BACKGROUND: Optimal management of metastatic non-clear cell renal cell carcinoma (non-ccmRCC) remains largely unknown. OBJECTIVE: To test the effect of systemic therapy (ST) and/or cytoreductive nephrectomy (CNT) on overall mortality (OM) in patients with non-ccmRCC. DESIGN, SETTING, AND PARTICIPANTS: Within the Surveillance, Epidemiology and End Results (SEER) registry (2006-2015), we identified patients with papillary, chromophobe, sarcomatoid, and collecting duct metastatic renal cell carcinoma (mRCC). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Temporal trends (estimated annual percentage change [EAPC]), Kaplan-Meier plots, and multivariable Cox regression models were used. RESULTS AND LIMITATIONS: Of 1573 patients with non-ccmRCC, 22%, 25%, 25%, and 28% underwent no treatment, ST, CNT, and CNT with ST, respectively. Between 2006 and 2015, rates of CNT and the combination of CNT and ST decreased (EAPC: -6.3% and -3.2%, respectively). Conversely, rates of no treatment and ST increased over time (EAPC: 4.6% and 7.5%, respectively). In multivariable Cox regression models, relative to no treatment, ST (hazard ratio [HR]: 0.5; p < 0.001), CNT (HR: 0.4; p < 0.001), and CNT with ST (HR: 0.3; p < 0.001) were associated with lower OM. Histological subtypes were associated with OM, relative to papillary renal cell carcinoma (RCC): chromophobe (HR: 0.7; p < 0.01), sarcomatoid (HR: 2.1; p < 0.001), and collecting duct RCC (HR: 1.9; p < 0.001). Limitations include the impossibility to stratify patients according to mRCC risk groups. CONCLUSIONS: Most non-ccmRCC patients are treated with a combination of CNT and ST or CNT alone or ST alone. The rates of ST alone are increasing. Conversely, the rates of combined CNT and ST and CNT alone are decreasing. These observed temporal patterns of treatment rates are counterintuitive with respect to associated OM benefits, where combination of CNT and ST, as well as CNT alone, resulted in the lowest absolute OM, relative to ST alone, or, even worse, no treatment. PATIENT SUMMARY: We investigated the effect of treatment modalities on survival of patients with metastatic non-clear cell renal cell carcinoma. The combination of cytoreductive nephrectomy and systemic therapy confers greater benefit with respect to single treatments alone.

Cancer Prognostics and Health Outcomes Unit Division of Urology University of Montreal Health Center Montreal Quebec Canada

Cancer Prognostics and Health Outcomes Unit Division of Urology University of Montreal Health Center Montreal Quebec Canada; Department of Urology and Division of Experimental Oncology URI Urological Research Institute IRCCS San Raffaele Scientific Institute Milan Italy

Cancer Prognostics and Health Outcomes Unit Division of Urology University of Montreal Health Center Montreal Quebec Canada; Department of Urology European Institute of Oncology IRCCS Milan Italy

Cancer Prognostics and Health Outcomes Unit Division of Urology University of Montreal Health Center Montreal Quebec Canada; Department of Urology San Luigi Gonzaga Hospital University of Turin Turin Italy

Cancer Prognostics and Health Outcomes Unit Division of Urology University of Montreal Health Center Montreal Quebec Canada; Martini Klinik Prostate Cancer Center University Hospital Hamburg Eppendorf Hamburg Germany

Cancer Prognostics and Health Outcomes Unit Division of Urology University of Montreal Health Center Montreal Quebec Canada; Urology Unit ASST Spedali Civili of Brescia Brescia Italy; Department of Medical and Surgical Specialties Radiological Science and Public Health University of Brescia Brescia Italy

Department of Hematology Oncology University of Montreal Hospital Centre Montreal Quebec Canada

Department of Urology and Division of Experimental Oncology URI Urological Research Institute IRCCS San Raffaele Scientific Institute Milan Italy

Department of Urology Comprehensive Cancer Center Medical University of Vienna Vienna Austria; Department of Urology Weill Cornell Medical College New York NY USA; Department of Urology University of Texas Southwestern Dallas TX USA; Department of Urology 2nd Faculty of Medicine Charles University Prague Czech Republic; Institute for Urology and Reproductive Health 1 M Sechenov 1st Moscow State Medical University Moscow Russia

Department of Urology European Institute of Oncology IRCCS Milan Italy

Department of Urology European Institute of Oncology IRCCS Milan Italy; Department of Oncology and Hemato Oncology University of Milan Milan Italy

Department of Urology IRCCS Fondazione Ca' Granda Ospedale Maggiore Policlinico University of Milan Milan Italy

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The Evolving Landscape of Cytoreductive Nephrectomy in Metastatic Renal Cell Carcinoma