title: Systemic therapy for non-clear cell renal cell carcinomas: a systematic review and meta-analysis.
abstract: BACKGROUND
  Clinical data supporting the use of targeted agents for the treatment of metastatic renal cell carcinoma (RCC) are based predominantly on patients with clear cell histology. Little is known about the efficacy of these drugs in non-clear cell variants.
  
  
  OBJECTIVE
  To evaluate the efficacy of different clear cell RCC (ccRCC)-approved targeted agents among patients with non-ccRCC compared with ccRCC.
  
  
  METHODS
  We conducted a systematic review of electronic databases to identify publications evaluating the outcomes of patients with non-ccRCC treated with targeted agents approved for treatment of ccRCC. Patients with sarcomatoid variant RCC were excluded from the main analysis but were evaluated as an independent cohort. End points of interest were response rate, median progression-free survival (PFS), and median overall survival (OS). Where possible, data were pooled in a meta-analysis. For studies of unselected patients with RCC, the outcomes of patients with non-ccRCC histology were compared with ccRCC. In exploratory analyses, outcomes of non-ccRCC with nonapproved agents were assessed.
  
  
  RESULTS
  A total of 49 studies comprising 7771 patients were included in the analysis. Of these, 1244 patients (16.0%) had non-ccRCC, 6300 (83.1%) had ccRCC, and 227 (2.9%) had sarcomatoid tumours. The overall response rate for non-ccRCC with targeted agents was 10.5%. In studies directly comparing non-ccRCC and ccRCC, there were significantly lower response rates for non-ccRCC (odds ratio for response: 0.52; 95% confidence interval, 0.40-0.68; p<0.001). For non-ccRCC treated with targeted agents, median PFS and OS were 7.4 and 13.4 mo, respectively; for patients with ccRCC, these were 10.5 mo and 15.7 mo, respectively (p value for difference<0.001 for both parameters).
  
  
  CONCLUSIONS
  Patients with non-clear cell renal cell carcinoma (non-ccRCC) have significantly lower response rates and poorer median progression-free survival and overall survival than those with ccRCC. The optimal treatment of patients with non-ccRCC remains unclear and warrants further study.
  
  
  RESULTS
  Systemic treatments for patients with renal cell carcinoma (RCC) tend to be significantly less effective for non-clear cell RCC, with lower response rates and worse progression-free survival and overall survival when compared with clear cell RCC. Optimal therapy remains unclear and warrants further study.
authors.affiliation: Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre, Department of Medicine, University of Toronto, Toronto, Canada.
authors.forename: Francisco E
authors.initials: FE
authors.lastname: Vera-Badillo
authors.affiliation: Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre, Department of Medicine, University of Toronto, Toronto, Canada.
authors.forename: Arnoud J
authors.initials: AJ
authors.lastname: Templeton
authors.affiliation: Department of Medical Oncology, Hospital Universitario "Virgen del Rocío", Sevilla, Spain.
authors.forename: Ignacio
authors.initials: I
authors.lastname: Duran
authors.affiliation: Translational Research Unit, Albacete University Hospital, Albacete, Spain.
authors.forename: Alberto
authors.initials: A
authors.lastname: Ocana
authors.affiliation: Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre, Department of Medicine, University of Toronto, Toronto, Canada.
authors.forename: Paulo
authors.initials: P
authors.lastname: de Gouveia
authors.affiliation: Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre, Department of Medicine, University of Toronto, Toronto, Canada.
authors.forename: Priya
authors.initials: P
authors.lastname: Aneja
authors.affiliation: Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre, Department of Medicine, University of Toronto, Toronto, Canada.
authors.forename: Jennifer J
authors.initials: JJ
authors.lastname: Knox
authors.affiliation: Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre, Department of Medicine, University of Toronto, Toronto, Canada.
authors.forename: Ian F
authors.initials: IF
authors.lastname: Tannock
authors.affiliation: Institut Gustave Roussy, Villejuif, France.
authors.forename: Bernard
authors.initials: B
authors.lastname: Escudier
authors.affiliation: Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre, Department of Medicine, University of Toronto, Toronto, Canada. Electronic address: Eitan.Amir@uhn.ca.
authors.forename: Eitan
authors.initials: E
authors.lastname: Amir
mesh_terms: D018262:Adenocarcinoma, Clear Cell / Q000473:pathology / Q000628:therapy*; D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000627:therapeutic use; D002292:Carcinoma, Renal Cell / Q000145:classification* / Q000473:pathology / Q000628:therapy*; D018450:Disease Progression; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents
keywords: Non-clear renal cell carcinoma; Systemic therapy