Progression-free survival as a surrogate endpoint in advanced breast cancer

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 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.

Applications for Oncologic Drugs: A Descriptive Analysis of the Oncologic Drugs Advisory Committee Reviews

“…Moreover, in a review of randomized control trials from 2004 to 2009 on breast, colorectal, and non-small cell lung cancer, Booth and Eisenhauer found a 26% increase in the use of PFS as a primary endpoint [19]. In contrast, breast cancer researchers showed that the prediction of OS based on PFS is uncertain [20,21]. Although we found an increased use of PFS as primary endpoint over time, this was not correlated with an increase in FDA approval rate.…”

Assessing Cancer Drugs for Reimbursement: Methodology, Relationship between Effect Size and Medical Need

“…[8][9][10][11] In nonvalidated cases such as breast cancer, PFS is considered an intermediate endpoint. [12,13] They are defined as the time between randomisation and local or distant recurrence for DFS, or the time between randomisation and progression, a second cancer or death by any cause for PFS. These endpoints have an undeniable clinical relevance because they measure the time during which there is no clinical evidence of tumour progression, thereby reflecting the anti-tumour action more directly than survival, and are not affected by later lines of treatment.…”

Critères et méthodologie d’évaluation au remboursement des anticancéreux

“…[8][9][10][11] Dans les cas non validés comme le cancer du sein, la PFS est considérée comme un critère intermédiaire. [12,13] La DFS est définie par le délai entre la randomisation et la récidive locale ou à distance. La PFS est définie par le délai entre la randomisation et la progression, un second cancer ou le décès quelle que soit la cause.…”