CONTEXT: While vascular endothelial growth factor-targeted therapy and mammalian target of rapamycin inhibition are effective strategies in treating clear cell renal cell carcinoma (ccRCC), the most effective therapeutic approach for patients with non-clear cell RCC (non-ccRCC) is unknown. OBJECTIVE: To systematically review relevant literature comparing the oncological outcomes and adverse events of different systemic therapies for patients with metastatic non-ccRCC. EVIDENCE ACQUISITION: Relevant databases including MEDLINE, Embase, and the Cochrane Library were searched up to March 24, 2016. Only comparative studies were included. Risk of bias and confounding assessments were performed. A meta-analysis was planned for and only performed if methodologically appropriate; otherwise, a narrative synthesis was undertaken. EVIDENCE SYNTHESIS: The literature search identified 812 potential titles and abstracts. Five randomized controlled trials, recruiting a total of 365 patients, were included. Three studies compared sunitinib against everolimus, one of which reported the results for non-ccRCC as a subgroup rather than as an entire randomized cohort. Individually, the studies showed a trend towards favoring sunitinib in terms of overall survival and progression-free survival (PFS; Everolimus versus Sunitinib in Patients with Metastatic Non-clear Cell Renal Cell Carcinoma hazard ratio [HR]: 1.41, 80% confidence interval [CI] 1.03-1.92 and 1.41, 95% CI: 0.88-2.27, Evaluation in Metastatic Non-clear Cell Renal Cell Carcinoma HR: 1.16, 95% CI: 0.67-2.01, Efficacy and Safety Comparison of RAD001 Versus Sunitinib in the First-line and Second-line Treatment of Patients with Metastatic Renal Cell Carcinoma HR: 1.5, 95% CI: 0.9-2.8), but this trend did not reach statistical significance in any study. Meta-analysis was performed on two studies which solely recruited patients with non-ccRCC reporting on PFS, the results of which were inconclusive (HR: 1.30, 95% CI: 0.91-1.86). Sunitinib was associated with more Grade 3-4 adverse events than everolimus, although this was not statistically significant. CONCLUSIONS: This systematic review and meta-analysis represent a robust summary of the evidence base for systemic treatment of metastatic non-ccRCC. The results show a trend towards favoring vascular endothelial growth factor-targeted therapy for PFS and overall survival compared with mammalian target of rapamycin inhibitors, although statistical significance was not reached. The relative benefits and harms of these treatments remain uncertain. Further research, either in the form of an individual patient data meta-analysis involving all relevant trials, or a randomized controlled trial with sufficient power to detect potential differences between treatments, is needed. PATIENT SUMMARY: We examined the literature to determine the most effective treatments for advanced kidney cancer patients whose tumors are not of the clear cell subtype. The results suggest that a drug called sunitinib might be more effective than everolimus, but the statistics supporting this statement are not yet entirely reliable. Further research is required to clarify this unmet medical need.

Academic Urology Unit University of Aberdeen Aberdeen UK; Department of Urology Aberdeen Royal Infirmary Aberdeen UK

Department of Cancer Medicine Institut Gustave Roussy Villejuif France

Department of Surgical and Perioperative Sciences Urology and Andrology Umeå University Umeå Sweden

Department of Urology and Urologic Oncology Hannover Medical School Hannover Germany

Department of Urology Cabueñes Hospital Gijón Spain

Department of Urology Coimbra University Hospital Coimbra Portugal

Department of Urology Faculty Hospital and Faculty of Medicine in Pilsen Charles University Prague Prague Czech Republic

Department of Urology Ludwig Maximilians University Munich Germany

Department of Urology Skåne University Hospital Malmö Sweden

Department of Urology Sunderby Hospital Sunderby Sweden

Department of Urology The Netherlands Cancer Institute Antoni van Leeuwenhoek Hospital Amsterdam The Netherlands

Department of Urology University Hospital Hamburg Eppendorf Hamburg Germany

Department of Urology University Hospital Schleswig Holstein Lübeck Germany

Department of Urology University of Rennes Rennes France

Division of Urology Maggiore della Carità Hospital University of Eastern Piedmont Novara Italy

Division of Urology University of Texas Medical School at Houston Houston TX USA

Patient Advocate International Kidney Cancer Coalition University Medical Centre Utrecht Department of Nephrology and Hypertension Utrecht The Netherlands

The Royal Free NHS Trust and Barts Cancer Institute Queen Mary University of London London UK

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Long Non-Coding RNA PANTR1 is Associated with Poor Prognosis and Influences Angiogenesis and Apoptosis in Clear-Cell Renal Cell Cancer