Assessment of Progression-Free Survival as a Surrogate End Point of Overall Survival in First-Line Treatment of Ovarian Cancer

Abstract

IMPORTANCE The Gynecologic Cancer InterGroup (GCIG) recommended that progression-free survival (PFS) can serve as a primary end point instead of overall survival (OS) in advanced ovarian cancer. Evidence is lacking for the validity of PFS as a surrogate marker of OS in the modern era of different treatment types. OBJECTIVE To evaluate whether PFS is a surrogate end point for OS in patients with advanced ovarian cancer. DATA SOURCES In September 2016, a comprehensive search of publications in MEDLINE was conducted for randomized clinical trials of systematic treatment in patients with newly diagnosed ovarian, fallopian tube, or primary peritoneal cancer. The GCIG groups were also queried for potentially completed but unpublished trials. STUDY SELECTION Studies with a minimum sample size of 60 patients published since 2001 with PFS and OS rates available were eligible. Investigational treatments considered included initial, maintenance, and intensification therapy consisting of agents delivered at a higher dose and/or frequency compared with that in the control arm. DATA EXTRACTION AND SYNTHESIS Using the meta-analytic approach on randomized clinical trials published from January 1, 2001, through September 25, 2016, correlations between PFS and OS at the individual level were estimated using the Kendall τ model; between-treatment effects on PFS and OS at the trial level were estimated using the Plackett copula bivariate (R 2) model. Criteria for PFS surrogacy required R 2 Ն 0.80 at the trial level. Analysis was performed from January 7 through March 20, 2019. MAIN OUTCOMES AND MEASURES Overall survival and PFS based on measurement of cancer antigen 125 levels confirmed by radiological examination results or by combined GCIG criteria. RESULTS In this meta-analysis of 17 unique randomized trials of standard (n = 7), intensification (n = 5), and maintenance (n = 5) chemotherapies or targeted treatments with data from 11 029 unique patients (median age, 58 years [range, 18-88 years]), a high correlation was found between PFS and OS at the individual level (τ = 0.724; 95% CI, 0.717-0.732), but a low correlation was found at the trial level (R 2 = 0.24; 95% CI, 0-0.59). Subgroup analyses led to similar results. In the external (continued) Key Points Question Is progression-free survival a validated surrogate end point for overall survival in first-line systemic treatment of ovarian cancer? Findings In this systematic review and meta-analysis of 17 unique trials with individual data from 11 029 unique patients, a high correlation between progression-free and overall survival was found at the individual level, but a low correlation was found at the trial level. Meaning These findings suggest that overall survival is the preferred end point in trials of first-line treatment or maintenance treatment, and progressive-free survival must be supported by additional end points if used as the primary end point.

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