Recurrence-free Survival as a Surrogate Endpoint for Overall Survival in Resectable Esophageal Cancer: Integrated Analysis of Individual Patient Data From Phase III Trials.

Abstract

This study evaluated recurrence-free survival (RFS) as a surrogate endpoint for overall survival (OS) in esophageal cancer. OS is regarded as the gold-standard efficacy endpoint of oncological treatments but requires long follow-up. An integrated analysis of individual patient data (IPD) from phase III trials comparing perioperative therapies for resectable esophageal and gastroesophageal junction cancer was conducted. Surrogacy between RFS and OS was assessed at the individual level using the Kendall rank correlation coefficient (τ) and at the trial level using the coefficient of determination (R²). A τ of 0.8 and an R² of 0.65 were considered thresholds for a good surrogate. Twenty-two eligible trials were identified, and IPD were available from 10 randomized trials, including 2,145 patients who underwent R0 resection. The 5-year OS and RFS rates were 53.2% and 46.2%, with median OS of 6.2 and RFS of 3.6 years. For individual-level surrogacy, Kendall's τ was 0.823 (95% confidence interval [CI]: 0.807-0.839). Subgroup analysis by treatment modality revealed τ values of 0.830 (95% CI: 0.800-0.861) for neoadjuvant chemotherapy (NAC; n=586), and 0.827 (95% CI: 0.803-0.850) for neoadjuvant chemoradiotherapy (NACRT; n=982). Trial-level surrogacy analysis across all 22 trials demonstrated an R2 of 0.735 (95% CI: 0.512-0.939). The surrogate threshold effect was 0.929. This study demonstrated strong individual- and trial-level surrogacy between RFS and OS in resectable esophageal cancer across all perioperative treatments. These findings may accelerate perioperative treatment development by shortening follow-up in esophageal cancer trials.