Heterogeneity of adjuvant therapy effectiveness across post-neoadjuvant pathologic strata in esophageal squamous cell...

Adjuvant therapy after neoadjuvant treatment and R0 esophagectomy for esophageal squamous cell carcinoma (ESCC) remains controversial, and benefit may vary by post-neoadjuvant pathology. We evaluated heterogeneity of adjuvant benefit across prespecified pathologic strata and quantified absolute survival gains.

In this two-center retrospective cohort (January 2018-May 2023), patients with ESCC who underwent neoadjuvant therapy followed by R0 resection were classified as pCR (ypT0N0), ypT+N0, or ypT0-4N+. The exposure was early postoperative adjuvant therapy initiated within 8 weeks after surgery. To reduce immortal-time bias, we used an 8-week landmark design with follow-up from the landmark. Confounding was addressed using stabilized inverse probability of treatment weighting (sIPTW) based on preoperative covariates, center, and surgical approach. Outcomes were overall survival (OS) and disease-free survival (DFS) using weighted Cox models with robust standard errors; absolute differences in survival probability (ΔS) were derived from weighted Kaplan-Meier curves.

Among 781 patients (pCR 142, ypT+N0 317, ypT0-4N+ 322), survival for pCR and ypT+N0 largely overlapped, whereas ypT0-4N+ had consistently worse outcomes. In the overall cohort, adjuvant therapy was not associated with improved OS (HR 0.99, 95% CI 0.75-1.31; P = 0.946) or DFS (HR 1.15, 95% CI 0.89-1.48; P = 0.283). Benefit was concentrated in ypT0-4N+ (OS HR 0.48, 95% CI 0.33-0.72; P < 0.001; DFS HR 0.64, 95% CI 0.46-0.90; P = 0.011), with ΔS +13.2 percentage points for DFS at 1 year and +21.0 percentage points for OS at 3 years. No clear benefit was observed in pCR or ypT+N0.

After neoadjuvant therapy and R0 resection for ESCC, post-neoadjuvant nodal status strongly stratified prognosis, with similar survival for pCR and ypT+N0. Adjuvant benefit is heterogeneous and concentrated in ypN-positive disease, supporting a pathology-informed, risk-adapted postoperative strategy targeting ypT0-4N+.