P1.072. Impact of Neoadjuvant Therapy on Survival After Esophagectomy for Squamous Cell Carcinoma: An International Multicenter Propensity Score Analysis

Abstract

Esophageal Cancer: Adjuvant and Neo-Adjuvant Therapies The survival benefit of neoadjuvant therapy for esophageal squamous cell carcinoma (ESCC) remains controversial, as landmark trials were conducted predominantly in adenocarcinoma populations. This study evaluated the association between neoadjuvant therapy and long-term survival in a large international multicenter ESCC cohort using propensity score methods and multivariable Cox regression. We retrospectively analyzed 2,449 patients with ESCC who underwent curative esophagectomy at five institutions across three countries (Japan, China, and South Korea) between 2008 and 2022. Patients receiving neoadjuvant therapy (n=941) were compared with a surgery-first cohort (n=880) after excluding 41 cases with inconsistent survival data. Propensity score matching (PSM) 1:1 was performed using nearest-neighbor matching (caliper=0.1 SD of logit propensity score) with exact matching on center, adjusting for sex, age, clinical T and N stage. Inverse probability of treatment weighting (IPTW) with trimming (1st–99th percentile) served as a sensitivity analysis. Center-stratified univariate and multivariable Cox proportional hazards regression were applied. Primary endpoints were overall survival (OS) and disease-free survival (DFS). In analysis, neoadjuvant therapy appeared protective for OS (HR 0.60, 95% CI 0.48–0.75, p<0.001) while DFS was worse (HR 1.57, 95% CI 1.34–1.84, p<0.001). This discordant finding reversed after center-stratified Cox regression, revealing substantial confounding by center. Univariate analysis showed neoadjuvant therapy was associated with worse OS (HR 2.22, 95% CI 1.75–2.83, p<0.001) and DFS (HR 2.31, 95% CI 1.89–2.82, p<0.001). Multivariable analysis confirmed neoadjuvant therapy as an independent predictor of worse OS (HR 1.48, 95% CI 1.11–1.96, p=0.007) and DFS (HR 1.39, 95% CI 1.09–1.77, p=0.007). PSM yielded 255 pairs; after matching, neoadjuvant therapy was associated with worse OS (HR 1.56, 95% CI 1.05–2.30, p=0.027) and DFS (HR 1.60, 95% CI 1.18–2.19, p=0.003). IPTW sensitivity analysis yielded consistent results (OS: HR 2.21, 95% CI 1.74–2.82; DFS: HR 2.30, 95% CI 1.89–2.81; both p<0.001). In this international multicenter analysis of 2,449 ESCC patients, neoadjuvant therapy was not associated with improved survival after esophagectomy and remained an independent predictor of worse OS and DFS across univariate, multivariable, PSM, and IPTW analyses. These findings underscore the critical importance of histology-specific evidence and support the urgent need for contemporary randomized controlled trials designed specifically for ESCC populations.