A Systematic Review and Meta-analysis Comparing the Effectiveness and Adverse Effects of Different Systemic Treatments for Non-clear Cell Renal Cell Carcinoma

Research output: Contribution to journalReview article


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.


  • Sergio Fernández-Pello
  • Fabian Hofmann
  • Rana Tahbaz
  • Lorenzo Marconi
  • Thomas B Lam
  • Laurence Albiges
  • Karim Bensalah
  • Steven E Canfield
  • Saeed Dabestani
  • Rachel H. Giles
  • Milan Hora
  • Markus A. Kuczyk
  • Axel S Merseburger
  • Thomas Powles
  • Michael Staehler
  • Alessandro Volpe
  • Börje Ljungberg
  • Axel Bex
External organisations
  • Sunderby Hospital
  • University Medical Center Hamburg-Eppendorf
  • University Hospital of Coimbra
  • University of Aberdeen
  • Aberdeen Royal Infirmary
  • Institut Gustave Roussy
  • University of Rennes I
  • University of Texas
  • Skåne University Hospital
  • University Medical Center Utrecht
  • Charles University in Prague
  • Hannover Medical School
  • University Medical Center Schleswig-Holstein Campus Kiel
  • Queen Mary University
  • Ludwig-Maximilian University of Munich
  • University of Eastern Piedmont
  • Umeå University
  • Netherlands Cancer Institute
  • University Hospital Cabueñes
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Urology and Nephrology
  • Cancer and Oncology


  • Chromophobe, Everolimus, Non-clear cell renal cell carcinoma, Papillary, Sunitinib, Systematic review
Original languageEnglish
Pages (from-to)426-436
Number of pages11
JournalEuropean Urology
Issue number3
StatePublished - 2017 Mar 1
Publication categoryResearch