title: A Systematic Review and Meta-analysis Comparing the Effectiveness and Adverse Effects of Different Systemic Treatments for Non-clear Cell Renal Cell Carcinoma.
abstract: 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.
  
  
  
  To systematically review relevant literature comparing the oncological outcomes and adverse events of different systemic therapies for patients with metastatic non-ccRCC.
  
  
  
  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.
  
  
  
  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.
  
  
  
  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.
  
  
  
  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.
authors.affiliation: Department of Urology, Cabueñes Hospital, Gijón, Spain.
authors.forename: Sergio
authors.initials: S
authors.lastname: Fernández-Pello
authors.affiliation: Department of Urology, Sunderby Hospital, Sunderby, Sweden.
authors.forename: Fabian
authors.initials: F
authors.lastname: Hofmann
authors.affiliation: Department of Urology, University Hospital Hamburg Eppendorf, Hamburg, Germany.
authors.forename: Rana
authors.initials: R
authors.lastname: Tahbaz
authors.affiliation: Department of Urology, Coimbra University Hospital, Coimbra, Portugal.
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Marconi
authors.affiliation: Academic Urology Unit, University of Aberdeen, Aberdeen, UK; Department of Urology, Aberdeen Royal Infirmary, Aberdeen, UK.
authors.forename: Thomas B
authors.initials: TB
authors.lastname: Lam
authors.affiliation: Department of Cancer Medicine, Institut Gustave Roussy, Villejuif, France.
authors.forename: Laurence
authors.initials: L
authors.lastname: Albiges
authors.affiliation: Department of Urology, University of Rennes, Rennes, France.
authors.forename: Karim
authors.initials: K
authors.lastname: Bensalah
authors.affiliation: Division of Urology, University of Texas Medical School at Houston, Houston, TX, USA.
authors.forename: Steven E
authors.initials: SE
authors.lastname: Canfield
authors.affiliation: Department of Urology, Skåne University Hospital, Malmö, Sweden.
authors.forename: Saeed
authors.initials: S
authors.lastname: Dabestani
authors.affiliation: Patient Advocate International Kidney Cancer Coalition (IKCC), University Medical Centre Utrecht, Department of Nephrology and Hypertension, Utrecht, The Netherlands.
authors.forename: Rachel H
authors.initials: RH
authors.lastname: Giles
authors.affiliation: Department of Urology, Faculty Hospital and Faculty of Medicine in Pilsen, Charles University in Prague, Prague, Czech Republic.
authors.forename: Milan
authors.initials: M
authors.lastname: Hora
authors.affiliation: Department of Urology and Urologic Oncology, Hannover Medical School, Hannover, Germany.
authors.forename: Markus A
authors.initials: MA
authors.lastname: Kuczyk
authors.affiliation: Department of Urology, University Hospital Schleswig-Holstein, Lübeck, Germany.
authors.forename: Axel S
authors.initials: AS
authors.lastname: Merseburger
authors.affiliation: The Royal Free NHS Trust and Barts Cancer Institute, Queen Mary University of London, London, UK.
authors.forename: Thomas
authors.initials: T
authors.lastname: Powles
authors.affiliation: Department of Urology, Ludwig-Maximilians University, Munich, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Staehler
authors.affiliation: Division of Urology, Maggiore della Carità Hospital, University of Eastern Piedmont, Novara, Italy.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Volpe
authors.affiliation: Department of Surgical and Perioperative Sciences, Urology and Andrology, Umeå University, Umeå, Sweden.
authors.forename: Börje
authors.initials: B
authors.lastname: Ljungberg
authors.affiliation: Department of Urology, The Netherlands Cancer Institute, Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands. Electronic address: a.bex@nki.nl.
authors.forename: Axel
authors.initials: A
authors.lastname: Bex
mesh_terms: D000813:Anilides / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D000077784:Axitinib; D001562:Benzimidazoles / Q000627:therapeutic use; D000068258:Bevacizumab / Q000627:therapeutic use; D002292:Carcinoma, Renal Cell / Q000188:drug therapy* / Q000473:pathology; D057186:Comparative Effectiveness Research; D018572:Disease-Free Survival; D000069347:Erlotinib Hydrochloride / Q000627:therapeutic use; D000068338:Everolimus / Q000627:therapeutic use; D006801:Humans; D007093:Imidazoles / Q000627:therapeutic use; D007191:Indazoles / Q000627:therapeutic use; D007211:Indoles / Q000627:therapeutic use; D007372:Interferons / Q000627:therapeutic use; D007376:Interleukin-2 / Q000627:therapeutic use; D007680:Kidney Neoplasms / Q000188:drug therapy* / Q000473:pathology; D009536:Niacinamide / Q000031:analogs & derivatives / Q000627:therapeutic use; D010671:Phenylurea Compounds / Q000627:therapeutic use; D011725:Pyridines / Q000627:therapeutic use; D011743:Pyrimidines / Q000627:therapeutic use; D011758:Pyrroles / Q000627:therapeutic use; D011760:Pyrrolidinones / Q000627:therapeutic use; D011804:Quinolines / Q000627:therapeutic use; D015363:Quinolones / Q000627:therapeutic use; D020123:Sirolimus / Q000031:analogs & derivatives / Q000627:therapeutic use; D000077157:Sorafenib; D013449:Sulfonamides / Q000627:therapeutic use; D000077210:Sunitinib
chemical_list: C500007:4-amino-5-fluoro-3-(5-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl)quinolin-2(1H)-one; C551661:ARQ 197; D000813:Anilides; D000970:Antineoplastic Agents; D001562:Benzimidazoles; D007093:Imidazoles; D007191:Indazoles; D007211:Indoles; D007376:Interleukin-2; D010671:Phenylurea Compounds; D011725:Pyridines; D011743:Pyrimidines; D011758:Pyrroles; D011760:Pyrrolidinones; D011804:Quinolines; D015363:Quinolones; D013449:Sulfonamides; C553176:tivozanib; C558660:cabozantinib; D009536:Niacinamide; D000068258:Bevacizumab; C401859:temsirolimus; C516667:pazopanib; D007372:Interferons; D000068338:Everolimus; D000077157:Sorafenib; D000077784:Axitinib; D000069347:Erlotinib Hydrochloride; D000077210:Sunitinib; D020123:Sirolimus
keywords: Chromophobe; Everolimus; Non-clear cell renal cell carcinoma; Papillary; Sunitinib; Systematic review