Stage IV Renal Cell Carcinoma. Changing Management in A Comprehensive Community Cancer Center. Susquehanna Health Cancer Center

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1 Stage IV Renal Cell Carcinoma Changing Management in A Comprehensive Community Cancer Center Susquehanna Health Cancer Center Warren L. Robinson, MD, FACP January 27, 2014

2 Introduction 65,150 new cases of renal cell carcinoma representing 3% of all adult malignancies are estimated to be diagnosed in ,600 deaths are anticipated from this disease during that time frame. The incidence of renal cancer has been increasing by 3.1% per year while the mortality rate has been falling by 0.5% per year since The principal prognostic factor in renal cell carcinoma is stage at diagnosis. 2 Stage IV disease is defined as any tumor which extends beyond Gerota s fascia or invades the adjacent adrenal gland, T4 with any N or M, or any metastatic tumor, M1 with any T or N. Approximately 30% of newly diagnosed patients present with this stage of disease which is generally recognized to have poor survival. Metastatic renal carcinoma has been resistant to traditional chemotherapy and impacted by the immune therapies of interleukin-2 and interferon to a limited extent. 3,4 New targeted therapies were introduced into routine practice in the mid 2000 s. 5 This review was undertaken to assess the impact of these new agents on daily practice. Methods All patients diagnosed with Stage IV Renal Cell Carcinoma at Susquehanna Health between January 1, 2000 and December 31, 2009 were identified from the Tumor Registry and included in this report. Records were analyzed for demographics, treatments and survival. The patients in the initial five years of the analysis were compared with the later five years. Results A total of 17 patients with Stage IV Renal Cell Carcinoma were diagnosed between January 1, 2000 and December 31, 2004 while 15 patients were diagnosed with this condition between January 1, 2005 and December 31, Demographics of these groups are displayed in Table 1. Table 1 Demographics Stage IV Renal Carcinoma Age, yrs Median Range Total Cases Sex Male 14 (82%) 10 (67%) Female 3 (18%) 5 (33%) The median age and range were comparable in the two intervals. The percent of females increased from 18% in the initial interval to 33% in the later interval. Males substantially outnumbered females in both time intervals. Treatment interventions differed markedly in the two time intervals as shown in Table 2. Table 2 Treatment Stage IV Renal Carcinoma Supportive Care 29% 13% Nephrectomy 24% 67% RT only 35% 7% Any RT 41% 40% Medical Rx 24% 73% Interferon 24% 13% Sunitinib 6% 60% Temsirolimus 6% 33% Everolimus 0% 20% Pazopanib 0% 7% Number Med Rx 1 18% 33% 2 0% 27% 3 6% 0% 4 0% 13% Unknown * 6% 0% *one patient lost to follow up The fraction of Stage IV Renal Cell Carcinoma patients receiving active therapy increased from 71% to 87% while use of support care only declined from 29% to 13% of patients. Overall use of radiotherapy did not change but use of radiotherapy alone declined from 35% to 7%.

3 Medical therapy saw the greatest increase in usage from 24% in the initial group to 73% of all patients in the second interval. During that time interferon usage decreased by half and was replaced by targeted therapies. Additionally, patients in the second interval received an increased number of serial medical interventions. Survival remained unchanged in the two time intervals as depicted in Table 3. Table 3 Survival Survival (mo) Median Range * ** *One patient lost to follow up **One patient still surviving Survival curves of patients treated at Susquehanna Health in the two time intervals compared with National Cancer Data Base statistics are shown in Figure 1. The overlapping curves demonstrate comparable survival in all three sets of patients. Discussion Patients with Stage IV renal cell carcinoma observed at Susquehanna Health Cancer Center have demographics similar to reported series. 6 Median age at diagnosis of 62 and 61 years in the two time intervals is consistent with the early 60 s expected. In most series males generally outnumber females by :1 as observed in our second time interval. The ratio of 4.7:1 in the first interval may reflect the small size of the sample population. This series demonstrates that the management of stage IV renal cell carcinoma has changed dramatically in the first decade of the 21 st Century. Use of active antineoplastic therapy increased substantially from 71% to 87% of patients while supportive care alone declined from 29% to 13%. Nearly three times as many patients underwent nephrectomy in the second half of the decade of observation. This likely stemmed from the 2001 report that median survival for patients with metastatic renal cell cancer treated with interferon increased when nephrectomy was performed. 7 Despite this increased use of surgery the overall median survival of our patients did not change during the two periods of observation. The usage of medical therapy in these patients also increased three fold from the first interval to the second. Sorafenib was the first targeted agent approved for use in metastatic renal cell carcinoma on December 20, 2005 based on a study which demonstrated an improvement in progression free survival from 2.8 months to 5.5 months compared to placebo. 8 Motzer first reported that compared to interferon sunitinib increased response rate from 4.7% to 24.8% and progression free survival from 5 to 11 months at the American Society of Clinical Oncology Annual Meeting in Overall survival was not addressed in the original abstract but was later reported to be improved from 21.8 to 26.4 months. 10 The median survival of our observed patients did not change between the intervals of and Nonetheless, survival of our stage IV renal cell carcinoma patients in both intervals was identical to that of same stage patients reported to the National Cancer Data Base. The absence of an observed improvement in median survival likely reflects the high degree of selection of patients in the reported studies compared to our unselected 8, 11 patients. The number of approved drugs for advanced renal cell carcinoma has now reached seven increasing the likelihood of patients being treated with multiple agents as seen in our series. 12 Optimal strategy for use of these 5, 13 agents remains to be defined.

4 Figure 1 Survival Stage IV Renal Cell Carcinoma Percent Surviving Year SH SH NCDB 03-05

5 References 1. Cancer Facts and Figures Shuch BM, Lam JS, Belldegrun AS, Figlin RA: Prognostic Factors in Renal Cell Carcinoma. Semin Oncol 2006;33: Figlin RA. Renal Cell Carcinoma: Management of Advanced Disease. J Urol 1999;161: McDermott DF, Atkins MB: Interleukin -2 Therapy of Metastatic Renal Cell Carcinoma-Predictors of Response. Semin Oncol 2006;33: Rini BI: Metastatic Renal Cell Carcinoma: Many Treatment Options, One Patient. J Clin Oncol 2009;27: McLaughlin JK, Lipworth L, Tarone RE: Epidemiologic Aspects of Renal Cell Carcinoma. Semin Oncol 2006;33: Flanigan RC, Salmon SE, Blumenstein BA, Bearman SI et al: Nephrectomy Followed by Interferon Alfa-2b Compared With Interferon Alfa-2b Alone For Metastatic Renal-Cell Cancer. NEJM 2001;345: Escudier B, Eisen T, Stadler WM, Szczylik C et al: Sorafenib in Advanced Clear-Cell Renal-Cell Carcinoma. NEJM2007;356: Motzer RJ, Hutson TE, Tomczak P, Michaelson MD et al: Phase III Randomized Trial of Sunitinib Malate (SU11248) Versus Interferon-alfa (IFN-a) as First-line Systemic Therapy For Patients With Metastatic Renal Cell Carcinoma. [Abstract] J Clin Oncol 2006;24(930s):LBA Motzer RJ, Hutson TE, Tomczak P, Michaelson MD, et al: Overall Survival and Updated Results for Sunitinib Compared With Interferon Alfa in Patients With Metastatic Renal Cell Carcinoma. J Clin Oncol 2009;27: Motzer RJ, Hutson TE, Tomczak P, Michaelson MD: Sunitinib versus Interferon Alfa in Metastatic Renal-Cell Carcinoma. NEJM 2007;356: Axitinib (Inlyta) for Advanced Renal Cell Carcinoma. Medical Letter 2012;54: Coppin C et al: Targeted Therapy for Advanced Renal Cell Cancer (RCC): A Cochrane Systematic Review of Published Randomised Trials. BJU International 2011;108:1556.