title: Progression-free survival as a surrogate endpoint in advanced breast cancer.
abstract: OBJECTIVE
  Progression-free survival (PFS) has not been validated as a surrogate endpoint for overall survival (OS) for anthracycline (A) and taxane-based (T) chemotherapy in advanced breast cancer (ABC). Using trial-level, meta-analytic approaches, we evaluated PFS as a surrogate endpoint.
  
  
  METHODS
  A literature review identified randomized, controlled A and T trials for ABC. Progression-based endpoints were classified by prospective definitions. Treatment effects were derived as hazard ratios for PFS (HRPFS) and OS (HROS). Kappa statistic assessed overall agreement. A fixed-effects regression model was used to predict HROS from observed HRPFS. Cross-validation was performed. Sensitivity and subgroup analyses were performed for PFS definition, year of last patient recruitment, line of treatment, and constant rate assumption.
  
  
  RESULTS
  Sixteen A and fifteen T trials met inclusion criteria, producing seventeen A (n = 4,323) and seventeen T (n = 5,893) trial-arm pairs. Agreement (kappa statistic) between the direction of HROS and HRPFS was 0.71 for A (p = .0029) and 0.75 for T (p = .0028). While HRPFS was a statistically significant predictor of HROS for both A (p = .0019) and T (p = .012), the explained variances were 0.49 (A) and 0.35 (T). In cross-validation, 97 percent of the 95 percent prediction intervals crossed the equivalence line, and the direction of predicted HROS agreed with observed HROS in 82 percent (A) and 76 percent (T). Results were robust in sensitivity and subgroup analyses.
  
  
  CONCLUSIONS
  This meta-analysis suggests that the trial-level treatment effect on PFS is significantly associated with the trial-level treatment effect on OS. However, prediction of OS based on PFS is surrounded with uncertainty.
authors.affiliation: Department of Medicine, Division of Hematology and Oncology, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Avenue, Boston, MA 02215, USA. rmiksad@bidmc.harvard.edu
authors.forename: Rebecca A
authors.initials: RA
authors.lastname: Miksad
authors.forename: Vera
authors.initials: V
authors.lastname: Zietemann
authors.forename: Raffaella
authors.initials: R
authors.lastname: Gothe
authors.forename: Ruth
authors.initials: R
authors.lastname: Schwarzer
authors.forename: Annette
authors.initials: A
authors.lastname: Conrads-Frank
authors.forename: Petra
authors.initials: P
authors.lastname: Schnell-Inderst
authors.forename: Björn
authors.initials: B
authors.lastname: Stollenwerk
authors.forename: Uwe
authors.initials: U
authors.lastname: Siebert
mesh_terms: D018943:Anthracyclines / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy*; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D016016:Proportional Hazards Models; D016032:Randomized Controlled Trials as Topic; D012680:Sensitivity and Specificity; D016019:Survival Analysis; D043823:Taxoids / Q000627:therapeutic use*
chemical_list: D018943:Anthracyclines; D000970:Antineoplastic Agents; D043823:Taxoids