title: Progression-free survival as a surrogate endpoint of overall survival in patients with metastatic renal cell carcinoma.
abstract: BACKGROUND
  The current study was conducted to investigate the dependence between progression-free survival (PFS) and overall survival (OS) in patients with metastatic renal cell carcinoma (mRCC) and to explore whether PFS can be used as an intermediate endpoint of OS in this patient population.
  
  
  METHODS
  A total of 1381 patients from 2 prospective phase 3 trials (Cancer and Leukemia Group B [CALGB] 90206 and AVOREN) of interferon-alpha with or without bevacizumab were analyzed. Both trials recruited previously untreated patients with clear cell mRCC with an Eastern Cooperative Oncology Group performance status of 0 to 2; adequate bone marrow, hepatic, cardiac, and renal function; and controlled blood pressure. The CALGB study served as the training data set, and the AVOREN study served as the testing data set. The dependence between PFS and OS was investigated using the Kendall tau for bivariate time-to-event endpoints.
  
  
  RESULTS
  In the training data set, the median OS times among patients who experienced progressive disease at 3 months or 6 months were 6 months and 8 months, respectively, compared with 25 months and 30 months, respectively, (P < .001) in patients who did not develop disease progress. The adjusted hazard ratios (HR) were 2.6 (P < .0001) and 2.8 (P < .0001), respectively, for patients who did and did not progress at 3 months or 6 months. The dependence between PFS and OS was 0.53. These associations were confirmed in the testing data set.
  
  
  CONCLUSIONS
  In patients with mRCC who were treated with interferon-alpha with or without bevacizumab, the PFS at 3 months and 6 months was found to be predictive of OS. A high dependence between PFS and OS was observed, suggesting that PFS may be used as a surrogate endpoint for OS. Although this is a novel observation for RCC, these findings require validation in patients with mRCC who are treated with other targeted agents.
authors.affiliation: Department of Biostatistics and Bioinformatics, Duke University Medical Center, Durham, North Carolina; Alliance Statistical and Data Center, Duke University, Durham, North Carolina.
authors.forename: Susan
authors.initials: S
authors.lastname: Halabi
authors.forename: Brian
authors.initials: B
authors.lastname: Rini
authors.forename: Bernard
authors.initials: B
authors.lastname: Escudier
authors.forename: Walter M
authors.initials: WM
authors.lastname: Stadler
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Small
mesh_terms: D000368:Aged; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D000068258:Bevacizumab; D002292:Carcinoma, Renal Cell / Q000188:drug therapy*; D017326:Clinical Trials, Phase III as Topic / Q000379:methods; D018572:Disease-Free Survival; D023381:Endpoint Determination; D005260:Female; D006801:Humans; D016898:Interferon-alpha / Q000008:administration & dosage / Q000627:therapeutic use*; D007680:Kidney Neoplasms / Q000188:drug therapy*; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D009362:Neoplasm Metastasis; D016016:Proportional Hazards Models; D011446:Prospective Studies; D016032:Randomized Controlled Trials as Topic; D016019:Survival Analysis
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D016898:Interferon-alpha; D000068258:Bevacizumab
keywords: clinical trials; overall survival; progression-free survival; renal cancer; surrogate