Author:
Miksad Rebecca A.,Zietemann Vera,Gothe Raffaella,Schwarzer Ruth,Conrads-Frank Annette,Schnell-Inderst Petra,Stollenwerk Björn,Siebert Uwe
Abstract
Objectives: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 HROSfrom 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 HROSand HRPFSwas 0.71 for A (p= .0029) and 0.75 for T (p= .0028). While HRPFSwas a statistically significant predictor of HROSfor 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 HROSagreed with observed HROSin 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.
Publisher
Cambridge University Press (CUP)