Treatments for esophageal cancer are evolving rapidly, highlighting the need for surrogate endpoints to expedite patient access to therapy. Overall survival (OS) remains the gold standard endpoint in oncology clinical trials, but its assessment often requires extended follow-up, delaying treatment evaluations. Event-free survival (EFS) has emerged as a promising surrogate for OS in resectable locally advanced esophageal cancer. However, its validity in the context of definitive chemoradiotherapy (dCRT), the standard treatment for unresectable disease, has not been established. We assessed the trial-level correlation between EFS and OS in this setting. A systematic literature review identified randomized controlled trials (RCTs) evaluating dCRT for unresectable locally advanced esophageal cancer. Studies reporting hazard ratios (HRs) for both EFS (or similarly defined early endpoints) and OS were included. Weighted linear regression (WLR) was used to assess the correlation between log(HR) for EFS and log(HR) for OS. The strength of the correlation was evaluated using the coefficient of determination (R2), with thresholds of ≥ 0.65 or ≥ 0.75 indicating good surrogacy. The robustness of the WLR model and correlation analyses was confirmed by leave-one-out cross-validations and sensitivity analyses, respectively. Fourteen between-treatment comparisons from 11 RCTs (N = 2,812) in unresectable locally advanced esophageal cancer were included. Eight studies were conducted in China and three in Europe, with sample size and follow-up ranging from 86 to 434 patients and 24 to 60 months, respectively. Reported median EFS was 17.5 months, whereas median OS was 25.1 months. Most patients had advanced-stage squamous cell carcinoma. The correlation analysis identified a strong EFS–OS correlation (estimated slope coefficient: 0.91; 95% confidence interval CI, 0.62–1.20, P<0.001; R2=0.80; 95% CI, 0.38–0.96), indicating that EFS was a significant predictor of OS. The leave-one-out cross-validation confirmed this association, with 71.4% of observed OS HRs falling within the predicted 95% CIs. Sensitivity analyses further supported the robustness of the correlation. We identified a strong, statistically significant, correlation between EFS and OS, suggesting that EFS may serve as a valid surrogate endpoint for OS in patients with unresectable locally advanced esophageal cancer receiving dCRT, with potential to streamline clinical trials and regulatory assessments.
Xue et al. (2026) studied this question.