Download Thirteenth International Kidney Cancer Symposium

Thirteenth International
Kidney Cancer Symposium
Presentation Notes: An Overview of the Proceedings
Summaries by:
JOYCE WILCOX GRAFF
ANDY DERR
MICHAEL B. LAWING - Editor
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In 2015
THE KIDNEY CANCER ASSOCIATION
Celebrates Twenty-Five Years
Of Service to those who are
afflicted with Kidney Cancer
The Kidney Cancer Association (KCA) is a charitable organization made up of patients, family
members, physicians, researchers, and other health professionals globally. It is the world’s first
international charity dedicated specifically to the eradication of death and suffering from renal
cancers. It is also by far the largest organization of its kind, with members in more than 100
countries. We fund, promote, and collaborate with the National Cancer Institute (NCI), American
Society for Clinical Oncology (ASCO), American Urological Association (AUA), and other institutions
on research projects. We educate families and physicians, and serve as an advocate on behalf of
patients at the state and federal levels in the United States and globally.
THE FOLLOWING ARE A FEW OF OUR MANY RESOURCES FOR PATIENTS
WWW.KIDNEYCANCER.ORG -- WWW.TWITTER.COM/KIDNEYCANCER
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To Our Dear Readers – A Comment from Michael B. Lawing - Editor
We are pleased to present this Patient Summary of the 13 th International Kidney Cancer
Symposium for your consideration. This collaborative assemblage of presentation summaries
written by Joyce W. Graff, Andy Derr, and myself are in many ways consistent with the
treatment as well as the ongoing research in the field of kidney cancer; it is approached in
various ways by the parties involved.
My survivorship journey with kidney cancer has now entered its 18th year. It began in the era of
cytokine treatments, has spanned the advent and rapid proliferation of targeted therapy
treatments, and witnesses the exciting possibilities that lie before us; I am ever optimistic of
further progress. With the new wave of immunotherapy research, trials in the combining of
immunotherapeutic agents with tyrosine kinase inhibitors, vaccines, and the rapidly-increasing
knowledge that is being gained through genetic studies, microbubble investigations, and the
ability to measure circulating tumor cells, I possess only a rudimentary and partial glimpse of
the energy and knowledge that is being focused upon this cancer. Throughout the world
inquiring minds in research facilities as well as in clinical practices and operating rooms have a
vision and commitment to make the survivorship and quality of life of kidney cancer patients
increasingly common and of longer duration.
Somewhere behind much of this is an organization whose goal is to eliminate the pain and
suffering and loss of life caused by kidney cancer. Through its commitment to research,
advocacy, and education, the Kidney Cancer Association (KCA) has served as a catalyst to
energize and unite the efforts of many and to remain behind the scenes through much of the
events in which it has played a part during the last 25 years. The annual symposia that it hosts
in Europe as well as the United States are two examples of how it has been able to bring
together experts in this cancer; a collaboration which has been mutually beneficial to the
science as well as the patient. During the 13th International Kidney Cancer Symposium Dr.
Elizabeth Plimack was asked by the European Medical Journal what the 2014 Kidney Cancer
Symposium in Chicago hoped to achieve. This is a summation of her reply.
What KCA brings together in these symposia are
urologists, medical oncologists, pharmacists, scientists,
and nurses. It gathers those of us who care for patients
on the front lines and those who are at the bench
developing new therapies; people with a passion for
kidney cancer that are finding new treatments for or
are taking care of patients with kidney cancer.
During these sessions we get to hear each other’s
points of view; the discussions are very rich and varied.
I LOVE THE OPPORTUNITY TO ATTEND THESE SYMPOSIA.
Warmest Wishes – Michael B. Lawing
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Symposium Summary: Joyce W. Graff
This year’s Kidney Cancer Symposium could most simply be characterized as an effort to
“fine-tune” diagnosis and treatment for kidney cancer. While at
some
80%
kidney
least
80%ofof
kidneycancer
canceris
clear
cell,
that
additional
percentage
is made
of a wide
variety
oftypes,
cell types,
of
is clear
cell,
that
additional
20 % is made
up ofup
a wide
variety
of cell
eacheach
of which
which
responds
differently
the targeted
therapies.
By targeting
the particular
molecular
responds
differently
to the to
targeted
therapies.
By targeting
the particular
molecular
process that is disrupted in each different cell type, better results can be obtained for the
patient. According to Dr. Michaelson, “by 2020 we will identify predictive factors for VEGF,
mTOR, and PD-1 therapies, determined by a piece of the tissue and genetics.”
Of all kidney cancer (including clear cell), 5-10% are hereditary. When an individual has a
hereditary kidney cancer syndrome, two important considerations apply to the immediate
care of this individual. One: there will likely be more tumors in future, so treatment choices
must be made considering more than this one tumor. Second: there may be other parts of
the body that need to be monitored as well. All people with kidney cancer younger than
age 45 should be screened for hereditary conditions.
Treatment choices may differ also depending on the circumstances of this individual
patient. For example, how many people who already have diabetes or some impairment of
kidney function are offered partial rather than radical nephrectomy? There is now greater
recognition that the long-term outlook for this patient’s kidney health is better if there is a
higher volume of remaining nephrons.
There is a great deal more to be learned, and more new treatment options on the horizon,
but we are asking better questions, and designing better studies, to improve our ability to
choose the optimal personalized treatment strategy for each individual patient. In his
keynote talk, Dr. Bradley Leibovich advised: “The better you get to know your patients the
better the outcome will be.”
Joyce Graff: Empowering Patients - from the Brookline (MA) Rotary Website
… For fifteen years she helped her late husband manage as best they could with the rare
von Hippel-Lindau disease. When their son was diagnosed with the same disease nine
years after his father's death, Joyce became his patient advocate, gathered information
from around the world, and in 1993 founded the VHL Alliance. Joyce also wrote a VHL
Handbook for patients and their families. The VHL Family Alliance is now a global
Joyce and Snowy
organization.
She has always been an advocate for folks with serious diseases and now is advocating for some diseases
which are even rarer than VHL. Through the Powerful Patient www.powerfulpatient.org she works to help
people understand what is going on, to ask better questions, and to work as a partner with their medical
teams. In 2014 Joyce had three published articles about the patient's perspective on radiation safety in
medicine: she was also a speaker at a Bulgarian conference on Radiation Protection in Medicine which was
sponsored by the International Atomic Energy Agency.
Source: http://portal.clubrunner.ca/3670/Stories/joyce-graff-empowering-patients#sthash.rIdLUHPu.dpuf
A portion of Joyce’s story also appears in We Have Kidney Cancer: Survivor’s Stories available for viewing on
the KCA Website http://www.kidneycancer.org/download-we-have-kidney-cancer/
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Symposium Summary: Andy Derr
I would like to thank the Kidney Cancer Association for the
opportunity to attend this year's Kidney Cancer Symposium in Chicago.
As the "rookie" on the team of patient liaisons reporting on the conference,
my hope is that I have contributed to this document at the same
outstanding level as my partners Mike and Joyce. It was truly a pleasure to
work on this project with them, and I definitely appreciate their mentorship.
By way of background, I was diagnosed with kidney cancer in 2003.
I am a researcher by nature, and can remember at that time reading
anything and everything I could get my hands on that dealt with the disease.
After a week of Internet research, I came to the stark realization that there
weren't a ton of options out there for stage 4 kidney cancer patients in
2003. I was lucky enough to have surgical treatment and escape metastatic disease at that time, and I
continued to follow discussion groups and read articles for a year or two after that. Like anything
though, you drift away from it over time when it’s not top of mind. After five years of disease free
existence, I felt good about my prognosis; after ten, really good. But, as we all know kidney cancer can
be a very sneaky disease, and after eleven years it returned for me metastatically. I again put my
research hat on, but this time I found an entirely different story. I discovered so many options that
became available in the decade that passed between my initial diagnosis and now, and I feel very
fortunate for the medical advances that have developed in that timeframe.
I attended all of presentations at this year's symposium, and the quality and amount of
information presented was outstanding. I especially enjoyed the sessions that dealt with protein
pathways and treatment drugs that interact with those pathways. With the aid of today's incredible
computing power, targeted drugs are being developed that can enhance or inhibit various protein
signaling in the body. I was amazed at the level of research devoted to protein signaling as related to
kidney cancer, but it also seems that we are only at the beginning stages of this research. It was also
clear to me that many advances are being made in the area of predictive biomarkers for kidney cancer.
Over the next few years, the hope is that these biomarkers can be used to better match a drug or a
combination of drugs to a patient. Biomarkers might even be able to show when drug resistance is
beginning to occur. Finally, I found the presentations around managing toxicity to be very informative.
Targeted therapy drugs are only useful if we can understand how to best manage the associated toxicity
effects, especially when these drugs are used in combination.
After a decade long absence, I am back to researching and learning everything I can about this
very complex disease called kidney cancer. There have been many advances in that decade for sure but
we still need to get to the ultimate advance, a disease-free treatment option for each and every patient.
Every effort has been made to present information in the general context of which it was delivered and as
accurately as possible. While the material in this overview is intended to be informative, it has not been reviewed
by a scientific or medical advisor or the Kidney Cancer Association for accuracy or completeness; the authors of
this summary are patient advocates with no medical standing or expertise. No endorsement of any Facility,
treatment, procedure or clinician is implied in this overview, nor is it a substitute for the medical advice provided by
the reader’s physician. MBL
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Table of Contents
03 Patient Advocate Comments – Joyce Graff, Andy Derr, Mike Lawing
08 Projecting Individual Probability for Developing Renal Cell Cancer – XiFeng Wu, M.D.
13 Epidemiology and Molecular Markers in RCC – Mark Purdue, M.D
14 The Benefits and Limitations of Biopsy for Risk Stratification in RCC – E. Jason Abel, M.D.
16 Patient and Tumor Characteristics Predict Indeterminate Renal Mass Biopsy Findings – Joel Prince
18 A Special Segment on Genetic Cancers – Joyce W. Graff
21 Management of Kidney Cancer in Young Patients – Brian Shuch, M.D.
23 Hereditary Syndromes in Kidney Cancer; Beyond VHL – Nicholas G. Cost, M.D.
26 Debate: Partial Nephrectomy for t1b/t2a RCC – Tim Masterson, M.D.
29 Debate: Radical Nephrectomy for t1b/t2a RCC – Vitaly Margulis, M.D.
31 AUA and NCCN Surveillance Guidelines for RCC: Do They Effectively Capture Recurrences Following Nephrectomy?
R. Houston Thompson, M.D
34 Quality Indicators in RCC Care – Antonio Finelli, M.D.
35 Neoadjuvant Targeted Therapy – Jose A. Karam, M.D.
36 Ablation of Larger and Recurrent Tumors – Thomas D. Atwell, M.D.
38 Pros and Cons of Node Dissection for Local Advanced RCC – Jonathan A. Coleman, M.D.
39 Latest on IVC Tumor Thrombus – Sarah Psutka, M.D.
41 Recurrence After Surgery in Non-Metastatic RCC with Thrombus; Risk Factors from a Contemporary Multicenter
Analysis – Michael L. Blute, Jr. M.D.
42 Cytoreductive Nephrectomy – Steven Culp, M.D.
44 Novick Lecture – Bradley C. Leibovich, M.D., FACS
47 Young Investigator Award & New Initiative on Precision Medicine – Collins & Varmus
49 Chromophobe RCC – James Hsieh, M.D.
50 Papillary RCC – Laurence Albiges, M.D., Ph.D.
52 XP11.2 / Translocation RCC – Gabriel Malouf, M.D.
53 Renal Medullary Carcinoma – JianJun Gao, M.D.
54 Sarcomatoid/Biology/Clinical – Abraham Hakimi, M.D.
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55 ESPN, ASPEN and Beyond – Toni K. Choueiri, M.D.
56 Basic Concepts and Future Horizons in Cancer Immunotherapy – Drew Pardoll, M.D.
58 Immunotherapy is the Optimal Front-Line mRCC Treatment – Michael B. Atkins, M.D.
59 TKIs are the Optimal Front-Line mRCC Treatment – M. Dror Michaelson, M.D., Ph.D.
60 Combinations of Immunotherapy and TKIs are the Optimal Front-Line mRCC Therapy – Elizabeth Plimack, M.D.
62 Biomarkers on Checkpoint Inhibition - Suzanne L. Topalian, M.D.
64 Follow-up of a Phase Ia Study of MPDL-3280A, An Engineered PD-L1 Antibody, in
Patients with Metastatic Renal Cell Carcinoma (mRCC) – David F. McDermott, M.D.
66 Immune Cell Repertoire in Patients with Metastatic Renal Cell Carcinoma: Data From Prospective Clinical Trial
Vijay Damarla, M.D., M.P.H.
67 Abstract- Phase 1 Study of Nivolumab in Combination with Ipilimumab (IPI) in Metastatic Renal Cell Carcinoma
(mRCC) – Hans Joerg Hammers, M.D.
69 Balancing Dose Delivery – Laura Wood, R.N., MSN, OCN
70 Sidebar: The KCA Nurse Advisory Board
72 Updates in Toxicity Management & Education Resources – Nancy Moldawer, R.N., MSN
74 Toxicity as a Biomarker – Frede Donskov, M.D.
76 Dose Reduction or Treatment Interruption: Pro Dose Reduction – David I. Quinn, M.D., Ph.D., MBBS, FRACP
78 Dose Reduction or Treatment Interruption: Pro Treatment Interruption/Schedule Alteration – Georg Bjarnason, M.D.
80 Sidebar: A Second Look At Georg A. Bjarnason, M.D.
81 Bateriomic Profiling Reveals Potential Etiology for Vascular Endothelial Growth Factor-Tyrosine Kinase Inhibitor
(VEGF-TKI)-Related Diarrhea in Patients with Metastatic Renal Cell Carcinoma – Sumanta Pal, M.D.
82 Biology-Based Classification of RCC – James Brugarolas, M.D., Ph.D.
84 MET Pathway as a Target in RCC – Harriet Kluger, M.D.
85 CTC’s in RCC – Joshua Lang, M.D., M.S.
87 Schonfeld Lecture – Bernard J. Escudier, M.D.
89 Commentary: For What It’s Worth – Patient Advocate Michael B. Lawing
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Projecting Individual Probability for
Developing Renal Cell Cancer
XIFENG WU, M.D.
University of Texas
M.D. Anderson Cancer Center,
Houston, TX
“Today I’m going to talk about risk prediction models for renal cell cancer;
risk prediction is much like fortune-telling – it is not like smoke and mirrors”.
INTRODUCTION/OVERVIEW: Dr. Wu described a working model of a multi-faceted approach to study
the risk of renal cell carcinoma that has been developed by her team. Preliminary results indicate it
has an estimated 80% accuracy rating. These risk prediction tools may someday help the clinical
medical team to answer four of the primary questions that patients often ask; namely, “what is my
risk of cancer, what can I do to lower my risk, what screening options are the best for me, and what
is the best treatment option based on my risk/benefit ratio”? Furthermore these tools can
potentially be very useful in educating healthy individuals on making efforts to remain healthy and
to reduce their risk of developing kidney cancer.
Dr. Wu explained that in risk prediction information is collected on environmental exposures,
lifestyle factors, and the genetics of the individual to develop an integrative risk assessment
model. By combining these data with the clinical characteristics of the disease or condition as
well as the phenotype or observable characteristics of the individual a very personalized outline
of future risk reductions and possible therapy for each patient can be developed.
While the screening and treatment options will vary widely from patient to patient, information
presented on exposures and lifestyle factors may be beneficial in identifying risks and behavior
patterns that could be modified to lessen the impact of these items to people who have been
diagnosed as well as to the general population.
MISSION STATEMENT OF THE NATIONAL CANCER INSTITUTE
The National Cancer Institute coordinates the National Cancer Program, which conducts and
supports research, training, health information dissemination, and other programs with respect to
the cause, diagnosis, prevention, and treatment of cancer, rehabilitation from cancer, and the
continuing care of cancer patients and the families of cancer patients.
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PUTTING KIDNEY CANCER INTO PERSPECTIVE: according to the American Cancer Society there were some
1.3 million cases of cancer diagnosed in the United States in 2014; of these an estimated 64,000 were
renal cell cancers. While there were some 13,800 deaths due to this disease it is important to realize
that there are over 200,000 survivors of kidney cancer in the US.
The chart below lists data compiled by the NCI that is on the American Cancer Society website:
Information presented by Dr. Wu on the following pages on diet, exercise, and environmental
exposures may be useful in reducing risks of cancer or risks of recurrence for some individuals.
“You need to learn as either the patient or the person that’s the advocate, to let go sometimes. Because
the same schedule you had when everything was fine and it was a sunny day is not the same schedule
you have based upon that illness. And then it takes a little more time, perhaps, or it takes a little bit
more understanding of how to actually do things, practical things like putting on your clothes, side
effects from the medicine, preparation of food, or preparation for travel. You have to learn to make
adjustments.”
Renee, a Caregiver -- We Have Kidney Cancer: Survivor’s Stories p. 51
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The risk items in the chart
at right are some of those
used by Dr. Wu and her
team for their risk
prediction model. The
environmental exposure
items have an accuracy
rating of 54% while the
medical items were more
accurate predictors of risk.
(A coin toss is 50%)
The physical activity and
diet components of the
study scored an accuracy
level of 75%. While little if anything can be done to overcome exposures to risk factors in the
past, awareness of these factors and avoidance or proper handling of them could be very
important in the future.
DIET AND EXERCISE
Low physical activity as well as a high amount of energy intake presents an increased risk of
RCC. Dr. Wu explained that persons who have had a history of body mass index readings that
indicated an overweight condition three years or more prior to diagnosis have an increased risk
factor of 1.7. Those in the obese range have a higher risk factor of 2.3 -persons who have been
obese for prolonged periods of time have an even higher risk factor of above 2.6.
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PHYSICAL ACTIVITY AND ENERGY INTAKE: JOINT EFFECTS ON RCC RISK
It appears there are great
benefits to maintaining a high
level of physical activity as well
as a low level of energy intake.
Persons who maintained their
weight between the ages of 20 and 40 or who had less than a 10 pound overall gain had no
increase in risk factor; those who gain between 10 and 25 pounds had an increased risk factor
of 1.6, while those with more than a 25 pound weight gain doubled their risk factor of being
diagnosed with RCC.
The study also examined different overall diets. Due to the location of the study (Southwestern
US) a Tex-Mex Diet, a traditional American diet, and a Vegetable/Fruit diet were observed.
Many
factors that increase the risk of developing
cancer are related to lifestyle, and it is estimated that
more than 50 percent of the 585,720 cancer deaths
expected to occur in the United States in 2014 will
be related to preventable causes. Most notable
among these causes are tobacco use, obesity, lack of
physical activity, exposure to ultraviolet light from
the sun or tanning devices, and failure to use or
comply with interventions that treat or prevent
infection with cancer-associated pathogens.
Source: American Association for Cancer Research.
AACR Cancer Progress Report 2014.
Clin Cancer Res 2014; 20(Supplement 1): SI-S112 pIX
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“Previously at our institution we have demonstrated that having 15 minutes of daily moderate
physical activity can reduce mortality by 14% and prolong lifespan by three years. An additional
15 minutes of moderate exercise can reduce mortality by another 4% and prolong lifespan
another year.” XIFENG WU, M.D.
THE TAIWANESE EXERCISE STUDY
Even without reaching the recommended 150 minutes per week, exercising at very light levels
reduced deaths by 14% from any cause in the observational study of more than 416,000
Taiwanese adults who participated in a standard medical screening program between 1996 and
2008. In the program run by MJ Health Management Institution participants were followed for
an average of eight years. The benefits applied to all age groups of both sexes and included
those with risk of cardiovascular disease. The study indicated that one in six deaths of inactive
people in Taiwan could be postponed by three years by exercising 15 minutes per day; persons
exercising 30 minutes per day added approximately four years of their life expectancy. These
results are likely to hold true for other populations although the total amount of time or
workout intensity required for a similar health benefit may be different. In the 2011 study it
was reported that an estimated 20% of adults in China Japan or Taiwan meet the weekly 150
minute/moderate intensity exercise recommendation of the World Health Organization while
one third of U.S. adults claim to meet that guideline.
Source: University of Texas M. D. Anderson Cancer Center. "Fifteen minutes of moderate daily
exercise lengthens life, Taiwanese study finds." ScienceDaily.
www.sciencedaily.com/releases/2011/08/110816112130.htm
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Epidemiology and Molecular
Markers in RCC
MARK PURDUE, M.D.
Ontario Institute of Cancer Research
Toronto, Canada
Broader use of high-dimensional molecular data in epidemiology regarding
Susceptibility, Biochemical Profile, and Tumor Phenotype will drive new
discoveries into the cause and development (the etiology and pathogenesis) of
Renal Cell Carcinoma.
Dr.
Purdue presented a brief overview of
the epidemiology of renal cell carcinoma. It
is the eighth most common cancer in the
United States with current estimates of
some 63,920 new cases diagnosed this year
and projected deaths of 13,860. For many
years there has been an increase in
incidence which is mostly due to incidental
findings of small or indolent tumors although
increased encounters with risk factors may
be playing a role as well. The incidence of kidney cancer is higher among men than women and in US
Blacks versus whites. Established risk factors are smoking, obesity, and hypertension; these are
estimated to account for 50% of the diagnosed cases. Other lesser established risk factors are exposure
to trichloroethylene and genetic factors; while several other factors are being studied conclusive
evidence linking them to kidney cancer have not been established.
Most studies in epidemiology for renal cell carcinoma have not considered the histology of subtypes;
clear cell subtypes comprise 80 to 90% of the total, papillary 10 to 15%, chromophobe 4 to 5%, and
others, some 2%. Each subtype have differences in overall prognosis and variations in risk factors. The
racial incidence of RCC per 100,000 US is about 20% higher for Blacks than whites, with clear-cell
subtypes slightly higher in the white population and papillary subsets having a threefold higher
incidence rate in the black population. Men make up 77% of papillary and 61% of clear-cell cases and
obesity is a stronger risk factor in clear-cell than other types. Kidney cancer with genetically linked
origins account for a small percentage of RCC, generally thought to be less than 10% with most
estimates somewhere between one and 2%. In cancers with sporadic origins there is increasing interest
in common low-risk polymorphisms which are now able to be identified through genome- wide
association studies (GWAS). These investigations are leading to important advances in the
understanding of susceptibility to sporadic RCC.
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This presentation will cover biopsies in small renal masses (SRM) of 4cm or less. The routine use of MRI
and CT scans has led to an increased detection of small and symptomatic incidental renal masses; these
masses are a mix of aggressive cancers, indolent cancers, and benign tumors. While the risk of
malignancy is often based on size, there is also need for predictive information about the mass to guide
treatments, especially in patients with comorbidities. Potential advantages of SRM biopsy include
identifying which patients have cancer, and possibly determining aggressive features and subtypes.
The optimal role of biopsy for SRM is not defined; SEER data for Medicare patients reported only one in
four SRM’s were biopsied and the rate for general patients who will be undergoing surgery is low.
Kidney mass biopsies are safe: at less than 5% the
complication rates are very low-significantly lower than
any procedure used to treat RCC. The most common major
complication of a biopsy is bleeding, but intervention is
required in less than 1% of cases. Tumor seeding of the
biopsy tract appears to have little risk with latest
techniques. Only one case has been reported in the last 20
years.
While the rate of “non-diagnostic” biopsies in SRM’s are
about 20%, the definition on what is “diagnostic” can vary.
However, the ability to determine whether a mass is
cancer or a tumor approaches 100%. The ability to predict
subtype is 85 to 90%.
The use of biopsy as a diagnostic tool
can improve the knowledge which is
presented in the informed consent
options; patients may change treatment
decisions if they know they have cancer,
and they may choose a different
treatment than surveillance if they know
they have a higher grade of cancer. By
identifying benign tumors the need for
intervention and treatment is often
avoided.
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Tumor grade is predictive of RCC
specific survival; in larger renal
masses we are finding inaccuracies
in determining grade because of
tumor heterogeneity as well as
sampling errors. In a 2014 study of
32 specimens of T1a small renal
masses it was found that of 16
masses which were classified as high
grade that 15 also had low-grade
tumor elements present. This
illustrates that sampling may miss
the high-grade component and
underestimate risk. In other data when biopsy results were compared with the surgically removed tissue
the accuracy of determining grade is between 60 to 80%.
Staging of a cancerous SRM by biopsy also presents a major issue since in about 10% of the cases there
is invasion of the perinephric fat; the metastatic rate of recurrence in a small renal mass with fat
invasion is over twice that of a 7 cm tumor with no fat invasion. The risk of death of small renal mass
with fat invasion is much higher than those with no fat invasion.
The use of biopsy as a diagnostic tool can improve the knowledge which is presented in the informed
consent options; patients may change treatment decisions if they know they have cancer, and they may
choose a different treatment than surveillance if they know they have a higher grade of cancer. By
identifying benign tumors the need for intervention and treatment is often avoided; at our facility the
number of surgical procedures on benign tumors has decreased from 20% to 10% and we have begun to
utilize biopsies more frequently.
Many small RCC masses progress very slowly and may not affect patient longevity. Biopsies may permit
some stratification and design of follow-up strategies for ablation techniques and for active surveillance.
A lot of cases in those circumstances have not had confirmed SRMs that show RCC.
RENAL MASS BIOPSY -CONCLUSIONS
–Biopsy is safe, major complications <1%
–Biopsy accurately predicts the presence of
cancer vs. benign tumor (non-diagnostic rate 15-20%)
–Biopsy is limited to risk stratify small RCC
•GRADE 1 in 4 patients’ biopsy low grade → high grade
•STAGE ~ 10% of patients will increase from cT1a to pT3a
–Biopsy improves informed consent
–If biopsy decreases treatment of benign masses, it may
improve overall treatment (renal function)
–Biopsy provides information that can be used to study
non-surgical management of small RCC
The use of biopsies should be
discussed with incidental SRM
patients considering treatments; it
can improve consent and possibly
overall treatment. Young healthy
patients as well as older very
unhealthy patients will likely benefit
the least from a biopsy; information
gathered will probably not change
their type of treatment.
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I need to start out by defining what a non-diagnostic or indeterminate biopsy is because
there is currently no standard definition… For the purposes of our study a non-diagnostic
finding included finding only fibrotic or necrotic tissue or only benign renal parenchyma.
Our objective was to identify anatomic and patient factors that
are predictive of nondiagnostic renal mass biopsies (RMB). We
had a population base to work with that was accrued from
January 2000 to April 2014 consisting of 565 renal mass
biopsies of ≤ 7 cm; a subset of that included 413 renal mass
biopsies of ≤ 4 cm.
parenchyma is the essential
or functional elements of an
organ, as distinguished from
its stroma (or framework)
renal parenchyma is the
functional tissue of the
kidney, consisting of the
nephrons.
We were most interested in looking at SRMs ≤4 cm because
Online Source:
free
medical
dictionary
they are the most clinically relevant in which a biopsy can be
most helpful. After analyzing our results we found four features which were independently
predictive of a non-diagnostic biopsy.
We performed a comprehensive analysis of prognostic factors which included:
•Technical factors –Type of guidance imaging, type of biopsy (fine-needle aspiration (FNA), core
or both), number of cores obtained
•Tumor factors –Laterality, shape, size of lesion, cystic appearance, presence of fat,
calcifications, or necrosis within lesion, proximity to other organs, enhancement with contrast,
location of tumor within kidney
•Patient factors –Body mass index, skin-to-tumor distance
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From our database we found 83/565 (14.7%) overall and 72/413 (17.4%) with a SRM ≤4cm
where the biopsy findings were non-diagnostic. There were no differences in age, BMI, Charlson
comorbidity score, or gender between diagnostic and non-diagnostic biopsy patient cohorts.
Although some physicians handling more difficult cases may use certain radiologists or
pathologists for procurement and analysis there appeared to be no significant differences
based on the experience of radiologist or pathologist in the percentage of non-diagnostic
RMB’s.
When biopsies of cystic masses were looked at almost 40% of them had a nondiagnostic rate.
Most of the cysts with a nondiagnostic rate were complex; 88% of those biopsies were done by
core sampling, 3% by fine needle aspiration, and 9% were done by a combination biopsy. Of the
50 cystic masses where a diagnosis was obtained by biopsy, 90% were malignant and 10% were
benign tumors.
After this analysis we were able to conclude the following;
•Non-diagnostic RMB is more common in masses that are:
–Cystic
–Non-enhancing ≤20 HU
–Small mean axial diameter
–Skin to tumor distance of ≥13 cm
The results of this study should aid us in patient selection; while the low risk of major
complications of an RMB are being discussed with patients, those whose clinical and tumor
characteristics indicate a low likelihood of biopsy success can be advised of that as well.
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S PECIAL S EGMENT ON G ENETIC C ANCERS
J OYCE W. G RAFF
Director, Powerful Patient
Executive Director, New England Regional Genetics Group
Genetic mutations play a role in the development of all cancers.
Most of these mutations occur during a person’s lifetime, but some mutations,
including those that are associated with hereditary cancer syndromes,
can be inherited from a person’s parents.



Inherited mutations play a major role in the development of about 5 to 10 percent of all cancers.
The genetic mutations associated with more than 50 hereditary cancer syndromes have been
identified, and genetic tests can help tell whether a person from a family with such a syndrome
has one of these mutations.
A genetic counselor, doctor, or other health care professional trained in genetics can help an
individual or family understand genetic test results.
source: National Cancer Institute, http://www.cancer.gov/cancertopics/factsheet/Risk/genetic-testing
Dr. Francis Collins, Chief of the National Cancer
WHAT IS DNA?
Institute and former head of the Human Genome
I T I S A H I STO R Y B O O K – A NA R R A TI VE
Project (HGP, now the Human Genome Research
O F TH E JO UR NEY O F O U R SP ECI ES
Institute), loves to say that having completed the
TH R O UG H TI M E .
initial phase of the HGP we now know how to spell
I T I S A SH O P M A N UA L , W I TH A N
the entire Human Genome. However, we are just
I NCR E DI B L Y D ETA I L ED B L UEP R I N T
beginning to scratch the surface of understanding
F O R B UI L DI NG E VER Y H UM A N C EL L .
what it means and how it works. We know what
A ND I T ’ S A TR A NSF O R M A TI V E
sequence of proteins is involved, but how they
TEX
TB O O K O F M EDI C I N E , W I TH
interact, how they influence each other, is the
I NSI G H T S TH A T W I L L G I V E H EA L TH
great mystery ahead of us in the 21st Century.
CA R E P R O VI DER S I M M EN SE N EW
Most of the mutations that cause cancer occur
P O W ER S TO TR EA T , P R EV ENT , A ND
during our lifetimes. However, an inherited
CUR E DI SEA S E .
mutation might make a person more vulnerable to
F R A N C I S S. C O L L I N S , M. D. , P H . D. ,
those changes. For example, in several of the
Director, National Institutes of Health (NIH).
hereditary kidney cancers (HRC) it takes “two hits”
http://www.genome.gov/Pages/Education/
to cause a cancer tumor to start. One is inherited,
Modules/BasicsPresentation.pdf
but all goes well until a second hit occurs during
one’s lifetime. Even then, our bodies have
mechanisms to identify and correct genetic alterations – it’s called the Immune System. It is
only when one of these changes slips through our defenses that a tumor begins.
Thirteenth Annual International Kidney Cancer Symposium – 2014
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That gives us an opportunity to influence the outcome – making choices that will strengthen
our own immune systems can prevent cancer, or can at least soften the course of a hereditary
cancer syndrome.
If a hereditary syndrome is suspected, it is important to identify it as early as possible so that
you can make those choices, watch out for the issues that are most likely to arise, find things
early, and treat them successfully. Once a cancer tumor is there, knowing which syndrome is at
work will influence the strategy for treatment and possibly the choice of which drug to use.
Each gene performs a different function in the cell. In genetics they call them “pathways,” so
let’s use that analogy. We are going down a pathway from point A to point B to point C. At
each point there are choices to be made. There might be an intersection, a traffic signal, or a
policeman directing traffic. Depending on those interactions and the turns we take, we may
wind up a different place.
Similarly, each genetic pathway has a certain prescribed purpose, a certain outcome that is
expected. But if one of those signals along the way is not functioning properly – if one of the
genes along the pathway has been modified and the expected interaction cannot take place -the outcome may be
different.
The interaction of genes
along these pathways is
like an elegant set of
sensors and controls. A
thermostat is a very
simple kind of sensor
and control. If the
temperature is low, the
heat comes on. When
the house is warm
enough, the heat stops
pumping. If the heat
sensor was broken and
the heat stayed on, the
house would overheat.
When a gene is altered,
one of the sensors is not
working properly. Instead of the growth and replication of the cell taking place normally and
then shutting off, cells may continue to proliferate and cause a tumor. Too much or too little of
some important ingredient may be created, causing safety alarms to go off. The body may
respond to this emergency by creating yet another unwanted effect. The challenge becomes
Thirteenth Annual International Kidney Cancer Symposium – 2014
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20
how to calm down this
cycle, fix the sensor, or
reduce the heat in some
other way, and get the
system back on track.
In engineering, we
would need to
understand which
system is going wrong,
which sensor is broken,
and how to fix it. In
medicine, we need to
understand which
genetic pathway is
going wrong, and which
drug could be used to
get the altered process
back on track. That is
the role of “targeted
therapies.” Do we need to
regulate HIF? or mTOR? or
FH? Which drug is most likely
to have a favorable outcome?
Knowing the cell type of the
tumor gives us the ability to
exert that finer control. And
in the case of an HRC, knowing
which genetic syndrome is at
work gives us - - the patients
and families – the power to
manage our health with
greater control, greater
influence. Living with any of
these syndromes is not easy, but knowledge is power. With knowledge, and with the power of
a community of people dealing with the same condition, you will be able to manage your health
with greater confidence and peace of mind than ever before.
Visit the Kidney Cancer Support Community Pages:
http://www.inspire.com/groups/kidney-cancer-association/
Thirteenth Annual International Kidney Cancer Symposium – 2014
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Management of Kidney Cancer
in Young Patients
B R IAN S HUC H , M.D.
Yale Department of Urology
New Haven, CT
Kidney cancer is the 8th most prevalent cancer in
the United States. Patients under the age of 45
represent the bottom decile of renal cell carcinoma.
They are often affected by hereditary syndromes,
and represent the “zebras,” the uncommon causes
of kidney cancer which are Dr. Shuch’s interest.
You should be aware when
you see a young patient…
These cases may require
different diagnostic and
management strategies
While biopsy is not often
used in the general
population,
it
is
increasingly used in this
younger population in
order to determine as
early as possible the
histology of the disease.
It may be preferable to
move directly to one of
the targeted therapies
rather than to radical or
partial nephrectomy.
Biopsy can also be useful in determining whether or not to do lymph node dissection (LND).
While LND is not often done in the general kidney cancer population, there are several tumor
types in younger patients that have a tendency to metastasize to the lymph nodes, even when
the tumor is small. Understanding the cell type of the tumor can help in making the decision
whether to do LND. There are still unanswered questions in the best way to do LND.
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Partial nephrectomy (PN) is preferred over radical nephrectomy (RN) in younger patients.
Randomized trials in the EORTC show no survival advantage to doing elective PN versus RN, but
the median age in that study was 62. However, removing one entire kidney reduces the total
number of working nephrons and may lead to chronic kidney disease (CKD). This risk is
somewhat subtle and takes time to develop, so concern is greater in younger patients who
hopefully have much longer to live. Treating a patient of 35 is different from treating a patient
who is 85 years old.
One recent study shows that there is a significantly higher risk of CKD among kidney donors
with an average age of 40, compared to the general population. These are people who have
voluntarily given up one entire kidney, reducing their volume of working nephrons, similar to
losing one kidney to a radical nephrectomy. Muzaale, A. D., et al. (2014). Risk of end-stage renal
disease following live kidney donation. JAMA
We performed an elective partial
nephrectomy on a 38-year-old
male with a 13 cm tumor.
While I would not consider this a
standard of care in a 68-year-old
patient, this patient with an
indolent chromophobe tumor has
40 years of potential life ahead of
him.
Dr. Shuch showed several cases where the cell
type identified by the biopsy influenced his
choice of surgical approach, allowing him to do
a partial nephrectomy, preserving as many
working nephrons as possible. He feels that
molecular diagnostic testing (PCR, FISH,
Karyotype) is essential in making a diagnosis
and choosing a treatment strategy.
Among them was a 29-year-old African
American man with medullary kidney cancer
who was not aware that he had sickle cell trait
and had not experienced other sickle cell
symptoms. For this patient, partial
nephrectomy was not the best choice.
Dr. Shuch urged his colleagues to consider these unusual cell type variants when making a
diagnosis of young (under 45) patients with kidney cancer.
Genetic factors have been linked to an increased risk of developing kidney cancer. A hereditary disorder called
von Hippel-Lindau (VHL) disease is associated with a high risk of developing kidney cancer, for example.
Scientists have isolated the gene responsible for VHL disease, and this discovery offers exciting future
possibilities for improved diagnosis and treatment of some kidney cancers. Another genetic mutation is
thought to be responsible for tuberous sclerosis, a disease characterized by small tumors of the blood vessels
that results in numerous bumps on the skin, mental retardation, seizures, and cysts in the kidneys, liver, and
pancreas. In some cases, tuberous sclerosis has been associated with renal cell carcinoma.
http://www.kidneycancer.org/knowledge/learn/about-kidney-cancer/
Thirteenth Annual International Kidney Cancer Symposium – 2014
Beyond VHL
NICHOLAS G. COST,
M.D.
Graff, Derr, Lawing
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A careful family and
personal medical history
and a physical
examination are necessary
to identify a hereditary
renal cancer syndrome.
University of Colorado
School of Medicine
Denver, CO
Some 65,000 people are diagnosed with kidney cancer each year in the United States. It is
estimated that 5-8% of these have some hereditary syndrome. There is some concern that this
is significantly underestimated. A recent pedigree study in Iceland found that nearly 60% of the
studied population had a genetic predisposition to kidney cancer. [Gudbjartsson et al. Int J Cancer 2002.]
There are many syndromes that have been described, the most prevalent of which is VHL.
This talk will not cover VHL – not because it is not important,
but in order to give more visibility in this talk to the lesser-known syndromes.
A careful family and personal
medical history and a physical
examination are necessary to
identify a hereditary renal cancer
syndrome. Patients should be
asked about any personal issues
with skin, eye, lung, and
neurological conditions. Similarly,
they should be asked about any
family history of these conditions.
The patient should then be carefully
examined by medical specialists in
dermatology, ophthalmology.
HPRC – Hereditary Papillary Renal Cell Carcinoma (RCC)
Autosomal Dominant (AD) with high penetrance (90% develop
RCC by 80yr) • Although typically diagnosed at 50-70 years
old, an early form has been described in 20-30 year olds •
Papillary renal tumors are the only phenotype associated with
this syndrome • Patients may have bilateral and multifocal
tumors of various sizes • Always Type 1 papillary RCC with low
nuclear grade • Typically hypo-vascular, enhance uniformly,
and grow slowly • CT/MR is preferable to Ultrasound (US) for
screening, because US easily can miss HPRC tumors • METproto-oncogene that encodes surface receptor for hepatocyte
growth factor • Rationale for targeted MET inhibition–50% of
those with germline MET mutations had a PR
Surveillance: Annually: Physical Exam -- Abdominal CT/MRI as
surveillance for renal masses given that US can miss these
lesions
BHD –Birt-Hogg-Dubé
AD syndrome characterized by skin, lung, and kidney lesions • Fibrofolliculomas • Lung Lesions = Lung cysts and
blebs • Nearly 30% experience a pneumothorax • Renal tumors occur in 25-35% with a wide range of onset
(mean age: 50yr) • Chromophobe RCCs and Hybrid Oncocytic tumors • ccRCC and pRCC have been reported •
Germline mutation of FLCN • Folliculin –tumor suppressor involved in the regulation of AMPK and mTOR
signaling pathways
Surveillance: Annually: Physical Exam • Dermatology • Pulmonary • Baseline Chest/Abdomen/Pelvis CT • No
renal lesions –Abdominal MRI/CT every 3 years • Renal lesion(s) present –Annual MRI/CT
The number of cases of hereditary kidney cancer syndromes is very likely underestimated.
It includes many more syndromes than just VHL.
Patients 45 years old and younger should be referred for genetic testing and counseling.
Thirteenth Annual International Kidney Cancer Symposium – 2014
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SDH-RCC –Succinate Dehydrogenase associated kidney cancer
AD syndrome affecting SDH (Kreb’s Cycle Enzyme) • Germline mutations in SDH subunits B/C/D have been seen
in relation to developing early RCC • Similar to FH mutation in HLRCC – Warburg effect and associated aggressive
phenotype • SDH mutations associated with Hereditary Paraganglioma/Pheochromocytomas and GISTs • Young
age of diagnosis with RCC (Median 30s -40s) • May represent varying subtypes of renal lesions –ccRCC,
chromophobe RCC, Oncocytomas • Like HLRCCs, these are aggressive hereditary renal tumors = Early Surgery •
Unlike HLRCC, there is potential development of metachronous, bilateral RCC, thus nephron-sparing surgery
should be considered • Because of the potential for aggressive tumors, wide surgical excision of SDH-RCC is
recommended • Potential role for PET as with HLRCC
Surveillance: Annually: Physical exam • Abdominal MRI/CT • Plasma Free Metanephrines • If Renal lesion(s)
present –FDG/PET for staging • Early, aggressive surgery if renal lesion of any size detected - Wide excision via
Partial Nephrectomy if possible
TSC –Tuberous Sclerosis Complex
70% with a spontaneous germline mutation and 30% have an AD inherited syndrome • Inactivating mutations in
either TSC1 (9q34, Hamartin) or TSC2 (16p13, Tuberin) • Hamartin and Tuberin bind together to form a
functional heterodimer that inhibits downstream mTOR pathways • Characterized by Seizures, Facial
angiofibromas, Mental retardation, SEGAs, Renal AMLs • Renal lesions occur in 50–80% of patients and primarily
include AMLs and Cysts AMLs are the most common renal lesions • RCC has been reported in 1–4% of TSC
patients • Overall incidence of RCC approximates that of the general population, BUT occurs at a younger age
(mean -28 yr) • TSC-associated RCCs are principally clear cell RCC • RCC may be difficult to distinguish from fatpoor AML or eAML–consider biopsy as therapy would vary • Potential for metachronous, bilateral AMLs or RCC,
thus nephron-sparing approaches encouraged
Surveillance: Annual Physical exam: Neurology • Dermatology • Dental • Ophthalmology • Brain MRI every 1-3
years (If lesion found –every year) • Chest CT every 5-10 years (If LAM found –every 2-3 years) • Cardiac Echo
every 2-3 years • Renal Ultrasound Annually or MRI Abdomen every 1-3 years
HLRCC –Hereditary Leiomyomatosis and RCC
AD syndrome -variant of Multiple Cutaneous and Uterine Leiomyomatosis (MCUL) • Uterine leiomyomas occur in
>90% of women with MCUL • Frequently requiring a hysterectomy at less than 30 yrs of age • RCC is found in
approximately 20% of MCUL families with an early onset (late 30s) • HLRCC associated RCCs are typically solitary,
unilateral, and high grade (Type 2 papillary RCC ) • HLRCC-related RCCs are the most aggressive hereditary renal
tumors • Most patients have died of metastatic disease within 5 yrs after diagnosis regardless of primary tumor
size • Early radical nephrectomy is indicated • Biallelic inactivation of FH gene (fumarate hydratase) • Kreb’s
cycle affected leading to metabolic shift towards anaerobic glycolysis (Warburg effect) • Metabolic activity may
provide rationale to stage with FDG-PET
Surveillance: Annually: Physical exam • Dermatology • Gynecology • Abdominal MRI/CT • If Renal lesion(s)
present –FDG/PET for staging •Early, aggressive surgery if renal lesion of any size detected
The median age of kidney cancer patients in the SEER database is 64 years old, and the
bottom 10% are below 46 years old. In the experience of the National Cancer Institute the
median age of diagnosis of someone with a hereditary kidney cancer (HRC) syndrome is 37
years. 70% of patients diagnosed with an HRC syndrome were under the age of 46.
Other described syndromes: MITF (microphalmia-associated transcription factor) associated RCC • Hereditary
hyperparathyroidism-jaw tumor syndrome • Papillary thyroid carcinoma with associated papillary renal
neoplasia • Constitutional chromosome 3 translocations • Familial clear cell RCC • Cowden syndrome
Cowden Syndrome Surveillance: Annually: Physical exam • Dermatology • Breast –monthly self-exams • Thyroid
• Gynecology • Labs: Fecal Occult Blood Test and Urinalysis • Every other year: Abdominal US or MRI •
Colonoscopy at age >40 years old
Thirteenth Annual International Kidney Cancer Symposium – 2014
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THE t1b/t2a RENAL CELL CARCINOMA TUMOR
T1a: The tumor is found only in the kidney and is 4 cm or smaller at its largest area.
T1b: The tumor is found only in the kidney and is between 4 cm and 7 cm at its
largest area.
T2: The tumor is found only in the kidney and is larger than 7 cm at its largest area.
T2a: The tumor is only in the kidney and is more than 7 cm but not more than 10 cm
at its largest area.
http://www.cancer.net/cancer-types/kidney-cancer/stages
Thirteenth Annual International Kidney Cancer Symposium – 2014
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Debate:
Partial Nephrectomy for t1b/t2a RCC
TIMOTHY A. MASTERSON, M.D.
Indiana University
Indianapolis, IN
We have clearly seen an increase in the utilization of partial nephrectomies (PN)
over time both with 1a and 1b tumors. However there is still an incredible
underutilization of the partial nephrectomy in the eligible patient population.
Chronic Kidney Disease (CKD) is an important risk consideration for kidney cancer patients. In
the general population base of 1.12 million Kaiser Permanente patients Stage III CKD or higher
was evident in 18%. CKD is strongly associated with more hospitalizations, cardiovascular
events, and death. In kidney cancer patients studies indicate that between 22 and 26% have a
baseline CKD of stage III or higher. Among patients with creatinine levels (CR) of less than 1.4
mg/dl, two kidneys, and a small renal mass of less than 4 cm, a radical nephrectomy (RN) nearly
always leads to stage III CKD or higher while a partial nephrectomy results in 40% of patients
developing CKD III or higher within six years.
A survey among surgeons of the American Urological Association indicates that underutilization
of partial nephrectomies are heavily influenced by the practice setting and surgeon as opposed
to the characteristic of the patient’s tumor.
Some of the primary surgical reasons listed for
not performing a PN on eligible patients were:
technical difficulty, greater risk of
complications, lack of training, and the lack of
appreciation of potential benefits for partial
nephrectomy. It appears that PN’s are
underutilized most in the elderly, in females, in
rural areas, and in cases where the tumor size
has been increasing.
Considerations for determining eligibility for a
PN include: is it technically feasible, is the
Thirteenth Annual International Kidney Cancer Symposium – 2014
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27
control of cancer and functional outcomes going to
be better, what are the risks and potential
complications for this surgery? Partial nephrectomy
does not seem to be controversial for those who have
a solitary kidney, or a mass on both kidneys, or
multifocal renal masses, or for those with CKD with a
Glomerular Filtration Rate (GFR) rating of 30 to 45
(stage III B), or hereditary cancer.
A RN is not controversial for those with end-stage
renal disease, those with infiltrative tumors, or those
with locally advanced involvement in either renal
vein or cavil vascular involvement.
The controversy over partial or radical nephrectomy is in the patient with a normal
contralateral kidney where the tumor is solitary, sporadic in origin and with a solid renal mass
of greater than 4 cm. Renal sinus tumors (the cavity where the ureter intersects), and those
with variant histologies should be also considered as possible candidates for PN.
In defining outcomes, we need to determine whether or not these are benign tumors prior to
operating on them; in the short term we need to consider the ability to obtain clear margins,
and risk of tumor violation and we need to consider the long-term possibilities of regional
recurrence, cancer specific survival, and overall survival.
In a Mayo Clinic report on partial nephrectomies by tumor size, benign tumors occurred in
smaller percentages as the tumor size increased; while some 22% of tumors in the 1 to 3 cm
range were noted, at 4 to 5 cm it was 15%, and at 6 to 7 cm it was 9%. Nuclear grades of one or
two in tumors similarly decreased as size increased; while 78% of the 2 to 3 cm tumors were in
the relatively indolent category, 57% of those with 5 to 6 cm tumors and 72% of 6 to 7 cm
tumors fell in that range
The utilization of biopsies to determine benign tumors, particularly in those who will be
undergoing a radical nephrectomy should become more common. While many studies indicate
no difference in cancer specific survival between partial and radical nephrectomies, a study of
older Medicare patients indicated a 46% decrease in risk of death in the PN cohort. In 2014 a
20-year review of over 16,000 patients in the SEER database from 1988 to 2008 showed
virtually no difference in cancer specific mortality. The mortality rates at five years were 4.4%
for PN versus 6% for RN and at 10 years the rate was 6.1 PN and 10.4 RN.
While the best source of information about your specific medical situation is your medical care
team, the Kidney Cancer Association has supplemental information that can help answer general
questions. Our publication We Have Kidney Cancer is available at www.kidneycancer.org
Our Kidney Cancer Support Community at Inspire.com allows members to share information and
questions with fellow survivors and caregivers. We look forward to seeing you there!
http://www.inspire.com/groups/kidney-cancer-association/
Thirteenth Annual International Kidney Cancer Symposium – 2014
Conclusion
•Partial Nephrectomy is under-utilized
as a treatment choice for larger renal
masses
•Partial Nephrectomy has comparable
oncologic efficacy as Radical
Nephrectomy in T1b and select T2a
tumors
•Partial Nephrectomy significantly
reduces the incidence of S-CKD
compared to Radical Nephrectomy
•M-CKD is more common than we
recognize, and severity correlates with
long term survival
•Complications are more common with
Partial Nephrectomy compared to
Radical Nephrectomy
Graff, Derr, Lawing
28
1988-2008
Turning
Surveillance,
End
Results
CancerSEER
Data
Program
Epidemiology,
Into
Discovery
and
(Surveillance, Epidemiology, and End Results)
16,333 T1b patients
5-& 10-years CSS (propensity)
•PN: 4.4 & 6.1% Mortality
•RN: 6.0 & 10.4% Mortality
Propensity adjusted, p = 0.03
Competing risk analysis
Type of surgery non-predictor between
RN & PN for cancer-specific mortality
Meskawi (WJU, 2014, 122)
Take Home Message
•Importance of emphasizing patient factors and not surgeon factors when making treatment
decisions
•For healthy patients with minimal medical comorbidities, surgical approach likely has little
impact on survival
•Benefits of nephron sparing surgery need to be weighed against higher risk of complications
•Randomized trials needed
From We Have Kidney Cancer – p4
I was diagnosed with Stage III kidney cancer and within 6 months it had metastasized into both
lungs and my brain. It was a pretty horrifying situation. But by then I had convinced myself that
this had to be a fight. I wasn’t going to give up. I was fortunate to find a specialist who steered
me toward gamma knife therapy, IL2 treatment and a clinical trial. My diagnosis was five years
ago and I’m in remission today.
…Once you make the decision to take control and actively fight the disease, you find yourself
moving with positive energy and you realize that there are more options than you may
have thought possible. After I was diagnosed I spent two full days researching and searching
the Internet with the intention of knowing everything I could about kidney cancer. And that’s
how I found out about the specialist who eventually led me to the treatments that got me
healthy again.”
Download a free copy of We Have Kidney Cancer from our website: www.kidneycancer.org …
Thirteenth Annual International Kidney Cancer Symposium – 2014
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Debate:
Radical Nephrectomy for t1b/t2a RCC
VITALY MARGULIS, M.D.
University of Texas
Southwestern Medical Center
Dallas, TX
The current dogma, mainly driven by
a set of retrospective studies, is that
maximizing nephron mass really
saves lives. This has led many of us to
offer indiscriminate elective partial
nephrectomies if we can do it, if it is
oncologically safe, and if a functional
renal remnant can be preserved.
Going forward however I would suggest that for
nephron sparing surgery (NSS) to really make sense
in a larger mass of t1b or above it has to offer a
distinct advantage in either oncologic outcomes, or
renal function outcomes and the downstream
effects, or procedure-related morbidity and have
equal outcomes in the other two categories.
While data from the EORTC Trial (European
Organisation for Research and Treatment of Cancer)
is often used to support partial nephrectomy (PN) citing “no difference” between partial nephrectomy
and radical nephrectomy (RN) in oncologic outcomes for renal masses <5 cm, there was a significant
difference in the local recurrence rate of 3.3% for RN vs. 6.1% for PN with 2/3 of the recurrences in the
PN cohort occurring elsewhere in the same kidney. While SEER data for 4 to 7 cm tumors indicate “no
difference” in cancer-specific
survival (CSS), the data for
tumors above 7 cm are not as
straightforward. In a 2012
summary of seven studies that
compared overall survival of
RN and PN patients with
tumors >7cm, three of the
studies reported inferior
oncologic outcomes in the PN
group. One of those studies
indicated a large increase in
cancer-specific death in the
PN cohort.
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While the EORTIC trial indicates no
significant difference between RN
and PN in developing CKD in tumors
less than 5 cm, the overall survival of
PN patients are less. We are also
learning that patients with surgically
induced CKD do better in overall
survival than patients with CKD of
medical origin.
Partial nephrectomies have an
inherent set of complications that
are unique to that procedure; urinary
fistula occurs in 4.4% of cases
whereas it doesn’t happen with RN;
there is a threefold risk of severe
hemorrhage, and almost double the
need for reoperation with partial
nephrectomies. As the size of the
tumor increases so does the probability of complications. Partial nephrectomies of larger tumors
experience more hemorrhage, and the need for transfusion and embolization etc. increases. Published
nephrectomy scores in 2011 that predict complications with PN indicate a complication risk of 6.4% for
tumors between 4 - 6 cm and 11.1% for 7 - 9 cm tumors; significant urine leak was predicted in 1.8% of 4
- 6 cm tumors and 6% in the 7 - 9 cm group.
While oncologic outcomes appear to be equivalent for tumors of 4 - 7 cm, the jury is still out for larger
tumors. In the case of renal function, while PN preserves renal function better there is no convincing
clinical evidence yet on the increased need for dialysis or overall survival in RN patients when compared
with PN data for the
same tumor size. The
complication rate is
clearly higher for PN
and it is increased
with tumor
complexity and size.
Based the facts I
have presented it is
evident that RN
should remain the
standard of care for
larger tumors.
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R. HOUSTON
THOMPSON, M.D.
Dr. Houston Thompson presented an overview of a report on behalf of lead author Dr. Suzanne B
Stewart, a Fellow at the Mayo Clinic on the capture rate for recurrence of renal cell carcinoma using
NCCN (National Comprehensive Cancer Network) and AUA (American Urological Association)
surveillance guidelines.
There are multiple existing protocols for the oncologic surveillance of RCC, two of the most
recognized and utilized are the NCCN and AUA guidelines. There are differences in guidelines
and no evidence has been established to determine which guideline is the most effective. This
has resulted in significant differences in surveillance care and over and underutilization of
testing for certain at risk patient groups.
Objectives
1. Evaluate the performance of the NCCN and AUA guidelines:
How many RCC recurrences are detected when abiding by prescribed protocols?
2. Summarize the total duration of surveillance required to capture 90%, 95% and 100% of RCC
recurrences
Guideline Protocol
2014 NCCN—stratified by stage and surgical approach
•pT1Nx/0: 3yrs for chest and 5 yrs. bone/other sites
•partial Nx: 3yrs for abdomen
•radical Nx: 1yr for abdomen
•pT2-3Nx/0 or pT1-3N1: 5yrs for all sites
•pT4Nx-1: Indefinite
•AUA—stratified by stage and surgical approach
•Low Risk -partial (pT1N0): 3yrs for all sites
•LR-radical (pT1N0): 1yr for abdominal and 3yrs for chest/bone/other sites
•Medium/High Risk (>pT2 or N+): 5yrs for all sites
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Methods
•Retrospective review of Mayo Clinic Renal Tumor Registry between 1970-2008
•N = 3,803 patients M0 RCC radical/partial nephrectomy
•Median postoperative follow-up 9yrs (year’s range 5.7, 14.4)
•Mayo surveillance strategy:
•Exam, chest/abdominal imaging, labs:
•3-6 months x3yrs then 6-12 months x2yrs then annually
Determining Recurrence
•Disease recurrence = local recurrence or metastasis on imaging or by biopsy >
30d from surgery
•Only first recurrence counted as an event
•1088 (29.8%) developed recurrence
•Median time to recurrence 1.9 yrs. (Low-Risk Years 0.6, 5.5; High-Risk Years 0.1,
38)
•Patients were stratified according to: Recurrence location: abdomen, chest,
bone and other
•Approximately 1/3 rd of recurrences were missed by latest NCCN and AUA
guidelines
•Most restrictive for low risk patients and capturing abdominal relapses
Limitations
•Retrospective design
•Mayo Clinic follow-up protocol was not standardized
•< 3%were lost to follow-up
•No strong evidence that surveillance will yield an increased survival benefit
•Despite this unknown, surveillance continues to remain an integral part of RCC
care
Conclusions
•First large scale study to evaluate NCCN and AUA guidelines for RCC
•Do not comprehensively capture recurrences
•Approximately 1/3rd (AUA and 2014 NCCN) of all recurrences are missed
•A longer duration of follow-up appears necessary
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B ecause relapse site influences recurrence patterns,
adding this feature to the stratification schemes
used in RCC surveillance may improve the number
of recurrences detected”
DR. SUZANNE B. STEWART, Lead Author
From: Targeted Therapies in Cancer, Resource Advocacy Network
The goal of targeted therapies is to rid the body of cancerous cells while leaving normal cells
unharmed. By focusing on changes in the cell that are specific to cancer, targeted cancer therapies may
be more effective than chemotherapy and radiotherapy. Their specific actions may also make targeted
therapies less harmful to normal cells than chemotherapy and radiotherapy. However, it is important to
note that we have not yet reached the ultimate goal of devising targeted therapies that are completely
specific for cancerous cells. Inevitably, some normal cells are still affected by targeted therapies and
these drugs still have side effects.
http://researchadvocacy.org/general-resources...
...
Thirteenth Annual International Kidney Cancer Symposium – 2014
Dr. Tony Finelli’s presentation dealt with the concept
of Quality of Care in cancer treatment. The
definition of quality of care is “the degree to which
health services for individuals and populations
increases the likelihood of desired health outcomes
and are consistent with current professional
knowledge”. It is of course important to know if
good quality of care if being delivered, mostly for the
patients, but also for other stake-holders such as
physicians, institutions, organizations, and funding
agencies.
Graff, Derr, Lawing
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How do we set the measures by which quality
care is provided?
Sometimes just by looking at something we can
tell if it has quality or lacks quality. ..
However, in medicine it can be much more
challenging, and definitely more open to bias…
Quality indicators should be
 Relevant
 Practical
 Measurable
and should enhance quality through the
identification of areas which need improvement
The key to understanding and improving quality of
care is to establish quality indicators, and then be sure to measure against those indicators. A quality
indicator is a measurable element of performance for which there is evidence or consensus that it can
be used to assess quality. In the medical field, establishing quality indicators is not always an easy task,
but it is definitely possible. Quality indicators need to be relevant, practical, and measurable. An
example of this for kidney cancer might be: “proportion of patients with clinically localized RCC
undergoing laparoscopic radical nephrectomy”. This is practical, easily measurable, and definitely
relevant.
In summary, it is important to develop quality indicators for cancer care, and to set benchmarks based
on measurable data. Ultimately, the goal is to improve the quality of care that kidney cancer patients
receive based on these quality indicator measurements.
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We need to better
understand the utility
of targeted therapy in
the preoperative
(Neoadjuvant)
setting…
…to do this we need to
be doing
multi-institutional
randomized trials
Neoadjuvant therapy (NAT) is defined as therapy used prior to nephrectomy in non-metastatic
disease patients. The term pseudo-neoadjuvant therapy (ψ-NAT) is defined as therapy used
prior to nephrectomy in patients with metastatic disease.
A study conducted in 2005 thru 2007 evaluated 17 patients where Sunitinib targeted
therapy was used with a primary tumor in place. The median reduction in tumor volume
across those patients was 31%.
With respect to the safety of using pre-operative targeted therapy, a study was conducted
that compared 70 patients that received pre-operative therapy versus 103 patients that did
not. There was no significant difference in the rates of major surgery complications
between these two groups. However, there was a higher rate of wound complications
between the two groups. More recent studies have shown comparable wound
complication rates.
Studies have shown that pre-operative targeted therapy can indeed shrink a primary tumor
in some patients. A recent study of 19 patients showed that in some of these patients preoperative targeted therapy changed their tumor from being unresectable to resectable.
Finally, studies have shown that neoadjuvant therapy can lead to a partial versus a full
nephrectomy in some cases.
Neoadjuvant Therapy Summary:
- Is it safe? Yes
- Shrink primary renal tumors? Yes
- Change from radical to partial? Sometimes
- Change from unresectable to resectable? Sometimes
- Downstage IVC thrombi? Rarely
-
Use routinely off-trial? Definitely Not
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Ablation of Larger and Recurrent Tumors
T HOM AS D. A TWEL L , M.D.
Mayo Clinic
Rochester, MN
We will be focusing on T-1b tumors of 4.1-7.0 cm. The 2009 American Urological Association
(AUA) guidelines state in part: “Clinical T1b tumors are difficult to adequately treat with
thermal ablation, and the risks of local recurrence and complications are high in this patient
population”
There are technical limitations related to the thermal devices that prevent us from treating
these tumors with consistency. While T-1a tumors are effectively treated at rates approaching
100%, a Massachusetts General Hospital study of 42 T-1b tumors treated with radio-frequency
ablation (RFA) had eight patients (or 19%) with residual disease and six patients (14%) that had
recurrent disease. Microwave ablation may have
some advantages; it is a more robust heat-based
thermal technique generating somewhat larger
ablations-it has shown some promise in larger
tumors (seven of 8 successes shown in one study), but I think there will always be some
limitations of heat and the inability to monitor the ablation
There are technical limitations
when it comes to treating these larger tumors. In the RFA
related to the thermal devices that
community we have adopted the terms primary and
prevent us from treating these
secondary effectiveness; indicating that a repeat ablation
tumors with consistency…
there will always be some may be necessary for control of thermal ablative
limitations of heat and the inability procedures.
to monitor the ablation…
In contrast I think there is a role for
Cyroablation in treating larger
tumors…
with these probes we can generate a
coalescing large ball of lethal ice
that we know kills tumor cells.
In contrast I think there is a role for Cyroablation in
treating larger tumors; there is the ability to place multiple
Cyro probes in the renal mass if needed. With these
probes we can generate a coalescing large ball of lethal ice
that we know kills tumor cells. We have known for many
years that Cyroablation of these larger tumors is feasible.
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Above: There were concerns of bleeding and the need for blood transfusion if a partial nephrectomy was
done with this patient. She was referred for Cyro; six years later all that is left is some retracting fat
necrosis in the ablation defect. Notr the number of probes inserted (center) to obtain desired coverage.
There is a lot of bleeding with Cyro; with large probes and cold temperatures where blood does
not easily clot, our major bleeding rate is about 8%. In a follow-up of 36 patients with T-1b
tumors while there was a 15% complication rate at procedure, at 24 months 35 of the 36 had
recurrent free survival.
While cancer recurrence
with a partial nephrectomy
is rare, less than 5%, a
repeat partial
nephrectomy is technically
very challenging with a 20 to 50% complication rate during surgery and recovery till discharge
accompanied with an average 12% renal function loss. On the other hand, Cyroablation involves
probe placement by imaging; there is no mobilization or control procedures necessary with the
organ and blood vessels, and there is less bleeding - possibly due to scarring from prior
treatment.
We looked at 48 patients who had undergone a previous PN that were treated at recurrence in
the same kidney with Cyroablation; of 68 tumors treated in that group there were 6% that had
complications and at a median follow-up time of 19 months the local recurrence rate was 9%.
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While RCC is a disease
primarily spread
hematogenously, about
26% of patients have nodal
invasion. Nodal invasion is
common in metastatic but
uncommon in locally
advanced disease. When
patients have node
positive disease the fiveyear disease specific
survival rate is around
20%.
Pros and Cons of Node
Dissection for Locally
Advanced RCC
While lymph node
Lymph node dissection at surgery in kidney cancer is a controversial
dissection is common in
topic. We often do remove lymph nodes because they are involved; and
some other malignancies as cancer surgeons it is hard to leave the operating room without
its role is fairly
removing disease which is easily accessible and can be safely removed.
undefined in RCC
However the overall benefit of lymph node dissection to patients has
procedures. It increases
been questioned
the complexity of the
surgery, the patient
selection criteria are varied, and its relevance in the TKI era is uncertain. However, a lymph
node dissection can provide tissue for genomic studies and lay the basis for eligibility in the
adjuvant trials.
Historically, studies dating back to the cytokine era
Controversy: Defining
showed that patients with lymph node involvement
The Role of LND in RCC
had a poor prognostic outcome very similar to the
•LND is effective in other malignancies
prognosis of those with metastatic disease. Patients
•Long term survival has been seen in
having both metastatic disease and lymph node
RCC patients with LNI following LND
involvement had the poorest prognosis.
•Problems:
–LND templates are large for RCC =
A European Organization for Research and Treatment
major surgery
of Cancer (EORTC) prospective trial of unselected
–Patient Selection –Who could benefit?
patients showed there was no difference in overall
–Undefined Biological Basis
survival of those undergoing partial nephrectomy or
–Relevance in the targeted therapy TKI
radical nephrectomy with no evidence of metastases
Era -uncertain
for those with or without a lymph node dissection. The
•Adjuvant trial eligibility
trial concluded that lymph node dissection should not
•Tissue for genomic studies
be routinely done. Other studies indicate that higher
risk patients, those with larger primary tumors or those having a higher grade, sarcomatoid
features, or having a greater than 10 cm necrosis could benefit from a lymph node dissection at
time of surgery.
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Of the 65,000 annual
cases of renal cell
carcinoma that will be
diagnosed in the year
approximately 4 to 10%
of these patients will have
venous invasion at
diagnosis.
The International Society of Urologic Pathologies recently submitted three recommendations
regarding tumor thrombus handling and staging of RCC:
 The thrombus length should not be included in the measurement of the main tumor
mass
 Positive vein margin: only when there is adherent tumor visible at the actual margin,
confirmed microscopically •Recommendation: sample 2 or more sections to assess for
adherent caval wall tissue
 Analysis of separate “caval thrombus” specimen
A retrospective study of 256 patients from 1993 – 2009 by Able and Colleagues which excluded
patients with grossly incomplete resections (readily visible remaining tumor) showed that
18.4% (47/256) had a positive vascular margin or microscopic tumor present at the margin of
resection invading the vein wall. Decreased rates of recurrence free, metastasis free, and
cancer specific survival was noted in these patients. At the Mayo Clinic we have observed that
positive vascular margins are associated with much more aggressive pathological features.
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The impact of the height of the tumor thrombus on prognosis has been debated significantly;
the most reliable prognostic factor appears to be the difference between a renal vein thrombus
and a thrombus in the inferior vena cava (IVC). There does not appear to be a significant
difference in the survival rates of upper-level thrombus whether it is above or below the
diaphragm. The presence of synchronous metastatic disease also impacts the overall prognosis.
Increased individual surgeon
volume/experience was associated with
the trend towards lower in-hospital
mortality. Patients managed
conservatively with no surgery have a
much lower one-year survival rate than
surgical patients.
In patients with an IVC tumor thrombus
and concurrent pulmonary embolism the
embolism is not equivalent to metastatic
disease and studies support the upfront
surgical treatment of the RCC tumor and
thrombus.
In level III & IV (upper level) tumor
thrombi major complications can be anticipated in about 35% of cases with a higher risk of
complication in level IV. The 90-day mortality rate is about 10%, mostly associated with a low
ECOG performance status and low serum albumin levels.
At present there is no level I trial evidence to guide integration of targeted therapy into the
treatment of RCC with tumor thrombus; however trials are ongoing with various outcomes
being reported.
Patients having a right side tumor with an AP (anterior-posterior) diameter of the IVC at the
renal vein ostium (opening) equal to or greater than 24 mm with complete occlusion (blockage)
at the renal vein have a 66% chance of needing extensive IVC resection and complex vascular
reconstruction. However, patients with none of these features have only a 2% risk of needing
extensive resection and reconstruction.
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Recurrence After Surgery
In Non-Metastatic RCC with Thrombus;
Risk Factors from a Contemporary Multicenter Analysis
M IC H AEL L. B LUTE , J R ., M.D.
University of Wisconsin School
of Medicine and Public Health
Madison, WI
The purpose of our analysis was to identify prognostic
About 10% of patients with RCC will have
locally advanced disease with tumors
invading the venous system. Many nonmetastatic patients may be cured with
surgery alone. Few prognostic factors have
been described for kidney cancer with a
tumor thrombus; no large contemporary
studies have evaluated this situation in
patients with non-metastatic disease.
factors for disease recurrence in RCC in cases having
venous tumor thrombus. We were able to utilize data of 430 non-metastatic RCC patients that
underwent attempted curative surgery between 2000 and 2013 using the databases of the University of
Wisconsin, UT Southwestern, and M.D. Anderson Cancer Center. We identified 191 patients or 40.7%
who had progression to metastatic disease within 55 months of surgery (the median average was 28.4
months). We were able to study the results of 188 patients and found that 128 of these patients or
68.1% of them had a solitary metastasis while 60 others 31.9% had multiple sites of metastasis at their
initial examination.
At the completion of our analysis we were able to identify several independent predictors of high
likelihood of disease recurrence within five years for patients presenting with IVC tumor thrombus: the
most prominent risk factors
were: anemia; perinephric fat
invasion; non-clear-cell histology;
and a body mass index <20. We
observed that patients with a
BMI < 20 were more likely to
have recurrence of disease than
patients with a BMI of 20 to 25
and the lowest risk of recurrence
was in the group with BMI > 25.
Thirteenth Annual International Kidney Cancer Symposium – 2014
Cytoreductive
Nephrectomy
S TE PHEN H. C UL P , M.D., P H .D.
Uni versi ty of Vir ginia
Char lo tte sville , VA
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42
S ome
studies have
shown that a patient
undergoing CN and
then
taking
TKI
therapy has a 40%
decrease in risk of
death versus TKI
therapy
alone.
However, CN is not
for everyone ....
Prior to the cytokine era (the use of IL-2 and interferon alpha) cytoreductive nephrectomy (CN)
was used primarily for palliation of symptoms; primarily bleeding and pain. There was the
occasional regression of metastatic disease when the primary tumor was removed. The
following study by Tufts University was the first to evaluate the role of CN in patients
undergoing systemic therapy with IL-2.
Subsequent studies indicated that patients
treated with existent systemic cytokine
therapies did better if CN had been
previously undertaken. A 2001 UCLA study
observed that if better systemic therapies
were available better benefits could be
expected. Today we have “better” systemic
therapies, but we lack any level one
evidence for the continued use of CN in
advanced disease followed by TKI therapy.
2014 NCCN guidelines for stage IV state that for potentially surgically resectable primary with
multiple metastatic sites… Cytoreductive nephrectomy in select patients prior to systemic
therapy is acceptable.
Patients over 75 tend not to have
surgery and surprisingly, AfricanAmericans are much less likely to
undergo surgery than other races. For
each one-year increase in age in the
SEER database of cytoreductive
nephrectomy there is a 5% decrease in
the amount of surgeries. Unpublished
data accumulated by Dr. Culp suggests
that despite the increasing use of targeted therapies the percentage of CN has been fairly
stable.
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Some studies have shown that a patient undergoing CN and then taking TKI therapy has a 40%
decrease in risk of death versus TKI therapy alone. However, CN is not for everyone;
retrospective studies of patients with poor performance status demonstrate virtually no
benefits.
This slide shows almost all of
the poor prognostic factors in
advanced or metastatic RCC.
While it is not one factor
other than performance
status that determines
benefit, it is the additive
nature of poor prognostic
factors that translates to
decreased patient survival.
The greatest benefit of CN is in patients who are expected to survive more than 12 months.
In follow-up discussion Dr. José Karam pointed out that doctors often struggle in continuing with
existing standards of care when the data has changed. However, in this situation the lack of
evidence is not evidence that CN should not be performed; the procedure should still be utilized
for carefully selected patients.
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Each year since 2009 a keynote lecture in honor of Dr. Andrew C Novick (1948-2008) has
been given at the International Kidney Cancer Symposium. The lecture is given by the
recipient of the Andrew C Novick Award for that year; additionally, an award of $10,000 is
made on behalf of the recipient by the Kidney Cancer Association to support the research of a
young investigator through the Urology Care Foundation of the American Urological
Association.
Dr. Andrew C. Novick was chairman of the Glickman Institute of the Cleveland Clinic. Known
worldwide for his dedication and contributions to kidney cancer research and innovative surgical
procedures, he pioneered the use of ice baths in surgery to preserve kidney function. His expertise in
treating kidney cancers and the use of nephron sparing surgery has been credited with giving many
patients longer lives. These procedures are now used regularly on a worldwide basis. Dr. Drogo
Montague of the Cleveland Clinic said in an interview in 2008 that Dr. Novick had “technically the best
hands anyone had ever seen”.
A report of his death which appeared in the Cleveland Plain Dealer in October 2008 received many
comments from readers; excerpts of a few of those comments follow.
 I really believe that Dr. Novick saved my life 12 years ago by removing my cancerous kidney
and lymph nodes. I am fortunate that I was able to be his patient…
 … I would most likely not be alive today if it were not for Dr. Novick. He performed renal
surgery on my kidney in 1988.I traveled to the Cleveland Clinic from Florida…
 Dr. Novick saved my husband's life in 2005 by performing partial nephrectomies on both
kidneys. His passion for his work and for his family were exemplary. He adored [his family] and
talked about them with such great love every time we saw him. I will be forever grateful for his
pioneering expertise in the urological field. And I will miss his gentle demeanor, his kindness
and his friendship.
The KCA is pleased to present Dr. Brad Leibovich of the Mayo Clinic this prestigious award in recognition
of his work, service and dedication to his patients and the entire kidney cancer community.
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… the key is not whose turf and
who does it, the key is what sort
of results you’re getting for the
patient.
I
T H IN K M OR E THA N A N YT H IN G
W OR K …
T H EY N EV ER
I
L EAR N ED FR OM M Y PAR E N TS WAS TH E V AL U E OF HAR D
TOL D M E T O WOR K HAR D ; TH EY JU S T D EM ON S TR AT ED IT .
In his presentation Dr. Leibovich marked many of the milestones in the field of kidney cancer
framed against milestones in his life during that same period. Below are some examples:
About the time I was born
in 1967 there was a leap in
the survival of kidney
cancer as the procedure of
radical nephrectomy
pioneered by Dr. Charles
Robson gained widespread
acceptance and some
other advances in surgical
care took place.
25 patients with metastatic cancer
treated with LAK and IL-2
 Partial Response in 11/25
patients
 1 Complete Response in
melanoma
 3 cases of mRCC
all with Partial Response
When I graduated from high school in 1985 crosssectional imaging was becoming more widely available,
my future colleagues at Mayo Clinic were reporting on
partial nephrectomies, and it was the beginning of an
exciting time for immunotherapy in kidney cancer as
work in the use of lymphokine-activated killer cells and
interleukin-2 began.
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I attended Cornell University
1985 – 1989 fully intending to go
into medicine but got fired up
about basic science research. So
from 1989 – 1991, I went to
Washington University, St. Louis. I
did research in a hematology lab
and realized that I really wanted to
pursue medicine. Difficult surgeries with vena cava thrombus and
laparoscopic nephrectomies were being performed, and the genetic What I learned from
changes leading to kidney cancer were identified.
family medicine docs was
From 1991 – 1995 I went to medical school and was completely oblivious
that the more time you
to kidney cancer… I wanted to be a family medicine doctor.… What I
spend with your patients,
learned from family medicine docs was that the more time you spend
the more you get to know
with your patients, the more you get to know them, and the more you
them, and the more you
care about them, the better your results will be.
care about them, the
Lacking the temperament to be a family doctor I turned to surgery
better your results will be
intending to be a cardiothoracic surgeon. I had an instructor who got me
interested in pediatric urology. Immunotherapy continued to be studied
and used and the people at Mayo were working on ways to do a partial nephrectomy without removing
the kidney.
In 1995 my wife and I moved to Rochester, Minnesota. My wife cried for two weeks; I promised her we
would only be there six years while I was in med school. On the medical front we were learning that
nephron – sparing surgery preserved a lot of renal function over a long period of time. In 2001 I went to
Indiana University for six months and did a lot of high-volume testis cancer surgery.
In 2002 I went to UCLA hoping to learn how they were getting such good results with high
dose IL-2… I found there was no “secret sauce” but that it required people with great passion
on a team who collaborate in research and who give really great clinical care to really drive
the outcomes for advanced kidney cancer.
In 2002 I returned to Mayo; “ nothing that we do at Mayo Clinic ever happens in a vacuum, it’s
all collaboration, it’s all friendship, and it’s all working together.”
Often I hear in urology meetings that people are concerned about
giving up a portion of their practice to interventional radiologists.
Well, the fact of the matter is if you’re going to do an image guided
ablation you should use an imaging specialist, and if you want good
outcomes you should go to the pros. The key is not whose turf and
who does it, the key is what sort of results you’re getting for the
patient.
While I did not interact with Andy Novak extensively, every time I did,
I received a word of encouragement…
He still shapes the way we do a lot of kidney cancer today.
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“Tonight, I'm launching a new Precision
Medicine Initiative to bring us closer to curing
diseases like cancer and diabetes — and to give
all of us access to the personalized information
we need to keep ourselves and our families
healthier.”
President Barack Obama,
State of the Union Address, January 20, 2015
Sidebar: Clinical Trials and Research
A NEW INITIATIVE ON PRECISION MEDICINE
Francis S. Collins, M.D., Ph.D., and Harold Varmus, M.D.
N Engl J Med 2015; 372:793-795February 26, 2015DOI:
10.1056/NEJMp1500523
THIS IS A SUMMARY OF THE ABOVE ARTICLE. IT CAN BE VIEWED IN ITS ENTIRETY AT:
HTTP://WWW.NEJM.ORG/DOI/FULL/10.1056/NEJMP1500523?QUERY=FEATURED_HOME
President Obama has long expressed a strong conviction that science offers great potential for
improving health. Now, the President has announced a research initiative that aims to
accelerate progress toward a new era of precision medicine. We believe that the time is right
for this visionary initiative, and the National Institutes of Health (NIH) and other partners will
work to achieve this vision.
The concept of precision medicine — prevention and treatment strategies that take individual
variability into account — is not new; blood typing, for instance, has been used to guide blood
transfusions for more than a century. But the prospect of applying this concept broadly has
been dramatically improved by the recent development of large-scale biologic databases (such
as the human genome sequence), powerful methods for characterizing patients (such as
proteomics, metabolomics, genomics, diverse cellular assays, and even mobile health
technology), and computational tools for analyzing large sets of data. What is needed now is a
Thirteenth Annual International Kidney Cancer Symposium – 2014
Graff, Derr, Lawing
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broad research program to encourage creative approaches to precision medicine, test them
rigorously, and ultimately use them to build the evidence base needed to guide clinical practice.
Oncology is the clear choice for enhancing the near-term impact of precision medicine. Cancers
are common diseases; in the aggregate, they are among the leading causes of death nationally
and worldwide, and their incidence is increasing as the population ages. They are also especially
feared, because of their lethality, their symptoms, and the often toxic or disfiguring therapies
used to treat them. Research has already revealed many of the molecular lesions that drive
cancers, showing that each cancer has its own genomic signature, with some tumor-specific
features and some features common to multiple types. Although cancers are largely a
consequence of accumulating genomic damage during life, inherited genetic variations
contribute to cancer risk, sometimes profoundly. This new understanding of oncogenic
mechanisms has begun to influence risk assessment, diagnostic categories, and therapeutic
strategies, with increasing use of drugs and antibodies designed to counter the influence of
specific molecular drivers. Many targeted therapies have been (and are being) developed, and
several have been shown to confer benefits, some of them spectacular. In addition, novel
immunologic approaches have recently produced some profound responses, with signs that
molecular signatures may be strong predictors of benefit.
These features make efforts to improve the ways we anticipate, prevent, diagnose, and treat
cancers both urgent and promising. Realizing that promise, however, will require the many
different efforts reflected in the President's initiative. To achieve a deeper understanding of
cancers and discover additional tools for molecular diagnosis, we will need to analyze many
more cancer genomes. To hasten the adoption of new therapies, we will need more clinical
trials with novel designs conducted in adult and pediatric patients and more reliable models for
preclinical testing. We will also need to build a “cancer knowledge network” to store the
resulting molecular and medical data in digital form and to deliver them, in comprehensible
ways, to scientists, health care workers, and patients.
About the Authors:
Francis S. Collins, M.D., Ph.D. is the Director of the National Institutes of Health (NIH). In that role he oversees the
work of the largest supporter of biomedical research in the world, spanning the spectrum from basic to clinical
research.
Dr. Collins is a physician-geneticist noted for his landmark discoveries of disease genes and his leadership of the
international Human Genome Project, which culminated in April 2003 with the completion of a finished sequence
of the human DNA instruction book. He served as director of the National Human Genome Research Institute at
the NIH from 1993-2008.
Harold Varmus, M.D., co-recipient of a Nobel Prize for studies of the genetic basis of cancer, was nominated by
President Obama as Director of the National Cancer Institute on May 17, 2010. He began his tenure as NCI Director
on July 12, 2010. He previously served as President and Chief Executive Officer of Memorial Sloan-Kettering Cancer
Center (MSKCC) and as Director of the National Institutes of Health (NIH).
Thirteenth Annual International Kidney Cancer Symposium – 2014
Photo: European Medical Journal
Chromophobe
RCC
Graff, Derr, Lawing
49
… if you look at the NIH
and the money that has
been spent overall on
cancer research,
kidney cancer receives
a very small amount of
funding;
this makes it very
difficult for us to
conduct any basic
research.
In the graph above it is clear that we have more success in prolonging survival times of clear cell patients.
We have made a lot of progress in clear-cell RCC which make up about 70 – 75% of all RCC cancers
despite the lack of government funding. In 10 years we have been able to increase the median survival
rate from one year to about three years in this large subtype.
When we look at chromophobe kidney cancer (chRCC) which comprises about 5% of the total of
RCC cases, we realize that most oncologists rarely, if ever, deal with this subtype. When it is
surgically removed the patient is “cured”. If it develops metastases, not a lot of information on
how to deal with it is available.
Our studies in papillary kidney cancer have helped us to have a better understanding of the
chromophobe subtype. Since ccRCC primarily results from loss in the 3P chromosome, drugs that target
the VHL pathway work fairly well. From a biological standpoint chRCC is more interesting and complex; it
has losses in seven chromosomes which makes it non-robust – in fact it is wimpy – that may be the
reason we can so often cure it with surgery.
As we seek to find further answers in our labs in the clinic we are undertaking
a phase 2 study of everolimus plus bevacizumab anticipating good results.
Thirteenth Annual International Kidney Cancer Symposium – 2014
Papillary
RCC
Dana-Farber Cancer Institute
Boston, MA
Photo: European Medical Journal
Graff, Derr, Lawing
50
Papillary renal cell carcinoma (pRCC) is a
heterogeneous (non-uniform) entity; under
the microscope specimens have many varied
characteristics. Over the past few years
pathologists have been attempting to better
characterize pRCC by adding new
classifications. While in the clinic setting
oncologists may be used to the traditional
papillary type 1 or non-1 (also called type 2)
terms, these new classifications will allow for
better understanding of cause-specific
subsets of pRCC in the future as we
accumulate data on them.
It is important to stress
that localized pRCC is not
the same as metastatic
pRCC. It is very likely that
these two entities are not
the same kind of tumors. In
the metastatic setting,
pRCC has a worse
prognosis than ccRCC with
an average overall survival
of 17.9 versus 23.5 months.
With localized pRCC the
cancer-specific survival (CSS) after
surgery is 94.5% with a plateau of
survival at about 90% at 12 ½
years, while the CSS of ccRCC is
86.9% with a plateau of survival at
about 17 years of 65%.
With pRCC there is no efficacy of
cytokines or chemotherapy
Since c-MET expression is high in
all pRCC, ongoing and new trials
with agents inhibiting this
expression have potentially great
promise.
S T AY U P T O D ATE …
Get The Latest News on Kidney Cancer
Visit the KCA Pressroom
on the bottom of each page
www.kidneycancer.org
Thirteenth Annual International Kidney Cancer Symposium – 2014
Graff, Derr, Lawing
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The International Metastatic Database Consortium (IMDC) metastatic Renal Cell
Carcinoma (mRCC) data providing information on overall response rate and medial
overall survival of patients previously treated with first-line targeted therapy (TT).
With pRCC there is no efficacy of cytokines or chemotherapy and two Phase II, first-line clinical
trials with TKIs were disappointing. The SUPAP trial was for untreated patients with localized or
metastatic disease using sunitinib as the agent. Of 60 patients enrolled, the overall response
rate was 12% with a 5.6 month period of progression free survival (PFS). The median overall
survival of the group was 12.5 months, with type 1 pRCC having 17.8 months overall survival
and type 2 having 12.4 months overall survival.
The RAPTOR trial was for previously untreated metastatic pRCC patients using everolimus. Of
92 patients enrolled, the median PFS time was 3.7 months with no one meeting the primary
endpoint of six months. The median overall survival was 21 months with type I attaining 28
months and type 2, 20.3 months.
A trial using Foretinib (which is a variable endothelial growth factor regulator and MET inhibitor
TKI) with 65 previously treated patients having metastatic disease has had a median
progression free survival rate of more than nine months and an overall survival rate of 70% at
one year.
Thirteenth Annual International Kidney Cancer Symposium – 2014
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Translational Cell RCC is a very
rare subtype of kidney cancer
which was first introduced in
2004 as a genetically distinct
entity in the World Health
Organization (WHO) classification
of renal tumors. It occurs in about
one-third of pediatric and 15% of
patients below the age of 45 who
are diagnosed with kidney cancer.
Its name arises from
translocation of genes at the
chromosome level which then
combine or fuse with another
gene; this action can lead to the establishment
of disease.
The histology of transitional-cell RCC
(tRCC) is heterogeneous: some cases
may present as clear-cell, some can be
papillary, and others present with
mixed histology (with clear-cell
surrounding papillary) as shown here.
Dr. Escudier and his associates began an extensive study
of this subtype four years ago by collecting information
on all the French cases of tRCC. Of 54 cases located
patients older than 21 had a high percentage of
metastatic disease at presentation. Patients above the
age of 25 typically can be expected to have poor
outcomes with the median survival time being about 14
months and with a very few number surviving longer
than three years.
Of eight cases that we were able to thoroughly evaluate
we discovered that two of them underwent chromatin
remodeling. As we establish Xenografts to model the
disease and continue testing in vitro and in vivo to isolate
novel agents targeting chromatin remodeling genes
and/or immune checkpoints we hope to be able to
launch the first clinical trials for this condition.
Thirteenth Annual International Kidney Cancer Symposium – 2014
MOLECULAR
CHARACTERIZATION
OF RENAL
MEDULLARY
CARCINOMA
Graff, Derr, Lawing
53
Renal Medullary Carcinoma
(RMC) is a rare and highly
Aggressive malignancy which
affects almost exclusively young
subjects of black race (median age
30) having sickle-cell trait.
IT IS VERY IMPORTANT FOR US TO
UNDERSTAND THE BIOLOGY OF THIS
TUMOR AND ALSO TO DEVELOP NEW
THERAPIES FOR THESE YOUNG,
PRODUCTIVE, BUT VERY UNFORTUNATE
Photo: European Medical Journal
PATIENTS.
At M D Anderson we have seen a total of 33 patients over the
past 10 years Of these 33 we have collected tumor tissue from As with other rare tumors the
17 patients, creating three xenografts and three cell lines for biggest challenge to study RMC
is to collect enough tissue for
further molecular characterization.
We think that the most important studies in RMC would be to
analysis and research.
evaluate mutations at the DNA level and also gene expression
changes at the mRNA (messenger Ribonucleic Acid) and protein levels.
We were able to run exome sequencing on nine tumor samples; all of them had mutations in the
hemoglobin beta gene (HBB) (this gene is also responsible for sickle-cell traits and other conditions). Of
160 proteins studied in these tumor samples we found that 49 of them were differentially regulated
(their normal function was changed). A mutational analysis of DNA, mRNA, and protein levels allowed us
to identify three pathways that have potential for development of treatment agents. One of the
pathways is involved in cell energy control, one is in cell cycle control, and another is involved in the
regulation of histone gene modifiers.
The energy control pathway is of particular interest where the AMPK gene is significantly down
regulated (the AMPK gene is the central switch of cellular metabolism).
AMPK has been identified as being down-regulated in several other tumor types.
Because gene expression can be controlled by mRNA, we
also performed microRNA profiling on the specimens in an
effort to find what mRNAs were differentially regulated.
We were able to determine:
 Down regulation of AMPK is important for RMC
tumor survival and proliferation
 Testing on one of our cell lines has shown that an
AMPK activator caused cell death
Since we found immune signaling pathways are activated
in RMC tumors, we are conducting studies to look at the
immune profiles of these tumors; our initial indicators are
that RMC may be responsive to immunotherapy,
particularly the immune-checkpoint therapies.
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FROM THE SURGICAL PERSPECTIVE
AS WELL AS THE ONCOLOGICAL,
SARCOMATOID TUMORS EXHIBIT
AN AGGRESSIVE BEHAVIOR
Renal cell carcinomas that have
sarcomatoid differentiation can occur in
any of the histological subtypes; their
higher numbers in clear-cell cases is due
to the higher numbers of clear-cell cases
overall. Occurring in 5 to 8% of RCC
cases this tumor presents with an
aggressive biological behavior and has
an extremely poor prognosis in either
the primary or metastatic setting. It
commonly has the high risk tumor characteristics of necrosis (90%) and/or microvascular
invasion (30%). Current available genomic data suggests that sRCC has different independent
pathways than other high grade RCC and the differentiation represents a further evolution of
tumorigenesis. This differentiation is a reversion of the specialized kidney cells to a more
unspecialized type of cell. Further ongoing investigation may reveal a different pattern of origin
as well as giving insights to druggable targets. Prior studies of sRCC are very limited; studies
which evaluated the molecular characteristics of specific sRCC instead of the entire tumor are
either old or unconfirmed.
The Mayo Clinic has recently reported on a study that shows a potential prognostic marker might be
the degree of sarcomatoid dedifferentiation. In this study all the tumor specimens were reviewed by
Dr. John Chevelle, providing a uniformity of evaluation as opposed of the gleaning of information from
numerous written sources where the percentage of dedifferentiation and other characteristics of the
tumor may vary according to interpretation of the observer. This study indicates that 30% of
dedifferentiation is the dividing line for whether the patient can be expected to do well or not. The
standard of care for sRCC is nephrectomy; cancer specific survival rates are uniformly low for all
epithelial subtypes with the five-year rate being in the range of 15 – 22%; there is a low rate of
objective response for systemic therapy with little increase in the average overall median survival.
Although it is important for people to know what factors or behaviors are associated with an increased risk
of kidney cancer, blaming yourself for past behavior is neither helpful nor healing . WHKC p.9
Download a free copy of We Have Kidney Cancer from our website: www.kidneycancer.org...
Thirteenth Annual International Kidney Cancer Symposium – 2014
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Despite having 10 years of
experience with targeted
therapies there is still little
conclusive evidence of which
agent is the best first-line
choice for treating non-clearcell histologies in kidney
cancer.
Both the European and United
States guidelines for treatment
of kidney cancer with
nonclear-cell subtypes recommend
participating in a clinical trial if
the patient is qualified and one
is available. One trial which Dr.
Choueiri discussed was the
ESPN trial that had been
reported on during the 2014
annual meeting of ASCO.
This trial had 73 enrolled
patients and after a clear
advantage was shown at the
first interim analysis of
results the Data and
Monitoring
Safety
Committee (DSMC) for the
trial decided to halt the
study.
Conclusions:
Although clinical trials are
preferred, VEGF and mTOR
inhibitors remain options for
non-clear cell RCC front-line
therapy
Immune checkpoint blockers
should be tested in all RCC
subtypes
Targeting the MET pathway
particularly in papillary
subtypes and some other
candidates may be a viable
option for trials and treatment
(The ESPN Trial): EVEROLIMUS VERSUS SUNITINIB
PROSPECTIVE EVALUATION IN METASTATIC
NON-CLEAR CELL RENAL CELL CARCINOMA
A Randomized Multicenter Phase 2 Trial Conducted at: The University of Texas
MD Anderson Cancer Center, Houston, TX; Beth Israel Deaconess Medical
Center, Boston, MA; Dana-Farber Cancer Institute, Boston, MA
In this study of patients of all non-clear-cell histologies with a
performance status of zero – one who had no prior systemic therapy were
randomized to either receive everolimus or sunitinib; primary endpoint
of the study was to evaluate length of progression free survival. Sunitinib
appeared to have the longest duration of PFS in all subtypes except for
the sarcomatoid with/clear-cell cohort. While in more common cancers
the small numbers enrolled in each study group would constitute an
insignificant number; these relatively rare subtypes of a cancer which
only reports about 65,000 new cases per year may have greater potential
value in determining the selection of an appropriate first-line therapy.
Thirteenth Annual International Kidney Cancer Symposium – 2014
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BASIC CONCEPTS AND FUTURE Kidney Cancer is one of
HORIZONS IN CANCER the great frontier cancer
types that has opened up
IMMUNOTHERAPY
the door for cancer
immunotherapy…
D REW P A RDOL L , M.D., P H .D.
Johns Hopkins School of Medicine
The Sidney Kimmel Comprehensive
Cancer Center
Baltimore, MD
our clinical experience
with PD-1 blocking
antibodies has taught us
more about the human
anti-tumor response than
decades of laboratory
studies in a test tube
Dr. Pardoll started in cancer immunotherapy 20 years ago. At
that time, there were vaccines invented that produced some
immune response. However, there was rarely tumor
regression with these types of treatment. Also around that time, the concept of “the brakes”
was discovered. The human body’s immune system can be extremely dangerous if not kept in
check, and there is constant feedback to keep everything in balance. These feedback
mechanisms are commonly called “checkpoints”, and “brakes” are applied as needed to
regulate the immune system.
There are many proteins and ligands
that either stimulate or inhibit immune
responses, and a summary of these as it
relates to immune system T cells is
shown. Ligands are small molecules
that bind to associated target proteins
to perform signaling in the
human body. The list on the
diagram only represents roughly a
quarter to a third of this list of protein
ligand interactions that occur as related
to the body’s T cells. New interactions
are constantly being discovered, and
there is still a lot to be learned as
related to immune responses. By individually studying each of these protein interactions, the
specific kind of therapies that is given to a patient can be greatly enhanced.
Thirteenth Annual International Kidney Cancer Symposium – 2014
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Currently, there is only solid patient data around the CTLA-4 and PD-1 inhibitors. The PD-1
pathway is considered to be a “Master Checkpoint” within the tumor immune
microenvironment, and many of the currently available cancer treatment drugs target this
pathway. By blocking the PD-1 pathway (anti-PD-1 or anti-PD-L1), the body’s natural “brakes”
are released and the immune system attacks cancer cells.
Cancer cells resist immune attack by
expressing PD-L1, and there are two
mechanisms by which they produce levels of
PD-L1. The first is innate, meaning that PD-L1 signaling is in cancer
cells intrinsically. But innate production of PD-L1 is not considered
to be the main method by which tumors resist immune system attack. There is also something
called adaptive resistance, which happens when the
tumor is being attacked by the immune system over
time. Adaptive resistance causes increasing
expression of PD-L1, thus stopping the
immune system from being effective.
A large proportion of cancer patients have an existing repertoire of -tumor T cells that have the
capacity to recognize and kill tumors with selectivity. These also are the patients that will tend
to have the most adaptive resistance happening by their tumors thru the production of PD-L1.
And, when an anti-PD-1 agent is used these patients will usually have a strong response.
For those patients with T
cells that tend to be less
active against their
tumors, there is a lower
amount of tumor
adaptive resistance and
therefore there is less
expression of PD-L1. An
anti-PD1 single agent will
tend to have less of a
response in these
patients. For these
patients, combination of
therapy can be very
effective such as a TKI
combined with anti-PD1.
Thirteenth Annual International Kidney Cancer Symposium – 2014
I n this presentat ion , Dr.
Atkin s p re sent s the ca se
that immunothe rap y is the
optima l first cho ice fo r
metasta tic k idn ey canc er.
The re are two ma in
therapeu tic d rug
treatment s p re sented ,
high do se IL -2 and
anti-PD 1.
Graff, Derr, Lawing
58
I MMUNOTHERAPY
IS THE O PTIMAL
F RONT -L INE M RCC
T REATMENT
Nivolumab has shown great
IL-2 provides a very desirable end result in patients that is when
promise and is an anti-PD1
ends but the benefits continue. This occurs in only about 6drug. Patients tolerate the drug treatment
10% of the patient population. However, it does give the patient a
very well, and in a similar
chance at a cure, and that is the reason high dose IL-2 has been given
as the front-line treatment for metastatic RCC for many decades.
fashion to IL-2 it can produce
treatment free survival
scenarios. In a phase 1
Nivolumab trial, the median
progression free survival time
was 7.3 months. But again,
many of the patients in this
clinical trial stopped therapy
and did not have disease
progression.
Another interesting point with
anti-PD1 drugs is that the
patient’s histology and tumor
grade can actually predict if they will respond better to immunotherapy. For example, patients
with higher-grade tumors tend to respond better to Nivolumab. This is similar to what was
seen with high dose IL-2 patient response.
Combinations of immunotherapy drugs are showing great results. One example is the
Nivolumab/Ipilimumab combination, which is showing response rates of 40-50%. This is similar
to TKIs, but likely with more durable responses.
There is one final point to consider when selecting immunotherapy as a front line treatment.
Studies have shown that there is still good response with TKIs / VEGF therapy if needed after
the immunotherapy.
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TKI S ARE T HE O PT IMAL
F RONT -L INE M RCC T REAT MENT
M. D RO R M ICHAELS ON , M.D., P H .D.
Massachusetts General Hospital
Boston, MA
Currently, most patients with metastatic kidney
cancer are getting VEGF TKI therapy as their frontphoto- ASCO 2012
line therapy (about 70% in 2013). When debating
whether to use a TKI or immunotherapy as the first
treatment choice, one needs to look at what we
know now based on empirical data. In the 2020’s,
treatment plans will likely become much more
individualized, and a specific treatment choice can be
made based on that individual data. But for now in
2010’s, Dr. Michaelson’s position is that VEGF is the
optimal front-line choice based on the currently
available data.
When selecting a VEGF TKI as a front-line treatment,
response rates will be 30-40% of patients, and stable
disease will be in an additional 25-40% of patients.
Progressive disease will occur in only about 25% of
patients. And the medium overall survival is somewhere around 2.5 years. This is higher than
Nivolumab, which as an overall survival of between 1.5 to 2 years.
TAKE HOME POINTS FOR TKI AS FRONT-LINE
TREATMENT:
- Ultimate goal is to develop predictive
markers of response to each type of
therapy.
- Therapy should be selected based on
which will most likely extend survival.
- Current front-line standard remains
VEGF
- Targeted therapy.
- There are many durable responses
- Observed with TKI therapy.
Thirteenth Annual International Kidney Cancer Symposium – 2014
THE EVOLUTION OF
TARGETED THERAPY IN
RENAL CELL CARCINOMA
HAS BEEN AMAZING…
THE FRONTLINE TOOLBOX
OF THE FUTURE WILL
CERTAINLY CONTINUE TO
Graff, Derr, Lawing
60
COMBINATIONS OF
IMMUNOTHERAPY
AND TKIS ARE THE
OPTIMAL
FRONT-LINE
MRCC THERAPY
INCLUDE THE VEGF-TKIS
AND UP AND COMING FOR
SURE ARE THE PD-1 AND
Photo: European Medical Journal
PD-L1 INHIBITORS
In
this presentation, Dr. Plimack
makes the case that a combination
of a TKI and an immunotherapy drug
is the best choice for front-line treatment of metastatic kidney cancer. The three main goals of
care in an mRCC setting are to prevent symptoms, preserve quality of life, and to extend length
of life. In the future, the goal of mRCC care will be to achieve durable disease control or
treatment-free survival.
IN THE PAST DECADE, THE ADVANCES IN TARGET THERAPY DRUGS FOR MRCC HAVE BEEN TRULY AMAZING.
Thirteenth Annual International Kidney Cancer Symposium – 2014
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Recently, studies have started to look at these various drugs in
different combinations. Up until now, none of these
combinations have proven to be an effective standard-of-care
choice as the overall toxicity has been too high. But in
the near future, the frontline toolbox will likely include
a combination of VEGF TKIs and PD-1 inhibitors.
The rationale for combining VEGF TKIs and PD-1
inhibitors is two-fold. First, there is thought to be an
immunologic effect when treated with a VEGF inhibitor
as it “primes” the immune system for a better effect
with an anti-PD-1 agent. And second, there is
empirical data from clinical trial studies that shows
that when VEGF and PD-1 inhibitors are used in combination the results are better than when
used separately.
In summary, TKIs can yield fast results
but many times these are non-durable
responses. Anti-PD1 agents can yield
deep and durable responses, but they
can sometimes be slow to act. The
combination of both therapeutic
treatment types can lead to early
responses due to VEGF inhibition that
are sustained due to PD-1 inhibition.
In Summary
•VEGF inhibitors can induce early responses, but eventual progression is inevitable.
•PD-1 targeted therapies can produce durable but often delayed responses.
•Combination inhibition of VEGF and PD-1 inhibition shows an encouraging response pattern
at the expense of higher toxicity.
•Further investigation of VEGF + PD-1/PD-L1 combinations should be of high priority in m RCC.
Thirteenth Annual International Kidney Cancer Symposium – 2014
BIOMARKERS ON
CHECKPOINT INHIBITION
SUZANNE L. TOPALIAN, M.D.
Johns Hopkins School of Medicine
The Sidney Kimmel Comprehensive
Cancer Center
Baltimore, MD
Graff, Derr, Lawing
62
Several PD-1 pathway blocking
drugs have proven to be very
successful in some types of
cancers. PD-1 and PD-L1
blocking agents have been
used successfully to treat
melanoma, lung, and renal
cancers. There is new
evidence that these same
drugs are showing success in
treatment of bladder,
head/neck, and ovarian
cancers.
And the cancer types for which antiPD-1 drugs are effective will continue
to expand over the next year or two. It
is interesting that a single pathwayblocking drug can now be used in
multiple types of cancers. This creates
high interest from the major
pharmaceutical companies, which is
great news for cancer patients.
There are other cancers such as
prostate and pancreatic where anti-PD-1 drugs do not seem to work. And, there are some patients that
respond well to PD-1 blocking drugs and some that unfortunately don’t respond at all. By using certain
biomarkers (measurable substances in the human body), it is possible that a prediction can be made on
how well a patient will respond to an anti-PD-1 drug treatment.
In order to identify the biomarkers that will
predict a successful response to anti-PD-1
therapy, the PD-1 pathway and how it works
needs to be understood. The PD-1 pathway
affects the body’s T cells and how they function.
T cells function with two different pathway
signals. Signal one allows the T cell to recognize
a tumor as something that should be attacked.
Signal two either activates or inhibits T cells.
When activated, T cells having killing activity
towards an identified target (in this case a
tumor), and they will multiply and migrate to the target site (again in this case the tumor). To guard
against excessive T cell attack and response, there are normal inhibitors or checkpoints that signal the T
cells to stop their attack. These checkpoints are normal mechanisms in the human body that control
immune responses, and they prevent excessive response that leads to high levels of inflammation.
Cancer cells evade the body’s immune system by expressing PD-L1, the signal that inhibits T cell attack.
Thirteenth Annual International Kidney Cancer Symposium – 2014
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The level of PD-L1 expression in a tumor
is the strongest biomarker predictor of
how effective a PD-1 blocking drug will be
in a patient. If a tumor is expressing a
high level PD-L1, there is a good chance
that anti-PD-1 and anti-PD-L1 will be
effective. If low levels of PD-L1 are
expressed, there is a high likelihood that
treatment will not be effective.
In the near future, a biopsy of a tumor
could be used to assess the level of PD-L1
that is being expressed (the PD-L1
biomarker). By using this biomarker
obtained in a biopsy, a pre-treatment
prediction can be made on how successful
a PD-1 pathway blockade treatment might
be for a patient.
CONCLUSIONS
• The immune system is dynamic and its interactions with cancer vary over space (anatomy) and time
(chronology of metastasis), posing challenges for biomarker development
• PD-L1 expression in pre-treatment tumor biopsies (IHC) is currently the strongest single predictor of
clinical response to PD-1 pathway blockade
• Responders in the “marker negative” population raise concerns for clinical application on a perpatient basis
• PD-L1 expression may identify cancer types amenable to PD-1 blockade
• Current limitations in tissue availability for in-depth biomarker studies may be addressed with
innovative clinical trials (neo-adjuvant, rapid autopsy)
Thirteenth Annual International Kidney Cancer Symposium – 2014
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FOLLOW-UP
OF A PHASE IA STUDY
OF AN ENGINEERED PD-L1
ANTIBODY MPDL-3280A
IN PATIENTS WITH METASTATIC
RENAL CELL CARCINOMA (MRCC)
This large phase I trial which has
Characteristics of 69 RCC patients in Trial
already been mentioned a few times in
Median age in years (range)
61 (33-81)
these proceedings was done with
Male
77%
multiple different tumor types using
ECOG Performance Status 0 / 1
54% / 46%
the Genentech PD – L1 antibody
Histologic subtypes, n (%)
Clear cell
62 (90%)
MPDL3280A. In this presentation we
Non–clear cell
7 (10%)
will look primarily at the 69 kidney
Fuhrman grade 4
20 (29%)
cancer patients included in this trial;
or with sarcomatoid histology
MSKCC risk for poor prognosis, n (%) 18 (26%)
the drug is administered intravenously
Prior nephrectomy, n (%)
66 (96%)
at three week intervals for as many as
Previous systemic therapies, n (%)
60 (87%)
16 cycles.
Cytokine-based
27 (39%)
At the 24-week evaluation, 51% of
Tyrosine kinase inhibitor
40 (58%)
the patients had progression-free
mTOR inhibitor
17 (25%)
Metastases at enrollment, n (%) Lung 49 (71%)
status with one complete
Liver16 (23%) Bone 24 (35%) / Brain 3 (4%)
response; 22% of those in the
sarcomatioid or Fuhrman grade 4 with
poor prognosis experienced a response to HELPFUL INFORMATION
For current information on clinical trials for
therapy.
patients with kidney cancer, visit the Pressroom
69 RCC Patients With Treatment-related
of the Kidney Cancer Association and go to:
Adverse Events (Data cutoff Apr 21, 2014)
KIDNEY CANCER CLINICAL TRIAL
All Grades n (%) Grade 3-4
SEARCH TOOLS FOR PATIENTS
Fatigue
15 (22%) 2(3%)
http://www.kidneycancer.org/news/pressroom/
Decreased appetite 11 (16%) 0
Arthralgia
(joint pain)
Rash
Diarrhea
Pruritus (itching)
Pyrexia (Fever)
Chills
Nausea
10 (15%)
0
10 (15%)
8 (12%)
8 (12%)
8 (12%)
7 (10%)
7(10%)
0
0
0
0
0
0
Clinical trials are highly regulated and monitored by the
Food and Drug Administration. They cannot begin until
rigorous intensive review has taken place, in order to
ensure the scientific rationale is valid and that there is a
fair balance of patient risk and benefit. Still, despite the
careful regulation of clinical trials, you should be aware
that there are potential drawbacks in addition to the
potential benefits of clinical trial participation.
Thirteenth Annual International Kidney Cancer Symposium – 2014
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65
MPDL3280A +
Bevacizumab:
Phase Ib Study
Design Arm A
As a single agent
bevacizumab
(10 mg/kg) has
demonstrated a 10%
overall response rate
in some types of RCC
This Anti-VEGF
therapy has
immunomodulatory
properties that
Increases trafficking
of T cells into tumors
and reduces suppressive cytokines,
infiltrating Tregs, and Myleo-Derived
Suppressor Cells
Primary objectives of study:
safety, tolerability, dose-limiting
toxicities (DLT) and maximumtolerated dose (MTD)
Secondary objectives: preliminary antitumor activity and Pharmacokinetics
(PK) – or plasma drug concentrations
Safety
Treatment-related Grade 3 Adverse
Effects (AEs) occurred in 3%
of patients (1 case of neutropenia –
low white blood cell count)
No Grade 4 AEs or deaths
Efficacy in patients with
1L clear cell RCC
4 of 10 patients demonstrated an
objective response
Additionally, 4 of 10 patients
experienced Stable Disease ≥ 24 weeks
9 of 10 patients with mRCC
remain on study treatment
4 of 10 RCC patients
in this study have
demonstrated an
objective response
No Grade 4
Adverse Effects
“It is only through research that we can produce
more cures. It is only through research that we
can reduce physical and emotional suffering. It is
only through research that we can reduce the
spiraling costs that threaten the medical system.”
DR. DAVID MCDERMOTT
http://www.bettermedicine.com/story/kidney-cancer-a-medicaloncologist-hono rs-a-tailored-approach-tocare;jsessionid=B96E2A09D6A4793D7924CEA97F3C1287?
redirect=beme
Thirteenth Annual International Kidney Cancer Symposium – 2014
Graff, Derr, Lawing
66
The following is a summation of Dr. Damarla’s presentation as well as information from other sources:
IMMUNE CELL REPERTOIRE IN PATIENTS
WITH METASTATIC RENAL CELL CARCINOMA
V I JAY D A M A RL A , M.D., M.P.H.
Cleveland Clinic
Cleveland, OH
This study was conducted in order to determine and compare any differences in the number of
immune cells present in blood samples of 22 healthy cancer-free volunteers (the control group)
compared with 40 patients having mRCC who had received no therapy and were being followed
by observation only (observation group) and also 34 patients who had been on therapy with
sunitinib (treatment group). Samples were tested by flow cytometry to determine the
circulating immune cell populations.
Flow cytometry is a technology that is used to analyze the physical and chemical
characteristics of particles in a fluid as it passes through at least one laser. Cell
components are fluorescently labelled and then excited by the laser to emit light at
varying wavelengths. The fluorescence can be measured to determine various
properties of single particles, which are usually cells. Up to thousands of particles per
second can be analyzed as they pass through the liquid stream.
http://www.news-medical.net/health/What-is-Flow-Cytometry.aspx
With the ability to use flow cytometry to evaluate immune cell repertoire in various
subgroups of kidney cancer patients researchers are hopeful that the knowledge gained
will provide a better understanding of how the disease develops and how various
therapies impact the immune cell repertoire. One of the cell types evaluated in this
study are Myeloid derived suppressor cells which some investigators feel is a very
important target for cancer treatments.
Myeloid Derived Suppressor Cells (MDSC) are a heterogeneous population of immature
myeloid cells that are increased in states of cancer, inflammation and infection. In
malignant states, MDSC are induced by tumor secreted growth factors. MDSC play an
important part in suppression of host immune responses through several mechanisms
such as production of arginase 1, release of reactive oxygen species and nitric oxide and
secretion of immune-suppressive cytokines. This leads to a permissive immune
environment necessary for the growth of malignant cells. MDSC may also contribute to
angiogenesis and tumor invasion.
http://www.immunotherapyofcancer.org/content/pdf/2051-1426-1-10.pdf
Thirteenth Annual International Kidney Cancer Symposium – 2014
Graff, Derr, Lawing
When I see a
patient for the first
time I usually spend
an hour plus.
67
A BSTRACT - P HASE 1
S TUDY OF
N IVOLUMAB IN
C OMBINATION WIT H
I PILIMU MAB (IPI)
IN M ET AST ATIC
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C ARCINOMA ( M RCC)
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Photo: European Medical Journal
WE
S AW AN OB J E CT IV E R E SP ON SE R AT E O F
43
AN D
48%
W H ICH GR E AT L Y E X CE E D S T H E
SIN GL E A GE N T N IV OL U M AB E X P E R IE N CE W H ICH I S AR OU N D
20%.
time between date of first response and date of disease progression or death
Due to the high percentage of ongoing responses, median duration of response may be
misleading; Median follow-up of 36.1 weeks for N3+I1 and 40.1 weeks for N1+I3 groups.
Dosing as follows: IV Infusion every three weeks for 4 cycles:
Arm N3 + I1 Nivolumab 3 mg/kg IV + Ipilimumab 1 mg/kg IV
Arm N1 + I3 (n=23) Nivolumab 1 mg/kg IV+ Ipilimumab 3 mg/kg IV
then: Continuous Nivolumab 3 mg/kg IV Q2W
Thirteenth Annual International Kidney Cancer Symposium – 2014
Graff, Derr, Lawing
68
The encouraging finding of this study
was clinical activity. We saw an
objective response rate of 43 and 48%
which greatly exceeds the single agent
nivolumab experience which is around
20%. This mirrors the experience
observed in melanoma where there
has been time for longer follow-up.
The data from this trial influenced the
design of a Phase III trial that is now
accruing patients. This trial
randomizes patients to either a
Nivo/Ipi combination arm or to
sunitinib. This larger Phase III
international trial will accrue up to
1000 patients with sites in the United
States, South America. and Europe.
Baseline characteristics (N3+I1 vs. N1 +I3, respectively)
Mean age (yr): 53.2 vs 53.5 • Gender, male: 81.0% vs 91.3% •
MSKCC risk: –Favorable: 23.8% vs 21.7% –Intermediate: 76.2% vs
78.3% • Prior systemic treatment: 81.0% vs 78.3% •
No. of prior systemic therapies: –1 line: 52.4% vs 47.8%
–≥2 lines: 28.6% vs 30.4% • Prior nephrectomy: n=20 vs n=21
Responders at first assessment (6 weeks):
N3 + I1 = 4/9 (44.4%) • N1 + I3 = 6/11 (54.5%)
Ongoing responders:
N3 + I1 = 7/9 (77.8%) • N1 + I3 = 9/11 (81.8%)
Patients discontinuing treatment
(not due to progression) who continued to respond:
N3 + I1 = 3/9 (33.3%) • N1 + I3 = 5/11 (45.5%)
I always see clinical trials as a window
of opportunity to really get access to
treatments that have not yet been fully
tested; that are not FDA approved. In a clinical trial you don’t necessarily forgo any other treatment
options you still have, for you are still eligible to receive the standard of care treatments if you decide to
take them. However, you may close a window the clinical trials if you start with the Sutent or Votrient
type drug-as an example the large international phase 3 trial with the Ipi/ Novo combination versus
sunitinib does not allow anyone with prior treatment to enroll.
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decision. Interview with European Medical Journal – 2014 IKCS, Chicago
Thirteenth Annual International Kidney Cancer Symposium – 2014
Graff, Derr, Lawing
69
PRESENTATIONS ON THE TOPIC OF:
BALANCING DOSE DELIVERY AND
TOXICITY OF SYSTEMIC THERAPY
Se ssio n Mo derator
Laura Wood, R.N., MSN, OCN
Cleveland Clinic - Cleveland, OH
Co-Chair Nurse Advisory Board
Kidney Cancer Association
In her introduction to the sessions covering Balancing Dose Delivery and Toxicity of Systemic
Therapy, Oncology Nurse Laura Wood, Session Moderator made the following remarks.
We have a lot of new drugs; it has been exciting to be involved in treating kidney cancer
over the past few years as these new drugs have come along. One of the most important
things that has been done is a recent survey that looked at current practices in the
management of adverse events. This survey was conducted among 119 tertiary care
specialists and community oncologists that treat kidney cancer. This survey found:
The biggest barriers to being able to maximize therapy for patients is
the unpredictability of the treatment-related toxicities and the lack of
adverse event education among physicians less familiar with the
treatment of metastatic renal cell carcinoma.
As we gain experience with these therapies it is important to know that understanding the
biomarker development and use of genomic testing may help us to have new information
that will allow us to treat our patients more effectively as well as new and existing resources
that are available to provide patient education for our patients and their family members.
From: the National Comprehensive Cancer Network (NCCN) overview of Kidney cancer 2014-15
All patients with advanced RCC require the best supportive care and advances have been in this area as
well. Strategies have been developed to enhance tolerability of the targeted agents including dose
reductions, schedule changes or alternative therapies. Progression/relapse and the need for subsequent
lines of therapy in patients with RCC are nearly universal. Sequencing the appropriate therapy for maximum
benefit is critical.
Despite the advances of the past ten years, the newer therapies have not yielded a long-term solution for
patients. The American Cancer Society estimated over 63,920 Americans will be diagnosed with kidney cancer
in 2014 and over 13,860 will die of the disease. Majority of patients are diagnosed with locally advanced or
metastatic disease. The 5-year survival rate is still dismal, in the order of 10%.
Thirteenth Annual International Kidney Cancer Symposium – 2014
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For over a decade the Kidney Cancer Association
has received invaluable guidance and assistance in
providing information for patients and their family
members who are dealing with this disease through
the collaboration of the Nurse Advisory Board. This
board co-chaired by Nancy Moldawer, RN, MSN, of
the Cedars-Sinai Medical Center and Laura Wood,
RN, MSN, OCN, of the Cleveland Clinic consists of a
group of dedicated oncology nurses from facilities
who have a specialized practice in the treatment of
renal cell carcinoma. Most of the nurses that serve
on this board have won national honors for their
individual accomplishments, have authored or coauthored many journal articles and chapters in
textbooks on nursing, patient care, and clinical
research and are in great demand as speakers and
panelists at medical meetings in the US and abroad.
We Have Kidney Cancer is an excellent resource book for
patients and family members of those who are dealing
with Kidney Cancer. This guidebook is written and
constantly updated through the efforts and collaboration
of the Nurse Advisory Board and is currently available in a
dozen languages. It is available as a free download or
online readable version at www.kidneycancer.org.
Another resource
that the KCA Nurse
Advisory Board
makes available to
patients and family
members is a series
of videos on
YouTube that
discuss some common side effects that patients may experience when using targeted therapies for
treatment of kidney cancer. To fully explore side effect management, be sure to watch the entire series.
These are fairly short videos, ranging in length from four to twelve minutes each.
https://www.youtube.com/playlist?list=PLEyXw_hOMY5Rv-aMI793eGCCoRVEL7q6d
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The Nurse Advisory Board provided the following resources and content for this summary.
The Kidney Cancer Association: The KCA is available to assist you in many ways, including providing
written information on the disease, treatment options, and resources. You can contact the Kidney
Cancer Association at 1-800-850-9132, or visit the website at www.kidneycancer.org
Drug information sheets: Information on the approved treatments for kidney cancer is available on the
KCA website. These are valuable resources for you and your family as you navigate your treatment.
Side effect information sheets: There are side effects that you may experience while taking these
medications. Most side effects can be successfully managed with early and ongoing communication
with your medical team. Side effect information sheets and educational videos are excellent resources
to assist you in managing these side effects. Prompt recognition and early treatment is key to a more
successful outcome and improved quality of life.
Patient empowerment: One way to increase your odds of survival after diagnosis is by becoming a
strong self-advocate in all phases of your care. This includes keeping good records, getting a second
opinion from a doctor who specializes in kidney cancer, choose an expert doctor with experience in
treating your condition, becoming accountable for your follow up and appointments, and
communicating professionally with your doctor. For tips on talking with your doctor see (We Have
Kidney Cancer Book, page 68) download a free copy www.kidneycancer.org
Clinical trials: Clinical trials have been largely responsible for advances in the treatment of kidney
cancer in recent years. Since 2005, seven drugs have been approved by the US FDA for kidney cancer,
and many new clinical trials offer additional options for treatment. Questions regarding the
effectiveness and safety of new treatments, and ways to improve current treatments are answered
through the clinical trial process. The Kidney Cancer Association can give you information on clinical
trials available in your area.
Disability resources: Aside from employer or personal disability insurance policies, the Social Security
Administration in the US may provide monthly benefits if you are determined to be “disabled“ according
to the government disability standards. This process can be confusing, and it is very important to be fully
informed of the guidelines for determination prior to applying, and to apply early. Applications for
disability in the US can be made online at http://www.ssa.gov/, or by visiting your local Social Security
office.
Additional tips on the US disability process is available at
http://www.disabilitysecrets.com/questions.html
Patient & Family Support Group meetings: There are a variety of ongoing patient and family support
groups for kidney cancer which may be available in your neighborhood. The KCA website has a link to
these meetings. These support groups provide another source of information and guidance on coping
with your diagnosis and treatment. If you don’t have a kidney cancer support group in your area, contact
the American Cancer Society www.cancer.org for other support groups in your area.
Thirteenth Annual International Kidney Cancer Symposium – 2014
U PDAT ES IN T OXICITY
M ANAGEMENT
&
E DUCATION R ESOURCES
N ANCY M OLD AWE R , R.N., MSN
Cedars-Sinai Medical Center
Los Angeles, CA
Co-Chair Nurse Advisory Board
Kidney Cancer Association
Graff, Derr, Lawing
72
Many times when
patients come to our
practice for a second
opinion we see that they
have been taken off these
medications way too
early in their therapy. It
is not uncommon for us
to restart them on the
same medication by
“tweaking” a few things.
It is good to see us develop new evidence that will
help us to guide clinical practice decisions; no
matter what these decisions are, patient education
and knowledge of resources available to help
patients and families manage their therapy will
really have a positive impact on outcomes.
•Seven FDA approved treatments since
December 2005
•Improved clinical outcomes
•Adverse effects have the potential to
chronically impact every organ system
•Treatment is chronic
•Toxicities are cumulative
•Side effect management is anecdotal
•CTCAE grading is inadequate
Since 2005 all our side effect management has
been anecdotal; we do the best we can and we
look at the best literature and go to experts to try to find out how to treat some of the side
effects. But we do not really have any universal guidelines or evidence one-based criteria with
which to treat side effects. Although the Common Terminology Criteria for Adverse Events
(CTCAE) listing/grading system is of vital importance in clinical trials, it doesn’t always translate
in the real world when we are dosing patients over an extended period of time.
How can we optimize outcomes in metastatic renal cell carcinoma with the current agents we
now have?
It boils down to effective therapy
management including: optimizing
the dose; maximizing duration of
most effective treatment; and
eliminating premature
discontinuation of therapy for
adverse events.
Thirteenth Annual International Kidney Cancer Symposium – 2014
Side Effects Cause:
•Reduced quality of life
•Diminished treatment adherence
•Multiple dose adjustments
•Treatment interruptions
•Premature discontinuation of therapy
•Compromised therapeutic efficacy
Graff, Derr, Lawing
73
Many times when patients come to our practice for a
second opinion we see that they have been taken off
these medications way too early in their therapy. It is
not uncommon for us to restart them on the same
medication by “tweaking” a few things. When patients
do stop their medications there is usually a cmpromise
in therapy efficacy.
It’s very important that we assess each patient prior to starting treatment. We need to review medical
history with close attention to cardiac, endocrine, and renal function. It is good to know the toleration,
history of side effects, and responses to treatment with previous TKI and mTOR therapies. If present, we
also need to correct and stabilize coagulopathy (a pathologic condition that affects the ability of the
blood to coagulate).
Patients need to be sure and confident they know their treatment schedule and how to take their
medications. With dosing schedules being different for each medication and often with schedule
adjustments being made the patient can easily become confused.
Probably the best intervention that I can do for patients in our practice is to be
proactive in the interventions to treat the toxicity of their medications.
This is especially important when it comes to mouth care
and addressing hand-foot syndromes.
We teach patients to tell us quickly about side effects when they begin to develop.
Gradually during the use of IL-2 we developed a very specific guidelines for treating patients; our side
effect management was developed to a high degree of early interventions. While we have learned a lot
about targeted therapies, I am not sure that we have developed any important guidelines for universal
interventions that assist all of us in managing side effects.
We have a lot of challenges in caring for patients with kidney cancer; we are finding that toxicities can
wax and wane unpredictably for patients in different intensities, different durations and at different
times. Due to the lack of category one evidence what I am doing to care for my patient with hand – foot
syndrome is probably totally different from what they are doing at the institution next door. This is true
for almost all management of side effects and adverse events for kidney cancer patients on the currently
approved oral medications.
We are not sure how differences in patient populations are affecting
how these drugs and different dosing regimens are metabolized.
With stomatitis good oral hygiene should be practiced before and during therapy. The patient
needs to be assisted in knowing what foods to avoid as necessary by consulting with a dietitian
or nutritionist familiar with these therapies. For the symptomatic problems encountered with
stomatitis we often treat them in a variety of ways, none of which are terribly effective; we
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T OXICITY AS A B IOMARKER
F REDE D ONS KOV , M.D., P H D
Chair, Danish Renal Cancer Group, (DARENCA)
Aarhus University Hospital, Denmark
… hypertension should no longer be associated
with an unwanted side effect [in patients taking sunitinib];
it’s actually the lack of hypertension that should be unwanted….
recommend warm water rinses, rinses with saltwater, with baking soda, the use of Biotene, and
magic mouthwash.
Dr. Donskov reported on several studies of various conditions that may allow them to be used
as predictive biomarkers for treatment outcomes with certain agents in kidney cancer patients.
(Definitions of underlined terms are at the end of the summary of his presentation.)
A 2011 study by Dr. Maria Schmidinger and colleagues on medically induced hyperthyroidism in a
large number of patients in conjunction with the use of sunitinib and sorafenib reached the following
conclusion:
… the current results indicated that sunitinib and sorafenib induced
hypothyroidism in a large number of patients. Hypothyroidism no
longer should be perceived as an unwanted side effect of treatment but,
rather, as a predictive marker for treatment outcome in patient with
metastatic RCC Carcinoma.
In that study, 11 patients who were receiving sunitinib and 5 patients who were receiving
sorafenib achieved either complete remission or partial remission, for an overall response rate
(ORR) of 19.3%. Fifteen of those 16 patients were diagnosed with (subclinical) hypothyroidism
treatment. There was a statistically significant correlation between the occurrence of
hypothyroidism and the achievement of remission.
http://onlinelibrary.wiley.com/doi/10.1002/cncr.25422/full
Also in 2011, a study by Dr. Brian Rini and colleagues on hypertension as a biomarker in
sunitinib patients demonstrated that. In contrast, those patients without hypertension had
poor overall survival. The incidence of hypertension should be considered as associated with
the likelihood of responsive treatment and should not be looked upon as an unwanted side
effect; it is the lack of hypertension that should be unwanted.
From the Study by Rini & Colleagues:
… hypertension was associated with a six-fold increased response rate, a five -fold progression free
response rate and a four-fold overall survival rate. Interestingly enough whether the hypertension was
treated with antihypertensive drugs, or by dose reduction of sunitinib, or both of those measures, or if
the hypertension was left untreated, the outcomes were not impacted…
Thirteenth Annual International Kidney Cancer Symposium – 2014
A third study in 2011 by a group in
which Dr. Donskov is a member
reported on neutropenia and
thrombocytopenia as a biomarker of
sunitinib efficacy in metastatic renal
cell carcinoma. The study
demonstrated that sunitinib may
induce neutropenia and
thrombocytopenia through binding to
the, Fms-like tyrosine kinase 3 (FLT-3)
which is expressed on the surface of
hematopoietic cells.
Dr. Donskov’s interest in neutrophils
came from studies in mRCC patients
treated with IL-2 therapy where
immune cells in the tumor and in the
blood were assessed to use as
prognostic response factors. With
targeted therapy medicines, the
platelets and granulocytes, in particular
the neutrophils, form important
compartments for circulating vascular
endothelial growth factor. The majority
of VEGF is contained within
neutrophils, with approximately 10% in
thrombocytes and only 1% of the total
VEGF is free in serum according to a
2003 paper on Angiogenesis by
Kusumanto.
Selecting a Clinical Trial?
It is important for you to understand
what a clinical trial is, why it is being
done, and how you can gather more
information regarding the trial you are
interested in. Discuss the trial in detail
with your oncologist and nurse and be
sure to ask any questions you have
regarding treatment and possible
participation.
http://www.kidneycancer.org/knowledge/
clinical-trials/about-clinical-trials/
Graff, Derr, Lawing
75
Hypothyroidism, or underactive thyroid, develops when
the thyroid gland fails to produce or secrete as much
thyroxine (T4) as the body needs. Because T4 regulates
such essential functions as heart rate, digestion, physical
growth, and mental development, an insufficient supply
of this hormone can slow life-sustaining processes,
damage organs and tissues in every part of the body, and
lead to life-threatening complications.
Non-medically induced Hypothyroidism is one of the
most common chronic diseases in the United States.
Symptoms may not appear until years after the thyroid
has stopped functioning and they are often mistaken for
signs of other illnesses, menopause, or aging. Although
this condition is believed to affect as many as 11 million
adults and children, as many as two of every three people
with hypothyroidism may not know they have the
disease.
http://medical- dictionary.thefreedictionary.com/Hypothyroidism
Neutropenia is an abnormally low count of neutrophils,
a type of white blood cell that helps fight off infections,
particularly those caused by bacteria and fungi.
The threshold for defining neutropenia varies slightly
from one medical practice to another. Neutropenia in
adults is generally defined as a count of 1,700 or fewer
neutrophils per microliter of blood.
Thrombocytopenia is the medical term for a low blood
platelet count. Platelets (thrombocytes) are colorless
blood cells that play an important role in blood clotting.
Platelets stop blood loss by clumping and forming plugs
in blood vessel holes.
Thrombocytopenia often occurs as a result of a separate
disorder, such as leukemia or an immune system
problem, or as a medication side effect.
Thrombocytopenia may be mild and cause few signs or
symptoms. In rare cases, the number of platelets may be
so low that dangerous internal bleeding can occur.
http://www.mayoclinic.org/diseases-conditions
Hematopoietic cells: cells that are lodged within the bone
marrow, and which are responsible for producing the
cells which circulate in the blood (red blood cells, white
blood cells, and platelets).
http://medical-dictionary.thefreedictionary.com/Hematopoietic+cells
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76
DOSE REDUCTION VS.
TREATMENT INTERRUPTION:
PRO DOSE REDUCTION
It is disappointing to me that
we have no compiled data with
a large number of patients on
decision points to modify the
administration of these agents
I would argue that while we have all done a dose reduction in treating patients we have done
so without truly understanding/appreciating what we are doing. The reason we stop or
temporarily suspend dosing when someone gets toxicity is that we don’t know what we are
doing. Dose interruptions were initially put into renal cancer therapies such as sunitinib
because of an accumulation of drug that the patient cannot tolerate. When the accumulation
builds to intolerance one of a number of things usually happen; either the concentration is
reduced by therapy modification with a break or a dose reduction, or there is tachyphylaxis
(decrease in response to a drug) at that level of toxicity.
While we have learned that some side effects are actually good — the problem is that we
have not “owned” the knowledge on side effects; the pharmaceutical companies have. They
have been reticent to push that data forward. This doesn’t mean that they are evil; it just
means that they think differently. We need to begin to drive this information on side effects
forward and compile other data as well so that we can begin to develop therapeutic
guidelines. We need to
pharmacokinetics the action of drugs in the body over a period
become able to adjust doses
of time, including the processes of absorption, distribution,
reasonably. Part of the
localization in tissues, biotransformation, and excretion
reasons that we sometimes
pharmacodynamics the study of the biochemical and
don’t dose reduce instead of
physiological effects of drugs and the mechanisms of their actions
taking a break is that we do
area under the curve the amount of a therapeutic agent that is
not know or understand what
present in the circulation in a determined time period
the target dose should be for
each individual; we do not
trough level the lowest concentration reached by a drug before
know what the optimum
the next dose is administered, as determined by therapeutic drug
monitoring
target concentration is. Most
agents have a single flat
Thirteenth Annual International Kidney Cancer Symposium – 2014
Graff, Derr, Lawing
77
starting dose. It doesn’t
Targeted therapies are now standard of care for the
therapy of Metastatic Renal Cell Cancer. Most agents
matter whether it is like the
have a single flat starting dose for every patient
Burmese woman I saw the
regardless of size, ethnicity and concurrent medications.
other day who weighs 46
Dose interruption occurs because drug accumulates to
produce toxicity or because the drug concentration is
pounds or a large person
inadequate and the cancer progresses
who is five times larger; the
Pharmacokinetic modeling demonstrates a correlation
starting dose is supposed to
between trough concentration or AUC and both efficacy
and adverse effects.
be the same for both
The therapeutic window between efficacy and toxicity
people. In addition to
for these drugs is small and currently in practice may
weight being an issue there
overlap for most patients.
In order to optimally dose and manage adverse effects
are also issues with the
we
need to better utilize pharmacokinetic models to
ethnicity of an individual
produce an initial dose and target concentration and to
and we also do not know
adjust treatment by calculated dose adjustments.
enough about the effects of
Dose interruption is for clinicians who are plain ignorant
regarding
pharmacokinetics
concurrent medications on
Poorly fitted dose optimization models without PK
these current therapies.
modeling risk under or over treating a proportion of
Years ago in the cytokine
patients. Most dose optimization models acknowledge the
need for dose reduction...
era we started out with a
one dose fits all approach with interferon and interleukin-2 we continue to do this today-the
only drug we dose adjust for weight is bevacizumab.
We have established with sunitinib that the more of the agent that is in the blood (I. E. Being
taken) the less likely that disease progression will occur. It is important for my point of view
to manage the PK and to maintain the maximum effective dose while minimizing unwanted
toxicities and undesirable side effects.
In a study on flat dosing of 50 mg Sutent on a 4/2 dosing regimen versus a
37.5 mg continuous dosing schedule the results favored the 50 mg schedule
although the results can be argued as inconclusive.
It is disappointing to me that we have no compiled data with a large number of patients on
decision points to modify the administration of these agents. The decision points to reduce
dose is also significantly different based on the expertise of the renal cancer physician
treating the patient. We are finding that the average community oncologist is making a
decision to dose reduce from the initial therapy amount about 50% of the time in the first six
months of administering sunitinib or pazopanib. On the other hand for oncologist with more
expertise in institutional or high-volume clinic settings the reduction only occurs about 20%
of the time. There are no written guidelines for this procedure; that is an area where we
need to gain some documented evidence to establish best practices.
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DOSE REDUCTION OR TREATMENT INTERRUPTION?
PRO: TREATMENT INTERRUPTION/
SCHEDULE ALTERATION
G EO RG A. B JAR NAS ON , M.D.
Sunnybrook Health Science Centre
Toronto, Canada
YOU MIGHT BE ABLE TO IMPROVE THE OUTCOME BY HAVING YOUR PATIENTS ON THERAPY FOR A
BRIEFER TIME AND OFF THERAPY FOR BRIEFER TIME. AT 10 TO 14 DAYS THE MAXIMUM AUC AREA
UNDER THE CURVE IS REACHED ON SUTENT SUNITINIB.
WE HAVE COME TO
RECOGNIZE THAT THE
INITIAL SUNITINIB
DOSE OF 50 MG ON A
4/2 SCHEDULE MAY
NOT BE OPTIMAL FOR A LOT OF PATIENTS.
THE LEVEL OF SUNITINIB IN THE TUMOR IN SKIN HAS
BEEN SHOWN TO BE 10 TO 30 TIMES HIGHER THAN
IN BLOOD PLASMA. THE AREA UNDER THE CURVE IN
TUMOR IS MORE THAN IN PLASMA, HAS ANTI-ANGIOGENIC AND ANTITUMOR EFFECTS AND THE DOSE INTENSITY IS
MORE IMPORTANT TO PRODUCE A DIRECT ANTITUMOR EFFECT.
Thirteenth Annual International Kidney Cancer Symposium – 2014
Patients who are able to stay on
sunitinib at 50 mg dose strength
on a 4/2 schedule without side
effects or any toxicity generally have
poorer outcomes. Patients with no
toxicity at 50 mg were elevated
incrementally to 62.5 mg and some
were elevated again to 75 mg per day.
Quite a few of these patients
tolerated the higher dosage levels
and responded to the therapy.
The slide below really highlights
how you have to individualize
therapy. In a study of 65 patients
there were those who had a partial
response and others who had
stable disease at dosages ranging
from 25 mg to 75 mg and with
varying amounts of days off of
therapy.
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SIDEBAR:
A Second Look at Georg A. Bjarnason, M.D.
By age 17, he was already a gliding instructor, flying
engineless over the local mountainside. He says that
the trick to flying safely was staying nimble and
adapting to the rhythms of nature’s air currents.
As a medical oncologist with Sunnybrook’s Odette
Cancer Centre, Dr. Bjarnason is an expert on kidney
cancer and one of Canada’s leading researchers in biological rhythms, or chronobiology.
At Sunnybrook, the responsive approach he learned from flying continues to guide his
research in understanding the human body to better individualize cancer treatment. All living
organisms have a 24-hour biological clock or circadian rhythm. Dr. Bjarnason has studied these
rhythms and the genes that control important biological processes such as cell cycle, and has found
important gender differences in genes at different times of the day that may explain gender
differences in the activity and side-effects of most drugs.
Chronotherapy (therapy based on an individual’s circadian rhythm) may help doctors improve
drug therapies and minimize side-effects. “Chronotherapy will not cure cancer but may make the
most of the few active drugs we have,” says Dr. Bjarnason. The senior scientist at Sunnybrook
Research Institute has studied timing of radiotherapy in patients with head and neck cancer and
timing of chemotherapy in patients with colorectal cancer. He and colleagues have confirmed that
abnormal sleep patterns are associated with poorer survival in cancer patients. Dr. Bjarnason, also an
associate professor in the Faculty of Medicine at the University of Toronto, has focused his clinical
work and research on kidney cancer. He is the inaugural recipient of The Anna-Liisa Farquharson
Chair in Renal Cell Cancer Research. He continues his long-standing collaborations with Drs. Robert
Kerbel, Peter Burns, Greg Stanisz and Stuart Foster at Sunnybrook Research Institute, most recently
investigating innovative scheduling of drugs using imaging technologies to understand how to best
deliver therapies that block the flow of blood to tumours.
https://lifeonplanetword.files.wordpress.com/2012/03/sunnybrook_spr2012_final1.pdf
“What I have learned is that with kidney cancer, it’s important to become your own advocate. You have
many choices after diagnosis, and you should do everything you can to educate yourself and get the
care that is best suited for your case. Knowledge is power.
I was told after my initial radical nephrectomy that the surgeon “had gotten it all.” I returned to
the life of a 50-year-old male, busy with career and family. It was 18 months later that the tumors were
found in my lungs and I was now living with Stage IV, metastatic renal cell cancer.
My oncologist’s plan of action after the second diagnosis seemed tentative, but I hesitated to
change doctors or seek out another opinion because I didn’t want to be disloyal.
Through the action and influence of my wife, we consulted an oncologist at a cancer center in
our state, along with two leading experts in the nation. …
I’ve learned that cancer care is not consistent and it is not standardized. I was in a kind of
emotional fog when I was diagnosed and at the first wasn’t really motivated to seek out
information and alternatives. Thanks to my wife I was able to shake off the lethargy and take
action. I’m convinced that the reason I am here today is through empowerment and a proactive
search to find the right oncologist, the right hospital and the right therapy.” from Rick’s Story p.64
Download a free copy of We Have Kidney Cancer from our website: www.kidneycancer.org...
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… A F IRST S TEP
Although patients with
mRCC have more treatment
options than ever before, one
of the continuing challenges
for the clinician is how to
help the patient to manage
side effects so that the dosing
schedule can be maintained…
A very disruptive and
pervasive problem with the
administration of VEGF-TKI
therapies is diarrhea; what
causes its occurrence is poorly
understood.
In a collection of studies of over
1100 patients among three of
the commonly used TKI’s the
overall incidence of diarrhea
was 51% (chart right).
To test the hypothesis that
protective species of bacteria in
the stool flora may be detected
by bacteromic profiling, an initial
study of a small group of
patients currently on VEGF-TKI
treatment was conducted. Twenty members of the study group submitted specimens of sufficient
quantity to be analyzed. In those samples while 141 bacterial specie were identified there were two
specie found to be more common and abundant in the eight patients in the cohort that had no
significant issues with diarrhea.
Due to the small sample size in this study, with no control for dietary intake and other factors the results
as expected were inconclusive. But the study indicated that bacteromic profiling may be an important
first step in finding ways to reduce or eliminate the incidence of diarrhea in TKI patients. If protective
bacteria are identified in subjects without diarrhea in larger studies, subsequent interventional studies
may identify probiotic supplements which can be administered prophylactically to patients taking these
medications.
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BIOLOGY-BASED
CLASSIFICATION OF RCC
Dr. Brugarolas’ presentation covered the
classification of genetic mutations that occur in
patents with clear cell renal cell carcinoma (ccRCC).
By understanding these various classifications,
eventually it is hoped that a specific therapeutic
drug will be used in certain patients based on their
tumor’s genetic makeup.
In ccRCC tumors, it is found that the VHL gene is
mutated or missing 50-75% of the time. Along with
the VHL gene, the PBRM1, SETD2, and BAP1 genes
are also mutated in ccRCC tumors at least 10% of
the time. All of these mutated genes are involved in
tumor suppression, meaning that their associated
proteins that signal cancer cells to stop multiplying
in an uncontrollable way are disrupted allowing
tumor development and growth.
The Problem Is…
In renal-cell carcinoma we are considering
all clear-cell carcinomas to be the same,
and we are also doing this with other RCC
histologies.
I would contend that they are not the same,
in fact there are no two tumors that are
exactly the same.
As a consequence, when patients get
treated we may find that the treatment
works well for a set of patients – but it
doesn’t work well for another set…
In the end we are left with a drug that if the
number of patients that are benefitted is
small we think that the drug doesn’t work.
The answer may be that it does work, but
only for a small group of patients.
What we need to evolve to is a model
where we are treating patients with
different tumor type/subtypes with
different drugs.
James Brugarolas, M.D., Ph.D.
University of Texas
Southwestern Medical Center
Dallas, TX
There are two interesting aspects to these four genes (VHL, PBRM1, SETD2, and BAP1). First,
BAP1 and PBRM1 are largely mutually exclusive. This means that when one of these genes is mutated or
missing, the other is present and intact. It should also be noted that when there is a BAP1 gene
mutation, the tumor is of high grade and likewise when there is a PBRM1 gene mutation the tumor is of
low grade. Second, all four of these genes are all located on chromosome 3p, the short arm of
chromosome 3. In a majority of patients with ccRCC, this portion of chromosome 3 is missing and of
course meaning that copies of all four of these tumor-suppressing genes are missing.
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Studying these four genes within
chromosome 3p has led to the creation of
a ccRCC development model. Kidney
cancer starts with an intragenic (internal)
mutation of the VHL gene. This could be
an inherited condition, caused by
environmental factors, or caused by
toxicity factors. The loss of VHL is usually
not enough for cancer to develop, as it’s
thought to be a fairly low tumor effector.
However, following the mutation of the
VHL gene, there is many times then a loss
of the 3p portion of chromosome 3. The
3p loss then leads to a mutation of PBRM1
or BAP1, which leads to the development
of either a low-grade or high-trade tumor.
In the future, a biopsy of a ccRCC tumor can reveal which specific genes are mutated, thus forming a
biologic classification of the tumor. Based on the type of gene mutations that are found, a specific
treatment drug can be chosen for the patient.
Slicing the Pie Thinner
The distribution chart at right shows the makeup of
the most common subtypes of rcc.
Breaking these subtypes into smaller categories of
genetic mutations could lead to better
understanding and administration of treatments for
patients.
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Various cancer treatment drugs have been developed in the past decade that target and block specific
protein pathways. Examples of these for kidney cancer include VEGF pathway inhibitors (ex: sunitinib)
and mTOR pathway inhibitors (ex: everolimus). The research community is in constant search for other
potential protein pathway inhibitors. c-MET (also called MET) is one of these pathways that is under
investigation. c-MET is a protein that helps to trigger tumor growth and contributes to angiogenesis
(formation of new tumor blood vessels). Research data has shown that by inhibiting the c-MET pathway,
tumor growth can be slowed.
Although protein pathway blocking drugs have shown great promise for kidney cancer patients, over
time tumor resistance increases and these drugs
During evaluation studies of c-MET with kidney tumors
become less effective. Also, combinations of
in place we found that the RCC kidney had higher
these drugs, specifically combining VEGF and
expression of c-MET than the adjacent normal kidney.
mTOR inhibitors have proven to be very toxic.
Clear-cell types had less expression than either
c-Met is rarely mutated:
papillary or sarcomatoid which were almost equal in
incidence of expression. Higher grade tumors had
In >400 clear cell RCCs sequenced by
higher levels of c-MET.
The Cancer Genome Atlas (TCGA)
Not surprisingly, higher levels of c-MET expression
it was observed in <1% of patients.
correlated with lower cancer-specific survival.
Loss of VHL results in increases in c-Met
expression and normal kidney secretes
HGF hepatocyte growth factor which binds to c-Met.
Inhibition of the c-MET pathway can assist in the slowing of tumor growth.
Currently, there are several clinical trials in progress that are measuring the effectiveness of c-MET
inhibitors. These trials have been mostly in a second line treatment setting, and there have been good
results. Also, research data is showing that a combination of VEGFR and MET inhibition is more effective
than inhibiting either pathway alone.
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Our great hope is that this process will allow us to
truly personalize the therapies that we are giving to
our patients so that we can say “based on certain
therapies this is a therapy that is going to be
effective”. If the test indicates otherwise it will allow
us to move to the next treatment option we have
available.
…it is an opportunity to continue to challenge and
reinform the work we do…
we can’t be complacent, we have to move
forward with something new every week
Circulating tumor cells (CTCs) are tumor
cells that have entered into a person’s
blood circulation system. They can come
from both primary and metastatic tumors.
In this presentation, Dr. Joshua Lang
describes research that he is working on to
“filter” and extract CTCs from a patient
blood sample. The hope is that in the
future, reliable techniques can be
developed based on this type of research
to collect CTCs and use them as biomarkers
to be used in a patient’s treatment plan.
By examining these biomarkers, a patient’s
treatment could be targeted to a specific
drug. Or, the biomarkers could indicate
when a patient is beginning to develop
resistance to a drug leading to switching their
treatment plan.
One of the challenges when dealing with
circulating tumor cells is that there are very
few of them when compared to the total
number of cells in the bloodstream. Dr. Lang
and his team are developing very creative
biomedical engineering techniques to separate
CTCs from “normal” cells. This involves
binding magnetic beads to the cells of interest,
and then using water and oil to aid in the
separation of cells. The device that they have
developed is called the VERSA chip, which
stands for Versatile, Exclusion-Based, Rare, Sample, Analysis chip. This device provides for
comprehensive molecular analysis of a blood sample, providing for DNA and RNA extraction.
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In the near future, clinical trials
will begin to examine the use
of CTCs as predictive cancer
biomarkers. It is very exciting
to think that someday, a
simple blood test might be able
to predict metastatic disease or
to aid in the selection of a drug
treatment option.
What we have found is there are many patients with
advanced cases of cancer which have tumor cells that can be found in
circulation…
Now, these are very rare cells;
Maybe 1 in every billion peripheral blood cells…
WE ARE WAY BEYOND JUST ANY NEEDLE IN A HAYSTACK!
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When Eugene P. Schonfeld, Ph.D. gathered a small group of kidney cancer patients and doctors
around his kitchen table in 1990 to organize what would become the present-day worldwide
organization, the Kidney Cancer Association, he did so due to the fact that no viable treatment
options other than surgery existed in the U.S. for that disease. High-Dose Interleukin-2 would be
U.S. approved for clinical use in a matter of years; much of the reason for the approval was due to
Eugene’s tireless efforts.
In Villejuif, France, a cardiologist with the Institut Gustave Roussy had been advising Dr. Thierry
Hercend since 1986 about the management of side effects in patients who were participating in a Phase
I clinical trial of this drug which had been touted a year earlier as the miracle therapy for cancer,
especially RCC. The cardiologist would continue to consult as a Phase II trial was conducted with
patients being infused in his Intensive Care Unit in 1988. A French immunotherapy group was organized
in 1989, and in 1992 when an Immunotherapy Unit was made operational at Institut Gustave Roussy the
cardiologist was asked to take the leadership role. While this offer was primarily due to the
recommendation of Dr. Thierry Hercend, it appears that there was very little interest on the part of
others to become deeply involved in the treatment of RCC.
In the ensuing years countless numbers of patients globally have benefitted from the commitment and
involvement of this cardiologist to improve the quality of life, survivorship, treatment options and
standard of care of persons diagnosed with kidney cancer. That French Cardiologist, Dr. Bernard
Escudier is this year’s Schonfeld Award Recipient.
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Dr. Escudier described his acceptance as the leader of
the Immunotherapy Unit at IGR as “Jumping into this
exciting adventure.” The clinical trials being conducted
with the “miracle” agent IL-2 as well as investigations of
another immunotherapy agent, Interferon Alpha yielded
results, but they were not the widespread successful
outcomes that were initially hoped for. Some patients
did not respond at all to the cytokine therapies, the
median overall survival was 14 months, studies of
combining the two agents did not improve survival even
though some increased overall response and
progression-free survival times were noted. Patients
treated with one drug that switched to the other did not
see any improved outcomes.
In 1998 Dr. Escudier was approached by Aeterna, a small
biotech company in Quebec about the data they had
accumulated on the use of shark cartilage extracts in
mRCC patients. This led to the decision to conduct an
international study and Escudier invited Dr. Ron Bukowski
of the Cleveland Clinic to co-chair the investigation.
Obstacles had to be overcome in conducting the study
including convincing US investigators that a double-blind
randomized study was necessary and feasible. This initial
contact with Bukowski led to other collaborations including
the design and implementation of the TARGET study in
2003 which led to the approval of sorafenib in Dec. 2005,
the first of the targeted-therapy drugs for treatment of
kidney cancer. Since that time the collaboration of the
European Union and the US in clinical trials for kidney
cancer agents have been a standard practice.
Dr. Escudier Answers:
What makes me happy?
• To see how many patients live longer and better
• To collaborate with a maximum number of people. Active collaboration is the only way to speed up
the progress
• To see how active are European KCA meetings that we launched in 2006 with Ron Bukowski, Martin
Gore and Peter de Mulder…..
What makes me anxious? • The replication of past mistakes…..
What I am dreaming of?
• Toxicity assessment is better done
• Good biomarkers to select our treatments
Biology has been moving very rapidly in the past 2 years, and I am quite optimistic
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Commentary: For What It’s Worth
Michael B. Lawing- Patient Advocate
As Andy Derr and I sat at the rear of the large meeting room in the Radisson Blu Aqua Hotel in Chicago
we briefly exchanged glances as the third or fourth slide of a presentation appeared on the large
screens. I knew that look on Andy’s face; I had personally experienced it years ago in another large
Chicago hotel when I attended my first Kidney Cancer Symposium. The speakers’ introduction was over:
he had made his disclosures; and as he quickly launched into his presentation he rapidly moved beyond
our limited knowledge of the subject of his talk. We were, after all, not the intended audience for his
discourse – the medical oncologists, scientists and other medical professionals seated in the room were
listening intently to the concept and research he was explaining. Over the years I have grown
accustomed to hearing these dialogues, realizing that once they have been delivered I will have the
pleasure of going through scribbled notes, reviewing audio and video files in order to summarize in
layman’s terms what I have just witnessed. I frequently refer to the NCI database of information, type
words and phrases into the medical dictionary on free dictionary.com, Google, and use a bunch of other
resources I have become familiar with over the years that helps to put the medical terminology into
something that I can understand. By the time the speaker got to slide 10 or so I glanced again at Andy as
he hastily scribbled notes and I breathed a small sigh of relief with the realization that this speaker was
one of a number of presenters that Andy would be covering. Of the many presentations that would be
given during this two day meeting of experts in kidney cancer assembled from Europe and the US this
one was probably the most complex and difficult. Andy wanted to learn; he was going to with this
speaker!
I sincerely hope that you have learned some things in this Patient Summary - MBL
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In 2015
THE KIDNEY CANCER ASSOCIATION
Celebrates Twenty-Five Years
Of Service to those who are
afflicted with Kidney Cancer
The Kidney Cancer Association (KCA) is a charitable organization made up of patients, family
members, physicians, researchers, and other health professionals globally. It is the world’s first
international charity dedicated specifically to the eradication of death and suffering from renal
cancers. It is also by far the largest organization of its kind, with members in more than 100
countries. We fund, promote, and collaborate with the National Cancer Institute (NCI), American
Society for Clinical Oncology (ASCO), American Urological Association (AUA), and other institutions
on research projects. We educate families and physicians, and serve as an advocate on behalf of
patients at the state and federal levels in the United States and globally.
THE FOLLOWING ARE A FEW OF OUR MANY RESOURCES FOR PATIENTS
WWW.KIDNEYCANCER.ORG -- WWW.TWITTER.COM/KIDNEYCANCER