifically targets the prolyl hydroxylated forms
dance with Knudson’s two-hit hypothesis [7–9]. of HIF-a. Thus, under low-oxygen conditions,
13 Biology of Renal Cell Carcinoma… 233

HIF PHD are unable to hydroxylate HIF-a sub- which we will discuss further in this chapter.
units, and unhydroxylated HIF-a escape recogni- HIF-3a exists in at least four splice variants
tion by the VBC complex. The HIF-afactors whose functions are still largely uncharacter-
translocate to the nucleus, by way of heterodi- ized, but are known to have additional DNA-
merizing with the nuclear transporter HIF-1b, binding elements that lack homology with
and promote the transcription of various target HIF-1a or HIF-2a. Future work with HIF-3a
genes involved in the cellular response to limiting will likely lend further insight into the influences
oxygen supply. Some notable target genes, which on an individual tumor’s transcriptional profile,
facilitate the hypoxic response, include platelet- but a full understanding of this factor’s partici-
derived growth factor (PDGF), vascular endothe- pation in ccRCC remains to be developed.
lial growth factor (VEGF), and carbonic
anhydrase IX (CAIX), all of which are current or HIF Regulation and Function
emerging targets of therapy. HIF-a subunits that have averted proteosomal
degradation, as a result of hypoxia or inactive
VHL as a Tumor Suppressor pVHL as previously described, accumulate and
In ccRCC, as a result of VHL mutation, HIF factor are able to bind HIF-b partners which are then
stabilization is a constant feature of the cancer referred to as HIF-1 or HIF-2, according to the a
cells. The role pVHL plays in the prevention of subunit component of the complex. These newly
cancer is a fascinating intersection of a normal formed HIF transcription factors translocate to
physiological response to environmental stimuli the nucleus, bind hypoxia response elements
derailed in the extreme. These cells, therefore, (HREs) in gene promoter or enhancer regions
have constitutive stabilization of HIF factors, con- and thereby regulate transcription of various tar-
stitutive target gene activation, and little dynamic get genes involved in numerous cellular func-
regulation of these factors. The condition of tonic tions. HIFs regulate a variety of cellular processes
activation of the hypoxia response pathway in the including: apoptosis, erythropoiesis, angiogene-
presence of oxygen has been termed pseudohy- sis, energy metabolism, and cell proliferation.
poxia. This condition sets the stage for a unique The most commonly dysregulated and explored
targeted therapy paradigm in RCC. target genes are VEGF [21], PDGF, CAIX,
GLUT1/SLC2A1, and genes involved in glycoly-
sis. We will discuss the implications of these
HIF Biology deregulated target genes for supporting tumor
cell growth later in this chapter.
HIF-1, HIF-2, and HIF-3: A Family of Although HIF-1a and HIF-2a deregulation in
Transcription Factors Deregulated ccRCC is primarily associated with VHL muta-
in Cancer tion or loss, there are other cellular processes that
HIFs-1, -2, and -3 form a family of basic helix– can influence the basal levels of each HIF factor.
loop–helix transcription factors that each het- At the transcriptional level there are factors which
erodimerize in the cytoplasm with a stably bind in the promoter region of either HIF-1a or
expressed nuclear transport protein, HIF-1b HIF-2a. One notable feature of HIF-2a tran-
also known as aryl hydrocarbon receptor nuclear scriptional regulation is the participation of iron
translocator (ARNT). HIF-1a and HIF-2a sub- regulatory protein (IRP1) in regulating HIF-2a
units are most similar in structure and DNA- gene expression. This iron-dependent process
binding domains; although they are known to involves IRP1 binding to a stem-loop structure in
regulate some of the same gene targets there is the HIF-2a 5¢ untranslated region, effectively
increasing evidence of their differential regula- blocking transcription [22]. Similar mechanisms
tion of hypoxia-inducible genes [20]. Difference may be involved in HIF-1a regulation and may
in the balance of HIF-1a and HIF-2a produces present unique opportunities for therapeutic
stable variation in the downstream target genes, targeting.
234 A. Arreola and W.K. Rathmell

Perhaps most intriguing to the present discus- emanating from tumor cells. Such growth factor
sion, it has been observed that HIF is also regu- ligands mediate their effects by binding and acti-
lated at a translational level by mTOR complex vating cognate receptors, which in the case of
1 (mTORC1) mediated cap-dependent transla- VEGF are present on the surface of endothelial
tion. HIF-1a is one of a panel of proteins cells. VEGF receptors (VEGFRs) are a part of a
specifically produced in response to mTOR- family of receptor tyrosine kinases (RTKs) that
related signaling, and this effect on translation are activated by extracellular growth factors to
feeds the high basal rate of protein production, initiate a signaling cascade and promote cell
such that HIF-1a can accumulate very rapidly mitogenesis. In addition to promoting angiogen-
under hypoxic conditions. This also provides a esis, VEGF has other activities detailed below
valuable strategy to limit the extent of HIF-1a that also enable this factor to have potent effects
protein that can achieve stabilization, by block- on the general health of the tumor. As such, this
ing this important pathway with mTOR inhibi- factor among the many transcriptionally activated
tors. However, HIF-2 does not appear to be genes associated with HIF provides an ideal tar-
affected by mTORC1, but rather its production get to select for therapeutic development.
occurs downstream of the alternate complex
mTORC2. We will review mTORC1 signaling HIF1 Vs. HIF2: Convergent and Divergent
mechanisms below, but new strategies with Activities in RCC
inhibitors which block activation of both com- Based on the differential regulation activity via
plexes are under development. pVHL and the VBC complex on the two major
HIF-a family members and the other means of
HIF Role in RCC Tumorigenesis and modulating HIF expression, it is no surprise that
Progression by Transcriptional Regulation the spectrum of HIF-1a and HIF-2 expression is
of HIF Target Genes: Focus on VEGF variable. However, adding to this source of tumor
A very large repertoire of hypoxia response variability, HIF-1a and HIF-2 appear to not only
genes are regulated by the HIF family of tran- maintain many similar gene targets, but also have
scription factors. We will focus on one of these sets of gene targets that are more commonly or
targets, VEGF, that has made major strides in specifically regulated by either HIF-1a or HIF-
the road toward the development of effective 2a [20, 24]. As such, varying levels of HIF-1a
therapeutic options for advanced RCC. Initiation and HIF-2a expression in renal carcinoma are
and progression of RCC is dependent on the associated with upregulation of certain pathways.
recruitment of endothelial cells to the tumor Tumors expressing both factors (H1H2) were
cells for the formation of new vasculature, the found to promote glucose consumption over
ability of cancer cells to overcome a hypoxic HIF-2a expressing tumors (H2) [25]. Similarly,
environment and thrive, as well as to manage an pVHL-deficient H1H2 clear cell renal carcino-
increased metabolic state of the cells. The sur- mas display upregulated mTOR and MAPK sig-
vival of renal cancer cells requires direct tran- naling pathways, while those H2 carcinomas
scriptional regulation of these pathways by HIF have upregulated c-Myc activity and showed
family members [23]. The development and increased proliferative capacity [26]. Both group-
maintenance of the dense vascular network asso- ings displayed increased angiogenesis and dereg-
ciated with RCC is largely driven by HIF’s tran- ulation of VEGF transcript. Differential
scriptional regulation of pro-angiogenic factors regulation of HIFs and their target genes can
such as VEGF. therefore provide valuable information as to what
VEGF is itself a soluble growth factor that is genetic and molecular perturbations influence
secreted from cells to promote pro-angiogenic tumor biology and may give clues as to the poten-
signals to the local environment. It therefore tial for response to therapies targeting the mTOR
presents an interesting and tractable target for or VEGF signaling pathways [27]. This chapter
inhibition as a strategy to intercept this signal will focus on two commonly targeted pathways
13 Biology of Renal Cell Carcinoma… 235

Fig. 13.1 Signaling pathways and current therapies for are currently in use targeting the intracellular kinase
advanced RCC. (1) The effects of VHL loss and HIF sta- domain to prevent activation of VEGF receptor-mediated
bilization on transcriptional activity provides the chief signaling pathways in endothelial cells. (2) Endothelial cells
mode of induction of VEGF, a secreted growth factor that responding to VEGF and tumor cells responding to other
stimulates the expansion and maturation of endothelial cells growth factor stimuli activate transmembrane receptor
by engaging VEGF receptors on the endothelial cell sur- tyrosine kinases and subsequently the PI3K/Akt/mTOR
face. One targeted antibody therapy, bevacizumab, directly signal transduction cascade, intersecting with HIF regula-
inhibits VEGF ligands from activating receptor tyrosine tion at the level of protein translation. Various targeted
kinases. Tyrosine kinase inhibitors are indicated which therapies against mTORC1 are indicated

for therapy in RCC: VEGF, a HIF target and it was recognized that regional tissues liberated a
potent regulator of tumor vascularity, and mTOR, substance that promoted the expansion of existing
a regulator of HIF expression and global cell blood vessel networks, termed angiogenesis,
maintenance (Fig. 13.1). and supported the formation of new vessels,
termed neovascularization. This process was also
noted to occur along a substrate gradient to reach
Vascular Endothelial Growth Factor a region of tissue in need of vascular supply. For
the next half-century these principles have formed
The Family of VEGF Ligands the foundation of investigations into normal and
and VEGF Receptors tumor angiogenesis, and VEGF has remained as
VEGF, a Historical Perspective the single most potent and ubiquitous angiogenic
VEGF was first identified in 1948, known then as growth factor in cell biology.
soluble “angiogenic factor X” which could promote VEGF, also known as vascular permeability
the growth of vessels [28]. Even in the early studies factor (VPF), functions as both a mitogen and
236 A. Arreola and W.K. Rathmell

an important regulator of endothelial vessel physiol- original VEGFA was identified as a secreted pep-
ogy. VEGF was formally identified in 1989 as a tide of 45 kDa, although the apparent molecular
secreted mitogen specific to endothelial cells [29, mass is approximately 20 kDa under reducing
30]. In tumors, VEGF exerts its mitogenic growth conditions, confirming substantial modification
effect on the vascular endothelial cells, promot- of the protein [31].
ing both proliferation and new vessel formation, The active portion of the protein is a 26 amino
as well as directing forward extension along a acid signal sequence at the N terminus of the
growth factor gradient. In many cancer situations, multiple isoforms of the protein. At least nine
oxygen diffusion is unable to penetrate into the isoforms arise due to the alternative splicing of a
deeper regions of the tumor. This triggers a single gene [32]. The primary protein of this fam-
hypoxic response as we have described above, ily is a 165 amino acid member (VEGF165) [29].
resulting in HIF stabilization and resultant tran- In addition to VEGF165, there are also two com-
scriptional activation of VEGF. For the case of mon 121 amino acid (VEGF121) and 189 amino
ccRCC, and other tumors that have acquired con- acid (VEGF189) forms. Finally, a 145 amino acid
stitutive HIF deregulation, it is important to con- isoform (VEGF145) has been identified in
sider that the driving transcriptional force for association with tumor angiogenesis. The various
VEGF expression is not regulated by physiologi- isoforms all arise from one 8 exon gene and arise
cal gradients of oxygen. In these conditions, through alternative splicing [33]. VEGF189 rep-
VEGF is being transcriptionally induced inde- resents the complete 8 exon transcript. VEGF165
pendently of tumor oxygen status, and therefore lacks exon 6, VEGF145 lacks exon 7, and VEGF 121
may achieve much higher levels and also promote lacks both exons 6 and 7. VEGF165 is the predomi-
an even more vigorously disorganized assortment nant isoform with basic charge and moderate
of endothelium as a result of unrestrained affinity for heparin, making it locally sequestered
endothelial mitogenic and neovascularization in the extracellular matrix following secretion
processes. with slow diffusion, setting up the gradient along
Because of the importance of VEGF in this which physiologic endothelial responses occur
critical process of tumor angiogenesis, it has [31]. By contrast VEGF121 has little affinity for
become a central player in the arena of targeted heparin and is liberated freely from the cell, but
drug development for many tumors, including VEGF189, as a result of additional basic residues,
RCC. For years, the influence of angiogenesis binds heparin strongly and is fully sequestered in
and the impact on oxygen and nutrient delivery to the extracellular matrix [34].
rapidly growing tumors has been a basic factor of The activity of the various isoforms continues
tumor biology as it impacts such key clinically to be an area of active investigation, but is beyond
relevant factors as drug delivery, surgical resec- the scope of this chapter. The important message
tion strategies, and sensitivity to radiation ther- is that all VEGFA isoforms are liberated in
apy. This chapter will provide an overview of the response to HIF-mediated transcriptional induc-
biology of VEGF and relevant pro-angiogenic tion, providing local and distant effects on the
cofactors, as well as the current status of thera- tumor environment. It stands to reason, however,
peutics specifically targeting this key molecule in that currently available neutralizing antibody
the treatment of RCC. preparations target common portions of VEGFA,
and thus restrict VEGFA signaling from most if
VEGF Protein Structure and Isoforms not all of the isoforms. This assessment requires
VEGF actually refers to a family of related pep- further validation, and failure to fully neutralize
tides, each with restricted tissue expression and isoforms due to exon selection or local environment
receptor specificity. VEGFA is the primary factor restrictions could be potentially a major source of
targeted in the treatment of cancer. The protein is drug resistance.
structurally related to the PDGF family, sharing Related family members, VEGFB, VEGFC, and
homology with both PDGF-a and PDGF-b. The VEGFD are also regulated by HIF transcriptional
13 Biology of Renal Cell Carcinoma… 237

activation and expressed in a host of tumor induce transcription at the VEGF locus [39–41].
environments. These distinct genes interact with a This transcriptional regulation via HIF appears to
separate group of related receptors, some involved be the dominant regulatory mechanism for major
in endothelial cell growth and others involved in VEGFA stimulation, and inhibition of binding at
lymphatic vessel development [35, 36]. In par- the consensus HRE promoter sequence sup-
ticular, VEGFB targets the endothelial receptor presses transcriptional activation of VEGF [42].
VEGFR1 (Flt1), whereas VEGFA isoforms Based on nuclear runoff transcriptional assays
engage the VEGF receptor 2 (VEGFR2, Flk1, the transcriptional rate for VEGF is increased at
KDR) to induce endothelial cell growth. However, least two- to threefold by hypoxia [43].
both VEGFA isoforms and VEGFB can bind to VEGF is also regulated in response to hypoxia
soluble VEGFR1. Although investigations con- at the level of mRNA stability. Both the 5¢ and 3¢
tinue to examine potential activities of these pro- untranslated regions of VEGF confer increased
teins in tumor biology, a definitive role for these mRNA stability. In particular the increase in
related proteins in tumor development or mainte- VEGF level in response to hypoxia is at least
nance has not been conclusively demonstrated. partly contributed by post-transcriptional mecha-
Therefore, although targeting these pathways nisms [44]. Under normoxic conditions VEGF
may eventually be developed in cancer therapy, mRNA is extremely labile, with a very short
there is no current role in RCC, and the focus of half-life [45–47], and experiments have demon-
this chapter will be exclusively on VEGFA. strated an increase in half-life by as much as
eightfold under hypoxic conditions. The specific
Regulation of VEGF: Management mechanisms of maintaining VEGF stability
at Many Levels remain to be determined, but likely involve com-
Much of what we understand about VEGF pensatory regulation by hypoxia or HIF-regulated
regulation does come from investigations of the tumor microRNAs [48].
expression in tumors or tumor-related tissues. The effect of hypoxia on VEGF translation
Major advances have been made in the quantitative has been understudied, and much less is known
assessment of parameters or factors directly asso- about the mechanisms and significance of these
ciated with tumor angiogenesis. Histologically, translational controls. Hypoxia appears to play
quantitation of intra-tumoral microvessel density opposite roles on cap-dependent translation and
(MVD) correlates well with the measurement of internal ribosomal entry (IRE) translation. Global
pro-angiogenic factors, primarily VEGF, in the protein translation that involves the traditional
serum of cancer patients. Most of the attention 5¢-m7-GTP capping processing is inhibited by
has been directed to VEGF and its cognate recep- hypoxic signals, whereas induction by IRE pre-
tors in tumor angiogenesis. serves the translation of a small number of fac-
Gene expression of VEGF is regulated by a tors critical for the physiological response to
variety of factors including growth factors, p53 oxygen deprivation, including VEGF as well as
mutation, estrogen receptor activation, thyroid- HIF-1a [49]. Much more is likely to be learned
stimulating hormone, nitric oxide, and hypoxia. about this dynamic and potentially important
Inappropriate activation of the hypoxia response mechanism of VEGF regulation in cancer as well
pathway, as discussed above, and elsewhere in this as normal physiology.
text, is a major mechanism of VEGF transcrip-
tional regulation in RCC [37, 38]. In RCC, HIF VEGF Function
complex binds to a conserved hypoxia response VEGF protein is a potent mitogen of both capil-
element (HRE) proximal to a CREB element lary and vascular endothelial cells [29, 31]. It is
(cAMP response element) located in the VEGF perhaps the only chemokine with direct activity
5¢ promoter region. The C-terminal transactiva- to stimulate proliferation and migration of
tion domain of HIF-a interacts with the p300/ endothelial cells, promoted through binding and
CBP (CREB binding protein) coactivator to dimerization of cell surface transmembrane
238 A. Arreola and W.K. Rathmell

VEGF receptors which also impacts the vascular As alluded to above, the vascularization of
physiology, causing vessel dilation and vascular tumors provides a provocative target for therapy
permeability. The receptors FLT1 (VEGFR1) and for several reasons. First, in adults, the formation
KDR/FLK1 (VEGFR2), mentioned above as of new vessels is an event essentially relegated to
receptors for VEGFB and VEGFA, respectively, pathologic conditions, with the exception of
comprise the major classifications of endothelial wound healing. The pathological event that dem-
receptors that bind VEGF. These receptors are onstrates the efficiency of this process most ele-
only present on endothelial cells and data sug- gantly is the growth of solid tumors. By promoting
gests that the multiple isoforms of VEGF com- VEGF signaling, cancer cells co-opt host vessels,
pete for binding on the receptor. Specifically, it is sprout new vessels from existing ones, and/or
important to note that VEGF145, the major recruit endothelial cells from the bone marrow.
tumor-associated isoform, will inhibit the bind- Second, the resulting vasculature is structurally
ing of VEGF165 to the KDR/FLK1/VEGFR2 and functionally abnormal, lacking vascular tone
receptor, although binding by either results in or proper pericyte support structures and is highly
receptor activation and downstream signaling. permeable with global disorganization. Therefore,
Both VEGF145 and VEGF189 have highly this unique tumor vasculature provides a distinc-
basic residues that permit them to reside stably in tive target for inhibitory therapy [37].
the extracellular matrix. This structural organiza- A large amount of data has supported the
tion of VEGFA species residing in the extracellu- importance of VEGF and its cognate receptors in
lar matrix surrounding the secreting cell spatially tumor angiogenesis given that VEGF is measur-
fixes them as chemokines to direct vessel growth ably increased in tumors and the surrounding
[50]. In addition, the VEGF family regulates the extracellular matrix. VEGF has also been shown
permeability of both mature and developing vessels to be elevated in the serum of patients with non-
in a dose-dependent manner [51–56]. Even these small-cell lung cancer, colorectal, breast, ovarian,
seemingly distant activities, however, occur through uterine, and RCC [58–63]. As detailed above, a
interactions with the FLT1 and KDR/FLK1 receptor variety of mechanisms account for the increase in
family. Finally, VEGF has been implicated in VEGF, with activation of the hypoxic response
maintaining the blood–brain barrier, and facilitat- pathway via the transcription factors HIF-1a and
ing glucose transport across this essential barrier HIF-2a as the most classic mechanism of induc-
during periods of physiological crisis. tion. Despite the consistency with which VEGF
is elevated in the tumor phenotype, it remains an
VEGF and Cancer unpredictable tumor marker [64]. Many other
It was not until 1995 that the importance of VEGF pathologic or inflammatory states can cause
and its receptor system in tumor angiogenesis serum elevations of VEGF and VEGF levels
was fully recognized as a feature not only pro- themselves vary somewhat widely in intrapatient
moting cancer growth, but essential for tumor measurement, limiting its use as an independent
maintenance as well. This suggested a potential biomarker. One potential problem with serum
therapeutic option specifically targeting this measurement of VEGF is the high concentration
aspect of tumor biology [57]. Since then, a revo- of VEGF in platelets, which release their contents
lution in targeted therapy has evolved multiple during the collection of serum samples [65, 66].
strategies to achieve the inhibition of tumor It is also interesting to note that disruption in
angiogenesis. Because of the unique molecular VEGF signaling with VEGF RTK inhibitors
characteristics of constitutive, non-hypoxia- leads to an increase in serum VEGF, presumably
dependent HIF activation and VEGF expression as a result of feedback mechanisms or reduced
in RCC, this cancer is an ideal system in which to turnover of the receptor/ligand pairs.
examine these emerging therapeutics specifically RCC presents a unique clinical setting in which
targeting VEGF signaling and provide important a tumor type nearly universally usurps a pro-
proof of concept work. angiogenic cellular homeostatic mechanism. Cell
13 Biology of Renal Cell Carcinoma… 239

culture model systems of RCC have demonstrated stroma. It is important to note that functional
a direct link between VHL mutation and upregu- VEGF receptors have not yet been identified on
lation of VEGF. RCC cells in which VHL is renal carcinoma cells. Thus, the effect of inhibiting
mutant express abundant levels of VEGF mRNA VEGF receptor signaling rests primarily in prevent-
and protein, and reconstitution of these cells with ing tumor angiogenesis; additionally, withdrawal
a wild-type VHL cDNA restores predicted pat- of the VEGF signal to endothelial cells induces
terns of VEGF hypoxia responsive regulation their regression. In elegant work by Bhatt et al., the
[21]. Thus, increased expression of VEGF and tumor vasculature is virtually absent from the
the consequences of that increased expression are tumor shortly after treatment with VEGF RTK
expected and predictable events in the develop- inhibitors [70, 71]. Indeed, RCC tumors treated
ment of most RCC. with VEGF receptor TKIs display marked central
necrosis, consistent with cell death as a result of
Targeting VEGF and VEGF Receptors removing the vascular supply [72, 73].
The notion of targeting tumor angiogenesis is not Later chapters in this volume will detail the
unique to RCC. Certainly, the requirement of development of VEGF RTK inhibitors, but the
increased vascularity, or recruitment of vascula- success of this therapeutic strategy is owed to the
ture by solid tumors, is a well-established hall- unique dependency of RCC on the disordered
mark of cancer [67]. VEGFA can be targeted by a vasculature. It is important to recognize that as
humanized neutralizing antibody, bevacizumab, with most tyrosine kinase inhibitors, those used
which was previously approved as an adjunct to for the treatment of RCC are not exclusively
chemotherapy for other cancers [68]. Although inhibitory to VEGF receptors. However, as more
bevacizumab has shown limited activity as a sin- is learned about the VEGF receptor inhibitors that
gle agent in many other tumors, the drug provides have been developed the theme that emerges is of
an important addition to chemotherapy, as the inhibition of VEGF receptor 2, as the critical
reduction in tumor-produced VEGF results in mediator of RCC tumor angiogenesis. The first
normalization of the vasculature for more effec- two tyrosine kinase inhibitors developed for
tive penetration of the chemotherapy. advanced RCC are sunitinib [74] and sorafenib
In advanced RCC the situation is somewhat [75]. Pazopanib is another tyrosine kinase inhibi-
different, as the tumor cells produce abundant tor (TKI) recently approved for use in RCC ther-
levels of VEGF in a manner unregulated by nor- apy targeting all VEGF receptors as well as
mal control mechanisms. The result is a notori- PDGFR-a and b, and c-Kit to inhibit endothelial
ously abundant and disorganized vasculature. cell proliferation [76] (Table 13.1). Finally, addi-
What was speculated, but was unknown, was tional VEGF RTK inhibitors currently emerging
whether as a result these tumors would be more are tivozanib [80] and axitinib, both of which
dependent on tumor endothelium to support con- inhibit VEGF receptors 1–3 as well as PDGFR-b
tinued growth. In fact, phase II data suggested [81]. These therapeutics will be discussed in depth
that these tumors were, in fact, highly dependent in the following chapters.
on the supporting vasculature, and reductions in
tumor volume followed treatment targeting
VEGF ligand [69]. As will be discussed else- Mammalian Target of Rapamycin
where in this volume, bevacizumab is now
approved for RCC in combination with inter- PI3Kinase, Akt, and mTOR, a Common
feron-alpha [69]. Pathway in Cancer Biology
Of course, as a secreted ligand, VEGF-mediated The mammalian target of rapamycin (mTOR) is
mitogen activity is dependent upon engagement of an intracellular serine-threonine kinase that can
its receptor. As discussed above, there are multiple be regulated by upstream growth factor signals
VEGF receptors expressed on tumor endothelial and acts as a master regulator of cell functions
cells and possibly other components of the tumor by influencing multiple downstream pathways.
240 A. Arreola and W.K. Rathmell

Table 13.1 Targeted receptors and tyrosine kinase inhibitor therapies [75–79]
Receptor Ligand Primary receptor role High affinity target therapy
VEGFR-1 (Flt-1) VEGF-A Angiogenesis, vasculogenesis Sunitinib, pazopanib, axitinib, tivozanib
VEGF-B
VEGFR-2 (Flk1/KDR) VEGF-A Angiogenesis, vasculogenesis Sorafenib, sunitinib, pazopanib, axitinib,
VEGF-C tivozanib
VEGF-D
VEFG-E
VEGFR-3 (Flt4) VEGF-C Lymphangiogenesis Sorafenib, sunitinib, pazopanib, axitinib,
VEGF-D tivozanib
PDGFR-a PDGF Angiogenesis Sunitinib, pazopanib, axitinib
PDGFR-b PDGF Angiogenesis Sorafenib, sunitinib, pazopanib, axitinib,
tivozanib
c-Kit SCF Mast cell growth Sunitinib
SCF cytokine stem cell factor, PDGFR platelet-derived growth factor receptor, VEGFR vascular endothelial growth
factor receptor

Evolutionarily conserved TOR is required for will be considered together, but which have
mouse embryonic development as is seen by variations in activity that can impact the degrees
embryonic lethality of mTOR−/− mice [82]. or direction of signaling through these pathways
mTOR is also a gatekeeper of many cellular regu- [86]. This signaling pathway is one of the many
latory roles including cell growth, metabolism, simultaneous levels of regulation, as well as
proliferation, and cell signaling. The pathway of feedback loops, such that straightforward inter-
signal transduction implicating mTOR complex pretation of the pathway is often difficult. As an
signaling will be discussed below, as well as the example, mTOR complex 2 (mTOR2), which we
effects of mTOR pathway inhibition on tumor will discuss below, also participates in Akt
and normal cells (Fig. 13.1). activation at the cell membrane.
Engagement of ligands to their cognate RTKs One downstream target of Akt is the tuber-
on tumor or supporting cells initiates a classical ous sclerosis complex (TSC, a heterodimeric
signaling cascade, which activates phosphoinosit- complex TSC1/TSC2), which normally func-
ide 3-kinase (PI3K) resulting in the generation of tions to inhibit the highly active Ras-related
phosphatidylinositol-3,4,5-triphosphate (PIP3) GTPase Rheb (Ras homolog enriched in brain),
from PIP2. PI3K activity is regulated by its het- by converting it to its inactive GDP-bound state.
erodimer subunits, p85 regulatory subunit and Thus, activation of Akt leads to the inactivation
the catalytic subunit p110 that together tightly of downstream TSC resulting in Rheb activa-
regulate cell growth and proliferation once stimu- tion and an increase of cell growth, prolifera-
lated by growth factor RTKs activated by ligand tion, and cell survival. The most significant
engagement, overexpression, or oncogenic muta- function of Rheb-GTP is its activation of
tion [83]. This enzyme is negatively regulated by mTOR. mTOR is a highly conserved ser/thr
the gatekeeper protein phosphatase and tensin kinase, first identified as the ultimate target of
homolog (PTEN), which acts as a major tumor inhibition of the immune suppressant rapamy-
suppressor protein in many cancers. cin. The activation of these targets results in
In a step highly dependent on intracellular cell growth and survival and is a potent pro-
localization, PIP2 propagates the PI3K signal by moter of tumorigenesis.
recruiting cytoplasmic protein kinase B (Akt/PKB)
to the cell membrane where it can be activated by Understanding the Role
polycystin-1 (PDK1) [84, 85]. It is important to of mTORC1/2 Subunits
note that Akt exists in three isoforms, Akt1, Akt2, mTOR is comprised of two signaling complexes
and Akt3, which for the purposes of this chapter mTORC1 and mTORC2 (mentioned above as a
13 Biology of Renal Cell Carcinoma… 241

feedback activator of Akt) which differentially translation of mRNAs that encode for HIFs,
regulate HIF-1a and HIF-2a protein transla- c-Myc, and cyclin D1 [94].
tion, respectively, and therefore have roles in dif-
ferent cellular processes with regards to RCC HIF Factors
biology [87]. mTORC1 is composed of mTOR, As alluded to above, mTORC1 is a known posi-
regulatory-associated protein of mTOR (raptor), tive regulator of HIF-1a. This upregulation of
and G protein b-subunit-like (GbL) and is largely HIF protein translation is required by cancerous
regulated through the PI3K/Akt pathway as dis- cells in times of hypoxic stress for the continued
cussed above [88]. mTORC2 is composed of transcriptional activation of angiogenic factors
mTOR, rapamycin-insensitive companion of tar- such as VEGF, as a way to maintain blood supply
get of rapamycin (Rictor) and GbL [89]. Rictor is for sustained cell proliferation [94]. HIF-1a pro-
necessary for a feedback phosphorylation of the tein levels are reduced upon treatment of renal
serine-threonine protein kinase Akt, reactivating carcinoma cells by the current mTOR inhibitors
this pathway [90]. [95]. However, issues remain with targeted effects
In an interesting twist on the VHL/HIF path- of these drugs in in situ tumors, and the degree to
way discussed above, the production of HIF fac- which HIF is downregulated in the continued
tors has been linked to mTORC1-mediated face of absent VHL regulation. Reducing overall
cap-dependent translation. In particular, HIF-1a HIF levels is likely one component of mTOR
protein translation appears to be dependent on inhibitor activity in renal carcinomas, but other
active mTORC1, and this mechanism of disrupt- features of the pathway that promote global cell
ing HIF signaling in RCC has been exploited in proliferation are also likely integral to its
the therapeutic arena as discussed elsewhere. activity.
What remains less certain is the influence of
mTOR signaling on HIF-2a translation. Recent mTOR Pathway as a Target
evidence suggests that HIF-1a abundance can be for Treating RCC
influenced by both mTORC1 and mTORC2, but Rapamycin was the first mTOR inhibitor isolated
that HIF-2a translation is specifically regulated from Streptomyces hygroscopicus that showed
within the mTOR signaling pathway via mTORC2 antiproliferative activity in human cancer cells
[86, 91]. [96]. Rapamycin binds an immunophilin recep-
tor, FKBP12, to inhibit mTOR activation.
mTOR Targets Dysregulated Temsirolimus and everolimus inhibit mTORC1
in Advanced RCC by a similar mechanism and have both been
S6 Kinase-1 and Eukaryote Initiation Factor 4E shown to reduce in vitro levels of HIF-1a and
Activation of mTOR leads to phosphorylation of further have been shown to have disease activity.
ribosomal S6 kinase-1 (S6K) and eukaryote Temsirolimus has been approved for use as first-
translation initiation factor 4E-binding protein line therapy of advanced RCC for patients with a
(4EBP), two translation-regulating factors to pro- poor prognosis [97–99]. Everolimus also binds
mote cell proliferation and survival. 4EBP FKBP12 to inhibit downstream mTOR signaling
directly binds eukaryote initiation factor 4E (eIF- [100]. It is approved for patients with advanced
4E) and prevents it from binding to the other RCC that have failed treatment with a VEGF
translation initiation factor complex subunits, RTK inhibitor such as sorafenib or sunitinib
and this repression is released upon mTOR- [101]. These compounds are functional by disen-
mediated phosphorylation [92]. When 4EBP is gaging a terminal step in a highly complex and
inactivated by phosphorylation, eIF-4E binds to intertwined signaling pathway, the understanding
its other partners as well as the 5¢cap of mRNA of which may help guide the most appropriate
transcripts [93]. Activated S6K results in a down- use of these agents, or the directions for develop-
stream effect of increased translation of mRNA ing next generation inhibitors of this signaling
encoding ribosomal proteins as well as increased pathway. Finally, the discussion in this chapter
242 A. Arreola and W.K. Rathmell

has focused on biological aspects of ccRCC, but time point, suggesting a break in tolerance that
it is important to note that mTOR signaling path- could potentially be rectified with therapeutic
ways can be important, and have indeed been immune modulation. The next section will discuss
implicated very strongly in non-clear cell histolo- what is known about T cell tolerance and RCC.
gies, suggesting that this pathway may be more uni-
versally applicable to renal tumor biology.

Immunosurveillance in RCC
Immunology in RCC
Immunosurveillance describes the process of
The Intersection of Immune System innate and adaptive immunity processes identify-
Physiology and Renal Tumor Biology ing and eliminating host-derived cells that have
been altered chemically or genetically [104]. The
Prior to the advent of targeted therapies taking concept of immunosurveillance has been recently
aim at VEGF and mTOR signaling, most thera- amended to put forward a proposal that host–tumor
peutic attention in ccRCC was directed toward relationships depend on a process termed immu-
immunotherapy. RCC remains one of the most noediting. According to this hypothesis, initially
immune-responsive solid tumors, for reasons that the immune system recognizes and eliminates the
remain incompletely understood. Despite the majority of immunogenic tumor cells, leading to a
promising moves forward with targeted therapy, state of equilibrium in which the immune system
immunotherapy remains the only treatment which holds the tumor cells in a steady state, where tumor
has been shown to induce prolonged and durable growth is equal to the immune system’s capability
complete responses, such that treatment with to control it. Finally, the tumor escapes immune
high-dose interleukin 2 (IL-2) remains a main- regulatory mechanisms by downregulating immu-
stay of therapy at many specialty centers, and nogenic epitopes, developing local or systemic
intensive efforts remain focused on the develop- immune suppressor mechanisms, or by increasing
ment of new less toxic and more broadly effec- the rate of tumor growth leading to the immune
tive therapies in this arena [102]. response being overrun [105].
Infiltration of immune cells is a frequently The tumor promotes this local immunosuppres-
encountered feature of RCC. This infiltrate is sion often as a result of tumor-secreted cytokines
highly heterogeneous, and can include T cells such as IL-10 and TGF-b. In an interesting inter-
(CD4 and CD8), regulatory T cells, dendritic section of immunology and angiogenesis, VEGF
cells, natural killer (NK) cells, macrophages, and secretion by tumors and stroma has also been
B cells of various stages of differentiation [103]. implicated in local immunosuppression. VEGFA
The impact of these various components on tumor can also act as a chemoattractant for macrophages
behavior or response to either immunotherapy or via VEGF receptor Flt-1, recruiting these potent
targeted therapies is not known at this time. This immune mediators to the tumor where they might
infiltrate commonly locates itself along the pleth- produce local responses or alternatively become
ora of vessels integrated in the tumor, but can reprogrammed to recognize tumor cells as self
also be found within the tumor stroma itself. [106]. These cytokines inhibit cytotoxic immunity
While the specific contributions of these immune and may also promote the differentiation and
infiltrates are not well understood, these factors recruitment of regulatory cells. These cells include
can produce a state of profound immunosuppres- regulatory T cells (Treg) and myeloid-derived sup-
sion of the tumor. This is seen not only in the pressor cells (MDSCs) [107]. These immune sys-
patients who elicit dramatic responses to immu- tem subsets provide an interesting opportunity to
notherapy, but also in the patients who reside target the balance of immunologic sensors and medi-
with dormant tumors for prolonged periods of ators shift the immune system in favor of increased
time, only to develop explosive disease at a later tumor immunosurveillance.
13 Biology of Renal Cell Carcinoma… 243

precisely target the specific mediators of tumor

Summary and a Look Forward growth will emerge from the more sophisticated
understanding of these pathways in RCC. We see
Conclusions the signs of these new therapies already on the
horizon: multifaceted targeting of the mTOR sig-
RCC is a tumor type that has established the para- naling pathway at the levels of PI3K, PDK, Akt,
digm that understanding the biology of the cancer and mTORC2 as well as mTORC1; new strategies
will lead to fruitful innovations in treatment of to target VEGF and alternate pro-angiogenic path-
patients. As a result of the discoveries relating fre- ways, as well as strategies to target HIF family
quent VHL loss or mutation to HIF family stabili- members directly, immune-modulating strategies
zation, the major source of VEGF elevation has that address issues of co-stimulation, T cell subset
been revealed. In addition to the canonical path- activation, and the restoration of immunosurveil-
way, there are influences on VEGF expression lance. The biology of this cancer continues to pro-
from within the pathway (mutation effects of vide an elegant roadmap for therapeutic strategy
VHL, patterns of HIF deregulation) as well as development, which in turn will direct us toward
extrinsic influences on VEGF expression (includ- increasingly effective and less toxic therapies.
ing transcriptional and translational regulatory
mechanisms). A robust understanding of these
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 Prognostic Factors in Advanced
Renal Cell Carcinoma 14
Michael M. Vickers and Daniel Y.C. Heng

We will review the most common prognostic

Introduction models (see Table 14.1) that have incorporated
combinations of these variables for the stratification
The management of metastatic renal cell carci- of mRCC patients treated with immunotherapy,
noma (mRCC) has undergone dramatic changes agents targeting the VEGF pathway and agents
over the past 5 years with the median progres- targeting the mTOR pathway.
sion-free survival (PFS) of patients with mRCC Previously studied prognostic factors for
improving significantly due to the introduction of advanced renal cell carcinoma can broadly be
agents targeting the vascular endothelial growth grouped into four categories (Fig. 14.1). Patient-
factor (VEGF) and mammalian target of rapamy- related factors such as performance status are a
cin (mTOR) pathways [1–8]. The heterogeneity large driver of prognosis. Tumor burden is intui-
of mRCC has long been recognized and as such, tively obvious as a larger tumor burden should
factors associated with clinical outcomes have lead to a poorer prognosis. Proinflammatory
been explored and identified. markers are elevated in mRCC because of the
A prognostic factor can be defined as a situa- immune response elicited by the primary tumor.
tion, condition, or patient characteristic that can Finally, treatment-related factors such as the time
be used to estimate the chance of recovery from a from initial diagnosis to treatment are important
disease or the chance of disease recurrence [9]. because a short interval suggests more aggressive
Early prognostic models for mRCC focused on disease while a longer interval suggests more
the anatomic extent of tumors [10], whereas more indolent disease.
modern models focus on patient, laboratory, and Most recently, hyponatremia has been
tumor- and treatment-related factors. This identified as an independent clinical prognostic
stratification of patients into different risk groups factor. In an assessment of prognostic factors in
is important for patient counseling, risk-directed 120 consecutive patients and validated in another
therapy, clinical trial design, and also for interpre- 120 patients treated with subcutaneous, low-dose
tation of study results. interleukin-2 or interferon-alpha, Jeppensen et al.
[17] demonstrated that hyponatremia (serum
sodium less than the lower limit of normal)
was an independent prognostic factor for worse
M.M. Vickers • D.Y.C. Heng () survival and was also predictive of lack of response
Department of Oncology, Tom Baker Cancer Centre, to cytokine therapy. Further, using retrospective data
University of Calgary, 1331 29th Street, NW, Calgary,
from 885 patients who received VEGF targeted
AB T2N 4N2, Canada
e-mail: [email protected]; therapies, hyponatremia (sodium < 135 mmol/L)
[email protected] remained a significant predictor for poorer overall

S.C. Campbell and B.I. Rini (eds.), Renal Cell Carcinoma: Clinical Management, Current Clinical Urology, 249
DOI 10.1007/978-1-62703-062-5_14, © Springer Science+Business Media New York 2013
250 M.M. Vickers and D.Y. Heng

Table 14.1 Summary table of variables included in prognostic models

Prognostic model
Immunotherapy era VEGF era
International Sunitinib
Groupe Française mRCC phase III
MSKCC [11] d’Immunothérapie IKCWG [13] Consortium [16] (10
(10 endpoint [12] (10 endpoint (10 endpoint CCF [14] (10 [15] (10 endpoint
Variable OS) OS) OS) endpoint PFS) endpoint OS) OS)
Performance status √ √ √ √ √ √
Interval to treatment √ √ √ √ √
Number of √ √
metastases
Bone metastases √
Disease-free interval √
Signs of √
inflammation
Immunotherapy √
treatment
Hemoglobin √ √ √ √ √
Corrected calcium √ √ √ √ √
LDH √ √ √
Neutrophils √ √
Alkaline phosphatase √
White blood cell √
count
Thrombocytosis √ √

Fig. 14.1 Prognostic factors in advanced renal cell carcinoma

14 Prognostic Factors in Advanced Renal Cell Carcinoma 251

survival (OS) and time to treatment failure (TTF) the time frame between these analyses, cytore-
on multivariate analysis even after adjustment for ductive nephrectomy was shown to improve sur-
other known poor prognostic factors [18]. The vival prior to IFN-a therapy, and, as IFN-a was
underlying mechanism is unknown but may be standard therapy at the time, time to IFN-a ther-
related to higher tumor burden causing SIADH in apy was a more appropriate risk factor. With these
patients with more extensive pulmonary or brain updated MSKCC risk groups, median survival
metastases. was 29.6, 13.8, and 4.9 months for favorable,
intermediate, and poor risk groups. This prognos-
tic model subsequently became the standard for
Prognostic Factor Models risk stratification for clinical trials.
in the Immunotherapy Era

Memorial Sloan Kettering Cancer Center Groupe Française d’Immunothérapie

The incorporation of clinical and laboratory vari- To further assess prognostic factors in the immu-
ables into a prognostic model for patients with notherapy era, Negrier et al. [12] evaluated
mRCC was first accomplished by Motzer et al. clinical and biochemical variables in 1,563
[19] from the Memorial Sloan Kettering Cancer enrolled on five clinical trials of IFN or IL-2, or
Center (MSKCC) and validated by the Cleveland both. Nine parameters were independent poor
Clinic group [20]. A retrospective analysis was prognostic factors and included signs of inflam-
performed on data from 670 patients enrolled on mation, time interval from renal tumor to metas-
24 consecutive MSKCC clinical trials (immuno- tases (<12 months), ECOG performance status
therapy and chemotherapy) from 1975 to 1996. (PS) (³1), number of circulating neutrophils
Patients were included if they had stage IV disease, (>7.5 × 103/L), presence of liver metastases, pres-
measurable lesions, adequate Karnofsky perfor- ence of bone metastases, number of metastatic
mance status (KPS), adequate organ function, sites (>1), elevated alkaline phosphatase
and nonsignificant comorbidities. Multivariate (>100 UI/L), and low hemoglobin level (<115
analysis revealed that low hemoglobin (< lower (female) and <130 (male) g/L). Five of these fac-
limit of normal), high lactate dehydrogenase tors (PS, number of metastatic sites, time inter-
(LDH) (>1.5 upper limit of normal), elevated cor- val from renal tumor to metastases, signs of
rected serum calcium (>10 mg/dL), absence of inflammation and hemoglobin level) were
nephrectomy, and low KPS (<80%) were inde- selected (based on literature survey) and inte-
pendent predictors of poor survival. Using these grated into two risk models for overall survival:
variables, patients were then placed into three risk one with five risk groups and the other with three
groups: favorable (0 risk factors), intermediate risk groups. In addition, four factors were
(1–2 risk factors), and poor risk (3–5 risk fac- significant for predicting rapid progression
tors). The median survival was significantly dif- (within 3 months of cytokine initiation) and
ferent with survivals of 19.9, 10.3, and 3.9 months included: presence of hepatic metastases, ele-
for favorable, intermediate, and poor risk groups, vated neutrophil count, <1 year from renal tumor
respectively. Subsequent exploration of prognos- to metastases, and two or more metastatic sites.
tic factors in patients treated on clinical trials with
interferon-a (IFN-a) revealed lactate dehydroge-
nase, hemoglobin, corrected calcium, KPS and International Kidney Cancer Working
interval from RCC diagnosis to IFN-a treatment Group Prognostic Model
remained significant in multivariate analysis [11].
Consequently, cytoreductive nephrectomy did not In an incredible collaborative effort, researchers
remain significant in this analysis and was replaced from Europe and the USA developed a large
by interval from RCC diagnosis to IFN-a. During database of 3,748 patients entered into clinical
252 M.M. Vickers and D.Y. Heng

trials between 1975 and 2002 [13]. The majority corrected serum calcium (<8.5 or >10 vs. 8.5–
of patients had received IFN-a or IL-2 therapy 10 mg/dL), high platelet count (>300 vs.
(72%), while the remainder received chemother- £300 K/mL), and higher absolute neutrophil
apy/hormonal therapy (25%) only or other treat- count (ANC) (>4.5 vs. £4.5 K/mL) (lymphocyte
ments (3%). Multivariable analysis revealed that count was dropped from the original model as it
treatment, PS, number of metastatic sites, inter- did not remain significant on bootstrap valida-
val from diagnosis to treatment, pretreatment tion). In calculation of risk, one point was given
hemoglobin, white blood cell count, LDH, alka- for each variable except for corrected serum
line phosphatase, and calcium were independent calcium which received two points. The median
prognostic factors. Integration of these factors PFS was 20.1, 13, and 3.9 months for favorable
into three risk groups revealed survivals of 27.8 (0–1 prognostic factors), intermediate (two prog-
months (favorable) 11.4 months (intermediate) nostic factors), and poor (>2 prognostic factors)
and 4.1 months (poor). risk groups, respectively. This was the first
report of prognostic factors for PFS in the
targeted therapy era.
Prognostic Factors in VEGF Era

As the therapeutic options for the treatment of International mRCC Consortium

mRCC have changed over the past decade, treat- Database
ment with cytokine therapy has lost favor as more
effective therapies have emerged. Agents target- To further explore and validate prognostic factors
ing VEGF and the mTOR have revolutionized the in the anti-angiogenic era, Heng et al. [15] per-
treatment landscape. Consequently, the prognos- formed a retrospective, multicenter study of
tic factors outlined above required reevaluation in patients with mRCC treated with VEGF-targeted
the setting of newer therapies. These prognostic therapy (sunitinib, sorafenib and bevacizumab).
factors may still be applicable as relevant patient, Using consecutive patient data from seven cancer
tumor, or laboratory factors. centers across North America, 645 patients were
identified and demographic, clinical and laboratory
variables were correlated with overall survival.
Cleveland Clinic Foundation Criteria Multivariable analysis revealed that like the
MSKCC criteria, low hemoglobin (<lower limit
With the development of multiple agents target- of normal), elevated corrected serum calcium
ing the VEGF pathway, reassessment of prog- (>upper limit of normal), low KPS (<80%), and
nostic factors in mRCC was necessary. Choueiri time from initial diagnosis to initiation therapy of
et al. [14] were the first to report the Cleveland <1 year, were independent predictors of survival.
Clinic experience of prognostic factors for In addition to these, absolute neutrophil count
patients with mRCC treated with VEGF inhibit- and thrombocytosis (both > upper limit of nor-
ing agents. Retrospective data was collected mal) were also found to be independent predic-
from 120 clinical trial patients who had histo- tors of survival. The biologic rationale behind the
logically proven clear cell mRCC and were use of platelet and neutrophil counts has not been
treated with anti-VEGF therapies. MSKCC risk clearly characterized. Platelets are acute phase
groups, CCF risk groups and a number of other reactants and contain VEGF, platelet-derived
clinical, biochemical/hematologic, and histo- growth factor, and transforming growth factor
logic factors were assessed for their prognostic beta which are important in angiogenesis and
value. Five factors proved to be prognostic for tumor progression [21, 22]. Neutrophilia may
PFS in multivariate analysis. ECOG PS (³1 vs. be representative of the inflammatory process
0), time from diagnosis to current treatment (<2 which has been implicated in the prognosis of
years vs. ³2 years), abnormal baseline patients [23].
14 Prognostic Factors in Advanced Renal Cell Carcinoma 253

Patients with, zero adverse factors (favorable treated with sunitinib. For OS, ECOG PS >0,
risk) had a median OS which was not reached, time from diagnosis to treatment <1 year, LDH,
one to two adverse factors (intermediate risk) had corrected calcium levels, hemoglobin levels, and
a median OS of 27 months, and three to six bone metastasis were found to be significant
adverse factors (poor risk) had a median OS of prognostic factors. Consequently, of the six prog-
8.8 months. The strength of this study was that it nostic factors for OS, five were described in the
was multicentered and included patients that original MSKCC model.
were treated on or off clinical trials with a variety The strengths of this study include that the
of VEGF-targeted agents which improved its model was derived from prospectively followed
generalizability. The model was tested in suni- clinical trials patients. This revealed that the
tinib and sorafenib-treated patients separately MSKCC model can be used in the era of targeted
which revealed similar results. This model was therapy and the presence of bone metastases
internally validated using the bootstrap method could be added. Evaluation of this new model
and studies are underway for external validation. will need to be performed on a larger set of
patients and prospectively evaluated.

Prognostic Factors from the Sunitinib

Phase III Trial Prognostic Factors in mTOR-Treated
Patients
As the standard treatment of mRCC moved away
from cytokine therapy and into the targeted era, In the phase III trial that established the efficacy
validation of MSKCC prognostic criteria was of temsirolimus in poor prognosis mRCC, eligi-
required. Using individual patient data (375 ble patients required at least three of the follow-
patients with clear cell RCC) from the sunitinib ing features: LDH > 1.5 times the upper limit of
arm of a phase III randomized clinical trial of normal, hemoglobin below the lower limit of nor-
sunitinib versus IFN-a [2], the following vari- mal, a corrected serum calcium >10 mg/dL (2.5
ables were assessed for their prognostic mmol/L), time from initial diagnosis to random-
significance: corrected calcium levels, the num- ization of less than a year, KPS of 60–70, and
ber of metastatic sites, hemoglobin levels, prior metastasis in multiple organs [7]. In an explor-
nephrectomy, presence of lung and liver metasta- atory analysis, patients younger than age 65 and
ses, Eastern Cooperative Oncology Group those with a serum LDH greater >1.5 times the
(ECOG) performance status, thrombocytosis, upper limit of normal had a greater overall sur-
time from diagnosis to treatment, and alkaline vival when treated with temsirolimus. It was
phosphatase and lactate dehydrogenase levels unclear why an elevated LDH would be associ-
[24]. Corrected serum calcium levels, the number ated with longer overall survival as other models
of metastatic sites, the presence of hepatic metas- have suggested this to be a poor prognostic fea-
tases, thrombocytosis, serum lactate dehydroge- ture. It is possible that of the six poor prognostic
nase levels, and the time from diagnosis to eligibility criteria, an elevated LDH may select
treatment were identified as important indepen- out a population that may benefit from temsiroli-
dent predictors of PFS and were incorporated mus. This finding will require external validation
into a predictive nomogram for 12 months PFS. to confirm its prognostic potential in this popula-
Patil et al. [16] reported prognostic factors of tion of patients.
PFS and OS in 750 patients treated in both the Similarly, pretreatment prognostic profiles
sunitinib and IFN-a arms of the trial outlined were assessed in the RECORD-1 trial which
above. Multivariate analysis showed that ECOG evaluated everolimus versus best supportive care
PS >0, absence of nephrectomy, LDH levels, after progression during or within 6 months of
platelet count, and ³2 metastatic sites were sunitinib and/or sorafenib [8]. The MSKCC risk
significantly associated with PFS in patients criteria was shown to influence OS with 12-month
254 M.M. Vickers and D.Y. Heng

probabilities of survival of 70% (favorable risk), nucleotide polymorphisms (SNPs) of these genes
56% (intermediate risk), and 26% (poor risk). were significantly associated with overall sur-
Multivariable analysis revealed that the risk of vival. These findings require prospective valida-
death was significantly higher in those with tion and could potentially be added to the current
intermediate or poor risk compared with favorable clinical prognostic models to increase their
risk patients. Additional factors associated with predictive ability.
decreased PFS and OS included liver or bone
metastases, elevated neutrophils, and prior treat-
ment with sunitinib. Conclusions

With the changing treatment paradigm of mRCC,

Limitations and How We Can Improve evaluation of preexisting and possible new prognos-
Prognostication tic factors are required. The most commonly used
prognostic model is the MSKCC risk criteria which
There are limitations to our current prognostic integrates two clinical and three laboratory values
models. All of these models are retrospective and and has been validated in clinical trial patients
have not been prospectively validated or com- treated with immunotherapy. The mRCC database
pared against each other. There are also limits to Consortium model is similar and was derived in the
their generalizability as some are from single era of contemporary VEGF-targeted therapies. All
institutions which may involve homogenous pop- of these models have stratified patients into favor-
ulations. Others involve only patients enrolled in able, intermediate, and poor risk groups and includes
clinical trials only which may have differing information which is easily available.
eligibility criteria and have a tendency to select The integration of biomarkers and clinical
for healthier populations. There are also issues of variables into nomograms has the potential to
missing data in these studies. For example, mark- provide more meaningful information on progno-
ers of inflammation such as C-reactive protein sis than either alone. Attempts at improving
are not routinely ordered and therefore are not prognostication through molecular profiling has
often collected in retrospective analyses. Finally, revealed some promising results [26]; however,
models developed from the immunotherapy era much work remains before biomarkers enter into
may not be relevant in VEGF era and require clinical decision making for mRCC.
validation in this new treatment paradigm.
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Ann Oncol. 2002;13(9):1460–8. and prognosis in renal cancer. Lancet. 1999;353(9163):
13. Royston P, Bacik J, Elson P, Manola J, Mazumdar M. 1494–5.
A consensus prognostic factor model for survival in 23. Donskov F, von der Maase H. Impact of immune
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Oncol. 2007;18(2):249–55. markers in angiogenesis- or exposure-related genes
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2009;27(34):5794–9. 2010;5(2):85–94.
 Integration of Surgery in Metastatic
Renal Cancer 15
Tom Powles and Axel Bex

neous regression of lung-only metastases after

Role of Nephrectomy nephrectomy. Before the advent of systemic
in Metastatic Disease immunotherapy, spontaneous regression of single
pulmonary lesions had been reported in up to
Historical Considerations approximately 5% of patients after cytoreductive
nephrectomy (CN). However, solitary metastasis
Historically, the incidence of spontaneous regres- occurs in under 5% of patients making this
sion, and the occasional indolent course of pul- approach an exception to the rule [6, 7]. Barney
monary metastases, had prompted the concept of et al. reported on a patient who survived 23 years
removal of asymptomatic primary tumours in after nephrectomy and lobectomy for pulmonary
metastatic renal cell carcinoma (mRCC) [1–4]. metastases [8]. Since then many authors reported
However, while most urologists agreed that pal- similar results with metastasectomy of solitary or
liative nephrectomy for symptomatic primary multiple lesions after CN. Skinner et al. reported
lesions in systemic disease is justified, removing a 29% 5-year survival in a series of 41 patients in
asymptomatic tumours without effective systemic whom one or two metastases were excised in
treatment was highly controversial. Freed [5] addition to nephrectomy [9], and Tolia et al.
suggested in 1977 that nephrectomy may be reported a 35% 5-year survival in a similar series
beneficial for patients with primary metastatic [6]. In a retrospective study on the natural history
disease. He speculated that nephrectomy may of untreated metastatic renal cell carcinoma
halt the disease progress via up-regulation of the (mRCC), deKernion et al. [1] noted that CN was
host immune mechanisms and that the immune- associated with a 6% mortality rate but overall
rich environment of the lung may explain sponta- these patients had a better outcome than those
who did not have surgery. In the absence of effec-
tive systemic therapy and randomized data in this
T. Powles ()
Department of Medical Oncology, arena, the consensus was that nephrectomy may
Barts Cancer Institute, St Bartholomew’s Hospital London, be beneficial when a limited number of metasta-
Queen Mary University of London, ses were present and aggressive treatment of
West Smithfield, London EC1A 7BE, UK
these metastases may be warranted [10]. This
e-mail: [email protected]
data was potentially influenced by selection bias;
A. Bex
therefore, two large randomized trials investigat-
Division of Surgical Oncology, Department of Urology,
The Netherlands Cancer Institute, Amsterdam, ing the role of nephrectomy were planned and
The Netherlands completed.

S.C. Campbell and B.I. Rini (eds.), Renal Cell Carcinoma: Clinical Management, Current Clinical Urology, 257
DOI 10.1007/978-1-62703-062-5_15, © Springer Science+Business Media New York 2013
258 T. Powles and A. Bex

Randomized Prospective Trials IL-2 (sc or IV) was widely given as an alternative
of Nephrectomy Followed to interferon. Indeed high-dose IL-2 is still given
by Immunotherapy Vs. to highly selected patients with curative intent
Immunotherapy Alone [18]. No randomized trial has been performed to
investigated the role of IL-2 with or without CN,
The emergence of immunotherapy for patients which is in part due to the conclusive findings of
with metastatic renal cell cancer provided the the randomised trials with interferon [12, 13]. In
basis for further investigation of the role of CN in a letter to the New England Journal of Medicine,
metastases [11]. Pantuck et al. published a retrospective analysis of
In 2001 data from two randomized phase III 89 selected patients who underwent nephrectomy
trials comparing nephrectomy followed by followed by sc IL-2 [19]. These patients had similar
immunotherapy vs. immunotherapy alone inclusion criteria for the SWOG trial and the
became available. These prospective trials of the median survival was 16.7 months. The authors
SWOG and EORTC groups both demonstrated a plotted the Kaplan–Meyer survival curves over
prolonged survival for the nephrectomy plus the data from the SWOG interferon trial and
interferon-a arms as opposed to the interferon argued that, despite the retrospective nature of
alone arms [12, 13]. In 2004 a combined analysis the data, nephrectomy followed by interleukin-2-
of these two trials showed a median survival of based immunotherapy may be preferable. This was
13.6 months for nephrectomy plus interferon vs. highly controversial and disputable. Nevertheless
7.8 months for interferon alone [14]. The sur- subcutaneous IL-2 was routinely used instead of
vival was strongly influenced by performance interferon in North America.
status. These trials had a number of concerns. The results of these prospective SWOG and
Importantly, 25% of the patients in each arm of EORTC-GU randomized phase III trials with
the SWOG study died within the first 4 months interferon established the role of CN in the era of
of treatment regardless of the study arm, sug- cytokine therapy [12, 13]. Subset analysis showed
gesting patient selection may be suboptimal. that performance status and the Memorial Sloan
Additionally, the responses in the metastatic sites Kettering Cancer Center (MSKCC) risk score
to IFN-a in both arms were low and did not dif- were both important in predicting benefit with CN
fer significantly from each other (3.6% vs. 3.3%). [20]. Other subgroups which appeared to benefit
These results question the hypothesis that neph- from CN included patients with a significant
rectomy makes interferon therapy more respon- tumour burden of the primary tumour, absence of
sive by enhancing the immune repertoire. Despite significant co-morbidity, absence of central ner-
the improvement in survival following CN in vous system metastasis and low risk of surgical
combination with IFN-a, the mechanism is still morbidity [21]. Culp and co-workers more
not fully understood and several factors have recently identified a number of prognostic factors
been proposed. The often large primary tumour predicting benefit from CN. These added a num-
may attract and trap circulating antibodies and ber of factors to the MSKCC prognostic score.
immune cells and secrete co-stimulatory mole- These factors included raised plasma lactate
cules that down-regulate immune responses. dehydrogenase, low serum albumin, symptoms
Alternatively, tumour cells may secrete pro- caused by metastatic sites, sites of disease (liver
angiogenic growth factors, such as vascular metastasis and specific lymphadenopathy) and
endothelial growth factor (VEGF), platelet- clinical ³T3 for the primary tumour stage [22].
derived growth factor, fibroblast growth factor Overall the data from the pre-targeted therapy
and transforming growth factor-b1 [15–17]. era showed that CN had a clear role in mRCC.
Removal of a large tumour bulk may result in Although it did not increase the response to cytokine
reduced expression of the oncogenic factors. therapy, it had a remarkable effect on overall sur-
This is especially true as immune therapy has at vival (a median of 6.3-month OS advantage [14]).
best only modest effects on tumour growth. Subgroups of patients were identified which
15 Integration of Surgery in Metastatic Renal Cancer 259

appeared to glean most benefit from this surgery, with metachronous mRCC have a more latent
including those with a good performance status and progression, this may influence the results. In
favourable MSKCC risk score. Therefore, the addition, little is known of the response rate of
combination of surgery and cytokine therapy was the primary tumours as most had been previ-
given as part of a multimodality management for ously removed. There is subgroup analysis com-
patients with systemic disease. paring the PFS of patients who did and did not
undergo initial CN. The results are hampered
by patient selection and sample size. However
Role of Nephrectomy in the Era the results showed a numerical advantage for
of Targeted Therapy prior CN [11 months (range, 11–13 months) vs.
6 months (range, 4–11 months), respectively;
The introduction of novel drugs targeting angio- p = 0.0889] [37]. Comparisons of responses in
genesis has resulted in a substantial improvement the metastatic sites and primary renal tumour
in outcome for mRCC. Currently approved agents show that the primary tumour response rates are
include receptor tyrosine kinase inhibitors (TKIs), lower (<10%) [33].
VEGF antibodies and mammalian target of Other retrospective series have reported a sim-
rapamycin inhibitors (mTORs) [23–27]. Details ilar advantage for patients undergoing CN.
on the efficacy of these agents are summarized in Choueiri et al. reported on 314 patients with
previous chapters. The vast majority of the data mRCC of whom 201 underwent CN [38]. Using
investigating CN and targeted therapy together univariable analysis, they showed that CN was
focus on the VEGF TKIs such as sunitinib [28– associated with a median OS of 19.8 months,
34], there is very little data on mTORs and VEGF compared with 9.4 months for patients who did
antibodies and CN [24, 35]. not undergo CN (p < 0.0001). However, the
Sunitinib is, at present, the most commonly benefit was absent in the poor prognostic risk
used first-line treatment in mRCC. It is associated group. Similarly, a retrospective population-
with an objective response rate of 39% (vs. 8% based study from Canada suggested that prior
with IFN-a) and median progression-free survival CN in patients treated with TKIs is associated
(PFS) was significantly prolonged at 11 months with improved OS in mRCC, independent of
(vs. 5 months for interferon) [36]. The median other prognostic variables [39]. A very recent
overall survival is over 2 years. Based on this piv- Dutch population-based study concluded that
otal trial, sunitinib was registered in the USA and even after accounting for prognostic profile
Europe in 2007. More recently pazopanib has patients with mRCC still benefited from CN with
been approved by both the FDA and EMEA in the a 50% reduction in mortality [40]. However, the
first-line setting. It also shows a PFS in the first- inherent bias of retrospective analysis does not
line setting of approximately 11 months with allow to definitely conclude that patients derive a
impressive response rates and is therefore an alter- benefit from CN. In addition, patients who
native to sunitinib [27]. While there is phase II received targeted therapy without CN, while CN
data and enrolling phase III studies investigating was considered as the standard of care, are
CN with sunitinib and other agents, there is cur- obviously different from those who had CN and
rently a lack of data with CN and pazopanib. subsequently received TKIs.
The majority of patients (~90%) in the piv- The assumption that CN has a role in the era
otal sunitinib and pazopanib registration studies of targeted therapy, based on the randomized data
had nephrectomy prior to entry. However, no with interferon, is flawed. It is argued by those
information is provided how many of these in favour of medical therapy alone that, unlike
patients had a previous nephrectomy for locally cytokine therapy, targeted therapy controls
confined disease and developed systemic metas- the disease in the majority of the patients and
tasis subsequently or had an upfront nephrec- CN does not change clinical outcome. Indeed
tomy for synchronous mRCC. Because patients the delay in starting targeted therapy during
260 T. Powles and A. Bex

Fig. 15.1 Randomized phase III trials to investigate role and sequence of cytoreductive nephrectomy (CN) in primary
metastatic renal cell carcinoma. The primary endpoint is overall survival in the CARMENA trial and progression-free
survival in the EORTC SURTIME trial

the preoperative period for nephrectomy may be sunitinib follows by CN (the EORTC 30073
counterproductive. Others feel that there is no SURTIME trial) [44] (Fig. 15.1).
reason why the data from the cytokine era should CARMENA (NCT00930033), which has been
not apply in the targeted therapy era, especially in recruiting patients in France and the United
those patients where primary renal tumour Kingdom since 2009, is the pivotal trial to inves-
accounts for the vast majority of the volume of tigate the impact of CN on outcome in the era of
the disease [41, 42]. In addition over 90% of targeted therapy. Patients with mRCC (with clear
patients in the pivotal studies in the era of tar- cell histology on biopsy) (ECOG PS 0 or 1),
geted had nephrectomies. Therefore it is argued without prior systemic therapy or surgical inter-
that it should continue as standard of care until ventions, are randomized to either nephrectomy
proven otherwise. followed by sunitinib or sunitinib alone [43]. The
To answer this important question two distinct primary endpoint of this non-inferiority trial is
randomized phase III trials, investigating CN, overall survival and will include over 1,000
have been developed and are now recruiting patients. The estimated completion date is 2016.
patients with untreated primary mRCC. The In this study patients in the systemic therapy only
CARMENA trial investigates the role of CN by arm can have palliative nephrectomy later in the
comparing sunitinib alone with nephrectomy fol- disease process if deemed necessary for symp-
lowed by sunitinib [43]. This design is identical tomatic control (Fig. 15.1).
to the positive trials performed in the cytokine It may be that as in the cytokine era, only
era. The second study addresses the sequencing specific subgroups of patients benefit from CN.
of nephrectomy and sunitinib by comparing ini- One area of interest is whether the fractional
tial CN followed by sunitinib with presurgical volume of the primary renal cancer removed
15 Integration of Surgery in Metastatic Renal Cancer 261

compared to the metastatic sites is relevant. It is mRCC [49]. Some authors recognized that initial
intuitive that the higher the proportion of tumour immunotherapy followed by nephrectomy may
burden removed the better. This theory is sup- have the advantage of circumventing the reported
ported by a retrospective series which shows if the morbidity of initial nephrectomy, without com-
fractional percentage of tumour volume removed promising the concept of immunotherapy and
at nephrectomy is greater than 95%, patients have cytoreduction. The potential advantages of sys-
a better outcome [45]. Recent data supports this temic therapy followed by nephrectomy were
association in the era of targeted therapy [46]. that those individuals with cytokine refractory
How this theoretical and clinical benefit from disease could be easily identified and selected
CN applies to targeted therapies is currently unre- out, sparing them nephrectomy. On the other
solved and the CARMENA trial is designed to hand if, as was speculated, nephrectomy was
answer this important scientific question. required to achieve a response to cytokine ther-
apy, this approach of initial cytokine therapy
could potentially miss responders.
Nephrectomy for Symptomatic The published series in the cytokine era are
Primary Tumours small. They focus on retrospective series of
highly selected patients, or subset analysis from
Patients with primary mRCC rarely present with larger series which is open to selection bias, or
debilitating symptoms related to the primary small prospective series which are difficult to
tumour, such as flank pain, gross haematuria or interpret [50–53] (Table 15.1).
paraneoplastic syndromes. In the pre-targeted Others reported selectively on those patients
therapy era the overall survival of these patients who responded to initial immunotherapy fol-
was short [47]. As expected, CN alone was unable lowed by complete surgical remissions by neph-
to reliably elevate symptoms from paraneoplastic rectomy or resection of residual lesions [54–56]
syndromes [48]. In the era of targeted therapy (Table 15.2).
symptomatic primary tumours should be removed In summary all these retrospective series noted
where possible. Starting with upfront systemic the feasibility of immunotherapy with the pri-
therapy should only be considered where the mary in situ and remarked on the significant
tumour is inoperable, or the disease is particu- disease-free survival that could be achieved in
larly aggressive (MSKCC poor risk disease). selected patients. Efficacy data is very difficult to
Angioinfarction of the primary renal tumour interpret from this data. It is noteworthy that
may be considered as a less invasive alternative to some authors reported an effect of immunother-
surgery. Data in the era of targeted therapy is lack- apy with IL-2 even on the primary tumour, which
ing. The authors would consider angioinfarction in was generally believed not to occur from the
a small minority of patients. These include patients prospective data [55, 57]. It should be remem-
with metastatic disease and who are deemed inop- bered that high-dose IL-2 is still given to selected
erable but have persistent symptoms from the pri- patients with curative intent in the era of targeted
mary tumours despite systemic therapy. therapy. A number of prognostic factors exist
which are used to identify these patients, one of
which is prior nephrectomy. Therefore upfront
Upfront Systemic Treatment Prior high-dose IL-2 prior to nephrectomy cannot be
to Nephrectomy in Metastatic Disease recommended.
While randomized prospective trials compar-
The History of Initial Systemic ing nephrectomy followed by IFN-a vs. IFN-a
Therapy Followed by Nephrectomy alone reported in favour of surgery and immuno-
therapy [14], no randomized trial was performed
To date, only few retrospective studies specifically addressing upfront cytokine therapy. This may in
addressed the combination of initial immunother- part be due to the lack of robust data and the low
apy followed by CN in patients with primary response rate seen in the primary tumour. As a
262 T. Powles and A. Bex

Table 15.1 Retrospective series of initial immunotherapy (IMT) followed by cytoreductive nephrectomy

No. of Response
No. of patients patients with MSa Median survival Survival after
Source receiving IMT IMT cytoreduction CR PR entire group (range cytoreduction
Fleischmann et al. 10 IL-2/LAK 2 3 5 months (2–18) 4, 9, 18 months
[50]
Spencer et al. [51] 12 IL-2/IFN-A 11 1 3 Not published Not published
Rackley et al. [52] 25 IL-2 based 3 2 1 14 months (1–48) 18, 42,
48 months
Wagner et al. [53] 51 IL-2 based 3 1 2 13 months (1–86) 4, 11,
88 months
CR complete response, PR partial response, IL-2 interleukin 2, IFN-A interferon-alpha, LAK lymphokine-activated
killer cells
a
MS metastatic sites

Table 15.2 Retrospective series of selected patients with objective response to initial immunotherapy (IMT) followed
by nephrectomy or resection of metastases to no evidence of disease
Source No. of patients IMT sNED Median survival (range)
Sherry et al. [54] 16 IL-2 16 11 months (4–44)
Sella et al. [55] 17 IFN-A 17 26 months (6–34)
Krishnamurti et al. [56] 14 IL-2 based 14 44 months (4–97)
sNED surgically resected to no evidence of disease, IL-2 interleukin-2, IFN-A interferon-alpha

consequence the timing of nephrectomy and progression in 30%, patient refusal in 23% and
immunotherapy in multimodality treatment of perioperative death in 19% [59]. CARMENA
primary mRCC remains controversial. This con- will address this important issue. It may be that
troversy continues in the era of targeted therapy. nephrectomy prior to systemic therapy in patients
with aggressive disease is counterproductive as it
denies to some patients the opportunity to receive
Presurgical Targeted Therapy Prior systemic therapy. This issue was not such a major
to Planned Nephrectomy concern in the cytokine era when treatment was
largely ineffective, but in the modern era, where
The randomized data supporting the role of neph- control of systemic disease is the norm, the delay
rectomy in metastatic disease in the era of associated with nephrectomy may be harmful in
cytokine therapy has resulted in it being adopted some individuals. A potential way around this
as standard of care in the targeted therapy era as problem is to perform a finite period of upfront
well [21, 58]. However there are concerns that systemic therapy prior to nephrectomy, resulting
the delay associated with planning, performing in a theoretically benefit from both immediate
and recovering from nephrectomy may result in systemic therapy and nephrectomy.
systemic progression of disease. Indeed it is Another potential advantage of this upfront
reported that a high percentage of patients do not targeted therapy approach may be the downsizing
receive systemic therapy after CN due to surgi- of the primary renal tumour facilitating surgery.
cal morbidity/mortality or disease progression. It was hoped that this reduction in the primary
In a multi-institutional experience, Kutikov et al. tumour would be in the region of 30% (as seen in
described that 43 of 141 patients undergoing CN the metastatic sites), and even make inoperable
never received systemic therapy due to rapid disease patients operable [60]. Two prospective studies
15 Integration of Surgery in Metastatic Renal Cancer 263

recently addressed this issue with sunitinib [33]. the principle of disease progression on treatment
A fixed period of sunitinib (12–18 weeks) was is concerning, rebound of the tumour during the
given prior to nephrectomy and showed the 2-week treatment-free interval is well described
median response rate of the primary tumour to be on sunitinib and may be less worrying.
only 14%. This series did include some patients Another area of concern is the potential for
with T4 disease (10%) who had a reduction in primary tumour growth during the period of
tumour size and subsequent surgery. Nevertheless upfront targeted therapy making operable
the overall effects on the primary tumour in terms tumours inoperable. Initial reports from a retro-
of size was modest and lower than those responses spective study of 19 patients with advanced renal
seen in the metastatic sites. Moreover, fibrosis cell carcinoma (RCC) and the primary tumour in
was reposted as being prominent at the surgery, situ showed nine (47%) had progressive disease
potentially making the operation more complex. (PD) in the primary tumour [61]. Others have
Therefore the conclusion that sunitinib facilitates observed progression of caval thrombi [62]. This
surgery is questionable. However this work with may indicate that in a proportion of patients
other series has shown that surgery can be per- upfront therapy may result in progression of the
formed safely after targeted therapy [32, 33]. primary tumour. More recent larger series coun-
Perhaps the most attractive aspect of upfront tered this argument showing that no patients
targeted therapy is that patients with primary became inoperable after a period of sunitinib
refractory disease, and a short life expectancy, can (Table 15.3). This work was supported by other
be spared nephrectomy. Again this is controver- studies with bevacizumab, where again no
sial as it could be argued that the nephrectomy patients became inoperable.
itself increased the response rate and therefore a While the reduction in the size of the primary
lower proportion of patients with primary refrac- tumour is modest, one of the more intriguing
tory disease. A recent phase II study reported on aspects of this is that the response itself may be
the PFS and OS of 66 patients treated with upfront prognostic. Recent data suggest a reduction in the
sunitinib prior to planned nephrectomy in primary longest diameter of 10–13% or more (median) is
metastatic disease [34]. This series included prognostic in multivariate analysis [34, 63]. This
patients with MSKCC intermediate and poor risk may turn out to be useful information in a setting
disease. Although numbers were small and the where identifying patients who are benefiting
study was not randomized, the proportion of from therapy has proved elusive. Another factor
patients with primary refractory disease was in which required further consideration is that the
line with expectations (17%). The study also median reported necrosis rate is over 50% in pre-
identified a subgroup of patients with a favourable treated tumours. Therefore while the tumours
outcome. These patients, with MSKCC interme- may not be reducing in size dramatically there are
diate risk disease and clinical benefit (stable dis- extensive changes at a molecular level. These are
ease by RECIST) prior to surgery, had a median nicely illustrated with functional imaging before
overall survival of over 2 years. One of the notable and after therapy (Figs. 15.2, 15.3, and 15.4).
features of this work was the frequent occurrence Another area of the major concern surround-
of disease progression (36% by RECIST v1.1) ing upfront targeted therapy prior to nephrectomy
during the surgery-related treatment break is that a large proportion of patients (approxi-
(median 29 days). Surgery requires treatment to mately 30%) do not go on to have the planned
be stopped for at least 1 day before and 14 days nephrectomy. The most common reasons for this
after surgery to avoid complications such as include primary progression of disease and
delayed wound healing. The consequences of the patients choice [34]. Some argue that selecting
progression during this treatment break remain out patients with TKI refractory disease is con-
unknown. However over 70% of patients structive as they can potentially switch to an
achieve subsequent disease stabilization when alternative therapy, while others argue that this
sunitinib was recommenced after surgery. While may be detrimental to outcome.
264 T. Powles and A. Bex

Table 15.3 Summary of studies investigating upfront targeted therapy prior to nephrectomy in metastatic disease
Study Cowey et al. [67] Powles et al. [33, 34] Jonasch et al. [35]
Number of patients 30 66 50
Duration of upfront therapy 1–8 weeks 12–16 weeks 8 weeks
Agent used Sorafenib Sunitinib Bevacizumab ± erlotinib
% Reduction of the renal tumour during 9.6% 14.5% Approximately 5%
upfront therapy
Duration in hospital (median) Laparoscopic = 3.7 days 7 days 5 days
Open = 7.5 days
Median blood loss (median) Laparoscopic = 150 ml 725 ml 400 ml
Open = 950 ml
Surgery-related deaths 0 1 2% 2 (4%)
Duration of surgery (median) Laparoscopic = 135 min 189 min 165 min
Open = 185 min
Delayed wound healing 1 (3%) 6 (13%) 9 (20%)
Serious complications (Clavien–Dindo NA 4 (11%) NA
classification III–V)

Fig. 15.2 FDG PET CT before (a) and after (b) sunitinib of sunitinib. However the tumour does show a metabolic
(18 weeks) in a large cystic renal tumour. This FDGPET CT response (63% reduction in SUV) to sunitinib. This demon-
shows no change in the size of the renal tumour after 18 weeks strates the dynamic changes occurring at a molecular level
15 Integration of Surgery in Metastatic Renal Cancer 265

Fig. 15.3 This pair of CT scans before and after sunitinib therapy shows how a dramatic response to sunitinib therapy.
(a) CT scan showing a large renal tumour prior to sunitinib therapy. (b) CT scan showing a large renal tumour respond-
ing to sunitinib therapy (72% reduction in largest diameter)

A further consideration for this approach is

the potential advantage of collection of sequential
tissue during systemic therapy. Initial reports
suggest that tissue taken at baseline does not predict
outcome. However dynamic changes to molecu-
lar markers during therapy, which could poten-
tially be identified from the tissue taken after a
period of systemic therapy, may unlock the key to
systemic resistance [64]. This drive towards per-
sonalized therapy is desirable in renal cancer, as
there are a number of systemic treatment options
without any truly predictive markers. These
changes are being investigated by a number of
consortiums and results are expected over the
next 2 years. Areas of concern focus on tumour
heterogeneity, unstandardized methods of tissue
collection, differing methods of analysis and
reproducibility of results.
Therefore, the principle of upfront targeted
therapy prior to nephrectomy has both advan-
tages and disadvantages and may even identify
mechanisms of acquired resistance. It requires
robust evaluation before it is incorporated into
Fig. 15.4 CT scan and diffusion MRI of a left-sided
treatment algorithms.
renal tumour. These pair of scans shows a primary renal A consistent feature of recent studies is a pro-
tumour with CT and diffusion MRI. At the centre of the portion of patients opt out of CN as they are reluc-
left renal tumour (red arrow) is a bright area which repre- tant to stop effective systemic treatment. This
sents necrosis, which is associated with a poor prognosis.
This diffusion MRI scan demonstrates the heterogeneous
may result in the need for delayed nephrectomy
nature of the renal cancer later in the disease process, when the patient may
266 T. Powles and A. Bex

be less well or the tumours become unresectable. identify particular concerns with the upfront
Therefore with the current data available the approach at this stage.
authors feel that nephrectomy should be encour- There is debate about the optimal duration of
aged where possible in patients opting for a targeted therapy prior to surgery in this popula-
period of upfront targeted therapy prior to tion. The effect of downsizing the primary tumour
planned nephrectomy. Indeed the combination of is most prominent in the first 3–5 months [63,
sunitinib and surgery (CN and metastasectomy) 68]. An underpowered exploratory analysis com-
has resulted in complete remissions in some pared two and three cycles of sunitinib prior to
selected individuals [65]. In a recent series 33% surgery and could find no difference between
of these patients were taken off treatment for these two regimens [33]. However only a few
a median of 7 months (range 1–31 months) after days of targeted therapy can induce maximal
achieving complete remission [66]. This approach, inhibition of cell proliferation [69], but these
with a treatment-free interval, is attractive. While changes are unlikely to be clinically meaningful.
it is outside the remit of standard guidelines it To formally test this paradigm of presurgical
is worthy of further investigation as targeted therapy prior to nephrectomy, a phase III trial
therapy is associated with significant short- and was designed to investigate the sequence of CN
long-term side effects. and systemic therapy. This prospective, random-
Other phase II studies have evaluated the role of ized EORTC trial has now opened in the
upfront bevacizumab and sorafenib in this setting Netherlands, Belgium, Italy, the United Kingdom
[35, 67]. Results appear similar to those seen with and Canada comparing immediate vs. deferred
sunitinib, although direct comparisons are not CN in patients with synchronous mRCC (EORTC
possible (Table 15.2). One notable feature is the 30073, SURTIME) [44]. The principal objective
gap between targeted therapy and surgery with of this trial is to investigate whether the sequence
bevacizumab is longer than that seen with the of nephrectomy in patients who receive sunitinib
TKIs (4 weeks vs. 24 h) due to its longer half-life has an effect on patient outcome. The primary
[35]. Surgical-related complications in these endpoint is PFS. Secondary endpoints include
studies were similar with 2% surgical-related OS, safety, overall response to treatment in the
mortality, 400–500 ml of blood loss during sur- deferred nephrectomy arm (including the propor-
gery and a postoperative stay between 5 and tion of patients who become unresectable) and
7 days. Targeted therapy was restarted 2–4 weeks the effect of nephrectomy on early progression in
postoperatively. The commonest postoperative both arms. The investigators plan to enroll 458
complication was delayed would healing, which patients over a 36-month period, with the final
occurred in 14–20%. It is speculated that restart- analysis performed after observation of 380 pro-
ing systemic therapy too early (before 3 weeks) gressions or deaths and a minimum follow-up of
may increase this proportion. Therefore, it 1.5 years for all patients. In addition, tissue and
appears that sunitinib can be safely discontinued serum will be collected to identify genetic- and
24 h prior to surgery [33]. However restarting tar- protein-profiles predictive of response. Together
geted therapy is more controversial and waiting CARMENA and SURTIME will address the role
until full healing of the surgical scar has occurred of CN in the targeted therapy era.
is important.
A retrospective analysis attempted to identify
whether upfront targeted therapy was associated The Role of the MSKCC Prognostic Score
with increased surgical morbidity or periopera- in Selecting Patients for CN
tive complications by comparing results with a
matched cohort of 58 patients who underwent Patients with metastatic renal cancer can be
upfront surgery [32]. Results showed no differ- stratified for outcome by the MSKCC risk score
ence between the two groups, and while this anal- [20]. All three groups benefit from targeted ther-
ysis is not robust, the above data is unable to apy, although temsirolimus rather than VEGF
15 Integration of Surgery in Metastatic Renal Cancer 267

TKIs is considered standard of therapy in patients with metastasectomy, especially in those patients
with poor risk disease [24, 70]. There are few data with isolated metastasis to the lung or loco-
on the role of CN in these risk groups. This is par- regional lymph nodes [73–75]. This data is gen-
ticularly relevant to the MSKCC poor risk group erated from a number of single institutional
which have a short overall survival, and where studies in the pre-targeted therapy era and is open
progression of disease may be rapid. These to patient selection bias. Moreover these patients
patients are often symptomatic from systemic dis- have an excellent outcome with targeted therapy,
ease at baseline and commencing targeted therapy high-dose IL-2 or even initial observation.
immediately appears wise. Retrospective data Therefore the applicability of the metastasectomy
questions the role of nephrectomy in this popula- data, generated from the cytokine era, is unclear.
tion and data on patients treated with upfront Targeted therapy seldom results in a complete
sunitinib followed by interval CN in this group remission; therefore, the continued investigation
showed no patients survived over 2 years [34]. of metastasectomy appears justified in selected
Therefore the role of surgery in this group appears individuals. Its role in conjunction with targeted
very questionable irrespective of its timing. therapy is exciting [76]. Down-staging limited
The role of CN in intermediate risk disease is metastatic disease with systemic therapy fol-
also unclear and controversial. The delay associ- lowed by surgical resection appears attractive and
ated with surgery may result in disease progres- is the focus of clinical trials [77]. Also surgery
sion while, on the other hand, removing large may be justified in isolated progression in a
bulky tumours accounting for the majority of the single metastasis after a period of targeted ther-
disease burden appears beneficial in retrospective apy. The benefit of removing this focus of resis-
series. Both initial nephrectomy and upfront TKI tance is unclear. Surgery is not uncommon in this
therapy followed by nephrectomy appear attrac- setting, especially to brain metastasis.
tive in this population. Provocative data from 42 There is a select group of patients with meta-
patients with intermediate risk disease showed static clear cell renal cancer who have prolonged
impressive OS results with the “upfront” approach survival. These patients are likely to have distinct
(over 70% 2-year survival in selected patients with biological and clinical characteristics. Long-term
clinical benefit) [34]. Finally patients with good remission or even spontaneous regression of
risk disease should usually be considered for metastasis can occur in this population. This
nephrectomy, at least until CARMENA reports, as same group tends to be the group offered metas-
delaying targeted therapy does not seem to have a tasectomy. Therefore it is almost impossible to
detrimental effect on outcome and may allow con- tell whether the surgery is altering the biology of
sideration of other approaches such as high-dose the disease. Other potently curative treatments
IL-2 or metastasectomy in this population. such as high-dose IL-2 are also offered to patients
with clear cell histology, isolated metastatic dis-
ease and a good performance status. Therefore in
Metastasectomy in Metastatic this distinct group, four potential competing
Renal Cancer treatment options are available including surveil-
lance, targeted therapy, metastasectomy or high-
Metastasis from RCC may be present at diagno- dose IL-2. Careful consideration of the pros and
sis or develop after nephrectomy. In the modern cons of each option is required. This section will
era, the vast majority of patients with systemic deal with the selection of patients for metastasec-
disease should be treated with targeted therapy. tomy in the era of targeted therapy. This may be
This is of proven benefit in randomized trials [71, used alone or in combination with one of the
72]. The decision to surgically remove metasta- other treatment options.
ses rather than treating with targeted therapy is The first report of metastasectomy goes back
complex and controversial. There is retrospective to 1939 [8]. One of the first series reporting on
data showing impressive outcomes associated metastasectomy described surgery in 41 selected
268 T. Powles and A. Bex

patients with solitary lesions in the lungs, pleura, [78]. One hundred and seventy-nine patients
central nervous system or abdomen and dates (8.5%) of 2,100 patients who were known to have
back to 1978. The disease-specific survival was metastatic renal cancer between 1984 and1997
27 months with a 3-year survival of 59% [1]. underwent resection for a solitary metastatic
These data supported by other similar results at lesion. While the overall survival for the cohort
the time [9] led to partial acceptance of metasta- was impressive (29% at 5 years), perhaps the
sectomy in selected individuals. most important factor to affect outcome was the
While it was acknowledged that an isolated anatomical site of surgical removal. Patients with
relapse, for example in the lung, after previous lung and loco-regional metastasis fared better
nephrectomy may be treated with metastasectomy than those with brain, bone or liver metastasis.
it was less clear about patients who presented with Five-year survival rates for solitary metastases
a synchronous unresected renal tumour and meta- were over 50% for lungs/local regional disease.
static disease. This was addressed in a study of This dropped to 20% for visceral organs, approx-
179 patients, in which the 5-year survival rate imately 15% for bone and 13% for brain. Other
after resection of solitary lesions at various sites studies have supported these findings [74, 82].
was 22% for synchronous vs. 39% for metachro- Therefore surgical removals of lesions outside of
nous metastases [78]. This data also supports the the lungs and loco-regional area as initial treat-
hypothesis that patients with isolated relapse run a ment for metastatic disease required careful con-
less aggressive course than those who present sideration in the era of targeted therapy. The one
with synchronous unresected disease. exception to this is the brain which required par-
This leads to the issue surrounding the number ticular consideration and will be discussed later
of metastatic lesions which can successfully be in this section.
removed. Recent retrospective reports suggest that Further attempts have been made to identify
the surgical resection of over three lesions is of patients with solitary metastases who benefit
benefit compared to unmatched controls who did from metastasectomy [73, 74, 83]. The most con-
not have surgery [74]. A further retrospective sistent findings are that those patients who have
series examined this issue in more detail and complete surgical removal of isolated lung or
showed that the outcome of removal of 1–6 lung loco-regional disease at first relapse have an
lesions was associated with a better outcome com- excellent outcome. This is perhaps the clearest
pared to seven or more lung lesions removed [79]. indication for metastasectomy, especially those
One of the consistent features of this retro- patients with lung or loco-regional disease and
spective data is that surgical complete resection should be considered an accepted treatment
is associated with a good outcome [79, 80]. option despite the absence of randomized data.
Negative surgical margins after resection of lung
metastasis were associated with a 46.6 months
median overall survival in one series [81]. There Surgical Removal of Multiple Metastasis
are two possible explanations for this. Firstly, in the Pre-TKI Era
patients who achieve a complete resection have a
lower tumour burden than those where complete The removal of multiple metastasis is more con-
resection is not possible, which will influence troversial. Logic dictates that as the number of
outcome. Alternatively the surgery is genuinely lesions increases, the chances of unidentified
altering the behavioural pattern of the disease. lesions being missed which are too small to char-
acterize with cross sectional.
Nevertheless, prior to the development of tar-
Removal of a Single Metastasis geted therapy these were few treatment options
in the Pre-TKI Era and metastasectomy was widely employed in
some institutions. The limited data available sug-
The largest series to report on removal of a single gests that removal of up to six lung metastases is
metastatic site originates from the MD Anderson warranted (5-year survival of 32% vs. 0% [81]).
15 Integration of Surgery in Metastatic Renal Cancer 269

However removal of multiple metastases from MSKCC Prognosis Score for Metastatic
multiple sites consistently shows poor outcome Disease and Metastasectomy
results [10, 84]. Systemic targeted therapy is
more attractive in these patients. One of the most commonly used prognostic
Perhaps the most comprehensive and convinc- models is the MSKCC risk score which stratifies
ing data supporting metastasectomy in multiple patients into three risk groups (good, intermediate
sites of metastatic disease comes from the Mayo and poor). Retrospective data comparing those
Clinic (1976–2006) [80]. Overall 125 (14%) patients who had metastasectomy with those who
underwent complete surgical resection of all did not suggest surgery is associated with the sur-
metastases. These patients were compared to the vival advantage in both the good and intermediate
remaining population with metastatic disease risk groups with conflicting data in the poor risk
(n = 762). Complete surgical resection was asso- group [87, 88]. It is unclear how much of this
ciated with a significant prolongation of cancer- benefit is due to patient selection rather than the
specific survival (median = 4.8 years vs. 1.3 years; surgery itself. These data are derived from the
p < 0.001). This benefit was not isolated to patients pre-targeted therapy era, initial treatment with
with disease isolated to the lungs. Patients with a metastasectomy in the intermediate and poor risk
complete resection of non-pulmonary metastasis group seems counterintuitive and should usually
had a 5-year cancer-specific survival rate of be avoided in the authors’ opinion.
32.5% vs. 12.4% for those without complete
resection (p < 0.001). Complete resection
remained predictive of improved survival for Site-Specific Metastasectomy
patients who had ³3 metastatic lesions (p < 0.001).
The authors of this work conclude that surgical Resection of Pulmonary Metastases
resection should be considered where complete Metastasis in the lungs occurs in 74% of patients
resection is possible irrespective of anatomical in autopsy studies making them the most com-
locations and number of sites of metastatic dis- mon metastatic sites [89] [90]. There are a num-
ease. Due to patient selection bias and in the ber of small retrospective studies focusing on the
absence of randomized data this approach cannot role of metastasectomy in the cytokine era [84,
be recommended. However when this data is 91–95]. These studies show the outcome is good
considered within the context of other series, (5-year survival rate of 37–54%) in this highly
multiple resections may be considered with cau- selected population [79, 80, 84, 96–104]. Also, a
tion where complete resection is easily achiev- number of prognostic factors were consistently
able, especially in those patients with a limited identified in multivariate analyses (Table 15.1),
number of lung metastasis. the most important of which were incomplete
Repeated surgical resection for metastatic resection and number of metastasis removed (>6)
disease has been described [85, 86]. It almost [79–81, 84, 100, 103, 104]. The occurrence of
certainly reflects a subgroup with a more simultaneous lymph node metastases and pulmo-
benign course of the disease and can result in nary metastasis has a detrimental effect on the
exceptionally long survival lasting more than outcome (median survival decreased from 102 to
10 years in these selected individuals. In a 19 months [104]). These less impressive results
series of 141 patients with complete resection associated with tumour resection from multiple
of solitary metastases 5-year survival rates organs are not consistent throughout the literature
after complete resection of second and third however [80], but it does underline the caution
metastases were not different compared with required before embarking on major surgery to
initial metastasectomy (46 and 44%, respec- multiple sites, especially in the era of targeted
tively, vs. 43% 5-year OS rates; p ³ 0.05) [84]. therapy. Other significant factors associated with
This data needs to be interpreted with caution a poor outcome include a short disease-free inter-
due to selection bias. val from nephrectomy to relapse and the presence
270 T. Powles and A. Bex

of synchronous metastasis [79, 81, 84, 99, 100, cancer [114]. In this study only a minority had
103, 105]. Interestingly, the type of resection was renal cancer. Nevertheless this surgical approach
not associated with a survival advantage and is justified in this population for palliative reasons.
modern ablation techniques may be an alternative In view of this randomized data, this is probably
to surgical resection in select patients [106]. the strongest indication for surgery to a metastatic
site. Surgery can also be performed to alleviate
Resection of Liver Metastases pain and for pathological fractures or strengthen-
Liver metastases occur in 8–30% of patients with ing a long bone which is prone to fracture due to a
RCC [20]. They rarely occur in isolation and are lesion [115]. While this surgery is often performed
often associated with a poor outcome [74, 78, 82]. there is limited data regarding outcome or fracture
Therefore there are few retrospective series focus- rate. These procedures are often given in conjunc-
ing on liver metastasectomy [107–112]. The 5-year tion with radiotherapy [114].
survival rates range between 8 and 38.9% in these In terms of the effect of surgery on outcome,
series. The largest retrospective study analysed the only small series in a select group have reported.
outcome of 88 patients with liver metastasis as the The results are conflicting. In a series of 38 cases
only site [110]. Sixty-eight patients underwent with bone metastasis from RCC 13 evaluable
resection and were compared to 20 who refused. patients had solitary lesions removed with a
The median 5-year overall survival rate after resec- 5-year survival rate of approximately 50% for the
tion was 62.2% vs. 29.3% in the retrospective con- entire cohort [116]. Conversely, two further
trol. In both cohorts 79% received systemic therapy reports show the 5-year survival results for surgi-
(immune-based therapy). These results appear cal resection of a single bone metastasis at only
impressive, although they contradict some of the 8–13% [80, 117]. A retrospective review of the
smaller series where outcome is much less good. literature showed a long disease-free interval,
More importantly, hepatic metastasectomy is asso- appendicular skeletal location and solitary metas-
ciated with significant morbidity (20%) and tases were correlated with longer survival [116].
mortality (30%) [110, 111]. Therefore some rec- The largest series addressing a variety of sur-
ommend ablative techniques in this population gery for bone metastasis includes over 300 patients
based on very small numbers [113]. Overall the [115]. While symptomatic benefit can occur in the
data on resection of liver metastasis is limited, majority of patients, the median 5-year survival
surgical-related morbidity is high and the remain- was 11 and 5% died in the postoperative period.
ing patients invariably die from metastatic disease This highlights the caution required for these
despite surgery. Resection of isolated liver metas- patients prior to embarking on a surgical proce-
tasis as the only site of relapse may be warranted. dure. Wider resection may lessen the risk of recur-
These patients should always be discussed in a rence at the same location [118]. Radiotherapy is
multidisciplinary setting. clearly attractive and established alternative to
surgery and these decisions should be made in the
Surgery for Bone Metastases context of a multidisciplinary setting. Surgery
Bone metastases are observed in up to a quarter seems most justified in those patients with bone
of patients with metastatic renal cancer and are disease threatening cord compression, where there
frequently symptomatic [20]. The true prevalence is randomized data to support its use.
of solitary bone metastasis is not known but they
rarely occur in isolation (5.3%) [84].
Randomized prospective data in patients with Metastasectomy of Brain Metastasis
bone metastasis from various malignancies dem-
onstrated that direct decompressive surgery plus Brain metastasis occurs in 2–17% of patients with
postoperative radiotherapy is superior to treat- renal cancer [119–121]. It is symptomatic in
ment with radiotherapy alone for patients with approximately 80% of cases. If left untreated,
spinal cord compression caused by metastatic median survival is less than 4 months [122]. The
15 Integration of Surgery in Metastatic Renal Cancer 271

selection of patients for metastasectomy is crucial [132]. However, more widespread involvement is
in this population as the majority of patients have more sinister [133, 134]. Surgical management of
aggressive disease. There is also uncertainty about local recurrence has been reported by the MD
the effectiveness of targeted therapy in the CNS. Anderson group [135]. Results show median
For patients who present with brain disease the survival of over 5 years and this approach should
performance status, number of metastasis, be considered in conjunction with subsequent
MSKCC prognostic score and extracranial tumour systemic therapy. Factors associated with a poor
burden should be considered [123–125]. A com- outcome included positive surgical margin after
bination of whole brain radiotherapy (WBRT) and resection, size of tumour recurrence, sarcomatoid
targeted therapy would be the standard treatment features of the tumour, raised serum alkaline phos-
options for the majority of these patients. phatase and increased lactate dehydrogenase.
A retrospective series of WBRT alone survival Small series also exist on the adrenalectomy
of patients with single brain metastases from in renal cancer. Isolated adrenal metastasis should
RCC was only 4.4 months, while different small be considered for surgery because it is associated
surgical series suggested a median survival of with excellent long-term survival in individual
over 12 months [123, 126, 127]. These are clearly patients [136–138].
not comparable and were performed prior to the There is a lack of comprehensive data reporting
development of targeted therapy. However surgi- on the management of isolated lymph node relapse.
cal excision of isolated metastasis in patients with Case reports detailing good outcomes are
a good performance status may be justified and available [139, 140]. Overall, as with other organ
associated with modest outcomes. involvement surgical resection of isolated metas-
Stereotactic radiosurgery (SRS) can provide tasis needs to be considered in the context of the
effective local control and is comparable to sur- renal cancer disease pattern.
gery even for multiple lesions and recurrent Perhaps the most useful data for lymph node
metastases [128]. Data from two series are avail- surgery comes from a retrospective series of 101
able and the median overall survival was patients who underwent resection of pulmonary
11–13 months, with the majority of patients dying metastases. In this work the prognostic value of
from systemic disease [125, 129]. Overall both concurrent hilar and mediastinal lymph node
SRS and surgery are being widely used in the era involvement was evaluated [104]. Overall 35% of
of targeted therapy, despite the lack of data. This patients had lymph node involvement which was
is especially true in patients on systemic targeted associated with a worse prognosis. Indeed this
therapy who have isolated relapse in the brain. poor outcome suggests patients with concurrent
Further data is urgently required. lung and thoracic lymph node involvement should
not be surgical candidates [104].
Overall surgical intervention of local recur-
Surgery for Locally Recurrent Disease rence appears attractive. The role of lymphadenec-
and Lymph Node Metastases tomy in metastatic disease is less certain and does
not seem warranted. Isolated lymph node relapse
Renal cancer-related nodal metastasis is an inde- is rare and data lacks on the role of surgery.
pendent predictor of prognosis in patients who do
not have metastatic disease [130]. The outcome of
these patients is poor with post-surgical recurrence Metastasectomy Following
occurs in 70% and median overall survival of Systemic Therapy
20 months. Retrospective analysis suggests that
removal of suspicious lymph nodes at the time of The introduction of targeted therapy had compli-
nephrectomy is associated with improved out- cated the role of metastasectomy in renal cancer.
come [131]. Indeed a portion of patients with local The principle of down-staging a tumour with
lymph node involvement are cured with surgery systemic treatment followed by surgery to remove
272 T. Powles and A. Bex

residual disease is attractive . In addition removal References

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 Immunotherapy for Renal Cell
Carcinoma 16
Diwakar Davar, Moon Fenton, and
Leonard J. Appleman

Cancer immunotherapy can generally be

Introduction characterized as active (requiring the participation
of antigen-specific host cells) or passive (depen-
The first suggestion that renal cell carcinoma dent on exogenous antibodies or T lymphocytes).
(RCC) could be a target of the immune system Cancer immunotherapy can also be specific to
came from the occasional spontaneous regres- particular tumor antigens or components or
sions that have been documented in patients with nonspecific (stimulation of the immune system
metastatic RCC over the past century [1–3]. by cytokines or adjuvant without specific antigenic
Spontaneous regressions are sometimes associ- material). Active and passive, specific and
ated with cytoreductive nephrectomy, although nonspeci fi c immunotherapeutic approaches to
the rate of regression is low and variable between RCC have all been investigated in the clinic.
series [4, 5]. In a randomized study of interferon-
g 1b, 6 patients out of 91 in the placebo arm had
spontaneous tumor regression [6, 7]. These cases Cytokine Therapy
were subjected to blinded central radiology
review, and there were three complete responses The use of cytokines represents an active,
and three partial responses (defined as greater nonspecific cancer immunotherapy. The premise
than 50% decrease in sum of tumor diameters). underlying cytokine therapy is that nonspecific
Conversely, recurrences of renal carcinoma after activation of immune system in a patient with
nephrectomy have been described as long as cancer will allow tumor-specific immune response
33 years after presentation. One explanation for to develop to the point that they acquire clinical
this observation is loss of immune control of a antitumor activity.
radiographically occult tumor population [8, 9].

Interleukin-2
D. Davar
Division of General Internal Medicine, Interleukin-2 (IL-2) was identified in 1976 as a
University of Pittsburgh Medical Center, 200 Lothrop soluble factor in the conditioned medium of phy-
Street, Pittsburgh, PA 15213, USA tohemagglutinin-stimulated human lymphocytes
e-mail: [email protected]
that selectively enabled the growth of T cells in
M. Fenton • L.J. Appleman () culture [10]. Initial in vitro and clinical studies
Division of Hematology-Oncology, University
were performed using IL-2 purified from culture
of Pittsburgh Medical Center, 5150 Centre Avenue,
Pittsburgh, PA 15232, USA supernatants of the Jurkat T leukemia cell line
e-mail: [email protected]; [email protected] [11]. Interleukin-2 was subsequently cloned and

S.C. Campbell and B.I. Rini (eds.), Renal Cell Carcinoma: Clinical Management, Current Clinical Urology, 279
DOI 10.1007/978-1-62703-062-5_16, © Springer Science+Business Media New York 2013
280 D. Davar et al.

produced recombinantly from Escherichia coli a cytokine release by immune cells activated by
[12, 13]. The availability of large quantities of IL-2, which results in a capillary leak syndrome
recombinant IL-2 allowed the in vitro expansion causing hypovolemia and fluid accumulation in
of lymphokine-activated killer (LAK) cells for the extravascular space. Systemic effects such
adoptive immunotherapy, as well as the direct as fever and a sepsis-like syndrome are thought
administration of large doses of IL-2 to patients. to be related to the IL-2-mediated release of
IL-2 was tested as an anti-neoplastic agent and tumor necrosis factor (TNF) by mononuclear
demonstrated antitumor activity in a range of cells. Other effects include cardiac (arrhyth-
murine tumor models [14, 15]. mia), renal (renal dysfunction), hematologic
The first phase I study of interleukin-2 in (thrombocytopenia, anemia, leucopenia), gas-
humans was reported by Lotze, Rosenberg and trointestinal (diarrhea), and metabolic (meta-
colleagues at the National Cancer Institute in bolic acidosis). Earlier studies did report an
1984 [11]. No responses were seen using the rel- approximately 20% incidence of catheter-
atively small quantities of IL-2 available as the related bacteremia but improved infection con-
nonrecombinant product purified from Jurkat trol measures and the use of removable
cells. Clinical responses in patients with mela- peripherally inserted central catheters (PICCs)
noma were seen in subsequent studies in which have reduced this considerably. IL-2-related
larger quantities of interleukin-2 available from toxicities generally resolve within 2–3 days of
recombinant production in E. coli were used [16]. cessation of therapy.
The NCI group subsequently showed that the
combination of high-dose IL-2 (720,000 or
600,000 IU/kg) with a LAK cell infusion had IL-2 Therapy: Alternative Schedules
activity in metastatic renal cell cancer [17]. Fyfe
and colleagues subsequently reported the com- The associated toxicities (up to 4% treatment-
bined results of seven phase II studies of bolus related mortality) and high cost associated with
high-dose IL-2 in patients with metastatic RCC IL-2 administration led some researchers to
[18]. In this report, patients with metastatic RCC investigate regimens containing lower doses of
were with recombinant IL-2 dosed at 720,000 or IL-2 or combinations of other agents—including
600,000 IU/kg delivered by a 15 min intravenous 5-fluorouracil and IFN-a—with low-dose IL-2 in
(IV) infusion every 8 h over 5 days consecutively an attempt to decrease toxicity whilst maintain-
for up to 14 consecutive doses. A single course of ing therapeutic efficacy.
therapy consisted of two cycles as described A French multicenter phase III trial published
above. Patients who had radiographic responses in the New England Journal of Medicine in 1998
or stable disease were retreated with a second compared continuous infusion intermediate dose
course after 12 weeks, generally for up to three IL-2 (5-day continuous infusion at 18 × 106 IU/m2
courses in total. Overall response rate (RR) was of body-surface area daily), subcutaneous IFN-a
14% (36/255) with a complete response (CR) and (18 × 106 IU/m2 thrice weekly for 10 weeks), and
partial response (PR) rates of 5% (12/255) and combination of the two agents in 425 patients
9% (24/255), respectively (see Table 16.1). This with metastatic RCC [22]. Response rates at
led to the United States Food and Drug 25 weeks were significantly greater in the com-
Administration (FDA) approving high-dose (HD) bined therapy group—overall RR of 14% (19/140)
bolus recombinant interleukin-2 (Aldesleukin, in the combined IL-2/IFN-a arm compared to
Proleukin) for the treatment of patients with met- 1% (4/138) and 6% (9/147) in the IL-2-alone and
astatic RCC in 1992. IFN-alpha alone arms, respectively. Event-free
High-dose bolus IV IL-2 administration is survival was also significantly higher in the com-
associated with severe multisystem toxicity bination group (20% at 1 year) vs. the IL-2-
[27]. Adverse manifestations are directly related receiving group (15%) or the interferon-alpha
to lymphocyte infiltration in various organs and group (12%) (p = 0.01). However, none of the
Table 16.1 Selected studies of cytokine therapy in advanced renal cell cancer
Author Design Participants Interventions Results
Rosenberg Single-center N = 97; median age 1. IL-2 2.16 MU/kg/daya i.v. with HD IL-2 with LAK
[19] phase III RCT 41–50 years (all LAK (24/85 = 28%) vs.
stratified by histol); PS(0) 77% 2. IL-2 2.16 MU/kg/daya i.v. with- HD IL-2 w/out LAK
tumour type (all histol); male out, LAK (16/79 = 20%)
66%

Yang [20] Single-center N = 56; median age 1. IL-2 2.16 MU/kg/daya i.v. alter- HD IL-2 (13/65 = 20%)
phase III RCT, 41–50; PS(0) 73% nating with PEG-IL2 3(−6) MU/ vs.
stratified by (melanoma + RCC); kg i.v. weekly LD IL-2 (9/60 = 15%)
melanoma vs. M/F NA 2. IL-2 2.16 MU/kg/daya i.v.
RCC,
nephrectomy
Yang [21] Single-center N = 305; median 1. IL-2 i.v. 2.16 MU/kg/daya HD IL-2 (33/155 = 21%)
phase III RCT age 41–50 years; 2. IL-2 i.v. 0.216 MU/kg/daya vs.
PS(0) 81%; male LD IL-2 (19/149 = 13%)
70%
Negrier Multicenter, N = 425; ECOG PS 1. HD IL-2 per protocola Response (CR + PR + SD)
[22] phase III RCT 0–2 (72–83% PS 2. SC IFN-a 18 × 106 IU/m2 3 days/
– At 10 weeks:
0); post-nephrec- week × 10 weeks (induction) 6.5% (group 1) vs.
tomy 92–94% followed by 13 weeks7.5% (group 2) vs. 18.6%
(maintenance) (group 3)
3. HD IL-2 per protocol with SC – At 25 weeks:
IFN-a 6 × 106 IU/m2 during each 2.9% (group 1) vs.
IL-2 cycle 6.1% (group 2) vs. 13.6%
(group 3)
Survival:
Event-free survival rates
at 1 year:
15% (group 1) vs. 12%
(group 2) vs. 20% (group
3)
Yang [23] Three-arm single N = 283; male 71% As for Yang 2003a(i), 3rd arm HD IL-2 (20/96 = 21%)
center phase III added: IL-2 0.125–0.25 MU/kg s.c. vs. LD IL-2 (10/92 = 11%)
RCT d 1–5/week vs. SC IL-2 (9/93 = 10)
McDermott Multicenter phase N = 193; median 1. IL-2 5–15 MU/m2/daya s.c. + IFN- HD IL-2 (22/95 = 23%)
[24] III RCT; stratified age 54 years; PS(0) a2b 5 MU/m2 thrice weekly vs. LD IL-2 + IFN
for site (liver/ 60%; male 68%; 2. IL-2 1.8 MU/kg/daya i.v. (9/91 = 10%)
bone Y/N), PS 0 Nx 69% (note only
vs. 1, nephrec- pts with PD were
tomy status enrolled)
Negrier Multicenter, N = 492; median 1. MPAb 200 mg daily Response (CR + PR)
[25] phase III RCT age 61 years; clear 2. SC IFN-a 9 × 106 IU/m2 thrice – At 12 weeks: 2% (group
cell histo 79%; weekly for 10 weeks 1) vs. 4% (group 2) vs.
post-nephrectomy 3. SC intermediate dose IL-2 4% (group 3) vs. 10%
96% (5-day continuous infusion at (group 4)
9 × 106 IU/m2 daily) – At 6 months: 2% (group
4. – (2) + (3) 1) vs. 8% (group 2) vs.
4% (group 3) vs.7%
(group 4)
Survival:
– OS (months): 14.9
(group 1) vs. 15.2 (group
2) vs. 15.3 (group 3) vs.
16.8 (group 4)
– PFS (months):
3.0 (group 1) vs. 3.4
(group 2) vs. 3.4 (group 3)
vs. 3.8 (group 4)
(continued)
282 D. Davar et al.

Table 16.1 (continued)

Author Design Participants Interventions Results
McDermott Multicenter, N = 120; median HD IL-2 per FDA Response (CR + PR) at
[26] nonrandomized, age unknown; approved-protocolc time of reporting (ASCO
prospective study PS(0) 60%; 2011):
MSKCC intermedi- – RR: 29% (35/120 with 7
ate risk 71%; clear CR, 28 PR and 20
cell histo 96%; ongoing responses)
post-nephrectomy Survival at time of
99% reporting (ASCO 2011):
– PFS (months): median
4.4 (20 ongoing)
a
HD IL-2 protocol—induction cycle consisting of 18 × 106 MU/m2/day × 5 days for two courses separated by 6 days with
3 weeks rest between cycles and maintenance cycle consisting of 18 × 106 MU/m2/day × 5 days followed by 3 weeks
rest
b
MPA medroxyprogesterone (Farlutal; Pfizer, Paris, France)
c
FDA-approved HD IL-2 protocol—18 × 106 MU/m2/day (6 × 105 MU/m2/dose q8) × 5 days (maximum 14 doses) fol-
lowed by 9 days rest, then repeated with each cycle = 5 days of treatment

three regimens tested had any advantage in terms every 8 h for a maximum of 28 doses) to combi-
of overall survival (OS). nation low-dose IL-2 (5 MIU/m2 subcutaneously
Multiple trials comparing various intermedi- every 8 h for three doses on day 1, then daily
ate-dose and low-dose schedules of IL-2 have 5 days/week for 4 weeks) and IFN-a (5 MIU/m2
been published—these trials produced response subcutaneously three times per week for 4 weeks)
and survival rates comparable to those reported in patients with metastatic RCC [24]. Three-year
for HD IL-2 with significantly less acute toxicity PFS was the primary endpoint. PFS in the HD
(see Table 16.1). Generally, objective response IL-2 group was 10.5% at 3 years vs. 3.3% in the
(OR) rates were 15% with a CR rate of 7% and low-dose IL-2/IFN arm (p = 0.082). HD IL-2
PR rate of 8%, respectively. resulted in response rate of 22%, significantly
A National Cancer Institute (NCI) phase III better than the 10% for LD IL-2/IFN. There were
study compared HD IL-2 to two different low more complete responses in the HD IL-2 arm
dose regimens—an inpatient intravenous bolus (8.3% vs. 3.3% for the IL-2/IFN combination
regimen using 10% of the standard dose (p = 0.214). Seven out of 95 subjects in the HD
(72,000 IU/kg/dose intravenously every 8 h for a IL-2 arm maintained complete remission through
maximum of 28 doses) and an outpatient regimen the last analysis, and none in the IFN arm
using SC IL-2 (250,000 U/kg/dose in week 1 and (p = 014). In addition, HD IL-2 administration
then 125,000 U/kg/dose during subsequent resulted in a median OS of 17.5 months (vs. 13
5 weeks) [23]. After noting that HD IL-2 appeared for IL-2/IFN-a; p = 0.211). Based on the results
to result in significantly more responses com- of the NCI and CWG group studies described
pared to either low dose IV IL-2 or SC IL-2, the above, HD IL-2 is the preferred regimen for fit
authors concluded that LD IL-2 regimens had patients who are treated with the objective of
some biologic activity in metastatic RCC but that long-term disease control.
given the higher response rates associated with
HD IL-2, this was to be recommended in suitable
patients with the caveat that none of the tested IL-2 Therapy: Adjuvant Therapy
regimens had demonstrated any survival benefit.
The Cytokine Working Group (CWG) con- IL-2 has been evaluated in the adjuvant setting by
ducted a randomized phase III trial to compare several investigators in an attempt to extend the
HD IL-2 (600,000 IU/kg/dose intravenously progression-free survival (PFS) benefit seen in the
16 Immunotherapy for Renal Cell Carcinoma 283

metastatic setting to patients at high risk of recur- p = 0.47). The reduction in risk was greatest for
rence post-resection. A pilot trial conducted by patients with lower tumor grade.
investigators at the University of Minnesota pub-
lished in 2006 studied the effects of adjuvant low-
dose IL-2 given in a dose-escalating fashion to 41 IL-2 Therapy: HD IL-2 Combinations
patients with resected RCC at high risk for recur-
rent disease (TNM stages III and IV resected dis- The toxicity profile of IL-2 has been previously
tant metastases) [28]. Patients received SC IL-2 detailed. In an effort to improve response rates
twice daily at either 4 or 8 MIU/m2 per day in two and/or survival benefit without significantly add-
different schedules for each dosing level. No sta- ing to toxicity, several groups have attempted to
tistically significant difference between any of the pair HD IL-2 with additional agents.
treatment arms with respect to disease-free sur- A CWG trial in which bevacizumab, a mono-
vival or 3-year survival was noted in this trial. clonal antibody-directed against the vascular
Clark et al. conducted a randomized trial of endothelial growth factor (VEGF) receptor, was
adjuvant high-dose therapy via the CWG. Sixty- added to standard dose HD IL-2 in patients with
nine patients who were at high risk of recurrence histologically confirmed metastatic RCC with pre-
post-nephrectomy were enrolled [29]. One course dominantly clear cell histology [30]. Overall RR
of standard dose HD IL-2 was given vs. observa- was 29% with CR 8% and PR 20%. Median PFS
tion in a randomized 1:1 fashion to patients who was 9 months with a 2-year PFS of 15%. Toxicity
were within 12 weeks status post-nephrectomy. was comparable to single agent HD IL-2.
At an interim analysis performed at 24 months, IL-2 has also been tested in combination with
only 72% of expected events had occurred lead- the small molecule tyrosine kinase inhibitors
ing the investigators to terminate the trial early as (TKIs). In a multicenter Italian study, 128 treat-
it was thought that there was a <1% chance of ment-naive patients with metastatic RCC were
observing the stated 30% actual improvement in enrolled to sorafenib alone or combination daily
2-year DFS, should the trend of events continue. sorafenib plus subcutaneous IL-2 administered
At the time of publication it was noted that DFS five times per week for 6 of every 8 weeks [31].
in the IL-2 treatment arm averaged 19.5 months The initial dose administered was 4.5 million
vs. 36 months in the observation arm. The authors international units (MIU), but after enrollment of
concluded that adjuvant HD IL-2 failed to dem- 40 total subjects, the dose of IL-2 was reduced to
onstrate a clinically meaningful benefit when 3 MIU due to asthenia. The primary endpoint of
administered postoperatively to patients with the study was PFS. The PFS of the combination
resected high-risk RCC. group was 33 weeks vs. 30 weeks for sorafenib
Italian investigators have investigated low-dose alone (p = 0.109). Although there was a trend
IL-2 in combination with IFN-a in resected high-risk toward improved PFS with sorafenib plus IL-2 in
RCC. Three hundred and ten patients have been the subjects with MSKCC low risk (47 weeks vs.
randomized to control vs. immunotherapy con- 41 weeks), the PFS in the intermediate risk group
sisting of a 4-week cycle of LD IL-2 (subcutane- was 21 weeks for sorafenib plus IL-2 vs. 29 weeks
ously 1 million IU/m2 twice daily on D1–2 for sorafenib alone. The authors concluded that
followed by 1 million IU/m2 once daily on D3–5) low-dose interleukin-2 failed to improve outcomes
with IFN-a (subcutaneously 1.8 million IU/m2 on with first-line sorafenib therapy for mRCC.
days 3 and 5). Cycles were repeated every 4 months
for the first 2 years and every 6 months for the
remaining 3 years for a total of 12 cycles in IL-2 Therapy: Predictors of Response
5 years. Whilst DFS was similar for the 5 years of
observation, at 10 years it appeared that treatment Given the antecedent toxicities associated with
reduced risk of relapse with an estimated hazard ratio IL-2 administration, there exists a clear and press-
(HR) for treatment of 0.84 (95% CI 0.54–1.33, ing need to identify reliable clinical predictors of
284 D. Davar et al.

response to limit therapy to those most likely to In an analysis of 321 patients using a mono-
benefit. The consistent survival benefit in a minor- clonal antibody designed to detect CAIX expres-
ity of nonselected patient populations treated sion, Bui et al. demonstrated CAIX expression in
with IL-2 suggests that there exist tumor-specific primary tumors was seen in 79% of all patients
and/or host-specific phenotypes that confer sus- and was associated with improved survival and
ceptibility to immunotherapy emphasizing the was independently associated with survival [36].
need to identify reliable predictors of response. Patients in the series who were long-term respond-
A clinical algorithm, the UCLA SANI score ers to IL-2-based treatment also had high CAIX
(survival after nephrectomy and immunotherapy), expression. A retrospective analysis performed
was developed based upon the outcomes in 173 by Atkins et al. further validated the utility of
patients who had nephrectomy followed by IL-2- CAIX analysis and established that CAIX expres-
based therapy. The factors that predicted survival sion is correlated with response to IL-2, OS and
and response to IL-2 were regional lymph node better histopathologic risk subtype [37]. When
status (N0 vs. N1 vs. N2), symptoms, location of the percentage of CAIX-positive tumor cells was
metastases (bone only or lung only vs. multiple used to dichotomize IL-2 treatment responders,
sites or other sites), sarcomatoid histology, and 78% of the IL-2 treatment responders had high
TSH level (2 mIU/L vs. 2.0–4.8 mIU/L vs. CAIX expression (>85%) compared with 51% of
>4.8 mIU/L) [32]. Median survival for the low non-responders.
risk group (0 risk factors) was 47 months after Genome-wide analyses are now being performed
nephrectomy and immunotherapy. Median sur- to identify alleles that are predictive of benefit from
vival for the intermediate risk group (one to three IL-2 and other systemic treatments. An array-based
risk factors) was 19 months, and median survival comparative genomic hybridization analysis
for the high risk group was only 5 months. identified loss of chromosome 4, 9, and 17p as pos-
Investigators have long known that certain sub- sible predictors of non-response to IL-2 [38].
types of RCC portend for especially poor out- Prospective assessment of candidate predic-
comes. MSKCC researchers established that tors of IL-2 response was evaluated in the High-
metastatic non-clear-cell RCC was associated Dose Aldesleukin (IL-2) “Select” Trial) [39,
with resistance to systemic therapy including IL-2 40]. One hundred and twenty patients with met-
and poor outcomes [33]. After analyzing patients astatic or unresectable histologically confirmed
with respect to therapy received, Upton et al. RCC of any histologic type were enrolled and
noted that patients with non-clear-cell RCC or treated with standard bolus HD IL-2. The pri-
clear-cell RCC with papillary or >50% granular mary endpoint of the study was tumor response
features tended to respond poorly to IL-2 [34]. rate. The primary objective was to determine
Researchers analyzing tumor tissue to identify whether prospective selection of patients would
putative biomarkers to aid in prognostication and/ result in a doubling of the response rate vs. his-
or prediction of response to therapy had previously torical series (from 14% to 28%). Surprisingly,
identified several candidates of interest. By gene the response rate for the entire study population
profiling tumor specimens, Pantuck et al. were was 28% (30% for the 115 subjects with clear
able to identify a set of 73 genes whose expression cell carcinoma), whereas the median PFS was
appears to distinguish complete responders from 4.2 months, close to the value seen historically.
non-responders [35]. Complete responders to IL-2 Surprisingly, the response rate in subjects in the
have a signature gene and protein expression pat- prospectively assigned poor risk histology group
tern that includes carbonic anhydrase IX (CAIX), was 33% (n = 24), and subjects with low CAIX
PTEN, and CXCR4. CAIX may function to help expression (hypothesized to predict poor risk)
cells proliferate in hypoxic conditions and appears had a response rate of 38%. Central review of
to be inductively increased in many tumor types as histology and CAIX expression did not predict
opposed to normal tissue. response to IL-2. No patients with a high risk
UCLA SANI score responded to IL-2, and this
16 Immunotherapy for Renal Cell Carcinoma 285

group had inferior PFS. Analysis of additional benefit with IL-2 therapy to limit therapy to those
biomarkers measured in blood and tumor tissues most likely to benefit.
is ongoing. The high response rate seen in this
study likely reflects the more stringent selection
of patients for study entry in the modern era of Interferon
alternative targeted therapies. It is likely that
only those subjects felt most likely to benefit Isaacs and Lindenmann discovered interferons
from IL-2 were identified for study screening. after noticing that heat-inactivated influenza virus
There is still much room to improve upon the appeared to inhibit the growth of live influenza
response rate of 30% seen among the patients virus in vitro in 1957. In the two decades that fol-
with clear cell RCC enrolled in the study. Given lowed, multiple experiments suggested that inter-
the toxicity of HD IL-2, the identification of ferons had antitumor effects in a broad range of
biomarkers predictive of response remains an laboratory models. Following the purification and
important unmet need. subsequent cloning of interferon genes in the
1980s, it became clear that far from being a single
molecule, interferons were a large family of struc-
IL-2 Therapy: Relapses turally related molecules with diverse effects.
Once the interferon gene was inserted into bacte-
Although complete and partial responses with ria using recombinant DNA technology, it was a
IL-2 therapy can be long-lasting, most patients mere matter of time before the commercial appli-
eventually relapse. A series from the NCI cations of interferon were discovered.
reported on the pattern of relapse in 107 patients IFNs are subclassified as types I and II accord-
with metastatic RCC who had previously ing to their structural and functional properties.
responded to IL-2-based therapy. Overall, 70% Type II IFNs (IFN-g in humans) are released by
of all treated patients relapsed with most (55/64, Th1 cells. Signaling via the IFN-g receptor (IFN-
86%) occurring in patients with prior PRs as gR), IFN-g recruits leucocytes to infected areas
opposed to less than half as often (20/43, 43%) resulting in inflammation, stimulates macrophages
in patients with prior CRs. Interestingly, relapses to phagocytose engulfed bacteria and up-regulates
tended to occur in previously identified sites of the Th2 response. Type I IFNs comprise a number
disease in patients with PRs whilst patients of structurally similar molecules that all signal via
relapsing after a CR tended to involve new sites. the IFN-a receptor (IFN-aR). Whilst several sub-
Repeat IL-2-based therapy was rarely effective types have been identified, IFN-a, IFN-b, and
in the recurrent setting [41]. IFN-w are the most important ones in humans.
Type I IFNs are produced in large quantities chiefly
by the plasmacytoid dendritic cell in response to
IL-2 Therapy: Current Indications infectious and other noxious stimuli. Connecting
and Future Directions the adaptive and innate arms of the immune
response, type 1 IFNs have potent immunoregula-
Bolus intravenous HD IL-2 therapy is a reason- tory, antiproliferative, differentiation-inducing,
able option in selected patients with good perfor- apoptotic, and antiangiogenic properties.
mance status and clear cell histology on the basis Several reports in the early 1980s suggested
of sustained CRs in approximately 5–10% of that IFN-a therapy resulted in objective responses
patients treated, despite the significant cost and in RCC and led to a series of trials that examined
toxicity entailed with treatment. Ongoing research the role of IFN-a in the metastatic setting against
efforts are aimed at exploring combinations of two major comparators—immunotherapeutic
high-dose IL-2 with other agents and at identify- (low-dose IL-2) and non-immunotherapeutic
ing predictive factors that portend for a greater agents (medroxyprogesterone and vinblastine).
286 D. Davar et al.

IL-2 was associated with an increased remission

IFN-a: Single Agent Therapy (Peto Odds Ratio 1.82–2.70 [39, 42]). Mortality
benefit was inconsistently observed—one study
Single-agent IFN-a dosed between 8 and 18 MU/ showed an improved OR of 0.95 (Peto OR 0.95,
dose given three times weekly by subcutaneous 95% CI 0.59–1.53) vs. low-dose IV IL-2 whilst
injection is associated with response rates of another study reported an OR of 0.71 (Peto OR
approximately 15–20%, the vast majority of 0.71, 95% CI 0.40–1.26) vs. combination of
which are partial and do not generally persist IFN-a and low dose subcutaneous IL-2.
beyond 12 months. In a Cochrane meta-analysis Multiple combinations of IFN-a and conven-
of four studies involving a total of 644 patients, tional chemotherapy have been evaluated—IFN-
IFN-a therapy was superior to comparator treat- a/5-fluorouracil [57–59], IFN/vinblastine [60,
ments and demonstrated a survival benefit with 61], and IFN-a/cis-retinoic acid [62, 63]. Whilst
an OR for death at 1 year of 0.56 (95% CI 0.40– initial reports from the phase II setting suggested
0.77) and an overall HR for death of 0.74 (95% an increase activity for combination therapy, this
CI 0.63–0.88) [42].The average median improve- benefit was not consistently observed in the phase
ment in survival with IFN-a treatment was III setting. The IFN-a/5-fluorouracil combina-
3.8 months. This improvement in survival, albeit tion appears to be the most active with a response
modest, coupled with the cost savings and rate that ranged from 13% to 33% in two studies.
reduced treatment-related toxicity compared to However, this has yet to be evaluated in the phase
IL-2 administration resulted in IFN-a becoming III setting.
a widely used treatment for metastatic RCC With the advent of the targeted therapies,
worldwide. interest expanded in combining these agents with
IFN-a. Several trials looked at the combination
of IFN-a/sorafenib [64, 65], IFN-a/sunitinib [66]
IFN-a Therapy: Combinations and IFN-a/bevacizumab [67–69].
The initial phase I trials involved the multi-
Knowing that IL-2 mediates its effects by poten- kinase inhibitors sunitinib and sorafenib in com-
tiating the cytotoxic effects of effector cells and bination with IFN-a dosed between 3 and 9 MU
that IFN-a appears to function by increasing subcutaneously three times a week. The IFN-a/
expression of HLA class I and tumor-associated sunitinib combination was poorly tolerated with
antigens, it was hypothesized that IL-2 and IFN-a dose reduction required in 18/25 (72%) patients
would work synergistically in combination. with an objective response rate (ORR) of
IFN-a was combined with various schedules of 12%—comparable to what was commonly
IL-2 including low-dose SC injections [24, 43– observed with IFN-a-alone but less than the 31%
49], intermediate-dose continuous infusions observed in phase II and phase III studies of sin-
[22]and high-dose intravenous boluses [50–55]. gle-agent sunitinib [70]. Additionally, the adverse
Although several phase II showed improved events reported in the study suggested that the
response rates than would be expected with high- toxicities of the respective agents were appar-
dose IL-2, phase III results did not show any ently additive—with a higher incidence of neu-
increase in either PFS nor OS benefit over IFN-a tropenia than previously reported for either agent
alone [56]. singly. As a result, this combination is no longer
Subsequently several phase II studies ought to being pursued.
further refine the regimen and compare high-dose Conversely, the combination of sorafenib plus
bolus IV IL-2 to various comparators. Generally, IFN-a resulted in response rates of 19–33% in
it was found that 5–7% of patients on the high- two phase II studies [64, 65]. A third phase II
dose intravenous IL-2 arms experienced durable study from Italy compared two different IFN-a
CRs compared with 0–2% on control arms. dosing options (9 MU three times a week vs.
Compared to control, the administration of HD 3 MU five times a week) combined with sorafenib
16 Immunotherapy for Renal Cell Carcinoma 287

(dosed at 400 mg BID). Overall, in both arms, 26 doses of 5-fluorouracil and gemcitabine delivered
responses (3 complete, 23 partial) were seen on days 1 and 8 in a 28-day cycle. Twenty-seven
resulting in a CRR of 26% [71]. Toxicities result- patients were enrolled. Fifty-nine percent had
ing in dose reductions were common, exceeded received prior systemic therapy. Thirty-three per-
the incidence for either drug alone and were cent of the subjects had a partial tumor response
dominated by adverse events common to IFN [72]. Median time to progression was 6.4 months,
administration. This suggested that outcomes with 8% of patients progression-free at 30 months.
could be improved by minimizing sorafenib dose Median overall survival was 22.6 months.
reductions whilst maintaining tolerability. In summary, when combined with cytotoxic
However, randomized phase III trial data to dem- agents or IL-2, combination chemotherapy with
onstrate any benefit for the sorafenib/IFN-a com- IFN-a has failed to provide significant improve-
bination over sorafenib alone is still lacking. ment in response rates and/or OS (see Table 16.2).
Two large international randomized trials— Notably the success of the IFN-a/bevacizumab
avastin and interferon in renal cancer (AVOREN) combination in demonstrating an improvement in
and cancer and leukemia group B (CALGB) PFS has led to this regimen being approved by
90206—examined the clinical efficacy of the the FDA.
IFN-a/bevacizumab combination vs. IFN-a
alone. In both studies, IFN-a was dosed at 9 × 106
MU thrice weekly whilst bevacizumab was dosed IFN-a Therapy: Prognostic Factors
at 10 mg/kg. The CALGB 90206 trial recruited and Predictors of Response
732 patients and reported an ORR of 25.5% for
the combination vs. 13.1% for IFN-a alone [68]. Five pretreatment clinical variables (low
Combination therapy was associated with a Karnofsky performance status, high lactate dehy-
higher PFS (8.5 months vs. 5.2 months) and an drogenase, low serum hemoglobin, high cor-
improved HR for the treatment arm (0.67, 95% rected serum calcium, and time from initial RCC
CI 0.57–0.79; p < 0.0001). In the AVOREN study, diagnosis to start of IFN-a therapy of less than 1
649 patients were enrolled and randomized either year) were identified as prognostic factors by
to IFN-a/bevacizumab or IFN-a alone [67]. The MSKCC investigators when they analyzed 463
median duration of PFS was significantly better patients with advanced RCC who received IFN-a
in the combination treatment arm (10.2 months as first-line systemic therapy in six prospective
vs. 5.4 months; p = 0.0001) and was noted to be clinical trials [81]. They were able to subclassify
irrespective of the MSKCC risk category. In the patients into three risk stratifications: zero risk
AVOREN study investigators were able to report factors (favorable risk), one or two (intermediate
a survival benefit for the combination therapy risk), and three or more (poor risk). Favorable
arm (23 months vs. 21.3 months, p = 0.1291) that risk patients had improved median survival
did not meet the criteria for statistical significance. (30 months vs. 14 months and 5 months for inter-
The results of these two pivotal studies led to the mediate and poor risk patients), survival at 1 year
approval of this combination for the first-line (83% vs. 58% and 20%), 2 years (55% vs. 31%
treatment of patients with metastatic RCC by the and 6%), and 3 years (45% vs. 17% and 2%).
FDA in August 2009. As yet, we have not yet identified clinical or
A trial combining IL-2/IFN-a with bevaci- pathological variables that are able to predict
zumab, 5-fluorouracil, and gemcitabine was response to IFN-a therapy. In the Italian
recently published. In this study IL-2 (1 MIU/m2 RAPSODY study of sorafenib plus IFN-a, inves-
bid subcutaneously days 8, 9, 15, 16 and 1 MIU/ tigators analyzed biomarkers including serum
m2/d subcutaneously from days 10 to 12 and from thrombospondin-1 (TSP-1), VEGF, VEGF recep-
17 to 19) and IFN-a (3 MIU subcutaneously on tor-2 (VEGFR-2), and basic-fibroblast growth
days 10, 12, 17, 19) were combined with bevaci- factor (b-FGF) to see whether levels would be
zumab (10 mg/kg days 1 and 15) and escalated correlated with response to therapy. Of the four,
Table 16.2 Selected studies of cytokine/targeted therapy combinations in advanced renal cell cancer
Author (year Design Participants Interventions Results
published)
SWOG-S0412 [73] Multicenter, N = 62; PS (ECOG 1) 40%; Sorafenib 400 mg BID + SC IFN-a2b 10 × 106 IU/ OR (CR + PR + unconfirmed PR) (19/62): 30%
(2007) nonrandomized, median age 61; clear cell m2 thrice weekly SD (24/62): 39%
phase II unknown; prior nephrectomy 87%
Gollob [64] (2007) Multicenter, N = 40; PS (ECOG-1) 15%; Sorafenib 400 mg BID + SC IFN-a2b 10 × 106 IU/ OR (CR + PR) (13/40): 33%
nonrandomized, median age 57; clear cell 88%; m2 thrice weekly SD (18/40): 45%
phase II prior nephrectomy 88%
AVOREN [67, 74] Multicenter, phase N = 649; median age 61; PS 1. SC IFN-a2b 9 × 106 IU/m2 thrice OR (CR + PR) (2007):
(2007) III, placebo-con- (KPS > 80) 94%; MSKCC weekly + Bevacizumab10 mg/kg every 2 weeks Bev + IFN-a 31% vs. IFN-a alone 13%
trolled RCT risk—intermediate (56%) and 2. SC IFN-a2b 9 × 106 IU/m2 thrice OS (months) (updated 2010):
poor (9%); predominantly clear weekly + placebo Median (ITT) Bev + IFN-a 23.3 vs. IFN-a alone 21.3
cell; post-nephrectomy 99%
By MSKCC risk category:
Favorable: Bev + IFN-a 35.1 vs. IFN-a alone 37.2
Intermediate: Bev + IFN-a 22.6 vs. IFN-a alone 19.3
Poor: Bev + IFN-a 6.0 vs. IFN-a alone 5.1
CALGB 90-206 Multicenter, phase N = 732; PS (ECOG—0) 62%; 1. SC IFN-a2b 9 × 106 IU/m2 thrice OR (CR + PR) (2008):
[68, 75] (2008) III, open label RCT median age 61 years; MSKCC weekly + Bevacizumab 10 mg/kg every Bev + IFN-a 25.5% vs. IFN-a alone 13.1%
risk—intermediate (64%) and 2 weeks OS (months) (updated 2010):
poor (10%); predominantly clear 2. SC IFN-a2b 9 × 106 IU/m2 thrice weekly alone Median Bev + IFN-a 18.3 vs. IFN-a alone 17.4
cell; prior nephrectomy 85%
By MSKCC risk category:
Favorable: Bev + IFN-a 32.5 vs. IFN-a alone 33.5
Intermediate: Bev + IFN-a 17.7 vs. IFN-a alone
16.1
Poor: Bev + IFN-a 6.6 vs. IFN-a alone 5.7
CWGS [30] (2010) Multicenter, phase N = 49; PS—KPS ³ 80%; median 1. HD IL-2 18 × 106 MU/m2/day (6 × 105 MU/m2/ Responses:
II, open label trial age 55; predominantly clear cell; dose q8) during two 5-day courses starting on CR (4/49): 8%;
prior nephrectomy unknown day 15 and 29 of each 84 day cycle PR (10/49): 20%;
2. + Bevacizumab 10 mg/kg every 2 weeks SD (21/49): 42%
PFS (months):
Median—9.0
2 year—15%
Author (year Design Participants Interventions Results
published)
MRC RE04/ Multicenter, N = 1,006; PS (WHO PS 0) 54%; 1. SC IFN-a 10 × 106 IU/m2 3 days/week Best overall response (BORR) at 3 years:
EORTC GU 30012 randomized, phase MSKCC risk group (58–60% 2. Combination therapy with IFN-a, IL-2 and 16% (1) vs. 23% (2)
[56] (2010) III medium, 17–19% high); prior 5-FU Survival:
nephrectomy 89–90%
At 1 year: 67% (IFN-a) vs. 67% (combination)
At 3 years: PFS—5.5 months (IFN-a) vs.
5.3 months (combination)
OS—30% (IFN-a) vs. 26% (combination)
Niwakawa [76] Phase I, open-label, N = 18; PS (KPS > 70%); 1. Sorafenib 200 mg BID + IM IFN-a 6 × 106 IU/ OR (CR + PR): 28%
(2011) nonrandomized predominantly clear cell histo; m2 thrice weekly SD (11/18): 61%
dose-escalation prior nephrectomy unknown 2. Sorafenib 400 mg BID + IM IFN-a 6 × 106 IU/
study m2 thrice weekly
3. Sorafenib 400 mg BID + IM IFN-a 9 × 106 IU/
m2 thrice weekly
TORAVA [77] Multi-center, phase N = 171; PS (ECOG 0–1) 88%; 1. Temsirolimus 25 mg weekly + Bevacizumab Responses:
(2011) II, open label trial median age 62; MSKCC risk 10 mg/kg q2weeks BORR: 27% (A) vs. 29% (B) vs. 43% (C)
group—intermediate (44–53%) 2. Sunitinib 50 mg/day for 4 weeks followed by CR: 2% (A) vs. 0% (B) vs. 0% (C)
and poor (10–17%); predomi- 2 weeks off PR: 25% (A) vs. 29% (B) vs. 43% (C)
nantly clear cell; prior nephrec- 3. IFN-a 9 × 106 IU/m2 thrice SD: 52% (A) vs. 48% (B) vs. 33% (C)
tomy 83–98% weekly + Bevacizumab 10 mg/kg q2weeks Duration (months): 7.7 (A) vs. 13.3 (B) vs. 13.9 (C)
Survival:
12 months: 77% (A) vs. 74% (B) vs. 90% (C)
Long term data—pending
RECORD-2 [78] Multicenter, phase First-line, metastatic RCC 1. Everolimus 10 mg PO daily + Bevacizumab Awaiting data
II RCT Trial in progress: 10 mg/kg q2weeks
N = 360; PS—KPS ³ 70%; 2. IFN-a 9 × 106 IU/m2 thrice
predominantly clear cell; partial weekly + Bevacizumab 10 mg/kg q2weeks
or complete nephrectomy allowed
INTORACT [79] Multicenter, phase 1st line, metastatic RCC 1. Temsirolimus 25 mg weekly + Bevacizumab Awaiting data
III, open label trial 10 mg/kg q2weeks
2. IFN-a 9 × 106 IU/m2 thrice
weekly + Bevacizumab 10 mg/kg q2weeks
290 D. Davar et al.

only low baseline serum VEGFR-2 was associated molecules for presentation to APC [83]. HSP–
with a significantly improved median PFS in peptide complexes enriched from cellular lysates
patients treated with sorafenib plus IFN [71]. are able to prime CD8+ T cells in a number of
protein, viral and tumor models, and can confer
tumor-specific protective immunity [84]. Jonasch
IFN-a Therapy: Current Indications et al. performed a study of autologous HSP gp96–
and Future Directions peptide complexes in patients with metastatic
RCC [85]. Eligible subjects had metastatic RCC
IFN-a has an overall response rate as high as with primary tumor in place. Cytoreductive neph-
15–20% in metastatic RCC. Responses tend to be rectomy was performed, and HSP gp96–peptide
partial and typically are not sustained. Treatment- complexes were enriched from homogenates pre-
related toxicity, especially a “flu-like” illness, is pared from the fresh-frozen tumor tissue. The
common and frequently requires dose reductions resulting autologous HSP gp96–protein com-
though symptoms appear to lessen with succes- plexes (vitespen, HSPPC-96, Oncophage) were
sive cycles of therapy. IFN-a therapy tends to be injected into subjects starting approximately
safe with no reported treatment-related deaths 4 weeks after surgery (six subcutaneous injections
(compared to the near 4% mortality associated over 6 weeks). There were 60 evaluable patients,
with IL-2 administration). Formal quality-of-life of whom two had a partial tumor response and
(QOL) assessments reported by Negrier et al. two achieved a complete response. The latter two
showed that IFN-a therapy was associated with were reported to have had some degree of tumor
QOL impacts in up to 16% of patients at 3 months shrinkage prior to starting the vaccine series.
compared to 11% in medroxyprogesterone con- Patients who had stable disease were able to con-
trols [25]. tinue the vaccine in combination with low-dose
However, IFN-a monotherapy has been subcutaneous IL-2. A randomized phase III study
upstaged by the advent of targeted therapies. In was performed in patients with localized RCC
this new paradigm, there still appears to be a role to study whether vitespen would prolong the
for the use of IFN-a as part of a combination recurrence-free survival after nephrectomy.
with various targeted therapies—most success- Subjects were randomized to receive vitespen
fully IFN-a/bevacizumab. As the mechanisms of injected intradermally weekly for 4 weeks then
IFN-a activity in RCC are better understood, every 2 weeks until vaccine depletion or observa-
rationale for additional combinations of IFN-a tion. There were 818 patients enrolled and 728
with other therapies may emerge. who were evaluable in total. Fourteen subjects
(2%) had AJCC stage I disease (6th edition), 253
subjects (35%) had stage II disease, 420 (58%)
Vaccines had stage III disease, and 41 (6%) had stage IV
disease at nephrectomy. After a median follow-up
Vaccines: Heat Shock Protein Vaccines of 1.9 years, there was no difference in recurrence-
free or OS between the two study groups. An
A novel tumor vaccination approach using heat exploratory analysis found a trend toward
shock proteins (HSPs) has been developed based improved recurrence-free survival in subjects with
upon the preclinical work of Dr. P. Srivastava [82]. AJCC stage I or stage II disease.
One function of HSPs is to chaperone antigenic
peptides for loading onto MHC molecules in the
endoplasmic reticulum for presentation to T lym- Vaccines: Oncofetal Antigen
phocytes. HSPs participate in the process of 5T4 Vaccines
immunological cross-priming, in which exoge-
nous protein antigens are internalized and pro- The oncofetal antigen, 5T4, has been studied as a
cessed by APC, then loaded onto MHC class I tumor antigen in vaccines in RCC and other
16 Immunotherapy for Renal Cell Carcinoma 291

cancers. 5T4 is normally expressed on trophoblasts 5 T4 antigen were detected post-treatment in 56%
in the placenta, and at low levels in the postnatal of MVA-5T4-treated patients, and antibody.
esophagus. High levels of expression are seen in
RCC and other carcinomas [86, 87]. MVA-5T4 is
an attenuated vaccinia virus that has been engi- Carbonic-Anhydrase IX Monoclnal
neered to express the 5T4 antigen for the purpose Antibody Treatment
of eliciting a cellular immune response. Phase II
studies have been performed evaluating MVA-5T4 G250 is a murine monoclonal antibody that rec-
as a tumor vaccine in RCC. Studies have exam- ognizes CAIX, a cell surface antigen on RCC
ined the agent in combination with IL-2 and with cells [91]. Normal renal epithelium and most
interferon alpha. One study randomized patients normal tissues do not express the G250 antigen,
to receive MVA-5T4 with or without subcutane- with the exception of gastric mucosa and bile
ous IFN-a. Fifteen subjects received the duct epithelial cells [92]. cG250 is a human-
MVA-5T4 vaccine alone and 28 subjects received murine chimeric mAb that was engineered from
MVA-5T4 plus subcutaneous IFN-alpha [88]. G250 for clinical investigation. A phase II study
Both antibody and cellular immune responses of cG250 was conducted in patients with meta-
(by interferon ELISPOT) were detected against static RCC [93]. Weekly intravenous doses of
the 5T4 antigen following vaccination. Twenty- cG250 were administered for up to 12 weeks.
one out of 25 subjects mounted a humoral Extended treatment was offered to patients with
immune response, and 14 out of 23 analyzed sub- stable disease or tumor responses. Thirty-six
jects mounted cellular immune responses against patients were enrolled, and all generally toler-
5T4 based on ELISPOT. A partial response was ated treatment well. Ten subjects showed stable
documented in one subject. The median PFS was disease after 12 weeks of study treatment, and
3.8 months and 14 patients had stable disease for eight of these still had stable disease after
some period of time. 24 weeks. One complete tumor response and one
Another phase II study treated 25 subjects minor response were observed. A study of radio-
with MVA-5T4 plus subcutaneous IL-2 [89]. immunotherapy using 131I-congugated cG250
Most had received prior treatments including was performed to assess dosimetry and pharma-
sunitinib, sorafenib, bevacizumab, everolimus, cokinetics [94]. Surprisingly, eight out of 27
IL-2, and IFN. There was one patient who had a subjects developed human antichimeric antibod-
partial tumor response and two patients who had ies. A study of cG250 monoclonal antibody con-
complete tumor responses. Six additional patients jugated to Yttryum-90 is ongoing. (Clinincal
had stable disease for >6 months. Median PFS trials.gov identifier NCT00199875).
was 3.37 months and median OS was 12.87+
months. A subsequent phase III study random-
ized patients to MVA-5T4 vs. placebo in combi- Non-myeloablative
nation with a “standard of care” regimen. The Allo-Transplantation
standard regimen could be subcutaneous IL-2,
subcutaneous interferon-alpha or sunitinib, at the Conventional allogeneic stem cell transplan-
discretion of the investigator. Seven hundred and tation for hematopoietic malignancies involves a
thirty-two were evaluable for the intent-to-treat myeloablative conditioning regimen of high-dose
analysis: 32.8% were given IL-2 as the standard cytotoxic chemotherapy and/or total body irradiation.
treatment, 22.6 interferon-alpha, and 51.2% sunitinib Myeloablative conditioning is followed by recon-
[90]. OS was equivalent between the two arms of the stitution with allogeneic hematopoietic stem cells
study: 20.1 months for the vaccine-treated patients derived from the bone marrow or peripheral
and 19.2 months for the placebo group. There blood. In addition to the direct cytotoxic effect of
was also no difference in PFS at 26 weeks or in the conditioning regimen on the malignancy, a
response rates. Antibody responses against the graft-vs. leukemia (GVL) effect has been well
292 D. Davar et al.

documented in hematologic malignancies such as replicated in the subsequent studies. The aggre-
leukemias, lymphomas, and multiple myeloma. gate tumor response rate was only 22% (vs. 53%
The increased rates of relapse in patients whose in the NIH series). There were fewer complete
donor stem cells undergo ex vivo T cell depletion responses and less durability of response.
[to reduce graft vs. host disease (GVH)] supports
this hypothesis, as does the decreased rate of
recurrence in patients who develop GVH [95]. In Therapeutic Manipulation
addition, the rate of relapse was higher in patients of Co-stimulatory Signals
who received stem cells from an identical twin
(syngeneic) than those who received a nonidenti- Stimulation of the T cell receptor (TCR) by major
cal graft. The clinical impact of GVL and results histocompatibility protein (MHC)-peptide com-
of non-myeloablative transplantation in plexes expressed on antigen-presenting cells
hematopoietic malignancies led to the hypothesis (APCs) triggers antigen-specific T lymphocyte
that non-myeloablative allogeneic transplanta- activation. However, a “second signal” delivered
tion might generate graft. vs. tumor responses in through the interaction between additional
metastatic RCC. Richard Childs and colleagues proteins on T lymphocytes and APC is essential
from the National Institutes of Health reported a to the outcome of these antigen-specific interac-
series of patients with metastatic RCC who tions. The second signal determines whether
underwent non-myeloablative peripheral stem TCR ligation by peptide antigen leads to prolif-
cell transplantation [96]. Seventeen of the 19 eration, cytokine secretion, differentiation,
patients had received prior cytokine therapy (IL-2 apoptosis, or tolerance/anergy. Co-stimulatory
or interferon). Seventeen of the 19 patients interactions are critical for mounting effective
received HLA-matched sibling transplants, and immune responses and for the maintenance of
two received sibling transplants with a single peripheral tolerance.
HLA locus mismatch. The conditioning regimen The primary positive co-stimulatory signal for
consisted of cyclophosphamide (60 mg/kg IV on naïve and resting T cells is ligation of CD28, a
day 5 and day 6) plus fludarabine 25 mg/m2 I.V. type I transmembrane protein expressed by T
on day 5 through 1 prior to transplantation. Anti- lymphocytes. CD28 is activated by binding to the
thymocyte globulin was also given to the two counter-receptors B7-1(CD80) and B7-2 (CD86),
patients who had an HLA mismatch. All patients which are type I transmembrane proteins
received cyclosporine prophylaxis against GVHD expressed by professional APC. After activation,
starting on day 4. Three patients out of 19 had a T cells upregulate CTLA-4, which binds to B7
complete radiographic response and seven had a with higher affinity than CD28, thereby inhibit-
partial response by W.H.O. criteria. Interestingly, ing TCR signaling, interleukin (IL)-2 transcrip-
six of the patients had initial tumor growth after tion, and T-cell proliferation. In addition,
transplantation, followed by tumor response after CTLA-4:B7 interaction results in the induction
cyclosporine was withdrawn. Engraftment of of indolamine 2, 3 dioxygenase in a subset of
myeloid and T cell populations was successful in dendritic cells, which switch to potent and domi-
all patients. Tumor responses correlated with the nant T cell suppressive properties [98].
development of GVH.
After the publication of this promising pilot
study, there were several studies of non-myeloab- Co-stimulation: Cytotoxic T
lative transplantation in RCC conducted in lymphocyte Antigen-4
Europe and the USA. These data are summarized
in a recent review by Tykodi et al. [97]. Their Cytotoxic T lymphocyte antigen-4 (CTLA-4)
review covered 389 patients reported in 17 sepa- (CD152) is a transmembrane protein that functions
rate case series. Overall, the clinical efficacy seen as a key negative regulator in CD4+ and CD8+ T
in the original series by Childs et al. was not cells [99, 100] as well as CD4+CD25+Foxp3+
16 Immunotherapy for Renal Cell Carcinoma 293

naturally occurring regulatory T cells (Tregs) of the colitis was due to neutrophil and lympho-
[101]. The role of CTLA-4 in the maintenance of cyte infiltration and could be managed with high-
peripheral tolerance as a negative regulator of dose corticosteroids or TNF alpha inhibitor,
adaptive immune response is illustrated by the infliximab, in steroid-refractory cases without
phenotype of CTLA-4 knockout mice, which affecting tumor response.
have massive polyclonal expansion of T cells, Ipilimumab was approved by the FDA for
and die at early age with multiorgan lymphocytic treatment of metastatic melanoma based upon the
infiltration resulting in severe myocarditis and results of a phase III study in which ipilimumab
pancreatitis in the absence of CTLA-4 [102, 103]. was shown to improve median OS compared to a
It was hypothesized that blockade of the peptide antigen derived from the melanosomal
inhibitory signal delivered by CTLA-4 might protein, glycoprotein 100 (gp100) [110]. This
allow development of antitumor T-cell immune peptide has been shown to be presented by the
responses in patients with cancer. Antibody HLA-A*0201 MHC, and so protocol eligibility
blockade of CTLA-4, alone [104, 105] or in was restricted to HLA-A*0201-positive individu-
combination with a GM-CSF-containing tumor als. Subjects were randomized in a 3:1:1 ratio to
vaccine was able to eradicate established tumors ipilimumab 3 mg/kg plus gp100 peptide vaccine,
in murine models including B16 melanoma [106] ipilimumab plus gp100 placebo or gp100 plus
and mammary tumors [107]. Two monoclonal ipilimumab placebo. Each subject received
antibodies against CTLA-4 have entered clinical assigned study treatment every 3 weeks × 4 doses.
development. Ipilimumab (MDX-010) and The median survival for the ipilimumab alone
tremelimumab (CP-675206) are fully human and ipilimumab plus gp100 groups were 10.1 and
monoclonal antibodies that recognize CTLA-4 10.0 months, respectively. A statistically
and block its interaction with B7 proteins. significant difference between each of these ipili-
Tremelimumab (CP-675,206) was first studied mumab-containing groups and the gp100 group
in a phase I trial in 2002–2003, where 39 patients (median survival 6.4 months) was demonstrated.
were accrued, of which 34 patients had mela- PFS was also superior in the ipilimumab-contain-
noma, four patients had stage IV RCC, and one ing groups. The overall response rate in the ipili-
patient had stage IV colon cancer [108]. Although mumab-alone group was 10.9 months.
the trial was not designed to detect tumor Interestingly, nine of 15 objective responses to
response, 13 patients with melanoma had clinical ipilimumab were durable beyond 2 years.
benefit from tremelimumab, and durable objec- The activity of ipilimumab in metastatic clear
tive tumor responses were observed 25+ to 36+ cell RCC was studied in a phase II trial reported
months (two patients with complete response by Yang et al. from the National Cancer Institute
and two patients with partial response). Not [111]. Ipilimumab was administered every
surprisingly, some patients developed autoim- 3 weeks intravenously. One cohort of 21 patients
mune thyroiditis, colitis, vitiligo, and hypophysitis, received a loading dose of 3 mg/kg followed by
indicative of breaking peripheral tolerance to 1.5 mg/kg per dose. A second cohort of 40
“self” tissues. patients received 3 mg/kg at each dosing. All of
Association between anti-CTLA-4 antibody- the subjects in the lower dose cohort and 26 of
induced tumor response and autoimmune colitis the patients in the higher dose cohort had received
was studied using ipilimumab in 189 patients prior high dose IL-2. Eight subjects had received
with metastatic melanoma or RCC [109]. The prior chemotherapy. Autoimmune toxicities were
overall response rate was 14%, and the ORR was observed including enteritis and colonic perfora-
36% for melanoma patients with enterocolitis tion, rash, aseptic meningitis, hypophysitis, and
and 35% RCC patients with enterocolitis, com- hypopituitarism. The rate of grade III toxicity
pared with 11% and 2% in patients without was 14% in the lower dose cohort and 35% in the
enterocolitis, respectively (p = 0.0065 and 0.0016, higher dose cohort. Five of 40 patients (12.5%) in
respectively). The authors showed the pathology the cohort who received 3 mg/kg q3week dosing
294 D. Davar et al.

responded—the durations of these responses reactive T cells [116]. Like CTLA-4, PD-1 also
were 7, 8, 12, 17, and 21 months [111]. All of functions as a negative regulator of immune
these responding subjects developed autoimmune responses, as supported by the development of
toxicity, whereas none of the subjects who did autoimmune glomerulonephritis, arthritis, and
not develop autoimmunity had an objective tumor cardiomyopathy in PD-1 knockout mice [117,
response. The association of autoimmune toxic- 118]. PD-L1 (B7-H1) is expressed abundantly on
ity from ipilimumab and tumor response was certain tumors and by cells of the tumor microen-
highly significant ( p = 0.0009). vironment [119, 120]. In RCC tumors, expression
Rini and colleagues reported the results of a of B7-H1 is prognostic for aggressive tumor
phase I dose escalation study in which tremeli- behavior and poor survival [119]. Furthermore,
mumab was combined with the multitargeted PD-1 expression on tumor infiltrating mononu-
kinase inhibitor, sunitinib in patients with meta- clear cells was greater in patients with high-risk,
static RCC [112]. Tremelimumab was adminis- larger, and/or symptomatic RCC tumors, higher
tered intravenously once every 12 weeks, and nuclear grade, more advanced tumor-node-metas-
sunitinib as administered daily at 37.5 mg or at tasis stage, coagulative necrosis, and sarcomatoid
50 mg on a 28-day on/14 day off schedule. The differentiation [121]. There was a correlation
most common dose-limiting toxicity (DLT) was between expression of B7H-1 on RCC tumor cells
acute renal failure, which was seen in four and expression of PD-1 on tumor infiltrating mono-
patients. One of these underwent renal biopsy, nuclear cells among the RCC specimens studied.
which revealed interstitial nephritis with eosino- Analogous to CTLA-4 blockade by ipilimumab
philic infiltration, consistent with hypersensitiv- and temelimumab, monoclonal antibodies that
ity reaction. One subject developed a DLT of block the interaction between PD-1 and B7-H1
colitis, and another experienced a sudden death at are being developed to test the clinical impact
home. The maximum tolerated dose (MTD) was of abrogating the negative signal delivered to
determined to be 10 mg/kg of tremelimumab T cells by PD ligand-expressing cancer cells. A
every 12 weeks in combination with sunitinib phase I study of a fully humanized, anti-PD-1
37.5 mg daily. However, there was unacceptable IgG4 monoclonal antibody, MDX-1106 (BMS-
toxicity in patients treated in the expansion cohort 936558/ONO-4538), was conducted in patients
at the MTD, and the authors did not recommend with refractory solid tumors [122]. Subjects
pursuing these doses of the combination in phase received MDX-1106 intravenously and had
II studies. restaging scans at 8 and 12 weeks. Repeat dos-
ing could be administered at 12 and 16 weeks to
patients who did not have intolerable toxicity,
Co-stimulation: Programmed Death-1 disease progression or development of antibod-
(PD-1) and PD-1 Ligand (B7-H1) ies against MDX-1106. Doses of 0.3, 1, 3, and
10 mg/kg were evaluated. There were no dose-
The programmed death-1 (PD-1, CD279) protein limiting toxicities as defined by the study dur-
is a member of the CD28 family that is expressed ing the 28-day evaluation phase following the
on activated, but not resting T cells, B cells, and first dose of MDX-1106. There was one case of
myeloid cells [113, 114]. PD-1 binds to the B7 grade 3 inflammatory colitis in a patient who
homolog, programmed cell death 1 ligand 1 (PD- received five doses of study treatment, as well
L1), also known as B7 homolog (B7-H1) and as as a case of grade 2 hypothyroidism and two
CD274. A second B7 homolog that binds PD-1 cases of polyarticular arthropathies. MDX-1106
has been identified and is known as PD-L2 [115] was deemed tolerable at the doses evaluated.
and as B7-DC. Interaction of PD-1 with PD-L1 One subject with colorectal cancer achieved a
inhibits T cell proliferation, survival, and func- complete response and one subject with melanoma
tion, whereas blockade of PD-1 increases achieved partial response. A patient who had
autoantibody production and generates auto- multiorgan metastatic RCC, who had failed
16 Immunotherapy for Renal Cell Carcinoma 295

sunitinib, sorafenib and an experimental histone solid tumors to receive BMS-936559 (dose range
deacetylase inhibitor previously, had a partial 0.3-10 mg/kg) in a standard 3+3 dose escalation
response that lasted 16+ months [122]. design. As with the BMS-936558 trial, responses
A second phase I study of this monoclonal were noted in multiple tumor types including
antibody included 18 patients with RCC—16 of ovarian cancer and NSCLC with an overall
whom were treated at a dose of 10 mg/kg. response rate of 12.6% in the 135 patients in
The toxicity profile of MDX-1106 (BMS936558) whom response was evaluable with a RCC-
was similar to that observed in the previous study. specific response rate of 12%.
Common adverse events included fatigue, diar- These studies suggest that checkpoint inhibi-
rhea, rash, endocrinopathies. There was one case tion is a viable option in advanced malignancies
of drug-related pneumonitis. Five of these patients with relatively minimal toxicity (overall inci-
(31.3%) achieved confirmed partial responses, dence of Grade 3/4 toxicity was 14% and 9% in
and another three (18.8%) achieved stable dis- the anti-PD-1 and anti-PD-L1 trials respectively)
ease lasting more than 6 months [123]. and durable responses even in traditionally non-
Recently, the final phase I trial results of the immunogenic cancers malignancies such as ovar-
anti-PD-1 (BMS-936558) and anti-PD-L1 (BMS- ian cancer and NSCLC. PD-1 blockade appears
936559) antibodies were published [123, 124]. The to be associated with greater responses than
phase I study of anti-PD-1 (BMS-936558) enrolled PD-L1 blockade suggesting that these drugs are
296 patients with a variety of advanced solid tumors not identical in their downstream effects. Further
to receive PD-L1 antibody as an infusion every 2 trials planned include phase I biomarker study
weeks of an 8-week cycle in 3 dose-escalations (1, (NCT01358721), phase II dose-finding study in
3 and 10 mg/kg) with response assessments after metastatic RCC (NCT01354431) and phase III
each cycle. Authors reported objective evidence of trials in renal cell cancer, melanoma and NSCLC.
response in a variety of tumor types including non- Emerging evidence implicates PD-L1 mediated
small cell lung cancer (NSCLC). Of the 33 patients immune-downregulation in tumors evasion of
enrolled with RCC, 9 responses were noted for an immune surveillance suggesting that combina-
objective response rate of 27% compared to 24.1% tions of checkpoint inhibitors such as PD-1/
for the trial overall. Notably responses were dura- PD-L1 antagonists and agents directly stimulat-
ble – greater than 12 months in 20 of 31 treated ing anti-tumor immunity may need to be com-
patients with greater than 1 year follow-up – and bined for effective immunotherapy [126].
consistent with prior patterns of immune-related
response previously described in patients treated
with ipilimumab [125]. Tumor PD-L1 expression Effect of the Kinase Inhibitor, Sunitinib,
was not required and expression status was only on Immune Responses
available on 61 tumor specimens from 42 patients
– 5 of whom had RCC. Interestingly, when Since the introduction of sunitinib, the effect of this
responses were dichotomized according to PD-L1 multitargeted kinase inhibitor on immune function
expression, objective responses were noted in 9/25 has been studied in efforts to better understand its
PD-L1 positive patients but none in the 17 PD-L1 mechanism and possible integration into immuno-
negative patients. Of the 5 patients with RCC on therapeutic options. It has been recognized that in
whom expression status was available (4 positive, 1 RCC patients, there is a shift from a type-1-medi-
negative), responses were noted in 2 (both PD-L1 ated CD4+ T cell response producing IFN-gamma,
positive). which is critical for antitumor effect, to a type-2
The study assessing PD-L1 blocking antibody cytokine response (IL-4, IL-5, IL-10) that mediates
(BMS-936559) which inhibits binding of PD-L1 humoral immunity [127, 128]. The type-2 bias of
to both PD-1 and CD80 was concurrently pub- CD4+ T cells from patients with mRCC can be
lished. This phase I trial enrolled 207 patients (17 reversed with sunitinib, as it promotes type-1
with renal cell cancer) with a variety of advanced cytokine response (IFN-gamma) and simultane-
296 D. Davar et al.

ously decrease the type-2 response (IL-4) [129]. adjuvant and metastatic settings. Of the
Furthermore, sunitinib suppresses the activity of nonspecific cytokines, IL-2 and IFN-a have
CD3+CD4+CD25hiFoxp3+ Tregs without inhibiting been the most extensively tested with only mod-
the expansion of CD3+CD4+CD25− T effector cells. est results in unselected patients populations.
It is widely recognized that there is an increased Once a mainstay of treatment, IFN-a, has been
frequency of CD4+CD25hi Tregs in tumor sites or supplanted by targeted agents which have dem-
the peripheral blood of patients with advanced, and onstrated PFS benefits in randomized clinical
depletion of Tregs in murine models with anti- trials. High-dose IL-2 produces durable com-
CD25 antibody enhances antitumor activity [130]. plete responses in a minority of patients with
The reduction in Tregs in mRCC patients metastatic disease—however given the associ-
treated with sunitinib is also associated with the ated morbidity, use should be restricted to highly
reduction in CD15+CD14− and CD33+HLA-DR− selected patients in appropriately experienced
myeloid-derived suppressor cells (MDSCs) [131]. centers. Putative biomarkers of IL-2 efficacy
MDSC represent a heterogeneous population of have been suggested but lack validation in pro-
cells that impair T effector function [132] and spective studies.
stimulate Treg formation [133]. MDSC have been Targeted therapies have redefined options for
detected in peripheral blood of patients with treatment of advanced RCC. The burgeoning of
tumors [134]. Elevated levels of MDSC were mea- molecularly targeted agents in recent years does
sured in mRCC patients compared to age-matched not negate a role for immunotherapy in RCC—
normal donors, which was decreased to normal rather it behooves us to consider identify predic-
levels with sunitinib. Furthermore, sunitinib- tive biomarkers for response to immunotherapy
mediated reduction in MDSC was correlated with and pursue rational combinations of immuno-
reversal of type-1 T cell suppression, as well as therapeutic and targeted agents based on tumor
reversal of CD3+CD4+CD25hiFoxp3+ Treg eleva- and patient characteristics.
tion [131]. Neither the reversal of type-1 T cell
suppression nor the reversal of Treg and MDSC
elevation in mRCC patients correlated with References
tumor response or PFS in sunitinib-treated
patients. To evaluate potential synergistic immune- 1. Rohdenburg GL. Fluctuations in the growth energy of
malignant tumours in man, with special reference to
stimulatory antitumor effects, a phase I trial of
spontaneous regression. J Cancer Res. 1918;3:193.
tremelimumab plus sunitinib was conducted in 2. Vogelzang NJ, Priest ER, Borden L. Spontaneous
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 Targeted Therapy: Vascular
Endothelial Growth Factor 17
Linda Cerbone and Cora N. Sternberg

In the past few years better understanding of the

main pathogenic mechanisms of development Bevacizumab
and progression of clear cell renal cell carcinoma
(RCC) has led to novel therapeutic approaches Bevacizumab (Avastin®) is a recombinant human
with improvement in the prognosis of patients monoclonal antibody that binds and neutralizes
with metastatic disease (mRCC) (Table 17.1). all active isoforms of VEGF. After promising
Inactivation of the Van Hippel–Lindau (VHL) data in phase II trials, two randomized (1:1)
gene and consequent vascular endothelial growth phase III trials demonstrated that the addition of
factor (VEGF) overexpression has been identified bevacizumab 10 mg/kg i.v. every 2 weeks to
as the first step of tumor growth in the majority of IFN-a (9 MIU × 3 s.c., weekly) leads to a statisi-
patients with RCC. The importance of VEGF cally significant advantage in progression-free
protein and its ligands vascular endothelial survival (PFS) in patients with previously
growth factor receptors (VEGFRs 1,2,3) has been untreated mRCC.
thoroughly investigated and due to its crucial role In both the European study (AVOREN, 649
in angiogenesis they have been considered the patients [2] and the U.S. study (CALGB 90206,
most relevant therapeutic targets to consider in 732 patients) [3], the majority of patients were of
patients with RCC [1]. There are numerous ways good or intermediate risk according to MSKCC
in which to inhibit VEGF, however, at present criteria [4] and less than 10% belonged to the
drug development has primarily focused upon the poor prognosis category. In both studies, the
anti-VEGF antibody (Bevacizumab) and VEGF addition of bevacizumab resulted in higher
receptor tyrosine kinase inhibitors (TKIs): sunitinib, objective response rates (RR) compared with
pazopanib, sorafenib, axitinib, and tivozanib IFN-a alone (25.5% vs. 13.1% in the AVOREN
(Fig. 17.1; Table 17.2). trial; 31% vs. 13% in the CALGB trial). PFS in
the AVOREN trial was 10.2 months vs. 5.4
months (HR = 0.6; p = 0.0001) and 8.5 months vs.
5.2 months in the CALGB trial (HR = 0.71;
p < 0.0001). Neither of the studies demonstrated
a statistically significant difference in overall
survival (OS) between the two treatment arms.
Survival in the CALGB trial was 18.3 months
L. Cerbone • C.N. Sternberg () vs. 17.4 months (p = 0.097) and 23.3 months vs.
Department of Medical Oncology, San Camillo-Forlanini
21.3 months (p = 0.33) in the AVOREN study.
Hospital, Circonvallazione Gianicolense 87,
Rome 00152, Italy However, it should be noted that the majority of
e-mail: [email protected]; [email protected] patients in both studies received further treatments

S.C. Campbell and B.I. Rini (eds.), Renal Cell Carcinoma: Clinical Management, Current Clinical Urology, 303
DOI 10.1007/978-1-62703-062-5_17, © Springer Science+Business Media New York 2013
304 L. Cerbone and C.N. Sternberg

Table 17.1 mRCC treatment algorithm

Regimen Setting Therapy Options
Treatment-naïve patient MSKCC risk: good or intermediate Sunitinib High-dose IL-2
Bevacizumab + IFNa Sorafenib
Pazopanib Clinical trials
Observation
MSKCC risk: poor Temsirolimus Sunitinib
Clinical trials
Treatment-refractory Cytokine refractory Sorafenib (axitinib) Bevacizumab
patient (³second line) Pazopanib Sunitinib
Pazopanib
TKI refractory Everolimus (axitinib) Clinical trials

Fig. 17.1 Anti-VEGF mechanism of action (reprinted with permission from B Rini. Vascular endothelial growth
factor-targeted therapy in metastatic renal cell carcinoma. Cancer (2009);2306–2312. John Wiley and Sons)

at the time of progression which impacted on Sunitinib

survival. Based on these two phase III trials, the
combination of Bevacizumab and IFN-a is Sunitinib (Sutent®) is an oral small molecule TKI
considered a first-line therapeutic option for that inhibits tyrosine kinases VEGFR-1,2,3,
patients with mRCC with favorable and interme- platelet-derived growth factor receptor (PGFR-
diate prognosis. a,b), c-kit, and FTL-3. It is considered a standard
17 Targeted Therapy: Vascular Endothelial Growth Factor 305

Table 17.2 TKIs in mRCC: summary of survival and response

Treatment No of patients Objective response (%) Median PFS (months) Median OS (months)
Bevacizumab + INFa vs. 649 25.5 10.2 vs. 5.4 23.3 vs. 21.3
INFa 732 31 TTP: (p = 0.33)
(AVOREN trial; 8.5 vs. 5.2 18.3 vs. 17.4
Escudier 2007) (p = 0.097)
(CALGB 90206 trial;
Rini 2010)
Sunitinib vs. IFNa 750 31 vs. 6 (p < 0.001) 11 vs. 5 (p < 0.000001) 26.4 vs. 21.8
(Motzer 2007) (p = 0.051)
Pazopanib vs. placebo 435 30 vs. 3 9.2 vs. 4.2 22.9 vs. 20.5
(Sternberg 2010) (p < 0.0001) (p = 0.224)
Sorafenib vs. placebo 903 10 5.5 vs. 2.8 19.3 vs. 15.9
(Escudier 2007) (p < 0.001) (p = 0.02)
Axitinib vs. Sorafenib 732 19.4 vs. 9.4 (p = 0.0001) 6.7 vs. 4.7
(Rini 2011) (p < 0.0001)

of care for first-line treatment in patients with compared to placebo was 9.2 months vs. 4.2
mRCC. The use of this multikinase TKI is sup- months, (p<0.0001). For patients who had no
ported by the results of two phase II trials in prior therapy, PFS was 11.1 months vs. 2.8 months
cytokine pretreated patients [5] and a randomized (p < 0.001) and for those who had prior cytokines
phase III trial whose primary objective was to PFS was 7.4 months vs. 4.2 months (p < 0.001).
determine PFS in patients with previously Overall objective responses were reported in 30%
untreated mRCC. Seven hundred and fifty patients of patients and the median duration of response
were randomized (1:1) to receive sunitinib (50 mg was 58.7 weeks. No difference in OS was observed
orally daily, 4 weeks on and 2 weeks off) vs. between the two arms (22.9 months vs. 20.5
IFN-a (9 MIU × 3 s.c., weekly). Sunitinib led to months; p = 0.224) [8]. This was most likely due
an advantage in terms of objective RR (31% vs. to the fact that 54% of patients in the placebo arm
6%, p < 0.001) and PFS (11 months vs. 5 months, crossed over to receive pazopanib and the fact that
p < 0.000001). The median OS was 26.4 months patients crossed over very early and remained on
for patients treated with sunitinib vs. 21.8 months treatment for long periods of time.
in the IFN-a arm (p = 0.051). In this study, Enrollment in the COMPARZ study
patients in the IFN arm also had access to subse- (NCT00720941), a head-to-head trial comparing
quent treatment with sunitinib which may have sunitinib and pazopanib in the first-line setting,
impacted upon the OS results [6]. was completed in August 2008 with 876 patients
enrolled. The primary endpoint of the study is
PFS and non-inferiority. Secondary endpoints
Pazopanib include: OS, objective RR, duration of response,
safety, and quality of life.
Pazopanib (Votrient®) is an oral TKI of VEGFR The PISCES trial (NCT01064310) has included
1,2,3, PDGFR-a,b, and c-kit. In a phase III study, approximately 160 patients in a randomized
435 patients with mRCC who had no prior ther- double-blind, crossover study of pazopanib vs.
apy or who had prior cytokine therapy were ran- sunitinib in patients with locally advanced or
domized in a 2:1 ratio to receive pazopanib mRCC who have received no prior systemic
(800 mg orally daily) or placebo [7]. Pazopanib therapy. The trial’s primary endpoint is patient
resulted in a 54% reduction in the risk of progres- preference (which will be assessed primarily by
sion or death (improvement in PFS), the primary questionnaires) and secondary endpoints will
endpoint of the study. The median PFS of pazopanib include quality of life, safety, pharmacokinetics,
306 L. Cerbone and C.N. Sternberg

and biomarkers. These two trials will help to NCT00678392) randomized (1:1) 723 patients to
inform the relative risks and benefits of each evaluate the impact of axitinib (5 mg BID orally
of these two common front-line agents in meta- daily) vs. sorafenib as second-line treatment after
static RCC. any approved first-line therapy for mRCC. In
both arms 94% of pts were of good-intermediate
risk according to MSKCC criteria. This trial met
Sorafenib its primary endpoint of improvement of PFS (6.7
months vs. 4.7 months, p < 0.0001); 19.4% of
Sorafenib (Nexavar®) is an oral small molecule patients in the axitinib arm had a partial response
that inhibits VEGFR 2,3, PDGFR-b, raf kinase vs. 9.4% in the sorafenib arm. Axitinib showed a
and FTL-3. A phase III trial, the TARGET trial, similar safety profile compared to sorafenib with
randomized 903 mRCC, patients who had the exception of a greater incidence of hyperten-
received prior therapy, primarily cytokines, and sion (40% vs. 29%) and hypothyroidism (19%
who had a favorable or intermediate prognosis to vs. 8%) and lower incidence of hand–foot syn-
receive Sorafenib (400 mg BID orally daily) vs. drome (27% vs. 51%) [12].
placebo [9]. The primary objective of the trial There appears to be an association of diastolic
was overall survival, but patients who experi- blood pressure (dBP) > 90 mmHg with OS in
enced progression on the placebo arm were patients treated with axitinib [13]. A prospective
allowed to cross over to sorafenib, most likely randomized phase II trial (NCT00835978) of
contributing to the lack of an overall survival dif- axitinib dose escalation based upon achieving
ference (19.3 vs. 15.9 (p = 0.02)). In the sorafenib hypertension has completed accrual. Two-
arm a benefit in PFS (5.5 months vs. 2.8 months, hundred treatment-naïve mRCC patients received
p < 0.001) was observed. Objective responses and an initial 4-week cycle of axitinib (5 mg BID).
stable disease were observed in 10% and 74% of Patients who do not experience dBP ³ 90 mmHg
cases. Sorafenib was the first TKI to be approved will be randomized 1:1 to receive axitinib + axi-
in many countries and reference treatment for tinib dose escalation or axitinib + placebo dose
second-line and later therapy. Its efficacy in the titration. The primary endpoint is overall RR;
first-line setting has not been established. In a secondary endpoints are PFS, OS, response dura-
phase II trial, 189 untreated patients were ran- tion, safety, pharmacokinetics, BP, and biomarker
domized to receive Sorafenib (400 mg BID) or correlations [14].
IFN (9 million units TIW). Dose escalation to Tivozanib (AV951) is another potent VEGFR
Sorafenib 600 mg BID or crossover to Sorafenib 1,2,3 and PDGFR inhibitor that has demonstrated
400 mg BID after disease progression were promising activity in mRCC. In a phase II ran-
allowed. Disease control rate was 79% vs. 64% domized discontinuation trial (NCT00502307) of
but the primary endpoint, PFS, was not reached 272 patients, PFS was 11.7 months and higher
(5.7 months vs. 5.6 months) [10]. (14.8 months), in patients with clear cell carci-
noma who had undergone a nephrectomy [15]. A
phase III trial, the TIVO-1 trial (NCT01030783),
Future Perspectives has randomized (1:1) 500 patients with recurrent
or mRCC, ECOG PS 0-1, treatment naïve or one
Axitinib (AG 013736) is an oral potent inhibitor prior non-VEGF targeted therapy to Tivozanib
of VEGFR 1,2,3, PDGFR-a,b and c-kit that has (1.5 mg orally daily 3 weeks on/1 week off) vs.
shown promising activity in phase 2 trials both in Sorafenib (400 mg BID continuously). Crossover
patients pretreated with cytokines (44.2% RR to tivozanib at the time of progression on sorafenib
and median time to progression of 15.7 was permitted. The primary endpoint is PFS [16].
months) and in patients refractory to sorafenib Dovitinib (TKI258) is a VEGFR 1,2,3 and
(PFS 7.4 months) [11]. A phase 3 trial (AXIS, FGFR inhibitor that has been evaluated in heav-
17 Targeted Therapy: Vascular Endothelial Growth Factor 307

ily pretreated patients (with sunitinib and/or therapies used to counteract side effects must take
sorafenib and/or mTOR inhibitor) in a phase I/II into account the risk of interaction with anti-
trial (NCT00715182). Promising results with VEGF drugs.
PFS of 6.1 months and OS of 16 months were The major problems that have been described
observed [17]. The FGFR pathway seems to be are constitutional (fatigue, anorexia, weight
involved in tumor escape from VEGF and pos- loss, and depression), cardiovascular (hyper-
sibly mTOR inhibitor therapy [18]. A phase III tension, decreased left ventricular ejection
randomized trial (NCT01223027) is comparing fraction, congestive failure), gastrointestinal
Dovitinib (500 mg orally daily 5 days on/2 days (stomatitis, nausea, diarrhea, gastrointestinal
off scheduled in 28-day cycles) vs. Sorafenib perforation), metabolic (hypothyroidism), der-
(400 mg BID) in the third-line setting following matological (hand-foot syndrome, rash, xerosis,
VEGFR and mTOR inhibition. The primary skin and hair depigmentation, yellowing of the
endpoint is PFS. Secondary endpoints include skin) renal (proteinuria, increased creatinine,
OS, RR, safety, patient-reported outcomes, and decreased renal function), and hematologic and
pharmacokinetics. laboratory (neutropenia, lymphopenia, throm-
Cediranib (AZD2171) is an oral inhibitor of bocytopenia, anemia, increased transaminases
VEGFR 1,2,3, PDGFR b (beta), c-kit and Flt-4 and lipase) [21, 22] (Table 17.3).
that has been studied in phase I–II trials. In com-
bination or alone cediranib has demonstrated
antitumor activity in mRCC in two phase I trials. Constitutional Toxicity
It has been investigated in an open-label phase II
trial (NCT00227760) in 43 untreated patients The main constitutional symptom described is
showing an 84% disease control rate (PR + SD) fatigue. Across studies, fatigue has been reported
and a median PFS of 8.7 months. In a random- with: Sunitinib 51% (high grade 7%), Sorafenib
ized, double-blind, phase II trial (NCT00423332) 37% (high grade 5%), bevacizumab plus INF-a
cediranib (45 mg daily) has been evaluated as 33% (high grade 12%) and pazopanib 19% (high
first-line therapy in 71 patients with mRCC. grade 2%). Likewise, with Axitinib patients
Patients were treated with drug or placebo (3:1) experience fatigue in 39% of cases and 11% are
for 12 weeks and then unblinded [19, 20]. The grades 3 and 4. To manage this side effect the
active treatment arm revealed a disease control first step is to understand whether there are other
rate of 81%. The median PFS was 12.1 months contributing factors such as anemia, hypothy-
vs. 2.7 months. More trials are needed to confirm roidism, or underlying depression. Recognition
these data. and treatment of these factors could decrease
fatigue during therapy with TKIs. If depression
is suspected, a psychiatric consultation is man-
Toxicities and Management datory and drugs such as selective serotonin
reuptake inhibitors (SSRIs) should be consid-
The mechanism of action of novel targeted thera- ered. Anorexia has been reported in 36% on
pies is responsible for off target side effects. Many bevacizumab plus IFN-a (3% grades 3 and 4),
of these differ from those that oncologists are 34% on sunitinib (2% grades 3 and 4), 22% on
accustomed to manage, related to chemotherapy. pazopanib (2% grades 3 and 4), 14% on sorafenib
To understand, recognize, and manage the side (<1% grades 3 and 4), and in 39% with axitinib.
effects of VEGFR TKIs is critical for the long- These data can also partially explain the percent-
term treatment of patients. Several studies have age of asthenia reported: 32% with bevacizumab
been published to update information on toxicity plus IFN-a, 20% with sunitinib and 14% with
rates, and severity and to create common guide- pazopanib. No data are readily available for
lines for their management. All concomitant sorafenib and axinitinib [23–25].
308 L. Cerbone and C.N. Sternberg

Table 17.3 Anti-VEGF therapy: toxicities

Sunitinib Sorafenib Bevacizumab + IFNa Pazopanib Axitinib
All grade % All grade % All grade % All grade % All grade %
High grade % High grade % High grade % High grade % High grade %
Fatigue 51 37 33 19 39
7 5 12 2
Anorexia 34 14 36 22 39
2 <1 3 2
Hypertension 24 17 26 40 40
8 4 3 3 15
Arterial thrombotic 2.9 2.4 3
events
Hemorrhage 30 15 33 16
10 2 3 2
Stomatitis 30 5
3
Diarrhea 44–76 6.2–36.5 7 52 43–46
4 2 9 3
Hypothyroidism 18–85 5–23 <10 19
2
Hand–foot skin 14.4 42 <10 14
reaction 4.7 8.9
Proteinuria 60 18 <10 18–36
7

Cardiovascular Toxicity dosages of drug (30 and 45 mg daily) with or

without antihypertensive prophylaxis. Hyper-
Arterial hypertension is the most common class tension was most common grade 3 adverse
side effect. Hypertension is secondary to inhibi- event, but prophylaxis increased the number of
tion of the VEGF/VEGFR pathway, leading to an patients who completed treatment at both dos-
increase in systemic vascular resistance by reduc- ages [30]. The different incidences are probably
ing microvessel density. Endothelial dysfunction related to the degree of inhibition and selectivity
reduces the production of nitric oxide and among the different agents.
increased oxidative stress, perhaps altering neu- Bevacizumab inhibits VEGF-A allowing
rohormonal factors involved in blood pressure VEGFR-2 to be activated by VEGF-C, unlike
regulation. These mechanisms are directly and other TKIs that selectively inhibit VEGFR-2. The
indirectly mediated by activation of VEGFR-2, “second generation” TKIs (axitinib and cediranib)
the main target of the anti-VEGFR therapies. have greater affinity for this receptor. Another fac-
As mentioned earlier, hypertension may be tor that may affect severity of hypertension is the
correlated with outcome [21]. Studies of suni- schedule of drug administration. A large meta-
tinib, sorafenib, bevacizumab plus IFN-a, analysis showed a significant difference between
pazopanib, axitinib, and cediranib report hyper- continuous and intermittent schedules of Sunitinib
tension in 24%, 17%, 26%, 40%, 40%, and 35% in favor of intermittent dosing. Although this data
respectively. Grade 3/4 hypertension has been requires validation, one can hypothesize that dur-
observed with axitinib (16%), sunitinib (8%), ing the rest period vascular injuries could be par-
sorafenib (4%), pazopanib (4%), and bevaci- tially resolved [31]. To improve management,
zumab plus IFN-a (3%). Cediranib was studied many variables must be considered. It is important
in a phase II trial (NCT00264004) were 126 to know whether the patient has known risk fac-
patients were randomized to receive two different tors for hypertension. Before starting therapy, in
17 Targeted Therapy: Vascular Endothelial Growth Factor 309

addition to a cardiovascular evaluation, renal sunitinib trials. Serum electrolyte levels should
function and the presence of proteinuria or micro- also be monitored [33–36].
scopic hematuria must be investigated. This may Increased risk of thrombosis and bleeding may
be an expression of silent kidney disease that be related to the important role of VEGF in main-
could predispose a patient to hypertension. taining hemostasis. Arterial thrombotic events
Effective antihypertensive therapy must be insti- such as cardiac ischemia or infarction have been
tuted prior to anti-VEGFR agents. Although no reported in 2.9% during sorafenib therapy, 2.4%
randomized studies favor one particular antihy- with bevacizumab, and 3% with pazopanib.
pertensive drug, some considerations and an Hemorrhage occurred in 30% on sunitinib, 16%
increasing literature provide suggestions. on pazopanib, 33% on bevacizumab and IFN-a,
Nondihydropyridine calcium channel blockers 15% on sorafenib, and was high grade in 10%,
such as Verapamil and Diltiazem should be 2%, 3%, and 2% respectively [2, 3, 7–9]. It is
avoided during therapy due to CYP3A4 inhibition important to investigate a history of coagulation
that can interact with metabolism of TKIs. disorders, avoid starting therapy if surgical scars
Antihypertensive drugs most often used are angio- are not completely healed, monitor patients on
tensin-converting enzyme (ACE) inhibitors, beta warfarin and if possible switch to low-molecular-
blockers, dihydropyridine calcium channel block- weight heparin therapy.
ers (dCCB), angiotensin 2 receptor antagonists
(ARA), and diuretics. Blood pressure monitoring
must be continued in all patients and in the case Gastrointestinal Toxicity
of hypertension, pharmacologic intervention is
essential before stopping or reducing drug dos- The major intestinal toxicities are diarrhea,
ages [25, 32]. stomatitis, nausea, and anorexia. Most are a con-
Cardiac toxicity is most likely related to sequence of VEGF inhibition commonly expressed
hypertensive injury rather than to inhibition of by normal intestinal mucosa. Diarrhea, often
intracellular pathways involved in cardiac repair. accompanied by abdominal pain, is observed in
Decreased left ventricular ejection fraction 20% of patients and has been reported as fre-
(LVEF) has been described in 21% of patients quently as 50% with bevacizumab, sunitinib, and
treated with sunitinib; 4% experienced grades 3 pazopanib. Sorafenib and axitinib are also associ-
and 4 toxicity. Left ventricular dysfunction and ated with diarrhea in 43–46%. Management of
congestive heart failure has been observed in less diarrhea is essential to prevent dehydration, elec-
than 1% of patients. Baseline evaluation of LVEF trolyte imbalances, and fatigue. Drugs such as
is suggested and control during treatment for loperamide are useful, as are dietary modifications.
patients with risk factors or in those developing Stomatitis has been reported with sunitinib (30%)
symptoms such as chest pain or dyspnea is funda- and sorafenib (5%). Nausea is observed with all of
mental. Drug should be stopped if symptoms the TKIs with an incidence ranging between 23%
appear or reduced if LVEF decreases to <50% or and 44%, though not with bevacizumab. All of the
decrease by >20% below baseline. In a single- common antiemetics not metabolized by CYP3A4
center study evaluating cardiotoxicity with TKI can be used. Gastrointestinal perforation has been
therapy, the introduction of a beta blocker such as reported in 2.4% of patients treated with bevaci-
carvedilol in case of cardiologic damage was zumab, in <1% treated with sorafenib and 0.9%
suggested based on the antioxidant properties with pazopanib [23–25].
of this drug and its protection against cardio-
myopathy.
ECG modifications during therapy must be Metabolic Toxicity
evaluated. QT prolongation occurred in <2% in
the pazopanib trial. Torsade de pointes was Hypothyroidism is the most common metabolic
observed in <1% and <0.1% in the pazopanib and side effect of anti-VEGFR targeted therapies.
310 L. Cerbone and C.N. Sternberg

The mechanism of thyroid dysfunction is not of all grade HFSR of 14.4 with 4.7% high grade.
clearly understood. For sorafenib, the all-grade incidence is 42% and
Hypothyroidism has also been described with high grade 8.9%. In phase I, cediranib produced
Bevacizumab. This suggests that the pathogene- HFSR in 10.8% of patients. Pazopanib and axi-
sis could be related to inhibition of VEGFR 1 and tinib reported <10% and 14% of HFSR cases,
2 which are expressed on endothelial thyroid respectively. The pathogenesis of this side effect
cells. Endothelial cells are involved in regulation, is still unknown but there are two main hypoth-
synthesis, and function of thyroid hormones. The eses. TKIs seem to be secreted into eccrine
true incidence of hypothyroidism has not yet glands and excreted in sweat causing direct skin
been defined. In patients treated with sunitinib toxicity, which is increased in the palms and
incidence ranges from 18% to 85%. For sorafenib, soles where a major concentration of these
hypothyroidism has been reported in 18% and glands exist. Another mechanism could be
hyperthyroidism in 3%. Of note, less than 10% related to inhibition of VEGFR and PDGFR that
has been reported during therapy with pazopanib. affect normal vascular repair and cause damage
Some of the variability can be explained by the in pressure sites. Although HFSR is not a life-
fact that early studies on TKIs did not include threatening toxicity, it can heavily affect quality
prospective study of thyroid function and did not of life and determine a suspension or reduction
investigate baseline values. The real incidence of therapy. To prevent HFSR, pedicures should
should be prospectively evaluated in ongoing be recommended in patients with skin hyperker-
studies. Experience in recent years has shown atosis or calluses. Patients should avoid very hot
that baseline screening of thyroid function is water and not wear constrictive footwear.
necessary and further testing on days 1 and 28 Pharmacological interventions have been sug-
during the first four cycles is recommended. After gested from such as keratolytic creams for grade
that period, if thyroid function is normal, evalua- 1 toxicity, topical clobetasol and analgesics for
tion is encouraged every two cycles. When abnor- grade 2 toxicity and temporary interruption for
mal levels of TSH with or without mild symptoms grade 3 toxicity [37–39].
of hypothyroidism are noted, monitoring is man-
datory. When hypothyroidism occurs, levothy-
roxine should be initiated. There is an emerging Renal Toxicity
body of data which correlate kidney and thyroid
gland function in physiological and pathological Impact on renal function is characterized by
non-cancer-related conditions and perhaps future proteinuria, an increase in creatinine and a
studies may clarify the true causes of thyroid dys- decrease in clearance. Proteinuria is a conse-
function during treatment for kidney tumors quence of VEGF inhibition that may affect
[26–29]. glomerular endothelial function and cause dam-
age to the glomerular filtration barrier. In this
scenario, VEGF-A seems to play an important
Dermatological Toxicity role, explaining the high incidence of proteinuria
with bevacizumab (18% all grade and 7% grades
Skin toxicity has often been reported with TKIs 3 and 4). The mechanism behind proteinuria is
and includes rash, xerosis, cheilitis, pruritus, not perfectly clear and proteinuria has also been
subungual splinter hemorrhages, modification of reported with sunitinib (6%), pazopanib (<10%),
skin and hair pigmentation, yellowing skin and and axitinib (18–36%). Proteinuria is dose
hand–foot skin reaction (HFSR). HFSR is dependent, may be related to hypertension, and
defined as a localized cutaneous reaction charac- in many cases decreases after drug suspension.
terized by erythema, numbness, dysesthesia, or Proteinuria is a cardiovascular risk factor and is
paresthesia of the palms and/or soles. A recent also involved in long-term loss of renal function.
meta-analysis of sunitinib revealed an incidence Correct monitoring with urinalysis dipstick and
17 Targeted Therapy: Vascular Endothelial Growth Factor 311

a 24-h urine collection are helpful in detecting The emerging need to identify the best treat-
and managing this side effect before progression ment for individual patients has focused research
to renal damage. Although specific guidelines on biomarkers predictive of response to anti-
are not unavailable, drugs that block the renin– VEGF therapies. Inactivation of the VHL gene
angiotensin system (ACE inhibitors and ARA) has been extensively studied to understand its
have shown antiproteinuric and renoprotective prognostic and/or predictive value, but in both
properties [21, 40]. cases its role remains unclear. Patients with VHL
gene methylation or mutation do not appear to
have a better clinical outcome to VEGF-targeting
Hematologic and Laboratory Toxicities therapy than patients with VHL wild type [41].
A small study conducted on tumor specimens
Common hematological toxicities correlated in 43 patients treated with sunitinib showed a
with VEGF/VEGFR therapy are leukopenia, predictive role for response with high HIF-2a
ranging from 37% to 78%, neutropenia, ranging expression.
from 7% to 72%, lymphopenia, ranging from Germline variants in angiogenesis- and expo-
23% to 60%, anemia, ranging from 10% to 71%, sure-related genes may predict treatment response
and thrombocytopenia ranging from 6% to 65%. to pazopanib. Genetic markers have been investi-
Sunitinib has a higher incidence of hematologic gated in a retrospective analyses to evaluate cor-
toxicities than pazopanib due to its low affinity relation with pazopanib efficacy. Genetic
for FLT-3 expressed on hematopoietic cells. All variations in genes may be predictive of tumor
grade increases in bilirubin, ALT and AST have angiogenesis (expression of variants of IL8,
been seen with pazopanib in 36%, 53%, and HIF1a, and sVEGFA that increase angiogenic
53% respectively. This is, however, a class effect activity) or of differences in metabolism [42]. It is
that is also seen with the other TKIs such as interesting to note that data are emerging about
sunitinib with 46%, 52%, and 19% increases in the potential role as predictive markers of response
AST, ALT and bilirubin, respectively. Liver to certain side effects such as the development of
function has to be monitored diligently during hypertension in patients treated with sunitinib and
all TKI therapy. Reduction or suspension of drug axitinib and the development of hypothyroidism
has to be considered based on the grade and the in patients treated with sunitinib and sorafenib.
duration of side effects. Other laboratory abnor-
malities such as hypophosphatemia, increased
amylase and lipase have been observed during Optimal Duration of Treatment
sunitinib therapy with an incidence of 31%, 35%
and 56% [2–25]. Treatment with TKIs is continued until disease
progression, and recently the debate of therapeu-
tic management in patients with complete response
Open Questions (CR) has been raised. Discontinuation of therapy
could have an important impact on quality of life.
Predictive Factors However, there are no data to support suspension
of therapy. The only information is from small ret-
The use of these novel agents permits a wide rospective single-center studies in which patients
choice of therapy while raising many unanswered with CR after treatment or surgery obtained with
questions. We still lack fundamental knowledge TKIs and unacceptable toxicities have been forced
which can help us to identify which patient would to suspend sunitinib or sorafenib. In patients with
benefit from one drug rather than another. What recurrent disease, the median TTP was 6 months
is the best sequence of therapy to maximize sur- and reintroduction of the drug was effective in
vival? How can we overcome resistance which all cases. There is, therefore, significant risk of
inevitably arises during treatment? relapse after CR. Validation of this therapeutic
312 L. Cerbone and C.N. Sternberg

approach requires further study. The phenomenon Sunitinib and sorafenib represent the most com-
underlying relapse, the so-called rebound or mon sequence due to their earliest approval. For
flare-up phenomenon, is recognized and its bio- sunitinib after sorafenib progression a retrospec-
logical background has been described [43]. tive analysis showed a median PFS of 6.5 months,
However, intermittent therapy related to unaccept- 15% PR and 51% SD, obtaining a total of 12.5
able toxicity requires further investigation. months of PFS for the complete treatment.
Another small retrospective analysis evaluating
the same sequence experienced an average TTP
Resistance, Sequential of 18.1 months with 21% PR and 38% SD during
and Combination Therapy sunitinib therapy. Both studies investigated the
inverse sequence. In the first analysis patients
Patients develop either primary or acquired resis- treated with sorafenib after sunitinib progression
tance to anti-VEGF therapy, the reason why anti- achieved a median PFS of 3.9 months, obtaining
VEGF therapies are curative in only rare cases. an overall PFS during all the treatment of 9
Overcoming resistance is a serious topic of study. months. During sorafenib therapy 9% of PR and
Among the mechanisms responsible for resis- 54% of SD were observed. A very similar overall
tance, the first identified is activation or up-regula- TTP was achieved in the other analysis (8.5
tion of signals and alternative pathways of months) with lowest disease control during
angiogenesis. To prevent this phenomenon, sorafenib therapy (5% PR; 30% SD). Another
attempts have been made to block multiple path- study achieved PFS of 10.3 months with sunitinib
ways at the same time in a horizontal blockade or after sorafenib failure with an average PFS of 19
to block the same pathway in more than one site in months [48, 49]. Considerable bias affects evalu-
a vertical blockade using combination therapies ation of such results. A retrospective analysis of
[44]. Two examples of vertical combinations with the AVOREN trial evaluated the effect of TKI
anti-VEGF agents have been evaluated. The first therapy after first-line bevacizumab plus IFN-a.
is a phase I/II trial (NCT00126503) investigating Patients receiving second-line sunitinib achieved
the association benefit of Sorafenib and an OS of 43.6 months, patients receiving sorafenib
Bevacizumab. In phase I an important increase of an OS of 38.6 months. These results suggest but
sorafenib-related toxicity (hypertension, proteinu- do not validate sequential therapy after bevaci-
ria, hand–foot syndrome) was observed, with zumab plus cytokines [50]. Other interesting data
Sorafenib dose reduction in 74% of patients. The concerning sequential therapy come from the
phase II is still ongoing. Another phase I trial previously described axitinib trial [12].
(NCT00421512) was conducted to study the com- The idea of rechallenge has also been investi-
bination of Sunitinib and Bevacizumab. Even gated in a retrospective analysis of 23 patients
though the response rate was 52%, grades 3 and 4 with mRCC retreated with Sunitinib. A partial
hypertension, hematologic and vascular toxicities response was demonstrated in 22% and a PFS of
were prohibitive and the authors did not proceed 7.2 months was achieved. Patients who experi-
to phase II [45]. A phase I trial (NCT00992121) enced an interval between the two Sunitinib treat-
studying the combination of pazopanib with beva- ments greater than 6 months had better PFS (16.5
cizumab is ongoing. The combination of TKIs can months vs. 6 months). A 6-month cutoff for rechal-
be expected to have drug interactions due to the lenge could be evaluated in clinical practice.
common CYP3A4 hepatic metabolism [46, 47].
Sequential therapy is most likely more effec-
tive and safer. Available data on anti-VEGF Conclusions
sequential therapies are derived from retrospec-
tive studies which show that after progression In recent years the therapeutic approach to mRCC
during VEGF targeted therapy, patients may has been revolutionized by the introduction of
respond to another anti-VEGF treatment. new and effective VEGF-targeted therapies. The
17 Targeted Therapy: Vascular Endothelial Growth Factor 313

current guidelines suggest Sunitinib, Bevacizumab results of a randomized phase III trial. J Clin Oncol.
plus IFNa or Pazopanib as first-line treatments for 2010;28:1061–8.
8. Sternberg CN. Randomized, double-blind Phase III
favorable and intermediate-risk patients with Study of Pazopanib in patients with advanced/meta-
mRCC. Sorafenib, Sunitinib, Pazopanib and soon static renal cell carcinoma (mRCC): final overall sur-
Axitinib can be recommended as second-line vival (OS) results. 35th European Society for Medical
treatments for cytokine refractory mRCC. Oncology ESMO Congress, October 2010 Milan
Italy. Abstract LBA22.
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 Mammalian Target of Rapamycin
in Renal Cell Carcinoma 18
Eric Jonasch and Michel Choueiri

Introduction Signaling Pathways

Mammalian target of rapamycin (mTOR), the mTOR/PI3K/Akt Pathway

eukaryotic homolog of the yeast TOR, is involved
in cell growth, metabolism, and response to Two yeast Saccharomyces cerevisiae TOR alleles,
stress. Located downstream of Akt in the PI3K/ TOR1 and TOR2 were originally identified by
Akt/mTOR pathway, it is a plausible target for Heitman in 1991, through mutations that con-
antineoplastic agents when this pathway is aber- ferred resistance to the growth inhibition effect
rantly activated in tumors including renal cell by rapamycin [1]. In this study, Heitman showed
carcinoma (RCC). Rapamycin and its analogs that rapamycin requires an intracellular cofactor,
inhibit the mTOR complex function and prevent FK506 binding protein 12 (FKBP12) to form a
progression from the G1 to the S phase. Two complex that subsequently binds and inhibits
rapamycin analogs are currently approved for the TOR function. The structure of the FKBP12-
management of patients with RCC; temsirolimus rapamycin complex was later described by Clardy
and everolimus. Temsirolimus has shown pro- et al. in 1996 [2]. This inhibition prevents the
longed overall survival as a first-line agent in progression from the G phase into S phase.
patients with poor prognostic features. Everolimus The TOR gene is highly preserved and has
has resulted in improved progression-free sur- thus far been identified in every eukaryote
vival vs. placebo in a phase III trial in patients genome [3]. The eukaryote gene, mTOR, was
who failed initial treatment with sunitinib or first described as FRAP/RAFT-1 by Brown et al.
sorafenib. Based on these results, many clinical in 1994 [4] and mTOR by Sabers et al. in 1995
trials have been designed and many questions [5]. It is a 289 kDa intracellular serine/threonine
remain about the most suitable modalities to use kinase and along with ataxia telangiectasia
these agents in conjunction with other available mutated (ATM), ATM and rad3 (ATR), and DNA
therapeutic options. protein kinases belongs to the phosphatidylinosi-
tol-3-kinase (PI3K) related kinases (PIKK) fam-
ily [6, 7]. It shares a similar serine/threonine
protein kinase domain at the carboxy-terminal
with this family.
E. Jonasch () • M. Choueiri In the amino-terminal half, mTOR has tandem
Genitourinary Medical Oncology, UT MD Anderson
HEAT repeats and a FRAP-ATM-TTRAP (FAT)
Cancer Center, Unit 1374, PO Box 301439, Houston,
TX 77230, USA domain of unclear function. An FKBP12-
e-mail: [email protected] rapamycin binding (FRB) domain links FAT to

S.C. Campbell and B.I. Rini (eds.), Renal Cell Carcinoma: Clinical Management, Current Clinical Urology, 317
DOI 10.1007/978-1-62703-062-5_18, © Springer Science+Business Media New York 2013
318 E. Jonasch and M. Choueiri

HEAT HEAT FAT FRB Kinase

Fig. 18.1 Structure of mTOR. The amino-terminal contains tandem HEAT repeats and a FAT domain of unclear func-
tion. The kinase domain lies on the carboxy-terminal of mTOR and is linked to FAT by FKBP12-rapamycin binding
domain (FRB)

the kinase site. Carboxy-terminal to the kinase (PTEN) gene located on chromosome 10 [22].
domain is the FATC domain (Fig. 18.1). The loss of PTEN function [23], or the presence
In the cell, mTOR binds to different proteins of genetic mutations in the PI3K gene lead to
to form two distinct complexes: mTOR complex constitutive phosphorylation of Akt and anoma-
1 (mTORC1) and complex 2 (mTORC2) [8]. lous activation, and hence to mTOR activation.
mTORC1 consists of mTOR, mammalian LST8 Another parallel pathway, activated under
(mLST8), proline-rich Akt substrate 40 nutrient or energy depletion conditions, involves
(PRAS40), and raptor [9–11]. Only mTORC1 is the adenosine monophosphate (AMP) kinase
sensitive to rapamycin analogs [10] and has been activation of TSC1/TSC2, and suppression of
more studied than mTORC2, on which our mTOR kinase activity.
knowledge remains limited.
mTORC1 responds to stresses like nutrient
availability, energy, stress, and growth factors [3, mTOR in RCC
12–17] to regulate cap-dependent translation, tran-
scription cell progression, and survival. Down- In RCC, neoplasia is driven by the inactivation of
stream, mTORC1 activates ribosomal S6 kinase-1 the Von Hippel Lindau (VHL) gene, a tumor sup-
(S6K1) and inactivates 4E-BP1through phosphory- pressor gene [24, 25]. The VHL protein is respon-
lation. S6K1 is involved in translation whereas sible for the proteasome-mediated degradation of
4E-BP1 is the suppressor of the mRNA cap-binding the hypoxia-induced factor (HIF)-1a and is
protein eIF4E. Upon phosphorylation, 4E-BP1 defective in the most common histologic subtype
dissociates from eIF4E, which becomes free to of RCC, clear cell carcinoma [26]. In the pres-
bind to a scaffolding protein, eIF4G. eIF4E, an ence of an altered VHL protein, HIF accumulates
mRNA cap-binding protein, selectively enables the and results in the nuclear transcription of genes
translation of key proteins involved in cellular that play a role in tumorigenesis such as VEGF-A,
growth, angiogenesis, survival, and malignancy such endothelial growth factor receptor (EGFR), plate-
as cyclin D1, Bcl-2, MMP-9, and vascular endothe- let-derived growth factor (PDGF)-b, and trans-
lial growth factor (VEGF) [18–20] (Fig. 18.2). forming growth factor-a (TGF-a) [27–32].
mTORC1 is activated through two pathways. In addition to the effects of a defective VHL
The first pathway involves the binding of extra- protein, PTEN is also inactive in 20–30% of RCC
cellular ligands such as insulin growth factor-1 tumors [33] and induce activation of mTOR
(IGF-1), epidermal growth factor (EGF), trans- through Akt, and consequently leads to HIF accu-
forming growth factor (TGF-a) to transmembrane mulation [27, 34]. mTOR increases the expres-
tyrosine kinases triggering their autophosphoryla- sion of HIF-1a through the downstream effects
tion. These kinases activate PI3K, which then of S6K1 and eIF-4E which enhance the transla-
activates Akt. Akt inhibits two downstream tion of ribosomal proteins and mRNA translation,
complexes, the tuberous sclerosis complex 1 respectively [35]. The inhibition of mTOR there-
(TSC1) and complex 2 (TSC2) [21], which then fore is likely to decrease proliferation, angiogen-
release their inhibition on the downstream mTOR esis in addition to a direct antitumor effect.
complex. Akt activation can be inhibited by the In an immunohistochemical study, phospho-
tumor suppressor phosphatase and tensin homolog mTOR staining showed moderate to strong signal
18 Mammalian Target of Rapamycin in Renal Cell Carcinoma 319

Fig. 18.2 Akt/PI3K/mTOR signaling pathway. mTOR as translation of HIF. In RCC, inactivated VHL is unable to
binds to raptor and mLST8 to form mTORC1. MTORC1 is facilitate HIF-a proteolysis leading to HIF accumulation.
activated by Akt, which is activated by PI3K. PTEN inhibits HIF production is also induced by the activation of the
the activation of Akt by PI3K. Downstream, mTOR phos- mTOR pathway. The active intranuclear HIF-a induces
phorylates p70S6K1 (S6K1) and 4E-BP1 leading to activa- transcription of HIF target genes such as VEGF and PDGF.
tion of pathways involved in cell growth and survival as well Adapted from Rini et al. Lancet Oncol 2009;10:992–1000

in 17 out of 25 tissue microarrays from clear cell features, indicating that these patients might be
carcinomas, suggesting that mTOR is activated in better candidates to treatment with mTOR inhibi-
a substantial percentage of patients with RCC [36]. tors (mTORi). The mTOR-related proteins could
In another immunohistochemical study [37] using also be helpful as predictors of response. In one
antibodies against pAkt, PTEN, p27, and pS6 on a study, Cho et al. found that p-S6K1 and pAkt
tissue microarray constructed from specimens might be predictive biomarkers for response to
from 375 patients with RCC, the mTOR pathway temsirolimus treatment and hence needed to be
was more active in clear cell carcinoma, high- investigated further for possible application in
grade tumors, and tumors with poor prognostic patient selection models for mTORi [38].
320 E. Jonasch and M. Choueiri

stages of investigation and the former two agents

mTOR Inhibitors have been more extensively studied.

Rapamycin and Rapamycin Analogs

Temsirolimus
Rapamycin (sirolimus) is a macrolide secreted by
Streptomyces hygroscopicus, isolated from an Temsirolimus (CCI-779) is a water-soluble ester
Easter Island (“Rapa Nui” island) soil sample derivative of rapamycin. In vitro, temsirolimus
and reported in 1975 by Vezina and Sehgal [39, was shown to inhibit the growth of multiple
40]. It was initially found to have antifungal normal and tumorous cells [45–48]. In vivo, it
properties with special activity against Candida. inhibited the growth of various tumors includ-
Soon however, additional immunosuppressive ing prostate cancer and breast cancer xenografts
[41] properties were found and rapamycin was from cell lines lacking the expression of PTEN
used in transplant patients [42]. In addition, anti- and overexpressing Akt [49, 50].
tumor properties were described [43, 44], making
it a potential antineoplastic agent. As described Phase I Studies
above, rapamycin exerts these functions through Dosing
the binding to the intracellular protein FK-506 The maximum tolerated dose, the dosing parame-
binding protein-12 (FKBP12) to form a complex ters, and safety profile of temsirolimus were estab-
that binds and inhibits mTORC1. lished in clinical trials with patients with advanced
Rapamycin and three rapamycin analogs, tem- solid tumors [51–54] (Table 18.1). The maximum
sirolimus, everolimus, ridaforolimus (formerly tolerated dose with a cyclic dosing regimen (daily
deforolimus), have therefore been investigated as for 5 days every 2 weeks) was 15–19 mg/m2 [55].
possible antitumorigenic agents. The three rapamy- In a dose-escalation phase I study, a weekly,
cin derivatives differ from the original rapamycin 30-min infusion regimen allowed the administra-
molecule at the C43 position through the addition tion of higher doses (7.5–220 mg/m2) [52]. The
of an ester, ether, or phosphonate group for temsi- maximal tolerated dose was not truly achieved,
rolimus, everolimus, and ridaforolimus, respec- despite the development of thrombocytopenia and
tively (Fig. 18.3). Ridaforolimus is still at early reversible rash and stomatitis, and objective partial

Fig. 18.3 Structure of rapamycin, everolimus, and temsirolimus. Everolimus and temsirolimus substitute the hydroxyl
group on carbon 43 in rapamycin by an ether and ester group, respectively
18 Mammalian Target of Rapamycin in Renal Cell Carcinoma 321

Table 18.1 Dose escalation studies of temsirolimus in patients with advanced cancer including RCC
Reference n Dose DLT (n) Results
Hidalgo [51] 63 with advanced 0.75–24 mg/m2/day Vomiting, diarrhea, asthenia, Half-life of 13–25 h
cancer (16 RCC) elevated transaminases (2) (19 mg/
m2/day)
Stomatitis (1) (24 mg/m2/day) Unconfirmed PR in 2
pts with RCC on (3.7
and 19 mg/m2/day)
Raymond [52] 24 with advanced 7.5–220 mg/m2 Neutropenia, thrombocytopenia, Maximal concentra-
cancer (6 RCC) hypophosphatemia (34 mg/ m2) tion and AUC
increase sub-propor-
tionally with dose
Thrombocytopenia, asthenia, 6.5-month PR in 1 pt
diarrhea (45 mg/m2) with RCC
Manic-depressive syndrome,
stomatitis (1), ALT elevation,
asthenia stomatitis (1) (220 mg/m2)

and minor responses were noted at doses below temsirolimus should be decreased to 15 mg
the maximal dose used. In addition, the variability weekly in patients with hepatic impairment.
predicted with flat doses was comparable with
body surface area-normalized treatment, and flat Metabolism
doses were hence used [52]. Temsirolimus is metabolized via oxidative hydro-
Subsequent clinical trials on different advanced lysis to form sirolimus, its active metabolite [62].
cancers hence used weekly IV doses of 25, 75, or Both temsirolimus and sirolimus are metabolized
250 mg [56–58]. by the cytochrome P450 (CYP)3A4 pathway to
The temsirolimus dose needed for biologic form various demethylated and hydroxylated iso-
activity, i.e., inhibition of mTOR activity was meric products [63, 64]. Sirolimus appears
studied in peripheral blood mononuclear cells 15 min after temsirolimus infusion and reaches a
(PBMCs) [59]. In those cells, the activity was peak at 0.5–2.0 h, followed by a monoexponen-
determined by a decrease in the activity of S6K1, tial decrease [52]. The concentration of sirolimus
and 25 mg was shown to be sufficient to induce is higher than temsirolimus with a mean AUC
inhibition. ratio (sirolimus/temsirolimus) of ~2.5–3.5. When
temsirolimus was administered at doses higher
Pharmacokinetics than 34 mg/m2, residual concentrations of siroli-
Absorption mus were noted before the scheduled treatment
Temsirolimus administered intravenously at a but did not result in rising concentrations of
dose of 25 mg weekly, results in a mean temsiroli- sirolimus after repeated cycles [52].
mus maximal concentration of 585 ng/mL in
whole blood and a mean AUC in blood of Elimination
1,627 ng h/mL [60]. Its active metabolite, siroli- Temsirolimus is excreted predominantly via the
mus, is approximately 40% bound to lipoproteins feces. When a single 25 mg dose of radiolabeled
in the blood and hence elevated plasma lipopro- temsirolimus was administered, 78% of the radio-
tein levels may increase sirolimus plasma concen- activity was recovered from the feces and 5%
trations. In 18 patients with mild to moderate was recovered in the urine suggesting a minimal
hepatic impairment who received a single dose of role for renal clearance of temsirolimus. Its mean
sirolimus, the clearance of sirolimus was decreased half-life at a standard dose of 25 mg is approxi-
by more than 30% [61], and hence the dose of mately 13 h with a total plasma clearance (CL) of
322 E. Jonasch and M. Choueiri

16 L/h. Its active metabolite has a longer half-life In two separate abstracts presented at ASCO in
with a mean between 61 and 69 h [65], and hence 2007 [67] and 2009 [68], Merchan et al. evalu-
results in higher concentrations than temsiroli- ated the safety and efficacy of this combination.
mus. The clearance is moderate and increases In the phase I part involving 12 evaluable patients
substantially with higher doses and has a mini- with stage IV clear cell RCC and who had pro-
mal patient intervariability. This is thought to be gressed on up to two previous regimens, seven
a result of saturable specific binding of CCI-779 patients experienced a PR and two patients suf-
to FKBP in the red blood cell [53]. fered DLTs (mucositis and hypertriglyceridemia).
Following this phase I, a regimen of 10 mg/kg of
Tumor Response and Toxicity bevacizumab IV every 2 weeks with temsiroli-
In addition to establishing the pharmacokinetics mus 25 mg IV weekly was established. In the
outlined above, the phase I studies yielded pre- phase II component [68], 35 patients were evalu-
liminary clinical results. In a study on 24 patients ated. Four patients had PR and 18 patients had
with advanced cancers, temsirolimus resulted in stable disease (SD), suggesting that 88% of the
two confirmed partial responses (PR) in patients patients had experienced clinical benefits.
with breast cancer and RCC. The patient with
RCC had documented tumor progression of lung Phase II Studies
and pleural metastasis on interferon-a (IFN) and In phase II settings, temsirolimus role has been
interleukin 2 and received 15 mg/m2 of temsiroli- investigated in multiple advanced cancers includ-
mus [52]. The partial response lasted 6.5 months ing heavily pretreated breast cancer [58], mela-
and was observed after 8 weeks of treatment. noma [69], small cell lung cancer [57],
Two additional patients with RCC experienced glioblastoma multiforme [70], neuroendocrine
minor responses after treatment with 15 and tumors [71], and mantle cell lymphoma [72],
45 mg/m2, and had 34% and 39% tumor reduc- with mixed results.
tions respectively, with the partial responses last- In RCC, phase II studies have determined the
ing for 3 and 4.9 months. efficacy of temsirolimus monotherapy
In another dose-escalation study on 63 patients (Table 18.2) and combination regimens. Atkins
with advanced cancers, including 16 patients et al. first investigated single-agent temsirolimus
with RCC, six patients had evidence of clinical on 111 patients with cytokine-resistant RCC
benefit, and two patients with RCC had [65]. The patients were randomly assigned to
unconfirmed PR. The first received 3.7 mg/m2/ weekly treatment with temsirolimus at a dose of
day of temsirolimus, and the second received 25, 75, or 250 mg. Tumor response, time to
19 mg/m2/day temsirolimus for five cycles and tumor progression, survival, and adverse events
then 15 mg/m2/day [51]. Three patients had dose- were recorded. An objective response rate of 7%
limiting toxicities (stomatitis, vomiting/diarrhea, (one complete response and seven partial
asthenia, and elevated liver transaminases). Five responses) was observed and 26% of the patients
patients required dose reduction. experienced minor responses; 51% of patients
Additional phase I studies examined the role overall experienced a PR or complete response,
of temsirolimus in combination with agents tar- or SD lasting more than 24 weeks. The median
geting VEGF. In the first cohort of a study on PFS was 5.8 months and the median OS was 15
three patients with mRCC, IV temsirolimus months. The most common grade 3 or 4 side
15 mg weekly was administered concomitantly effects were hyperglycemia (17%), hypophos-
with oral sunitinib 25 mg daily (4 weeks on, 2 phatemia (13%), anemia (9%), and hypertriglyc-
weeks off) but resulted in two DLTs (rash, throm- eridemia (6%). Other grade 1 or 2 side effects
bocytopenia, cellulitis, and gout) and the study included maculopapular rash, mucositis, asthe-
was not pursued [66]. nia, and nausea and occurred in more than two
Another combination, bevacizumab/temsi- thirds of the patients. When these patients were
rolimus appears to have a better toxicity profile. stratified along good-, intermediate-, or poor-risk
18 Mammalian Target of Rapamycin in Renal Cell Carcinoma 323

Table 18.2 Phase 2 studies on temsirolimus in patients with advanced RCC

CR PR MR SD PD TTP (mo) OS (mo)
Reference Treatment dose n (total) (total) (total) (total) (total) (total) (all pts) (all pts)
Atkins [65] 25 mg weekly 36 0 2 5 20 6 6.3 13.8
50 mg weekly 38 0 3 13 11 9 6.7 11.0
250 mg weekly 37 1 2 11 11 7 5.2 17.5
(111, 10 (1) (7) (29) (42) (22) (5.8) (15.0)
unknown)
Motzer [73] IFN 6 MU + temsi- 71 8 25 9.1 18.8
rolimus 5–25 mg
weekly
CR complete response, PR partial response, MR minor response, SD stable disease, PD progressive disease, TTP time
to progression, OS overall survival, pts patients

groups according to the MKCC criteria, OS were eligibility criteria differed from other phase III
23.8, 22.5, and 8.2 months, respectively. The OS trials on other targeted therapies by including all
in the poor risk group was longer than the tradi- histologic subtypes of RCC. The trial also allowed
tional reported OS of 4.9 months in patients hav- for enrollment of patients with CNS metastases
ing received IFN [74] and justified further and patients were not required to have undergone
studying in this patient subset. a nephrectomy prior to enrollment. Six hundred
Another multicenter dose escalation phase I/II and twenty-six patients were recruited and ran-
study examined the effect of temsirolimus/IFN domized to three treatment arms: (1) weekly
combination [73]. An ascending dose (5, 10, 15, 25 mg dose of IV temsirolimus weekly (n = 209),
20, or 25 mg) of temsirolimus was administered (2) 3 MU IFN (with an escalation to 18 MU or
weekly in combination with IFN (6 or 9 million maximum tolerated dose) subcutaneously three
units) administered three times per week. Based times weekly (n = 207), and (3) a combination of
on the dose-limiting toxicities, a dose of temsirolimus (15 mg weekly) plus IFN (3 MU
15 mg/6 MU was recommended. Among the 39 with an escalation to 6 MU three times weekly)
patients who received the recommended dose, (n = 210). Twenty percent of the patients had non-
three patients achieved partial response and 14 had clear cell histology and 67% had undergone pre-
stable disease for at least 24 weeks, with a median vious nephrectomy.
PFS for all patients in the study of 9.1 months. The The primary endpoint was OS and the second-
most common reported grade 3 or 4 side effects ary efficacy endpoints were PFS, the ORR, and
included leukopenia, hypophosphatemia, asthenia, the clinical benefit rate, defined as the proportion
anemia, and hypertriglyceridemia. of patients with an objective response or stable
disease for at least 24 weeks. No statistical differ-
Phase III Trial ence was observed when the combination group
Because of the prolongation in OS noted in and the IFN group were compared with OS of 8.4
patients with poor risk features, a phase III trial and 7.3 months, respectively (HR 0.96, p = 0.70).
was initiated. In 2007, Hudes et al. published the However, a prolonged OS of 10.9 months was
results of the multicenter global advanced renal observed in the temsirolimus monotherapy arm
cell carcinoma (Global ARCC) [75]. This trial vs. 7.3 months in the IFN arm (HR 0.73, p = 0.008).
compared temsirolimus to IFN and to the temsi- The objective response rates were not statistically
rolimus/IFN combination as a first-line treatment different between the three groups, but more
in patients with poor prognosis who were treat- patients in the temsirolimus monotherapy (32.1%)
ment naïve. The patients had three or more of six experienced a clinical benefit compared to the
features: five MSKCC prognostic model criteria combination group (28.1%) and IFN monother-
[76] and metastases in multiple organs [77]. The apy (15.5%). An improvement in PFS was also
324 E. Jonasch and M. Choueiri

Table 18.3 Side effects occurring in >10% of patients receiving temsirolimus

in the global ARCC trial [75]
Side effect Grade 3 or 4 (%) All grades
Asthenia 11 51
Rash 4 47
Nausea 2 37
Anorexia 3 32
Pain 5 28
Dyspnea 9 28
Infection 5 27
Diarrhea 1 27
Peripheral edema 2 27
Cough 1 26
Fever 1 24
Abdominal pain 4 21
Stomatitis 1 20
Constipation 0 20
Back pain 3 20
Vomiting 2 19
Weight loss 1 19
Headache 1 15
Laboratory abnormalities 20 45
Anemia 3 27
Hyperlipidemia 11 26
Hyperglycemia 1 24
Hypercholesterolemia 3 14
Elevated creatinine 1 14
Thrombocytopenia

observed (p < 0.001) in the temsirolimus arm question about the possible role of combination
compared to the IFN alone arm, and the reported therapies with the mTORi in RCC. A successful
PFS were 3.8, 1.9, and 3.7 months in the temsi- combination therapy should target different path-
rolimus, IFN and combination arms, respectively. ways simultaneously, improve clinical outcome,
Subsequent subset analyses were performed and have an acceptable safety profile. As described
and the improvements in OS and PFS were inde- earlier, the combination of temsirolimus/bevaci-
pendent of the histological type or the nephrec- zumab yielded encouraging preliminary results,
tomy status [78, 79]. but the final results are still pending.
Patients receiving temsirolimus experienced a In contrast, the combination of temsirolimus
higher incidence of hyperglycemia, hyperlipi- with VEGFR TKIs appears to be less tolerated.
demia, and hypercholesterolemia compared to For example, a study on three patients receiving
patients receiving IFN. They also experienced temsirolimus (15 mg weekly) in conjunction with
more rash, stomatitis, and peripheral edema but sunitinib (25 mg daily for 4 week-on therapy, 2
had a lower incidence of grade 3 and 4 side effects week-off therapy cycles) was terminated because
(Table 18.3). of DLTs occurring in two patients (rash and cel-
lulitis/thrombocytopenia) [80]. This combination
Ongoing Trials is therefore not recommended.
The availability of agents against the VEGF mol- The combination of temsirolimus and sorafenib,
ecule and the VEGF receptor (VEGFR) raised the a VEGFR and Raf kinase inhibitor, is less conclu-
18 Mammalian Target of Rapamycin in Renal Cell Carcinoma 325

sive [81]. DLT consisting of mucocutaneous side ment with sunitinib (NCT00474786). The trial is
effects occurred at the full dose of 400 mg of currently enrolling patients with an accrual goal
sorafenib twice daily in conjunction with temsi- of 480 patients. The primary endpoints are safety
rolimus. But there was no evidence of pharmacoki- and tolerability of both temsirolimus and sorafenib
netic drug–drug interaction. The DLTs necessitated in the second-line setting, and an independently
a reduction in half of the sorafenib dose. assessed PFS. The secondary endpoints are OS,
Many clinical trials have therefore been duration of response, and response rates.
designed to study the efficacy of combination
therapy in addition to clinical trials focused on
sequential therapy options. Everolimus

Combination Treatment Everolimus (RAD-001) differs from rapamycin

Investigation of TORISEL and Avastin through the addition of an ether group. It was first
Combination Therapy developed as an oral immunosuppressive agent to
Because of the clinical benefits observed in the prevent allograft dysfunction following organ
phase II trials for the combination of bevaci- transplantation. It is well tolerated and is widely
zumab/temsirolimus, trials were launched to used for prophylaxis of rejection in patients who
further evaluate this regimen. The Investigation have undergone cardiac, liver, and renal trans-
of TORISEL and Avastin Combination Therapy plants [85, 86]. The dose is 1.5 mg twice daily up
(INTORACT) trial is a phase 3b [82], random- to a dose of 6 mg/daily [87, 88].
ized, open-label study comparing bevaci- Everolimus binds to a cytoplasmic protein, of
zumab + temsirolimus to bevacizumab + IFN as a FK-506 binding protein-12, to form a complex
first-line treatment option in patients with that interacts with mTOR. This interaction pre-
advanced RCC (NCT00631371). The trial has vents the phosphorylation of S6K1 and 4E-BP1
completed accrual of 791 patients and the final and activation, and therefore affecting the tumor
results are pending. The primary outcome is cell metabolism and growth.
independently assessed PFS and the secondary
endpoints are safety, OS and investigator In Vitro and Animal Studies
assessed PFS. In addition to its immunosuppressant effects,
everolimus displays antiproliferative properties
BeST against endothelial cells following injury and
Another trial sponsored by ECOG, bevacizumab, against tumor cells. In a rat model of renal micro-
sorafenib, and temsirolimus in advanced RCC vascular injury, everolimus inhibited glomerular
(BeST), is a randomized phase II study compar- endothelial cell proliferation by up to 60%, an
ing bevacizumab to the combinations of temsi- effect that was associated with a reduced phospho-
rolimus/bevacizumab, sorafenib/bevacizumab, rylation of the p70S6 kinase and reduced VEGF
and temsirolimus/sorafenib (NCT00378703) levels in the glomeruli. It also inhibits the growth
[83]. This study has also completed accrual and of human derived cell lines in culture and in xeno-
data should be forthcoming. graft models [89]. In a syngeneic rat pancreatic
tumor model, everolimus showed dose-dependent
Sequential Treatment antitumor activity with both daily and weekly
Torisel 404 administration schedules, and statistically
In addition to combination therapy, sequential significant decrease in the tumor size among the
treatment is being investigated in patients who treated subjects of 70–95% depending on the dose.
have failed initial TKI treatment. The Torisel 404 In this preclinical study, everolimus was well tol-
phase III trial, sponsored by Wyeth [84], will erated and had an antitumor potency similar to
compare temsirolimus to sorafenib as a second- that of the cytotoxic agent 5-fluorouracil. Because
line treatment in patients who have failed treat- everolimus also displays immunosuppressive
326 E. Jonasch and M. Choueiri

effects, it was important to find an adequate thera- the drug should be taken consistently either with
peutic window to balance the benefits of adequate food or without. The absorption is possibly also
tumor control with minimal immunosuppression. affected by the activity of P-glycoprotein, which
For that purpose, Boulay et al. biochemically reduces the oral bioavailability of drugs that are
profiled the mTOR signaling pathway in tumors, CYP3A substrates [95].
skin, and PBMCs, and found a decrease in the The protein binding of everolimus is not
phosphorylation of 4E-BP1 and inactivation of influenced by moderate hepatic impairment [96].
S6K1 after a single administration of everolimus.
This finding suggested that S6K1 from the PBMC Metabolism
could possibly be used as a marker for mTOR Unlike temsirolimus, everolimus is not degraded
inhibition and as a means to assess everolimus to sirolimus, but is metabolized essentially in the
treatment schedules in cancer patients. gut and liver by cytochrome P450 3A4, −3A5,
and −2C8 and PgP enzymes into hydroxylated
Phase I Studies and demethylated metabolites [64, 97]. Hydroxy-
Dosing Schedule everolimus is the most important metabolite,
Based on these preliminary findings, a phase I accounting for half of the dose-normalized AUC
study was conducted by Tanaka et al. [90] to pre- of the first 24 h (AUC24) of everolimus AUC24.
dict optimal clinical regimens of everolimus. The different metabolites appear within 1.2–
S6K1 from PBMC was used as a marker of 2.0 h after administration, vs. 1.5 h for everoli-
mTOR inhibition. A pharmacokinetics/pharma- mus [98, 99].
codynamics model was used to plot the associa- To identify the optimal regimen and dosage of
tion between everolimus concentrations and level everolimus, O’Donnell et al. (Table 18.4) per-
of S6K1 inhibition in PBMCs in both human formed a dose-escalation study on 92 patients
subjects and rats. A time- and dose-dependent with advanced cancer with an everolimus dose
S6K1 inhibition with everolimus was shown. In range of 5–30 mg/week initially based on trans-
the rat model, a relationship was shown between plantation data. However, in view of the preclini-
S6K1 inhibition and antitumor effect. This model cal data favoring daily dosing, two regimens of
allowed the prediction of PBMC S6K1 inhibition- 50 and 70 mg weekly and daily doses of 5 and
time profiles in patients receiving everolimus, 10 mg were investigated. S6 kinase 1 activity in
and a daily administration was found to yield a PBMC was inhibited for at least 7 days at doses
greater effect than weekly administration at ³20 mg/week. Evaluation of the stable predose
higher doses. serum trough concentration levels from 26 of the
31 patients treated with the weekly regimen indi-
Pharmacokinetics cated minimal accumulation at all weekly dose
The pharmacokinetics evaluation of everolimus levels, with steady-state achieved by the second
was done in conjunction with the pharmacody- week of treatment. The area under the curve
namics evaluation described earlier. increased proportionally with the dose, but the
maximal serum concentration increased less than
Absorption proportionally at doses ³20 mg/week. Evaluation
Everolimus is administered orally, has a low bio- of profiles from ten patients on the daily regimen
availability in rats of 10% [91], but has a fast patients showed that a steady-state level was
absorption. The peak everolimus concentration reached within a week. Both maximal serum con-
(44.2 ± 13.3 mg/L) is reached within 30 min to 1 h centration and AUC increased in a dose propor-
after administration with an area under the curve tional manner.
of 219.69 ± mg h/L [92], with an approximate
half-life of 30 h [93]. The steady state is reached Excretion
within 7 days. High-fat meals decrease the No definite excretion study has been undertaken,
absorption of everolimus by half [94], and hence but in patients receiving concurrent cyclosporine
18 Mammalian Target of Rapamycin in Renal Cell Carcinoma 327

Table 18.4 Dose escalation studies of everolimus in patients with advanced cancer including RCC
Reference n Dose DLT (n) Results
O’Donnell 92 with advanced Group 1: weekly dose 5 mg No toxicity S6K1 activity was inhibited
[93] cancer (10 RCC) vs. 10 mg vs. 30 mg (n = 18) for >7 days at doses higher
than 20 mg/week
Group 2: weekly dose 50 mg Stomatitis and Everolimus was tolerated at
vs. 70 mg (n = 37) fatigue (1) (50 mg) dosages up to 70 mg/week
and 10 mg/day
Group 3: daily dose 5 mg vs. Hyperglycemia (1) Five of ten patients with RCC
10 mg (n = 37) (10 mg) had PFS ³6 months
Tabernero 55 with advanced Group 1: weekly dose 20 mg 70 mg: stomatitis Complete inhibition of S6K1
[100] cancer (2 RCC) vs. 50 mg vs. 70 mg (n = 31) (2) neutropenia (1), and peIF-4G at 10 mg/day and
hyperglycemia (1) ³50 mg/week
Group 2: daily dose 5 mg vs. Stomatitis (1) One of two patients with RCC
10 mg (n = 24) (10 mg) had stable disease for
14.6 + months at 50 mg
weekly

radiolabeled everolimus, 80% of the radioactivity was seen in one out of six patients [93] receiv-
was recovered from the feces, and 5% was ing everolimus at a weekly dose of 50 mg
excreted in the urine, after the administration of a (stomatitis and fatigue), and in four patients
3 mg single dose of everolimus (Everolimus- receiving 70 mg weekly. Among the patients
Summary of Product Characteristics. Novartis treated with a daily regimen, one of the six
Pharma AG, Basel, Switzerland). patients receiving 10 mg developed hyperglyce-
mia, and another patient also receiving 10 mg
Tumor Response and Toxicity developed stomatitis [100].
Fifty-five patients were studied by Tabernero in
a dose escalation phase I setting at doses of 20, Phase II Trials
50, and 70 mg weekly or 5 and 10 mg daily Two phase II studies have recently investigated
[100]. A dose and schedule-dependent inhibi- the safety and efficacy role of everolimus mono-
tion of the mTOR pathway was observed with therapy [101] and the combination of everolimus
complete inhibition of pS6K1 and p-eIF-4G at a and bevacizumab [102] in the treatment of
daily dose of 10 mg or weekly dose of 50 mg or patients with mRCC (Table 18.5).
greater. Only two patients had RCC. Clinical Amato et al. conducted a 2-stage, single-arm,
benefit was noted in four patients including one phase 2 trial to determine the PFS of patients with
patient with RCC who experienced stable dis- metastatic clear cell RCC receiving everolimus at
ease of 14.6 months on 50 mg/week dose. One a daily dose of 10 mg. Forty one patients were
patient developed grade 3 stomatitis on the daily recruited, and 37 patients were evaluable for
dose of 10 mg. On the weekly dose at 70 mg, response. Eligibility criteria included ECOG PS
two patients had grade 3 stomatitis, one had £2, satisfactory hematologic, hepatic, renal, and
grade 3 neutropenia, and the last developed cardiac function. Patients with brain metastases
grade 3 hyperglycemia. were excluded. The majority of the patients
Among the 92 patients evaluated in the phase (83%) had received prior systemic treatment,
I trial by O’Donnell, four patients experienced mostly cytokine therapy with IL-2 and/or IFN-a
partial responses, and 12 patients had a PFS of (61%). 59, 37 and 5% had intermediate, good and
6 months or more, including five of the ten poor risk per MSKCC criteria, respectively.
patients with RCC. In the two previously The results showed a median PFS of 11.2
described phase I studies, dose-limiting toxicity months and a median OS of 22.1 months.
328 E. Jonasch and M. Choueiri

Table 18.5 Phase 2 studies on everolimus in patients with advanced RCC

Reference Treatment dose n CR SD PR PD PFS (mo) OS (mo)
Amato 10 mg daily 41 (37 >6 5 11
[101] evaluated) months: (14%)
21 (57%)
Hainsworth 10 mg Group A: 50 1 (2%) 25 (50%) 14 3 9.1 21.3
[102] daily + Bevacizumab (previously (28%) (6%) (6.3–11.7) (16.7—NR)
(10 mg/kg every 2 untreated)
weeks) Group B: 30 1 (3%) 19 (64%) 6 3 7.1 14.5
(Previous TKI (20%) (10%) (3.7–10.9 (10.8—NR)
treatment)

Five patients (14%) experienced a partial however, showed a median PFS of 9.1 and 7.1
response, and 27 had a stable disease duration months in the untreated and treated patients,
longer than 3 months, with 21 (57%) having a respectively, with similar overall response rates
stable disease lasting more than 6 months. More were similar in both groups (30% and 23%). The
than 70% of the patients therefore had partial discrepancy between the preliminary and the final
response or SD > 6 months. The most common report have put into question the role of using
grade ½ side effects were nausea (38%), anorexia preliminary results from small phase II trials, and
(38%), diarrhea (31%), stomatitis (31%), pneu- as a basis for designing phase III studies [104].
monitis (31%), and rash (26%). The grade 3/4 The most commonly reported nonhematologic
side effects included pneumonitis (18%), grade 1/2 side effects were fatigue (76%), mucosi-
transaminase level elevations (10%), thrombocy- tis (60%), skin rash (47%), diarrhea (45%),
topenia, hyperglycemia, and alkaline phosphatase hypertension (43%), nausea/vomiting (43%),
elevations (8%), and hyperlipidemia (5%). proteinuria (41%), hyperlipidemia (40%),
In the phase II study by Hainsworth et al., the anorexia (33%), epistaxis (30%), constipation
efficacy and toxicity of the combination of beva- (24%), and the most common hematologic grade
cizumab and everolimus in mRCC or unresect- 1/2 side effects consisted of anemia (63%),
able locally recurrent clear cell RCC with good thrombocytopenia (40%), and neutropenia (17%).
performance status was evaluated [102]. Eighty The most common grade 3/4 side effects included
patients were enrolled in the study and divided proteinuria (26%) which was reversible after
into two groups depending on whether they were bevacizumab discontinuation, mucositis/stoma-
targeted therapy-naïve (n = 50) or had received titis (15%), fatigue (12%), and diarrhea (9%).
previous treatment with either sorafenib and/or Eleven patients (14%) stopped treatment due to
sunitinib (n = 30). The patients received everolimus toxicity and 25 patients (31%) underwent dose
10 mg orally daily and bevacizumab 10 mg/kg adjustments but were able to tolerate treatments
intravenously every 2 weeks, and were evaluated at lower doses.
after 8 weeks of treatment. Patients who demon-
strated either an objective response or stable dis- Phase III Trials
ease were continued on treatment and reevaluated In view of the phase II results using everolimus
every 8 weeks until disease progression or devel- as a second-line agent in mRCC, a phase III study
opment of severe toxicity. was designed to examine the role of everolimus
The preliminary results from 59 patients were in patients who had progressed on TKIs. The
first partly presented at the 44th Annual Meeting renal cell carcinoma treatment with oral RAD001
of the American Society of Clinical Oncology in given orally (RECORD-1), launched in 2005,
Chicago, IL in 2008 [103], and suggested a PFS was a randomized double-blind phase III trial to
of 12 and 11 months in the untreated group and investigate the role of everolimus in patients
treated groups, respectively. The final analysis, who had progressed within 6 months of stopping
18 Mammalian Target of Rapamycin in Renal Cell Carcinoma 329

treatment with sunitinib or sorafenib or both. Comprehensive Cancer Network for treatment
Four hundred and sixteen patients were therefore of patients with advanced RCC after failure of
randomized in a 2:1 ratio to either everolimus at TKIs [106].
a daily dose of 10 mg/day (n = 277) or placebo The preliminary results were confirmed in the
(n = 139) with best supportive care. The primary final report [107], the median PFS was 4.9 months
endpoint was PFS by central review, and the in the everolimus group vs. 1.9 months in the pla-
secondary endpoints included safety, objective cebo group [hazard ratio (HR), 0.33; p < 0.001] by
response rate, OS, and quality of life. independent central review. No difference was
29, 56%, and 15% had favorable, intermediate, observed in OS with a median duration of 14.8
and poor MSKCC risk respectively, and 97% of months in the everolimus group vs. 14.4 months in
the patients had undergone prior nephrectomy. 44, the placebo group (p = 0.126). These values, how-
30%, and 26% had received prior sunitinib, ever, were likely confounded by a crossover effect
sorafenib or both drugs, respectively, and more from the placebo group into the everolimus group.
than 85% had received immunotherapy, hormonal When the confounding factors were accounted for,
therapy, or other treatments. the corrected OS for crossover was 1.9-fold longer
At the second interim analysis, a significant with everolimus compared with placebo only.
difference in efficacy between the two study The most common side effects (Table 18.6)
arms was observed and the trial was stopped were stomatitis (44%), infections (37%), asthenia
after 191 progression events had been observed (33%), fatigue (31%), diarrhea (30%), cough
[105]. A median PFS of 4.0 months was observed (30%), rash (29%), nausea (26%), anorexia
in the everolimus group vs. 1.9 months in the (25%), and peripheral edema (25%). The com-
placebo group (Fig. 18.4). These results prompted mon grade ¾ side effects (³5%) included infec-
the approval of everolimus by the FDA for the tions (10%), dyspnea (7%), and fatigue (5%).
treatment of patients with advanced RCC after Four percent of the patients developed pneumoni-
failure of treatment with sunitinib or sorafenib, tis, necessitating interruption and/or reduction
and a level 1 recommendation by the National and corticosteroid use in selected patients.

Fig. 18.4 Kaplan–Meier estimates of progression-free survival by the independent central radiology review in patients
receiving everolimus in the RECORD-1 study. Reproduced from [105]
330 E. Jonasch and M. Choueiri

Table 18.6 Side effects occurring in >10% of patients receiving everolimus [105]
Side effect Grade 3 or 4 (%) All grades
Stomatitis 3 40
Rash 1 25
Fatigue 3 20
Asthenia 1 18
Diarrhea 1 17
Anorexia 1 16
Nausea 0 15
Mucosal inflammation 1 14
Vomiting 0 12
Coughing 0 12
Dry skin 1 12
Infections 2 10
Laboratory abnormalities 10 91
Anemia 3 76
Hypercholesterolemia 1 71
Hypertriglyceridemia 12 50
Hyperglycemia 1 46
Elevated creatinine 14 42
Lymphopenia 1 37
Elevated alkaline phosphatase 4 32
Hypophosphatemia 0 26
Leukopenia 1 21
Elevated AST 1 20
Thrombocytopenia 1 18
Elevated ALT 0 17
Hypocalcemia 0 11
Neutropenia

Ongoing Trials with the secondary endpoints being OS, ORR, and
Based on the preliminary results suggesting a safety profile of the combination regimen in addi-
benefit for the everolimus/bevacizumab combi- tion to patient reported quality of life outcomes.
nation, and on the results showing a benefit for Another phase II study currently underway is
everolimus as a second-line treatment after TKIs, the renal cell cancer treatment with oral RAD
phase II and phase III studies were designed. 001 given daily-3 (RECORD-3) which is a ran-
domized, open-label, multi-center, phase 2 study
Phase II investigating the role of sequential treatment
The Renal Cell Cancer Treatment With Oral RAD with first-line everolimus followed by sunitinib
001 Given Daily-2 (RECORD-2) is a randomized, vs. sunitinib followed by everolimus in patients
open-label, multi-center phase II study that aims at with mRCC (NCT00903175). The study is
comparing the everolimus-bevacizumab to the sponsored by Novartis Pharmaceuticals and is
established bevacizumab/IFN combination [108– currently recruiting patients with an estimated
111] as a first-line treatment (NCT00719264) enrollment of 390 patients. The primary end-
[112]. This study, sponsored by Novartis point is non-inferiority of PFS after first-line of
Pharmaceuticals, has completed accrual with an treatment with everolimus compared to PFS of
estimated accrual of 360 patients but the final patients who receive first-line sunitinib. The
results are pending. The primary outcome is PFS secondary endpoints include PFS after treatment
18 Mammalian Target of Rapamycin in Renal Cell Carcinoma 331

with everolimus as second-line following Histologically, the tumor samples must have some
sunitinib vs. PFS in patients receiving sunitinib component of clear cell elements.
as second-line after everolimus, safety profile of
everolimus vs. sunitinib as first-line and overall Adjuvant Phase III
for both the first-line and second-line. Other To better understand the role of mTORi in the
second endpoints are the patient reported out- adjuvant setting, the Southwest Oncology Group
comes in disease-related symptoms and overall has launched the everolimus in treating patients
quality of life during each line of treatment, with kidney cancer who have undergone surgery
ORR and duration of response differences dur- (EVEREST) study (NCT01120249). This trial is
ing each line of treatment and OS rates during recruiting individuals with clear or non-clear cell
each line of treatment RCC immediately post-nephrectomy whose
A further study evaluating the sequencing of tumors show intermediate high-risk to high risk
mTORi vs. antiangiogenic therapy is the sequen- features. Patients are randomized between 12
tial two-agent assessment in renal cell carcinoma months of everolimus and placebo. The primary
therapy (START) trial, which randomizes previ- endpoint is recurrence free survival, and both
ously untreated patients with mRCC between tissue and blood samples are being collected for
upfront everolimus, pazopanib, and bevacizumab future biomarker studies.
(NCT01217931). This 240-patient study then
rerandomizes individuals to one of the two
remaining agents. The statistical design allows Ridaforolimus
for prediction of the best sequence with a high
degree of probability. Extensive biomarker anal- Another rapamycin analog, ridaforolimus
ysis is being performed as part of this clinical (AP23573), contains phosphorus and is also
trial, with the hope of developing predictive bio- being studied as an antineoplastic agent.
markers to select individuals most likely to benefit Ridaforolimus was initially tested in sarcomas
from a particular sequence or class of agent. [113] with encouraging results. Its combination
with capecitabine was recently evaluated in a
Phase III phase Ib study on 32 patients with multiple
Based on the interim phase II results investigating advanced solid tumors, including seven patients
the safety of the everolimus/bevacizumab combina- with RCC [114]. Two recommend doses of 50 or
tion, the Cancer and Leukemia Group B designed 75 mg weekly were used with capecitabine and
and sponsored a phase III, randomized, placebo- were tolerated. One patient with ovarian cancer
controlled, double-blind clinical trial to compare the had a partial response and ten patients experi-
efficacy of this combination to everolimus plus pla- enced stable disease. Unlike temsirolimus and
cebo in patients with mRCC who progressed after everolimus, the dose used is close to the maximal
treatment with TKIs (NCT01198158). This study is tolerated dose. Another phase II study has evalu-
currently recruiting patients and has an estimated ated the ridaforolimus/paclitaxel combination on
enrollment of 700 patients. The primary endpoint 29 patients with different cancers, including one
will be OS and the secondary endpoints will include patient with clear cell carcinoma. The patient
PFS, ORR, and toxicity. The patients should not with RCC did not respond but two partial
have active brain metastases, and no renal, cardiac, responses were observed in pharyngeal squamous
or hepatic dysfunction to enroll. Samples might be cell and pancreatic carcinoma and eight patients
collected from the blood, urine, and tumor tissue achieved stable disease ³4 months [115]. The
periodically for pharmacogenomic and correlative most common DLT is mucositis while other mild
studies, and the patients will be followed up every 8 to moderate side effects include fatigue, nausea,
weeks after completion of the study treatment until rash, anemia, neutropenia, diarrhea, hyperlipi-
disease progression and every 6 months afterwards. demia, and thrombocytopenia.
332 E. Jonasch and M. Choueiri

TORi in the treatment algorithms remains to be

Mechanisms of Resistance determined. Temsirolimus is currently beneficial
as a first-line agent in patients with metastatic
Unlike high-dose interleukin-2, no durable com- RCC and with poor risk features. Everolimus
plete response has been observed with the improves PFS as a second-line agent and can be
mTORi, and although a clinical benefit has been used in patients who have progressed on suni-
noted with these agents, RCC invariably recurs. tinib, sorafenib or both. Multiple clinical trials
These agents appear to be cytostatic, and hence are currently underway and hence the use of the
the mechanisms through which the RCC cells mTORi will probably change to parallel the
overcome mTOR inhibition are critical to under- results obtained in the phase III trials.
stand to be able to formulate adequate treatment Despite the encouraging results with mono-
combinations. therapy, the improvements remain modest and
The currently available agents inhibit mTOR hence sequential and combination treatments are
in the mTORC1 complex. However, mTORC 2 being investigated as a means to improve clinical
phosphorylates Akt [116] in a positive biofeed- benefit. Combination therapies offer the benefit of
back mechanism, and hence can limit the effec- inhibiting two different molecular pathways
tiveness of mTORi. Therefore, agents capable of simultaneously. However, despite the theoretical
inhibiting the kinase activity of both mTOR com- benefit of combining mTORi with VEGF TKI,
plexes could result in better antitumorigenic early data evaluating the temsirolimus/sunitinib
effect. Mutations affecting mTOR or FKBP12 can combination suggest this treatment option might
lead to an improper attachment to rapamycin and have unacceptable side effects. As an additional
hence are associated with resistance to rapamycin cautionary lesson that more therapy is not always
[117–119]. In addition, defects or mutations in better, the combination of temsirolimus with IFN
downstream effectors such as S6K1 [120, 121], was inferior to temsirolimus monotherapy in the
and 4E-BP1 can result in rapamycin resistance global ARCC trial. In contrast, bevacizumab
[120]. In contrast, activation of the upstream Akt appears to be better tolerated when administered
protein appears to induce sensitivity to the mTORi. along with an mTORi, but single-arm trials pub-
Another mechanism of resistance involves the lished so far have not provided reassurance that
IGF receptor (IGFR)/PI3K/Akt pathway disrup- the combination of bevacizumab and an mTORi is
tion. Insulin receptor substrates (IRS) 1 and 2 are superior to monotherapy. Nevertheless, studies
activated by IGF-1 and insulin and induce PI3K evaluating the role of mTORi in combination with
and mTOR activation. As a downstream protein, bevacizumab have been performed, and include
S6K1 phosphorylates the IRSs in a negative feed- the mentioned INTORACT and RECORD-2 tri-
back mechanism and hence decreases the insulin/ als looking at combining bevacizumab with tem-
IGF-1 activation of the PI3K/Akt pathway [122]. sirolimus and everolimus, respectively. We look
Under mTOR inhibition [123–125], this feedback forward to the mature data from these trials to
mechanism is lost leading to unopposed IGFR/ provide definitive evidence of the utility of com-
PI3K/Akt activation. This in turn could possibly bination anti-VEGF and mTORi therapy.
decrease the effect of mTORi. Using IGFR inhibi- In addition to combination treatment, the
tors or inhibitors of PI3K and Akt could help recent approval of many antineoplastic agents
overcome this resistance. against RCC has raised the question of how to
best maximize the efficacy of those agents when
used in sequence. The exact sequence of treatment
Conclusion will change when the many studies currently
investigating different sequential options are con-
mTORi are a new class of antineoplastic agents cluded. For example, important studies include
against RCC. Because of the different available the RECORD-3 and START trials which will
targeted agents in RCC, the exact place of the evaluate sequencing of mTORi and antiangiogenic
18 Mammalian Target of Rapamycin in Renal Cell Carcinoma 333

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 Palliative and Supportive Care
for Renal Cancer 19
Armida Parala-Metz* and Mellar Davis*

Introduction Cancer Pain Management

A national cross-sectional study [1] of adult renal Pain is one of the most common and dreaded
cell cancer patients showed that more than 50% symptom of patients with cancer. However, it is
of patients with both localized and metastatic dis- often suboptimally treated in cancer patients [5,
ease reported pain, weakness, fatigue, sleep 6]. Under-treated pain impairs patients’ daily
disturbance, urinary frequency, worry, irritabil- functions and adversely affects their emotional
ity, and depression as being moderate to highly and psychological health and may lead to suicide
relevant. This is similar to other studies [2, 3] that and the desire of hastened death [7].
have also mentioned fatigue, weakness, pain, Pain management has been guided by the
lack of appetite, nausea, irritability, and sleep dis- World Health Organization’s three-step analge-
turbance as commonly reported symptoms among sic ladder (Fig. 19.1) [8]. Analgesic choice is
patients with renal cell carcinoma. These symp- based upon pain intensity. For mild pain, non-
toms need to be managed to improve the quality opioid and/or adjuvant analgesics (Table 19.1)
of life of these patients. are used, weak opioids (Table 19.2) are substi-
Advancements in targeted therapies for tuted for non-opioids for moderate pain and
renal cancer have made this condition a chronic strong opioids (Table 19.2) are substituted for
illness [4]. Renal cancer patients now live with weak opioids for severe pain. In countries where
their disease longer and may experience a strong opioids are readily available and where
multitude of symptoms that come with both palliative care is established, Step 2 is bypassed
advanced disease and treatment-related side and low doses of potent opioids are used instead
effects. [9] (Table 19.3). Morphine is generally accepted
as the opioid of choice for moderate to severe
cancer pain [10, 11].
Cancer pain has different temporal patterns
(Fig. 19.2) which dictate the opioid dosing strat-
*
A World Health Organization Demonstration Project in egy. Continuous pain is managed with around-
Palliative Medicine. the-clock (ATC) opioids either as sustained
A. Parala-Metz, MD • M. Davis, MD () release morphine (or oxycodone or hydromor-
The Harry R. Horvitz Center for Palliative Medicine phone) every 12 or 24 h or with oral immediate
and Supportive Oncology, Taussig Cancer Institute,
release morphine (or oxycodone or hydromor-
Cleveland Clinic Health Systems, 9500 Euclid Avenue,
Cleveland, OH, USA phone) every 4 h. A majority of patients with
e-mail: [email protected] continuous cancer pain will also have transient

S.C. Campbell and B.I. Rini (eds.), Renal Cell Carcinoma: Clinical Management, Current Clinical Urology, 339
DOI 10.1007/978-1-62703-062-5_19, © Springer Science+Business Media New York 2013
340 A. Parala-Metz and M. Davis

STEP 3

Strong opioids +
Non-opioid
analgesics +/-
STEP 2

Weak opioids +
Non-opioid
STEP 1 analgesics +/-

Non-opioid
analgesics +/-

Fig. 19.1 WHO analgesic ladder

Table 19.1 Non-opioid analgesics and adjuvant analgesics

Non-opioid analgesics Adjuvant analgesics
Acetaminophen Systemic corticosteroids
NSAIDs Antiepileptics (e.g., gabapentin, pregabalin, carbamazepine, lamotrigine, valproic acid)
Salicylates Antidepressants (e.g., venlafaxine, duloxetine, amitriptyline)
NMDA receptor blockers (e.g., ketamine, amantadine, magnesium sulfate, memantine)
Alpha 2 adrenergic agonists (e.g., clonidine, dexmedetomidine)
Skeletal muscle relaxants (e.g., diazepam, tizanidine, baclofen)
Smooth muscle relaxants (e.g., glycopyrrolate, dicyclomine, atropine, scopolamine
Bisphosphonates

Table 19.2 Weak opioids

Codeine ATC opioid dose rather than shortening the
Hydrocodone (commercially available as Vicodin) dosing interval [12]. Successful cancer pain man-
Tramadol agement requires ATC opioids plus rescue doses
Tapentadol for intermittent pain, titrated against the patient’s
Propoxyphene (Darvocet) was pulled out of the market in pain severity. Both non-opioid and/or adjuvant
November 2010 analgesics should be used to optimize analgesia
at each step of the WHO analgesic ladder [15].
flares of pain, known as breakthrough pain. Effective pain management with opioids
Breakthrough or intermittent pain may be inci- requires adequate analgesia without excessive
dent (i.e., related to movement or activity), non- adverse effects. Common initial side effects are
incident (spontaneous), or end-of-dose-failure mild nausea and vomiting, drowsiness, lighthead-
[12, 13]. Rescue (as needed) doses of short-acting edness, and sedation [9]. These normally resolve
opioids are given for breakthrough pain. several days after initiating the opioid. Nausea
Recommendations for rescue dosing are 25–50% may require the use of antiemetics. Constipation
of the 4 hourly dose, or the 4 hourly dose given is a common side effect that persists and does not
hourly, or 10–20% of the daily dose [11, 12, 14]. improve with time. It should be treated proac-
End-of-dose failure is due to suboptimal doses of tively with stool softeners and laxatives. A minor-
ATC opioids and is improved by titrating the ity of patients develop intolerable side effects
19 Palliative and Supportive Care for Renal Cancer 341

Table 19.3 Strong opioids and starting doses for opioid naïve patients
Oral formulation Parenteral formulation
Opioid Dose Interval Dose Interval (prn dosing)
Morphine 5–10 mg 4h 0.5–1 mg 1h
Hydromorphone 2 mg 4h 0.2 mg 1h
Oxycodone 5–10 mg 4h N/A N/A
Fentanyl N/A N/A 25 mcg 1h
Methadone 5 mg (2.5 mg in the elderly) 12 h 0.2 mg 1h

Cancer Pain

Continuous Pain Breakthrough or

Intermittent Pain

Incident End-of
dose-
Non- Failure
Incident

Fig. 19.2 Temporal pain patterns

prior to achieving pain relief. One strategy in this side effects include: (1) reducing the systemic
setting is opioid rotation, a planned switch from opioid dose by 25–50% and simultaneously adding
one opioid to another [16] to achieve a good bal- a non-opioid analgesic or adjuvant analgesic to
ance of analgesia and side effects [17, 18]. A ret- maintain pain control [22]; (2) symptomatic man-
rospective study [19] on terminal cancer patients agement of opioid adverse effects (Table 19.4);
showed that common reasons for opioid rotation and (3) changing the opioid route [23]. Around
were cognitive failure, hallucinations, myoclonus, 10–30% [24–26] of cancer patients will not have
nausea and vomiting, local toxicity, and refractory acceptable pain control with systemic opioid
pain. Opioid rotation results in resolution of side therapy and will need other approaches to pain
effects and improved pain control in >50% of control such as radiation therapy and interven-
patients [19, 20]. In choosing a new opioid, it is tional treatments like neurolytic procedures,
important to consider relevant patient and disease- intrathecal drug therapy, kyphoplasty or vertebro-
related factors, medical comorbidities, concomi- palsty, or image-guided tumor ablation [27–32].
tant pharmacotherapy, patient’s history of any
drug sensitivities, the clinical care setting (outpa-
tient, inpatient, long-term care, and hospice) and Hypercalcemia and Bisphosphonate
financial- or insurance-related issues [16, 21]. Therapy
Switching to a different opioid is just one of
the strategies that can be utilized when managing Hypercalcemia is a serious complication of
unacceptable outcomes associated with opioid admi- malignant diseases. It most often occurs in renal
nistration. Other ways to manage opioid-related cell carcinoma [33] and its incidence increases
342 A. Parala-Metz and M. Davis

Table 19.4 Common opioid adverse effects

Adverse effect Intervention
Nausea and vomiting May use metoclopramide, or neuroleptics (e.g., haloperidol, olanzapine) as needed.
Common at the start of therapy and usually resolves in 7–10 days
Constipation Stool softeners and laxatives. Prevention is key as no tolerance is developed to this side
effect
Sedation Reassurance. Need to review medication list to rule out other medications potentially
causing sedation. Tolerance is developed days after starting opioid therapy. If persistent,
consider reducing opioid dose and use a stimulant (e.g., methylphenidate)
Confusion Reduce dose of opioid and start haloperidol as needed. Need Review medication list to
remove other drugs that may cause delirium and rule out other potential causes
(e.g., sepsis). Consider switching to a different opioid
Myoclonus Reduce dose of opioid and prescribe clonazepam as needed. Consider adding an adjuvant
analgesic to optimize pain control and lessen intolerable side effects

with the stage of the disease [34]. There are four which may have toxicity which mimics the
proposed mechanisms of hypercalcemia associ- neurologic symptoms of hypercalcemia [35].
ated with cancer [35]. Humoral hypercalcemia of When managing hypercalcemia, it is important
malignancy (HHM) accounts for 80% of cases to discontinue all calcium supplements and
and is caused by secretion of parathyroid-related medications that can increase serum calcium
protein (PTHrP) by the tumor cells. PTHrP level [35]. Intravenous hydration with normal
increases bone resorption and enhances reabsorp- saline corrects dehydration increases glomerular
tion of calcium in the renal tubules. Other humoral filtration rate (GFR) and inhibits calcium reabsorp-
factors which potentiate PTHrP activity and tion [35, 39]. Loop diuretics (e.g., furosemide)
increase osteoclastic bone resorption have been should not be routinely given because if used pre-
implicated as well and include IL-1, IL-6, TNF-a, maturely, dehydration will get worse and GFR
and tumor growth factors (TGF) a and b [36–38]. will be further reduced [35, 39]. They should be
Another cause of hypercalcemia is osteolytic used only when managing clinical volume over-
activity from sites of skeletal metastases which load [4, 40].
account for 20% of malignancy-related hypercal- Intravenous (IV) bisphosphonates (pamidronate
cemia. A less common cause is secretion of and zoledronic acid) are the treatment of
1,25-dihydroxyvitamin D which increases osteo- choice for hypercalcemia of malignancy [41].
clastic bone resorption and intestinal calcium Bisphosphonates have a very high affinity to
absorption. A rare cause of hypercalcemia is PTH bone mineral and achieve a high local concentra-
secretion from ectopic hyperparathyroidism. tion [42]. They work by inhibiting osteoclastic
Individuals with hypercalcemia associated with bone resorption [42, 43]. In most cases, serum
cancer should have low levels of PTH (with the calcium levels will normalize within 4–7 days
rare exception of ectopic hyperparathyroidism). and the response may last for 1–3 weeks [35].
Individuals with elevated PTH levels should be Other agents like glucocorticoids, calcitonin, and
assessed for primary hyperparathyroidism. gallium can be used if bisphosphonates are con-
Common symptoms associated with hypercal- traindicated or ineffective (Table 19.5).
cemia include nausea, vomiting, constipation, Denosumab, an anti-RANKL (receptor activator
confusion, lethargy, and coma [39]. Symptom of nuclear factor-kappaB ligand) antibody, inhib-
severity is dependent on the serum calcium level, its osteoclast-mediated bone resorption and
the rate of increase of calcium, the presence of a reduces skeletal-related events (SREs) [44, 45].
comorbid neurologic or cognitive impairment, Further research is needed to validate the use of
and concomitant use of sedatives and opioids denosumab in hypercalcemia.
19 Palliative and Supportive Care for Renal Cancer 343

Table 19.5 Management of malignant hypercalcemia

Comment
(a) Initial intervention
Intravenous saline hydration 200–300 mL/h. Consider a slower rate in patients with underlying cardiac or renal
disease. Use loop diuretics (e.g., furosemide) if signs of fluid overload develops
Bisphosphonates May use pamidronate (30–90 mg IV )or zolendronic acid (4 mg IV). Monitor serum
creatinine level and ensure adequate hydration
(b) Second-line medications
Calcitonin 4–8 units/kg subcutaneously every 4–6 h. Do not use for more than 48 h as tachyphy-
laxis develops. Use in symptomatic patients with serum calcium level of >14 mg/L.
Use with saline hydration and bisphosphonates in the management of severe
hypercalcemia
Glucocorticoids For example, prednisone 20–40 mg/day
Gallium nitrate 200 mg/m2/day for 5 days. Contraindicated in patients with severe renal impairment
Dialysis Indicated for symptomatic patients with severe hypercalcemia and renal impairment
or heart failure, in whom hydration cannot be safely administered

Bisphosphonates reduce pain [43] and prevent There was also a significant delay in the median
SREs associated with bone metastases (patho- time to first SRE by more than 80 days. There
logic fractures, development of new osteolytic was a significant reduction in the annual inci-
lesions, spinal cord compression, the need for dence of SREs with zoledronic acid (1.74 per
radiation therapy or surgery caused by bone year with the 4-mg dose vs. 2.71 per year with
metastases) [43, 46]. In the absence of bone- placebo; p = 0.012). Zoledronic acid was found to
targeted therapy, 30% patients with advanced be well tolerated. A retrospective subset analysis
renal cell carcinoma will experience symptom- [52] on 74 renal cell cancer patients from the
atic bone metastases [47]. The associated SREs original study showed a 50% reduction in the
adversely affect quality of life and decrease percentage of patients who developed SRE with
functional independence and may also increase zoledronic acid (37% vs. 74% placebo; p = 0.015).
mortality [48]. The risk for developing an SRE was also reduced
Parenteral pamidronate disodium and zolen- by 61% and the time to first SRE was significantly
dronic acid are approved for use to prevent skel- delayed. Zoledronic acid should be considered in
etal events in those with bone metastases. all patients with bone metastases from renal cell
However, only zoledronic acid has been shown to carcinoma [53].
prevent or delay SREs in a broad range of malig- Parenteral bisphosphonates cause systemic
nancies, including renal cell carcinoma [49]. A inflammatory reactions within 48 h after admin-
phase III, placebo-controlled, double blind, ran- istration resulting in fever, arthralgia, myalgia,
domized controlled trial in patients with bone nausea and vomiting..These symptoms are usu-
metastases from lung cancer and other solid ally mild and are treated with acetaminophen or
tumors showed that zoledronic acid (4 or 8 mg) NSAID and they generally resolve within 24–48 h
given every 3 weeks for 9 months, reduced SREs [9]. Nephrotoxicity is a concern with intravenous
and increased the time to the first skeletal event bisphosphonates, particularly in patients who
by more than 2 months [50]. A follow-up study have had nephrectomy. It is recommended that
[51] on the same population which looked at serum creatinine levels be monitored, use the rec-
long-term efficacy and safety revealed that fewer ommended dose and infusion rate, ensure ade-
patients treated with zoledronic acid developed quate hydration, and avoid concurrent use of
an SRE at 21 months compared with placebo. nephrotoxic drugs [9, 54].
344 A. Parala-Metz and M. Davis

Bisphosphonate-related osteonecrosis of the lipolysis leading to muscle wasting and loss of

jaw (BRONJ) is a major but rare complication of fat; and (3) induction of pro-inflammatory
parenteral bisphosphonate therapy. The American cytokines (i.e., tumor necrosis factor {TNF},
Academy of Oral and Maxillofacial Surgery interleukin {IL} 1, IL-6, interferon (IFN) g) and
(AAOMS) defined BRONJ by the presence of all tumor-derived catabolic factors (proteolysis-
of the following characteristics: (1) current or inducing factor {PIF} and lipid-mobilizing
previous treatment with a bisphosphonate; (2) factor) which are primarily responsible for reduc-
exposed bone in the maxillofacial region that has tion of muscle synthesis, increase in protein deg-
persisted for more than 8 weeks; and (3) no his- radation, and lipolysis, causing muscle wasting
tory of radiation therapy to the jaw bones [55]. in cancer patients [62–67].
The incidence in cancer patients is estimated to It is important to identify reversible causes of
be between 0.6% and 15% and is most commonly anorexia and cachexia. Clinicians should make
seen in breast cancer (0.6–6.2%) and multiple sure that their patients have a functional gastroin-
myeloma (1.7–15%) patients [56]. A retrospective testinal tract (i.e., no obstruction or malabsorp-
analysis of 4,000 patients treated with bisphos- tion), have optimal anti-emetic therapy, and that
phonates reported BRONJ only in patients with pain and depression have been addressed [62,
multiple myeloma and breast cancer. There were 68]. It is also important that the patient has a
no cases of BRONJ in other malignancies (lung, desire to eat again and want their anorexia treated
renal, or prostate cancer) or in benign diseases [68] before pharmacologic treatment is started.
like osteoporosis and Paget’s disease [57]. Risk At best, appetite stimulants palliate anorexia but
factors for BRONJ include dental extractions, do not reverse cachexia [69]. It is important for
duration of bisphosphonate treatment, and type clinicians to educate patients and families that
of bisphosphonate used. Management is aimed at anorexia is common symptom in cancer patients
decreasing pain, controlling oral infections, and and is not due depression or “giving up” or to
minimizing the progression of bone necrosis lack of willingness to eat on the patient’s part or
[55]. Bisphosphonates should be stopped and poor food choices on the family’s part [69].
patients should have close dental follow-up [9, The most effective appetite stimulants are cor-
55]. Long-term outcomes for patients who ticosteroids (e.g., dexamethasone, methylpredni-
develop BRONJ are generally poor with only a solone, prednisone) and progestational agents
minority of patients reporting improvement or (e.g., megesterol acetate, medroxyprogesterone
resolution of symptoms [58]. acetate). The mechanism of action of corticoster-
oids is unclear but may be related to its euphori-
genic effect, down-modulation of prostaglandin
Anorexia and Cachexia metabolism or cytokines release, or up-regulation
of orexigenic hormones within the hypothalamus
Most patients with advanced cancer suffer from [62, 70]. Corticosteroids produce immediate
lack of appetite and loss of weight [59], these improvement in appetite, however, their effects
predict poor outcomes and decreased survival in are short-lived and may only last a few weeks
this setting [60, 61]. [71]. Corticosteroids are also associated with
Cancer anorexia and cancer cachexia (pres- more side effects including, fluid retention,
ence of involuntary loss of lean body mass, change in mental status, gastritis, cushingoid
weight, and appetite) occur by way of several body habitus, and proximal myopathy with long-
overlapping mechanisms which include: (1) neu- term use. Megesterol acetate (MA) is the best
rohormonal changes leading to loss of appetite, studied progestational agent in palliating anorexia
early satiety, chronic nausea, malabsorption, and in cancer patients. Its mechanism of action is not
autonomic failure; (2) metabolic alterations that known but in animal models, MA appears to
lead to increased energy expenditure, increased increase neuropeptide Y (a potent central appe-
glucose and protein turnover, and accelerated tite stimulant) synthesis, transport, and release
19 Palliative and Supportive Care for Renal Cancer 345

[72]. A meta-analysis [73] which included 30 Initial management involves treating underlying
studies, involving 4,123 patients showed a benefit associated symptoms such as pain, insomnia, and
of MA compared with placebo or other drugs, depression, correcting anemia, and screening for
particularly with regard to appetite improvement hypothyroidism. Psychostimulants such as meth-
and weight gain in cancer patients. MA is nor- ylphenidate have a small but significant benefit
mally well tolerated. Side effects include hyperg- whereas antidepressants (paroxetine) and progesta-
lycemia, fluid retention, hypertension, nausea, tional steroids are ineffective [83, 84]. Erythropoeitin
vomiting, impotence, reduced libido, and an to correct anemia during chemotherapy and exer-
increased risk of thromboembolism (5%) [62, cise (resistance and aerobic) have modest benefits
74]. The optimal dose of MA is between 400 and when used during chemotherapy [83, 84].
800 mg/day. It is reasonable to use 160 mg/day in
initial therapy of cancer anorexia [75]. A recent
randomized study which compared MA alone Summary
with MA plus olanzapine (5 mg at night) found
that the drug combination was significantly better Renal carcinoma and its therapy are associated
than MA alone [76]. Promising agents in the with a variety of symptoms that adversely affect
management of cancer anorexia–cachexia include patients’ quality of life. Palliative and supportive
melatonin, thalidomide, oxandrolone, ghrelin, therapies should be combined with oncologic
and antimyostatin therapies [68]. treatment to optimize and improve patient care.

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Committee of the European Association for Palliative
 Index

A Advanced
Ablative therapies, 163–164 CD4+CD25hi Tregs, 295
Abouassaly, R., 107, 180, 181, 186 cytokine/chemotherapy combinations, RCC, 287–289
Abou Youssif, T., 179, 181, 184, 187 cytokine therapy, RCC, 280–282
Active surveillance (AS), SRM IFN-a, 287
biomarker, 190 mTOR targets dysregulation, RCC, 241
competing risk assessment in RCC, 135–136, 219
EORTC trial, 170 Allen, N.E., 16
nomogram evaluation, 171, 172 Allmer, C., 204
pathologic characteristics, 170 Alshumrani, G., 110
cross-sectional abdominal imaging, 189 Amato, R.J., 325, 326
description, 168–169 Angermeier, K.W., 135
imaging techniques, 174 Angiomyolipoma (AML), 54
malignant and metastatic potential Anorexia
biopsy, 170 anti-VEGF therapy, toxicities, 306
high-grade disease vs. tumor size, 169 clinicians, 342
radiographic characteristics, 169 corticosteroids, 342
von Hippel–Lindau syndrome, 170 magesterol acetate (MA), 342–343
management, 168 overlapping mechanisms, 342
metastases problems, VEGF drugs, 305
growth kinetics and pathologic characteristics, side effects, ARCC trial, 322
185–188 Antiangiogenic therapies
limitations, 189 RECISTs, 74
patients, 189 tumor size change, 74
zero net growth, 189 ARF. See Acute renal failure (ARF)
molecular markers, 173–174 Atkins, M.B., 284, 320, 321
natural history (see Natural history, observed Avastin and interferon in renal cancer (AVOREN)
renal masses) CALGB trial, 301
non-extirpative assessment, 175–176 cytokine/chemotherapy combinations, advanced
observation and contemporary, RCC, 288
176–177 IFN-a/bevacizumab combination vs. IFN-a, 287
percutaneous biopsy, 172–173 MSKCC risk, 301
stages, 167, 168 retrospective analysis, 310
Acute renal failure (ARF), 146–147 TKIs, mRCC, 303
Adjacent organ invasion AVOREN. See Avastin and interferon in renal cancer
adrenal gland, 212–213 (AVOREN)
liver, 212 Axitinib (AG 013736)
median survival, patients, 213 anti-VEGF therapy, toxicities, 306
preoperative imaging, 211, 212 description, 304
renal tumors, 211 mRCC treatment algorithm, 302
retrospective study, 213 receptors and tyrosine kinase inhibitor therapies, 240
surgical approach, 212 TKIs, mRCC, 303

S.C. Campbell and B.I. Rini (eds.), Renal Cell Carcinoma: Clinical Management, Current Clinical Urology, 349
DOI 10.1007/978-1-62703-062-5, © Springer Science+Business Media New York 2013
350 Index

B BRONJ. See Bisphosphonate-related osteonecrosis of the

Baba, M., 46 jaw (BRONJ)
Barney, J.D., 257 Brown, E.J., 315
BCS. See Budd–Chiari syndrome (BCS) Budd–Chiari syndrome (BCS), 209–210
Beisland, C., 180, 181, 187
Benign renal tumors
papillary adenoma C
clinical features, 33 Cachexia
molecular genetics, 33 clinicians, 342
pathology, 33 corticosteroids, 342
WHO definition, 31 magesterol acetate (MA), 342–343
renal oncocytoma overlapping mechanisms, 342
clinical features, 33–34 symptoms, 86
molecular genetics, 34 CAIX. See Carbonic-anhydrase IX (CAIX)
pathology, 34 CALGB. See Cancer and leukemia group B (CALGB)
Beroukhim, R., 113 Cancer and leukemia group B (CALGB), 287, 288,
BeST. See Bevacizumab, sorafenib and 301, 303
temsirolimus (BeST) Cancer outcomes, 94
Bevacizumab (Avastin®) Cancer pain management
AVOREN study, 301 analgesic choice, 337
CALGB trial, 301 description, 337
description, 301 initial side effects, 338
phase III trials, 302 non-opioid and adjuvant analgesics, 337, 338
Bevacizumab, sorafenib and temsirolimus (BeST) opioid adverse effects, 339, 340
cytokine/chemotherapy combinations, advanced opioid rotation results, 339
RCC, 288–289 radiation therapy and interventional treatments, 339
definition, 323 rescue recommendations, 338
Bhatt, R.S., 239 strong opioids and naïve patients, 337, 339
BHD syndrome. See Birt–Hogg–Dube (BHD) syndrome temporal pain patterns, 337, 339
B7 homolog (B7-H1). See Programmed cell death 1 weak opioids, 337, 338
ligand 1 (PD-L1) WHO analgesic ladder, 337, 338
Bilateral renal masses, 134 Cancer-specific mortality (CSM), 108
Biology, RCC Cancer-specific survival (CSS), 197, 209
HIF, 233–235 Cancer syndromes
immunology, 242 BHD, 31
mTOR, 239–242 HLRCC, 31
pro-angiogenic pathways, 243 HPRCC, 31
VEGF, 235–239 VHLD, 28, 31
VHL, 231–233 Canfield, S.E., 199, 213
Biomarkers, 254 Carbonic-anhydrase IX (CAIX)
Biopsy. See T1 renal tumors and mass biopsy gene and protein expression, 284
Birnbaum, B.A., 110 genes, hypoxic response, 233
Birt–Hogg–Dube (BHD) syndrome IL-2-based treatment, 284
autosomal dominant transmission, 47–48 monoclonal antibody treatment, 291
cutaneous lesions and histology, Cardiovascular toxicity
fibrofolliculomas, 47 arterial hypertension, 306
major and minor diagnostic criteria, 47 arterial thrombotic events, 307
organ systems, 47 bevacizumab inhibition, VEGF-A, 306
pulmonary cysts, 47 definition, cardiac, 307
RCC syndrome, 46 description, 226
renal tumors, 46 ECG modifications, 307
Bisphosphonate-related osteonecrosis of the jaw effective antihypertensive therapy, 307
(BRONJ), 342 nondihydropyridine calcium channel blockers, 307
Blumenfeld, A.J., 111 CCRCC. See Clear cell renal cell carcinoma (CCRCC)
Blute, M.L., 199, 203, 206 CDRCC. See Collecting duct renal cell carcinoma
Bonsib, S.M., 211 (CDRCC)
Boorjian, S.A., 207 Cediranib (AZD2171), 305
Bosniak, M.A., 60, 63, 179, 181, 184, 186 CGH. See Comparative genomic hybridization (CGH)
Boulay, A., 324 Chawla, S.N., 177, 178, 183
Breau, R.H., 204 Cheville, J.C., 199
Index 351

Childs, R.W., 292 renal central sinus and urothelial invasion, 70

Cho, D., 317 renal vein and inferior vena cava tumor, 71
Choueiri, T.K., 252, 259 sagittal plane contrast-enhanced, 74, 77
Chromophobe renal cell carcinoma (Chromophobe RCC) tumor size, 70
clinical features, 26–27 multiphasic technique
molecular genetics, 27 CMP, 55
pathology, 27 NP scan, 55
Chronic kidney disease (CKD) Consolidative nephrectomy. See Neoadjuvant targeted
cardiovascular disease, 126 therapy
definitions, 126 Cooperberg, M.R., 168
dialysis or renal transplantation, 126 Corticomedullary phase (CMP), 55, 66
invasive techniques, 119 Cost, N.G., 224
multivariable analysis, 126 Cowey, C.L., 223, 264
Ciancio, G., 208 Crispen, P.L., 107, 180–184, 186, 187, 204
CKD. See Chronic kidney disease (CKD) Cryoablation
Clardy, J., 315 description, 158
Clark, J.I., 283 freeze/thaw cycles, 159
Clayman, R.V., 123, 136 RFA, 159
Clear cell renal cell carcinoma (CCRCC) CSM. See Cancer-specific mortality (CSM)
clinical features, 23–24 CSS. See Cancer-specific survival (CSS)
molecular genetics, 25–26 CT. See Computed tomography (CT)
pathology, 24 CTLA-4. See Cytotoxic T lymphocyte antigen-4 (CTLA-4)
CMP. See Corticomedullary phase (CMP) CWG. See Cytokine working group (CWG)
CN. See Cystic nephroma (CN) Cystic nephroma (CN), 68–69
Collecting duct renal cell carcinoma (CDRCC) Cytokine working group (CWG)
hypovascular tumors, 68 adjuvant high-dose therapy, 283
medullary carcinoma, 68 HD IL-2, 282, 283
renal cortex, 68 randomized phase III trial, 282
sarcomatoid differentiation, 36 Cytotoxic T lymphocyte antigen-4 (CTLA-4)
Combination therapy and resistance antibody blockade, 293
anti-VEGF therapy, 310 autoimmune toxicities, 293–294
retrospective analysis, AVOREN trial, 310 description, 292
sequential therapy, 310 DLT and MTD, 294
sunitinib and bevacizumab, 310 ipilimumab, 293
Comparative genomic hybridization (CGH), 113 role, 292–293
Competing risks tremelimumab, 293
EORTC trial, 170 Czerny, V., 133
nomogram evaluation, 171, 172
pathologic characteristics, 170
RCC, 171–172 D
SRMs, 170 deKernion, J.B., 257
Complications Delacroix, S.E., 198
ablation, 162 Dermatological toxicity, 308
radical nephrectomy, 125 DeRoche, T., 108
Computed tomography (CT) Dimashkieh, H.H., 200
detection and characterization, renal masses, 55 DLT. See Dose-limiting toxicity (DLT)
and MRI Dose-limiting toxicity (DLT)
adrenal metastases, 71 acute renal failure, 294
antiangiogenic therapies, 74–75 dose escalation studies, 325
hematomas, 73 renal toxicity, 295
imaging, staging, 69–70 side effects, 329
lymphadenopathy, 70 sorafenib dose, 323
metastatic disease, 71–72 Dovitinib (TKI258), 304–305
papillary and chromophobe, 77
partial nephrectomy, 72
pathologic tumor stage, 73 E
pelvic and chest, 70 Epidemiology, RCC, 8, 197
percutaneous cryoablation, 74, 76 Everolimus
post cryoablation changes, 74, 75 adjuvant phase III, 329
pseudoaneurysm, 73 vs. best supportive care, 253
352 Index

Everolimus (cont.) G
cytokine/chemotherapy combinations, advanced Gastrointestinal toxicity, 307
RCC, 288–289 Genetics
description, 323 components, RCC, 219
in vitro and animal studies, 323–324 markers, 309
mTORi vs. antiangiogenic therapy, 329 molecular, 33
phase III trials mutations, PI3K gene, 316
Kaplan-Meier estimation, 327 uncommon RCC subtypes, 29
preliminary results, 327 Giuliani, L., 198, 201
risks, MSKCC, 327 Gollob, J.A., 288
role, 326
side effects, 327, 328
phase II trials H
bevacizumab and everolimus, mRCC, 326 Hainsworth, J.D., 326
nonhematologic grade 1/2 side effects, 326 Han, K.R., 213
in patients, 325–326 Haramis, G., 107
role, 325 Heat shock protein (HSP) vaccines, 290
phase I studies Heitman, J., 315
dosing schedule, 324 Hellsten, S., 202
pharmacokinetics, 324–325 Heng, D.Y., 252
RECORD-2 and RECORD-3, 328 Hereditary leiomyomatosis renal cell carcinoma
ridaforolimus, 329 (HLRCC)
sunitinib vs. PFS, patients, 329 cutaneous leiomyomas, 49
Extracapsular extension kidney cancer syndrome, 48
collecting system invasion, 211 molecular pathway, 48
perinephric fat invasion, 210 Hereditary papillary renal cell carcinoma (HPRCC), 31
renal sinus invasion, 210–211 bilateral multifocal tumors, 45
genetic mechanism, 45–46
Herring, J.C., 49
F Herrlinger, A., 201
Familial kidney cancer Herts, B.R., 110
forms, 43 Hidalgo, M., 319
pathology and molecular genetics, 43 HIF. See Hypoxia-inducible factor (HIF)
renal masses, 50 Histological classification
renal tumors, 48 CCRCC, 23–26
Familial RCC ChRCC, 26–27
BHD, 46–48 PRCC, 26
biologic mechanisms, 43 subtypes
hereditary syndromes, 43, 44 clinical, pathological, and genetic features, 27, 29
HLRCC, 48–49 mucinous tubular and spindle cell carcinoma,
HPRCC, 45–46 27, 31
kidney cancer, 50 multilocular cystic, 27, 30
molecular genetics, 43 renal medullary carcinoma, 27, 30
surgical treatment, 49–50 unclassified type, 27
VHL, 43–45 Hoffmann, R.T., 160
Fernando, H.S., 179, 187 Hollingsworth, J.M., 86, 171
Ficarra, V., 210, 213 HPRCC. See Hereditary papillary renal cell carcinoma
Fine needle aspiration (FNA), 111 (HPRCC)
FISH. See Fluorescence in situ Huang, W.C., 128
hybridization (FISH) Hudes, G., 321
Flaherty, K.T., 19 Hunt, J.D., 14
Fleischmann, J.D., 262 Hutterer, G.C., 204
Fluorescence in situ hybridization Hypercalcemia
(FISH), 111, 222 bisphosphonates and SREs, 341
FNA. See Fine needle aspiration (FNA) BRONJ, 342
Frank, I., 74, 91, 106, 169 calcium supplements and medications, 340
Freed, S.Z., 257 description, 339
Fuhrman, S.A., 33, 35, 36, 88, 93 intravenous (IV) bisphosphonates, 340
Fujimoto, N., 173, 179, 181, 184, 186 management, 340, 341
Fujita, T., 210 nephrotoxicity, 341
Index 353

parenteral pamidronate disodium and zolendronic renal mass detection

acid, 341 cysts and complex cystic, 60–63
retrospective subset analysis, 341 infiltrative, 63–65
symptoms, 340 solid, 59–60
Hypertension staging, CT and MRI
antihypertensive medication adrenal metastases, 71
blood pressure, 18 antiangiogenic therapies, 74–75
role, 19 hematomas, 73
types, 19 lymphadenopathy, 70
biological mechanisms, 18 metastatic disease, 71–72
kidney cancer, 18 papillary and chromophobe, 77
Hypoxia-inducible factor (HIF) partial nephrectomy, 72
convergent and divergent, 234–235 pathologic tumor stage, 73
RCC tumorigenesis, 234 pelvic and chest, 70
regulation and function, 233–234 percutaneous cryoablation, 74, 76
transcription factors, 233 post cryoablation changes, 74, 75
pseudoaneurysm, 73
renal central sinus invasion and urothelial
I invasion, 70
IFN-a renal vein and inferior vena cava tumor, 71
AVOREN and CALGB, 287 sagittal plane contrast-enhanced, 74, 77
and chemotherapy, 286 tumor size, 70
cytokine/chemotherapy combinations, advanced Immune therapy, 258, 270
RCC, 287–289 Immunology, RCC
“flu-like” illness treatment, 290 immune system physiology and renal tumor
high-dose bolus IV IL-2, 286 biology, 242
and IL-2, 286 immunosurveillance, 242
monotherapy, 290 Immunotherapeutic strategy, 164
mortality benefits, 286 Immunotherapy
phase I, II, III trials, 286–287 Française d’Immunothérapie, 251
prognostic factors and predictors, 287, 290 IKCWG, 251–252
QOL assessments, 290 MSKCC, 251
single agent therapy, 286 Incidence, RCC, 3
IKCWG. See International Kidney Cancer Working Inferior vena cava (IVC), 85
Group (IKCWG) Interferons (IFNs)
IL-2. See Interleukin-2 (IL-2) antitumor effects, 285
Imaging, RCC classification, 285
MDCT, 53 IFN-a (see IFN-a)
methods recombinant DNA technology, 285
contrast-induced nephropathy, 54 Interleukin-2 (IL-2)
CT, 55–56 adjuvant therapy, 282–283
MRI, 57–58 bolus intravenous HD therapy, 285
pseudoenhancement, 56–57 clinical response, 280
ultrasound, 54–55 CWG randomized phase III trial, 282
MR imaging hardware, 53 cytokine therapy, advanced RCC, 280–282
primary and secondary renal neoplasms definition, 279
AML and fat-containing renal event-free survival, 280, 282
tumors, 69 5-fluorouracil and IFN-a, 280
CN/MEST, 68–69 French multicenter phase III trial, 280
metastatic disease, 69 HD IL-2 combinations, 283
oncocytoma, 68 high-dose bolus IV administration, 280
renal lymphoma, 69 in vitro and clinical studies, 279
renal carcinoma subtypes multiple trials, 282
CCRCC, 66 murine tumor models, 280
chromophobe, 66, 68 NCI phase III study, 282
collecting/bellini duct carcinoma, 68 predictors
medullary carcinoma, 68 antecedent toxicities, 283–284
neoplasms, 65 CAIX expression, 284
PRCC, 66 gene profiling tumor specimens, 284
sarcomatoid, 68 genome-wide analysis, 284
354 Index

Interleukin-2 (IL-2) (cont.) L

nonselected patient populations, 284 Lambert, E.H., 208
prospective assessment, 284 Lamb, G.W., 107, 179, 181, 187
toxicity, HD IL-2, 285 Lane, B.R., 86, 91, 106, 170, 172, 175
UCLA SANI score, 284 Launonen, V., 48
radiographic response, 280 Lawrentschuk, N., 174
relapses, 285 Lebret, T., 111
systemic effects, 280 Lechevallier, E., 111
International Kidney Cancer Working Group (IKCWG), Lee, C.T., 108
251–252 Lee, J.E., 17
INTORACT. See Investigation of TORISEL and avastin Leibovich, B.C., 91, 199
combination therapy (INTORACT) Levy, D.A., 213
Intravenous (IV) bisphosphonates, 340 Libertino, J.A., 208, 209
Investigation of TORISEL and avastin combination Lindblad, P., 16
therapy (INTORACT) Liu, J., 112
cytokine/chemotherapy combinations, advanced Liu, N.W., 163
RCC, 288–289 LND. See Lymph node dissection (LND)
definition, 323 Locally advanced disease, RCC
Ito, K., 212 adjacent organ involvement, 211–213
IVC. See Inferior vena cava (IVC) extracapsular extension
collecting system invasion, 211
perinephric fat invasion, 210
J renal sinus invasion, 210–211
Jacobsohn, K.M., 160 lymph node disease (see Lymph node)
Jeldres, C., 175 postoperative surveillance
Jeppesen, A.N., 249 lymph node positive disease, 213–214
Jewett, M.A., 107, 188 surgical treatment, 213
Johnsen, J.A., 202 surveillance system, 214
Johnson, D.B., 162 primary targeted therapy, 219–220
Jonasch, E., 226, 264, 290 surgery, 197
Joslyn, S.A., 200 tumor thrombus, seeTumor thrombus
Jung, S.J., 210 Lohse, C.M., 199
Lotze, M.T., 280
Lucas, S.M., 160
K Lymph node
Kadesky, K.T., 84 cancer-specific survival, 199
Kanao, K., 91 CT imaging, 198
Karakiewicz, P.I., 91, 93, 94, 224 extranodal extension, 200
Karellas, M.E., 211 LND (see Lymph node dissection (LND))
Kato, M., 107, 173, 179, 181, 183, 184, 186 management, 205
Kattan, M.W., 86, 91 metastasis, 199
Kidney cancer, 119 non-metastatic disease, 199
Kidney mobilization and vascular control nuclear grade, 198
minimally invasive transperitoneal approach, staging, 198
139–141 vascular infiltration and distant metastases, 198
open approach, 138, 139 visceral metastatic disease, 197
retroperitoneal approach, 141 Lymph node dissection (LND)
Kim, H.L., 90, 91 benefits, 200
Kim, J.K., 69 patient survival, 200
Kirkali, Z., 206 types
Kitamura, H., 55 anatomic location, 204
Klatte, T., 91, 211 bulky retroperitoneal lymphadenopathy,
Klaver, S., 209 200, 201
Knudson, A.G., 25, 232 extensive neovascularization, 200
Kouba, E., 107, 179, 181, 184 inferior vena cava/aorta, 200–202
Kowalczyk, K.J., 163 interaortocaval region, 201, 203
Krishnamurthi, V., 262 intraoperative risk, 204
Kume, H., 209 low-stage and low-grade disease, 203
Kunkle, D.A., 107, 170, 185 nomograms, 203, 204
Kutikov, A., 92, 94, 171, 175, 262 randomized trial examining, 203
Index 355

RCC, 202 tumor size comparisons, 176–177

stages, 201 McDermott, D.F., 281, 282
tumor size and symptom classification, 204–205 MDCT. See Multidetector computed tomography
(MDCT)
Mellemgaard, A., 17
M Memorial Sloan Kettering Cancer Center (MSKCC), 251
MA. See Magesterol acetate (MA) Menko, F.H., 47
Magesterol acetate (MA), 342–343 Merchan, J.R., 320
Magnetic resonance imaging (MRI) MEST. See Mixed epithelial and stromal tumor (MEST)
characterize and stage RCC, 57 Metabolic toxicity, 307–308
and CT Metastasis
adrenal metastases, 71 adrenal, 24
antiangiogenic therapies, 74–75 imaging characteristics, 170
hematomas, 73 lung, 74, 150
imaging, staging, 69–70 Metastatic renal cell carcinoma (mRCC), 227
lymphadenopathy, 70 Metastectomy
metastatic disease, 71–72 of brain metastasis
papillary and chromophobe, 77 description, 270–271
partial nephrectomy, 72 recurrent disease and lymph node, 271
pathologic tumor stage, 73 systemic therapy, 271–272
pelvic and chest, 70 WBRT and SRS, 271
percutaneous cryoablation, 74, 76 description, 267
post cryoablation changes, 74, 75 long-term remission/regression, 267
pseudoaneurysm, 73 MSKCC prognosis score, 269
renal central sinus and urothelial invasion, 70 negative surgical margins, 268
renal vein and inferior vena cava tumor, 71 pre-TKI
sagittal plane contrast-enhanced, 74, 77 removal, multiple metastasis, 268–269
tumor size, 70 removal, single metastasis, 268
hardware, 53 retrospective series, 268
identification, calcium, 58 site-specific
NSF, 57 bone metastases surgery, 270
Mammalian target of rapamycin (mTOR) resection, liver metastases, 270
cancer biology resection, pulmonary metastases, 269–270
pathway inhibition, 240 targeted therapy, 267
RTKs, 240 Minervini, A., 202
serine-threonine kinase, 239 Mixed epithelial and stromal tumor (MEST), 68–69
TSC, 240 Moinzadeh, A., 209
description, 315 Molecular genetics
HIF factors, 241 CCRCC, 25–26
inhibitors (see mTOR inhibitors) ChRCC, 27
mTORC1/2 subunits, 240–241 papillary adenoma, 33
pathway, treating RCC, 241–242 PRCC, 26
resistance mechanisms, 330 renal oncocytoma, 34
signaling pathways Moore, S.C., 17
mTOR/PI3K/Akt, 315–316 Mortality
in RCC, 316–317 Europe, 10
S6 kinase-1 and eukaryote initiation factor 4E, 241 United States of America, 9
Management Mortensen, H., 120
nephron-sparing surgery, 49 Motzer, R.J., 251, 321
renal tumor size, 49 mRCC. See Metastatic renal cell carcinoma (mRCC)
Margulis, V., 198, 199, 211, 212, 225, 226 MRI. See Magnetic resonance imaging (MRI)
Martinez-Salamanca, J.I., 205 MSKCC. See Memorial Sloan Kettering Cancer Center
Masoom, S., 111 (MSKCC)
Matin, S.F., 158, 161, 162 MTD. See Maximum tolerated dose (MTD)
Matsumoto, E.D., 159 mTOR. See Mammalian target of rapamycin (mTOR)
Matsuzaki, M., 179, 181, 184, 186 mTOR inhibitors
Maturen, K.E., 111, 173 everolimus (see Everolimus)
Maximum tolerated dose (MTD) rapamycin and analogs, 318
description, 294 ridaforolimus, 329
renal lesion growth, 177 temsirolimus (see Temsirolimus)
356 Index

mTOR/PI3K/Akt pathway FDG PET CT, 263, 264

mTORC1 and mTORC2, 316 MSKCC, 263
PTEN function, 316 retrospective analysis, 266
S. cerevisiae TOR alleles, 315 sequential tissues collection, 265
serine/threonine protein kinase domains, 315 sunitinib, 263
structure, 316–318 surgical-related complications, 266
Multidetector computed tomography (MDCT), 53 upfront targeted therapy, 263, 264
primary targeted therapy, 223–224
renal medical impact, 125–128
N renal neoplasm, 92
Natural history, observed renal masses symptomatic primary tumours, 261
clinical and cross-sectional imaging, 177, 179–180 targeted therapy
delayed intervention CARMENA trial, 260–261
cross-sectional imaging and growth kinetics, CN assumption, 259–260
183, 184 metastatic sites and primary renal tumour, 259
patients, 185 novel drugs angiogenesis, 259
SRMs, 183 randomized phase III trial, 260
growth kinetics, 177 retrospective population-based study, 259
pathologic characteristics, 178, 181 sunitinib, 259
radiographic predictors, 182–183 Nephrogenic systemic fibrosis (NSF), 57
tumor size vs. time, 177, 178 Nephrographic phase (NP) scan, 55
“Zero Net Growth”, 185, 186 Nephron-sparing surgery (NSS)
Negrier, S., 251, 281, 290 bilateral renal masses, 134
Neoadjuvant targeted therapy closure, collecting system, 144
cytoreductive nephrectomy, 226 complications
description, 219 acute kidney injury, 146–147
mRCC, 227 bleeding, 147
primary targeted therapy (see Primary hemorrhage, 147
targeted therapy) nephrectomy, 148
TKI therapy, 227 surgical approach, 145–146
Neoadjuvant therapy, 225 urinary fistula formation, 146
Nephrectomy contralateral kidney, 135
cytoreductive, 226–227 demographic/perioperative factors, 145
cytoreductive nephrectomy (CN), 257 description, 133
debulking radical, 223–224 excision, tumor (see Tumor excision)
immunotherapy vs. immunotherapy alone familial/hereditary disease, 135
IL-2, 258 functional and oncology
metastatic sites, IFN-a, 258 minimally invasive approaches, 148
MSKCC prognostic score, 258–259 preservation, 148
proangiogenic growth factors, 258 robotic-assisted approaches, 149
SWOG and EORTC groups, 258 functionally/anatomically solitary kidney, 134–135
initial systemic therapy hemostasis, 143–144
efficacy data, 261 kidney mobilization and vascular control, 138–141
IFN-a vs. IFN-a, 261 laparoscopic and robotic assisted PN
potential advantages, 261 body habitus, 137
retrospective series, initial immunotherapy laboratory evaluations, 138
(IMT), 261, 262 RP, 137
retrospective studies, 261 surgical principles, 138
laparoscopic and robotic, 137–138 open vs. minimally invasive
molecular therapy, 88 patient characteristics, 136–137
mRCC, 257 tumor characteristics, 137
MSKCC prognostic score, 267–268 prevention, ischemic injury
nephrotoxicity, 341 depth, tumor, 142
organ/structure resection, 211 hilum and suture, 142
patient selection and preoperative evaluation, 120–121 satinsky clamp, 143
presurgical targeted therapy segmental clamping, 143
CARMENA trial, 262 sinus, 142
CT scans and diffusion MRI, 263, 265 steps, 141–142
description, 262 RCC, 135–136
EORTC trial, 266 surveillance schedule, 149, 150
Index 357

tumor localization, 141 Pantuck, A.J., 198, 201, 258, 284

urinary protein measurement, 149 Papillary renal cell carcinoma (Papillary RCC)
X-ray, 150 clinical features, 26
Neuzillet, Y., 111 molecular genetics, 26
Nguyen, C.T., 163 pathology, 26
Nguyen, M.M., 170 Paraneoplastic syndromes, 87
Nicodemus, K.K., 16 Parker, A.S., 15, 18, 90, 91, 200
Niwakawa, M., 289 Partial nephrectomy (PN)
Nomogram approach, 145, 146, 148
nephrectomy, 204 description, 133
node-positive disease, 204 laparoscopic and robotic-assisted, 137–138
renal function, 94 Pathology, RCC
TNM stage, 93 cancer syndromes, 28–31
Non-myeloablative allo-transplantation classification, 23
GVL and GVH, 291–292 common benign renal tumors, 31–34
myeloablative conditioning, 291 and molecular characteristics
tumor response rate, 292 CCRCC, 23–26
Novick, A.C., 147, 148 ChRCC, 26–27
NP scan. See Nephrographic phase (NP) scan PRCC, 26
NSF. See Nephrogenic systemic fibrosis (NSF) subtypes, 27
NSS. See Nephron-sparing surgery (NSS) unclassified type, 27
primary kidney tumors, 23
prognosis parameters
O Fuhrman nuclear grading, 35
Obesity microvascular invasion, 38
cancer development sarcomatoid and rhabdoid differentiation, 35–36
consumption, fatty fish, 17 tumor necrosis, 36–38
fat and protein intake, 16 Patil, S., 253
genetic factors, 16 Paul, R., 212
macro and micronutrient variation, 16 Pavlovich, C.P., 46
physical activity, 17 Pazopanib (Votrient®)
cancer-specific survival outcome, 17–18 COMPARZ study, 303
insulin resistance and hyperinsulinemia, 15 description, 303
metabolic function, liver, 15–16 PISCES trial, 303–304
metastatic patients, 18 PD-1. See Programmed death-1 (PD-1)
Observation PD-L1. See Programmed cell death 1 ligand 1 (PD-L1)
and contemporary, 176–177 Pharmacokinetics
SRM, 181, 184, 186–188 endpoints, PFS, 305
Oda, T., 173, 179, 181 everolimus, phase I studies
O’Donnell, A., 324, 325 absorption, 324
Oncocytoma, renal excretion, 324–325
clinical features, 33–34 metabolism, 324, 325
molecular genetics, 34 tumor response and toxicity, 325
131
pathology, 34 I-congugated cG250, 291
PISCES trial, 303
temsirolimus, phase I studies
P absorption, 319
Pahernik, S., 106 elimination, 319–320
Pain. See Cancer pain management metabolism, 319
Palliative and supportive care, renal cancer tumor response and toxicity, 320
anorexia and cachexia, 342–343 Phosphatase and tensin homolog (PTEN) gene, 316–318
cancer pain management (see Cancer pain PN. See Partial nephrectomy (PN)
management) Powles, T., 264
chronic illness, 337 Prevalence, RCC, 8–9
description, 337 Primary targeted therapy
fatigue, 343 cardiovascular toxicity, 226
hypercalcemia and bisphosphonate therapy debulking radical nephrectomy, 223–224
(see Hypercalcemia) locally advanced RCC
Palliative care. See Palliative and supportive care, renal potential limitations, 220
cancer rationale, 219–220
358 Index

Primary targeted therapy (cont.) tumor burden and patient factors, 249, 250
VEGF, 219 VEGF era, 252–254
von Hippel–Lindau tumor, 219 Programmed cell death 1 ligand 1 (PD-L1), 294–295
neoadjuvant therapy, 225 Programmed death-1 (PD-1), 294–295
NSS, 224–225
patient selection, 220, 221
radiographic response, 222 Q
renal mass biopsy, 220, 222 Quality-of-life (QOL) assessments, 290
targeted molecular therapy, 222
thromboembolic complications, 226
tumor thrombus, 224 R
wound healing, 225–226 Rabbani, F., 207
Prognosis, RCC Rackley, R., 262
Fuhrman nuclear grading, 35 Radical nephrectomy (RN)
microvascular invasion, 38 adverse renal medical impact
sarcomatoid and rhabdoid differentiation, 35–36 benign tumors, 127–128
tumor necrosis CKD, 126
CCRCC, 36–37 eGFR, 126
histological, 37 kidney failure, 125
role, 38 radical vs. partial nephrectomy, 126, 127
Prognostic algorithms, 93 bilateral tumors, 128
Prognostic factors, RCC historical considerations, 120
biomarkers, 254 imaging techniques, 119
consortium model, 254 intensity, treatment, 125
description, 249 invasive radical nephrectomy
histologic subtype EBL, 125
HIFs, 89 laparoscopic training, 124
papillary and chromophobe, 89 LRN, 123
histopathologic factors patient selection and preoperative evaluation
invasion, renal sinus, 88 brain imaging, 121
nuclear grade, 87–88 regional adenopathy, 120
renal tumors, 89 regional lymphadenopathy, 129
sarcomatoid differentiation, 88 risk factors, kidney cancer, 119
tumor necrosis, 88–89 surgical anatomy
hyponatremia, 249, 251 ipsilateral adrenalectomy, 123
immunotherapy era, 251–252 kidneys, 121
integrative predictive tools miniflank surgical incision, 122
algorithms/nomograms, 91 urological oncology community, 128
cancer-specific, 90 Radiofrequency ablation
nomograms for suspected renal CT, 158
malignancy, 92 needle biopsy, 157
postoperative prognostic algorithms, 92–94 RFA, 157
predictive algorithms, 94 tumors, 158
laboratory-related factors, 87 Radiofrequency ablation (RFA), 155, 157, 159
molecular factors Raj, G.V., 91, 92
gene expression profiling, 89 Raman, J.D., 160, 163
T-cell-mediated antitumoral Rapamycin and analogs, 318
immunity, 90 Raymond, E., 319
tissue microarrays, 89–90 RCCs. See Renal cell carcinomas (RCCs)
mRCC patients, 249, 250 Receptor tyrosine kinases (RTKs), 234, 240
paraneoplastic syndromes, 87 RECISTs. See Response evaluation criteria in solid
patient-related factors, 86–87 tumors (RECISTs)
prognostication, 254 Remzi, M., 106, 169
proinflammatory markers, 249, 250 Renal cancer. See Surgery integration, metastatic renal
refinement, tools, 95 cancer
systemic therapies, 83 Renal cell carcinomas (RCCs) See also Biology,
TNM staging system RCCaggressive surgical treatment, 105
pathologic findings, 84 CAIX monoclonal antibody treatment, 291
renal sinus involvement, 85 co-stimulatory signals
vascular involvement, 85–86 CD28, 292
Index 359

CTLA-4, 292–294 obesity, 15–18

kinase inhibitor and sunitinib effect, 295 smoking, 12–15
PD-1 and PD-L1 (B7-H1), 294–295 RMB. See Renal mass biopsy (RMB)
stimulation, TCR, 292 RN. See Radical nephrectomy (RN)
cytokine therapy Robert, G., 223
description, 279 Roberts, W.W., 210
IFN (see Interferons (IFNs)) Robotic-assisted approach, 137–138, 143, 145
IL-2 (see Interleukin-2 (IL-2)) Robson, C.J., 120, 133
definition, 279 Rosales, J.C., 107, 109, 180, 181, 184, 188
demographics Rosenberg, S.A., 281
age, 10–11 Rothman, J., 169
ethnicity, 12 RTKs. See Receptor tyrosine kinases (RTKs)
sex, 11
description, 133
environmental risk factors for RCC S
hypertension, 18–19 Sabers, C.J., 315
obesity, 15–18 Saidi, J.A., 213
smoking, 12–15 Santos Arrontes, D., 170
incidence Schafhauser, W., 203
Europe, 6 Schlomer, B., 106
incidence rate, tumor size, and stage, 8 Schmidbauer, J., 111
United States of America, 3–6 Sehgal, S.N., 318
worldwide, 6–8 Sella, A., 262
kidney cancer, 19 Sequential therapy, 310
medullary, 109 Shannon, B.A., 111
mortality Shapiro, J.A., 19
Europe, 10 Sherry, R.M., 262
United States of America, 9 Silberstein, J.L., 225
nephrectomy, 108 Siu, W., 180, 181, 183, 186, 187
non-myeloablative allo-transplantation, 291–292 Skeletal-related events (SREs)
NSS (see Nephron-sparing surgery (NSS)) bisphosphonates, 341
PN, 135 description, 340
prevalence, 8–9 retrospective subset analysis, 341
regressions, 279 zoledronic acid, 341
tumors, 106 Skinner, D.G., 206, 257
vaccines (see Vaccines) Smaldone, M.C., 178
Renal function Small renal mass (SRM)
concomitant disease processes, 134–135 active surveillance and natural history, 107
preservation, 148 growth kinetics, 176
Renal mass biopsy (RMB) management, 172
anticoagulation medications, 113 pathology data, 106
diagnosis and management, cancer types, 110 preoperative radiographic characteristics,
evolving role 168–169
CGH, 113 Smoking
genome-wide and proteome-wide analysis, 113 cancer development, 13, 14
pan-genomic mutational analysis, 113 gender-specific differences, 14
historical noninformative rate, 111 kidney cancer, 14
noninformative, 112 tobacco consumption, 15
techniques and cancer, relationship, 13, 14
contemporary data, 111 cancer-specific survival outcome, 15
cytological preparation and pathologic carcinogens, 12
analysis., 112 excretory pathway, 12
FNA, 111 Somani, B.K., 111
Response evaluation criteria in solid tumors Sorafenib (Nexavar®), 304
(RECISTs), 74 Sorbellini, M., 91, 92
Retroperitoneal (RP) approach, 137 Sowery, R.D., 179, 181, 187
RFA. See Radiofrequency ablation (RFA) Soyer, P., 110
Rini, B.I., 113, 294, 317 Spencer, W.F., 262
Risk factor SREs. See Skeletal-related events (SREs)
hypertension, 18–19 Srivastava, P., 290
360 Index

SRM. See Small renal mass (SRM) pharmacokinetics, 319–320

Stephenson, A.J., 213 sequential treatment, Torisel 404, 323
Sunitinib (Sutent®) wound healing, 225–226
CARMENA trial, 260 Terrone, C., 199, 211
CT scans and diffusion MRI, 263, 265 Thermal ablation
description, 302 biopsies, 159
FDG PET CT, before and after, 263, 264 complications, 162
multikinase TKI, 303 cytotoxic mechanisms, 155–156
nephrectomy, primary metastatic disease, 263 description, 155
treatment, mRCC, 259 diagnostic biopsy, 156
upfront targeted therapy, 263, 264 functional outcomes, 160
VEGF TKIs, 259 immunotherapeutic strategy, 164
Sun, M.R., 110 multi-quadrant core biopsy
Surgery integration, metastatic renal cancer specimens, 160, 161
metastasectomy oncological outcomes, 160–162
of brain metastasis, 270–272 patient selection and preparation, 156–157
metastasis removal, pre-TKI, 268–269 salvage, treated kidneys, 162–163
MSKCC prognosis score, 269 techniques
site-specific, 269–270 cryoablation, 158–159
nephrectomy radiofrequency ablation, 157–158
historical considerations, 257 therapies, 163–164
history, initial systemic therapy, 261–262 treatment, 159–160
immunotherapy vs. immunotherapy alone, 257–259 Thomas, A.A., 223, 225
MSKCC prognostic score, 266–267 Thompson, R.H., 169, 170, 210, 211
presurgical targeted therapy, 262–266 Thromboembolic complications, 226
symptomatic primary tumours, 261 TKIs. See Tyrosine kinase inhibitors (TKIs)
targeted therapy, 259–261 TNM staging system
Sweeney, P., 210 pathologic findings, 84
Sweeny, C., 15 renal sinus involvement, 85
Swierzewski, D.J., 206 vascular involvement
IVC, 85
metastatic disease, 85–86
T tumor thrombus, 85
T1. See T1 renal tumors and mass biopsy Tolia, B.M., 257
Tabernero, J., 325 Torisel 404, 323
Tanaka, C., 324 Toro, J.R., 47
Targeted therapy. See Mammalian target of rapamycin Toxicity management
(mTOR) anti-VEGF therapy, 305, 306
T4 disease. See Adjacent organ invasion cardiovascular (see Cardiovascular toxicity)
Temsirolimus constitutional, 305
clinical, 323 dermatological, 308
combination treatment description, 305
BeST, 323 gastrointestinal, 307
INTORACT, 323 hematologic and laboratory, 309
description, 318 problems, 305
everolimus inhibition, mTORC1, 241 renal, 308–309
molecule and receptor, VEGF, 322 Treatment
mRCC treatment algorithm, 302 combination
phase III trial BeST trail, 323
features, patients, 321 INTORACT trial, 323
IFN and temsirolimus/IFN combination, 321 sequential, Torisel 404, 323
OS and secondary efficacy endpoints, 321 T1 renal tumors and mass biopsy
side effects, global ARCC, 322 CKD, 105
subsequent subset analysis, 322 contemporary management
treatment arms, patients, 321 absolute indications, 115
phase II studies coronary artery disease, 115
in advanced RCC, 320–321 counseling, patients, 115
multicenter dose escalation phase I/II study, 321 nephron-sparing modalities, 114
role, 320 oncocytic tumor, 115
phase I studies evolving role, RMB, 113–114
dosing, 318–319 identification, novel biomarkers, 116
Index 361

natural history van der Velt, A.A., 222, 223

analysis, growth rates, 107 Van Poppel, H., 206
CSM, 108 Vascular endothelial growth factor (VEGF)
SRM, 107 agents, mRCC, 259
zero net growth, 107 angiogenic factor X, 235
pathologic features anti-VEGF mechanism, 301, 302
contemporary SRM data, 106 axitinib, 304
pathologic distribution, 106 bevacizumab, 301–302
risk assessment and cancer, 238–239
contrast enhancement, 109–110 cediranib, 305
demographic factors, 108 cleveland clinic foundation criteria, 252
features, 110 functions, 237–238
patient demographic factors, 108–109 International mRCC Consortium database, 252–253
radiologic tumor size, morphology management, 237
and staging, 108 mitogen activity, 239
size, 109 mRCC treatment algorithm, 301, 302
RMB, 110–113 mTOR-treated patients, 253–254
TSC. See Tuberous sclerosis complex (TSC) optimal duration, treatment, 309–310
Tsui, K.H., 213 oxygen and nutrient delivery, 236
Tuberous sclerosis complex (TSC), 240 pazopanib, 303–304
Tumor excision predictive factors, 309
parenchyma, 143 proangiogenic, 258
PN, 143 protein structure and isoforms, 236–237
simple enucleation, 143 receptors, 239
Tumor thrombus resistance, sequential (see Combination therapy)
BCS, 209–210 sorafenib, 304
clinicopathological features, 207 sunitinib, 302–303
imaging, 205 sunitinib phase III trial, 253
patient survival, 208–209 targeting tumor angiogenesis, 239
staging, 205, 206 temsirolimus, 266–267
surgical resection tivozanib, 304
infrahepatic, 207, 208 TKIs, mRCC, 301, 303
IVC thrombectomy, 205 toxicities and management (see Toxicity management)
metastatic disease, 206 Vatten, L.J., 18
non-metastatic disease, 205–206 VEGF. See Vascular endothelial growth factor (VEGF)
radical nephrectomy, 206 Veltri, A., 111, 112
renal artery, 207 Verhoest, G., 108
vena caval clamping, 207 Vermooten, V., 133
venous wall involvement, 209 Vezina, C., 318
Tykodi, S.S., 292 VHL syndrome. See von Hippel–Lindau (VHL)
Tyrosine kinase inhibitors (TKIs) syndrome
CN patients, 259 Volpe, A., 107, 111, 112, 179, 181, 184, 186
hypothesis, 272 von Hippel–Lindau (VHL) syndrome
mRCC agent, 259 clinical criteria, 44, 45
and nephrectomy, 267 disease, 231–232
pazopanib, 239 EGFR, 44
pre-TKI, 268–269 gene mutation, 43–44
refractory disease, 263 genotype–phenotype correlations, 44, 46
sunitinib, 259 hereditary syndrome, 43
molecular pathway, 44, 45
regulation, HIF and cellular hypoxic response,
U 232–233
UCLA SANI score, 284 sporadic RCC, 232
Upton, M.P., 284 tumor suppressor, 233
Urinary fistula formation, 146 Vricella, G.J., 159

V W
Vaccines Wagner, J.R., 262
HSPs, 290 Wang, R., 111
oncofetal antigen 5T4, 290–291 Wehle, M.J., 107, 179, 181
362 Index

Weisbrod, A.J., 160, 163 Y

Wells, S., 133 Yang, J.C., 281, 293
Wong, J.A., 180, 181, 186, 187 Youssif, T.A., 107
Wood, D.P. Jr., 112, 202, 203
Wotkowicz, C., 208
Wszolek, M.F., 208 Z
Wyeth, A., 323 Zagoria, R.J., 156
Zhang, J., 107, 110
Zhu, Y., 13
X Zincke, H., 199
Xp11.2/TFE3 renal cell carcinoma, 28–30 Zini, L., 108, 197, 209
Xu, C., 254 Zisman, A., 91, 198, 206