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Thirteenth International Kidney Cancer Symposium Presentation Notes: An Overview of the Proceedings Summaries by: JOYCE WILCOX GRAFF ANDY DERR MICHAEL B. LAWING - Editor Thirteenth Annual International Kidney Cancer Symposium – 2014 Graff, Derr, Lawing 2 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 Thirteenth Annual International Kidney Cancer Symposium – 2014 Graff, Derr, Lawing 3 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 Thirteenth Annual International Kidney Cancer Symposium – 2014 Graff, Derr, Lawing 4 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/ Thirteenth Annual International Kidney Cancer Symposium – 2014 Graff, Derr, Lawing 5 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 Thirteenth Annual International Kidney Cancer Symposium – 2014 Graff, Derr, Lawing 6 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. Thirteenth Annual International Kidney Cancer Symposium – 2014 Graff, Derr, Lawing 7 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 Thirteenth Annual International Kidney Cancer Symposium – 2014 Graff, Derr, Lawing 8 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. Thirteenth Annual International Kidney Cancer Symposium – 2014 Graff, Derr, Lawing 9 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 Thirteenth Annual International Kidney Cancer Symposium – 2014 Graff, Derr, Lawing 10 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. Thirteenth Annual International Kidney Cancer Symposium – 2014 Graff, Derr, Lawing 11 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 Thirteenth Annual International Kidney Cancer Symposium – 2014 Graff, Derr, Lawing 12 “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 Thirteenth Annual International Kidney Cancer Symposium – 2014 Graff, Derr, Lawing 13 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. Thirteenth Annual International Kidney Cancer Symposium – 2014 Graff, Derr, Lawing 14 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. Thirteenth Annual International Kidney Cancer Symposium – 2014 Graff, Derr, Lawing 15 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. Thirteenth Annual International Kidney Cancer Symposium – 2014 Graff, Derr, Lawing 16 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 Thirteenth Annual International Kidney Cancer Symposium – 2014 Graff, Derr, Lawing 17 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. Thirteenth Annual International Kidney Cancer Symposium – 2014 Graff, Derr, Lawing 18 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 Graff, Derr, Lawing 19 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 Graff, Derr, Lawing 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 Graff, Derr, Lawing 21 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. Thirteenth Annual International Kidney Cancer Symposium – 2014 Graff, Derr, Lawing 22 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 23 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 Graff, Derr, Lawing 24 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 Graff, Derr, Lawing 25 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 Graff, Derr, Lawing 26 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 Graff, Derr, Lawing 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 Graff, Derr, Lawing 29 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. Thirteenth Annual International Kidney Cancer Symposium – 2014 Graff, Derr, Lawing 30 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. Thirteenth Annual International Kidney Cancer Symposium – 2014 Graff, Derr, Lawing 31 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 Thirteenth Annual International Kidney Cancer Symposium – 2014 Graff, Derr, Lawing 32 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 Thirteenth Annual International Kidney Cancer Symposium – 2014 Graff, Derr, Lawing 33 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 34 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. Thirteenth Annual International Kidney Cancer Symposium – 2014 Graff, Derr, Lawing 35 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 Thirteenth Annual International Kidney Cancer Symposium – 2014 Graff, Derr, Lawing 36 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. Thirteenth Annual International Kidney Cancer Symposium – 2014 Graff, Derr, Lawing 37 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%. Thirteenth Annual International Kidney Cancer Symposium – 2014 Graff, Derr, Lawing 38 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. Thirteenth Annual International Kidney Cancer Symposium – 2014 Graff, Derr, Lawing 39 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. Thirteenth Annual International Kidney Cancer Symposium – 2014 Graff, Derr, Lawing 40 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. Thirteenth Annual International Kidney Cancer Symposium – 2014 Graff, Derr, Lawing 41 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 Graff, Derr, Lawing 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. Thirteenth Annual International Kidney Cancer Symposium – 2014 Graff, Derr, Lawing 43 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. Thirteenth Annual International Kidney Cancer Symposium – 2014 Graff, Derr, Lawing 44 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. Thirteenth Annual International Kidney Cancer Symposium – 2014 Graff, Derr, Lawing 45 … 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. Thirteenth Annual International Kidney Cancer Symposium – 2014 Graff, Derr, Lawing 46 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. Thirteenth Annual International Kidney Cancer Symposium – 2014 Graff, Derr, Lawing 47 “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 48 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 51 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 Graff, Derr, Lawing 52 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. Thirteenth Annual International Kidney Cancer Symposium – 2014 Graff, Derr, Lawing 54 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 Graff, Derr, Lawing 55 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 Graff, Derr, Lawing 56 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 Graff, Derr, Lawing 57 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. Thirteenth Annual International Kidney Cancer Symposium – 2014 Graff, Derr, Lawing 59 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 Graff, Derr, Lawing 61 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 Graff, Derr, Lawing 63 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 Graff, Derr, Lawing 64 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 Graff, Derr, Lawing 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 R ENAL C ELL C ARCINOMA ( M RCC) I try to tell them what the emerging landscape of treatment options for kidney cancer are. 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. When I seeI asee patient for the usually spend an houran plus. I tryplus. to tell them what the emerging When a patient forfirst thetime firstItime I usually spend hour I try to tell them what landscape of treatment options kidney cancer are.for I tell themcancer about the of care therapies the emerging landscape offor treatment options kidney are.standard I tell them about the about the therapies have potential andthat lasting response, as for welldurable as aboutand clinical trials. standard of carethat therapies, about for thedurable therapies have potential lasting asbe well as about clinical trials. It patients is important to be strategic; I understand when It isresponse, important to strategic; I understand when are first diagnosed with kidney cancer or patients are first diagnosed with kidney cancer or recurrent metastatic kidney cancer that recurrent metastatic kidney cancer that they are scared. They want to start treatment yesterday. But I they are scared. want tokidney start treatment yesterday. But Ihelpful do believe going an do believe going to anThey experienced cancer expert can be really to devise antoindividualized experienced kidney cancer expert canorgan be really helpful devise individualized strategy for your medical condition for your function etc. to what is thean most useful approach for strategy for your medical condition, for your organ function, and for your etc. your treatment for your histology? Don’t miss opportunities because you’re scaredhistology get informed: offered you have time to talk with over physicians, get second opinions, I don’t have a problem with patients looking at other informed then decide what youscared: want to do and we will respect Don’tplaces. miss Get opportunities because you’re get informed: often your decision no matter what. you have time to talk with other physicians, get second opinions. I don’t have a problem with patients looking at other places. Get informed, then decide what you want to do and we will respect your 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 Graff, Derr, Lawing 70 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 Thirteenth Annual International Kidney Cancer Symposium – 2014 Graff, Derr, Lawing 71 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 Thirteenth Annual International Kidney Cancer Symposium – 2014 Graff, Derr, Lawing 74 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 Thirteenth Annual International Kidney Cancer Symposium – 2014 Graff, Derr, Lawing 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. Thirteenth Annual International Kidney Cancer Symposium – 2014 Graff, Derr, Lawing 78 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. Graff, Derr, Lawing 79 Thirteenth Annual International Kidney Cancer Symposium – 2014 Graff, Derr, Lawing 80 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... Thirteenth Annual International Kidney Cancer Symposium – 2014 Graff, Derr, Lawing 81 … 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. Thirteenth Annual International Kidney Cancer Symposium – 2014 Graff, Derr, Lawing 82 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. Thirteenth Annual International Kidney Cancer Symposium – 2014 Graff, Derr, Lawing 83 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. Thirteenth Annual International Kidney Cancer Symposium – 2014 Graff, Derr, Lawing 84 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. Thirteenth Annual International Kidney Cancer Symposium – 2014 Graff, Derr, Lawing 85 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. Thirteenth Annual International Kidney Cancer Symposium – 2014 Graff, Derr, Lawing 86 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! Thirteenth Annual International Kidney Cancer Symposium – 2014 Graff, Derr, Lawing 87 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. Thirteenth Annual International Kidney Cancer Symposium – 2014 Graff, Derr, Lawing 88 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 Thirteenth Annual International Kidney Cancer Symposium – 2014 Graff, Derr, Lawing 89 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 Thirteenth Annual International Kidney Cancer Symposium – 2014 Graff, Derr, Lawing 90 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