Clinical Response Improves the Prognostic Stratification of Pathological Response After Neoadjuvant Chemotherapy in Esophageal Adenocarcinoma

Background Docetaxel-based neoadjuvant chemotherapy (NAT) has emerged as a leading standard of care therapy for locally advanced esophageal adenocarcinoma (EAC). Response in resected specimens is routinely assessed using the modified Ryan scheme Tumor Regression Grading (TRG) score and may affect the prediction of survival and choice of adjuvant therapy. While TRG at the extremes (complete/near complete response, TRG0/1; poor response, TRG3), appears to have clear prognostic significance, moderate response (TRG2) lacks consistent prognostic value due to heterogeneity. This study aims to refine the characterization of TRG2 patients to improve survival prognostication. Methods Patients undergoing curative-intent NAT and esophagectomy for EAC between 01/2007 and 12/2023 were identified from a prospectively collected database. Data on demographics, tumor characteristics, NAT, surgical technique, pathological findings, and overall survival (OS) were collected. Clinical/objective response rates to NAT was assessed at diagnosis and post NAT with CT (RECIST), PET (change in SUV), dysphagia score (range: 0, best to 4, worst), and endoscopic response (range: 0, complete- to 3 none), and correlated to pathological response and survival. Kaplan–Meier analysis and Cox-regression models were used to evaluate the association between factors and OS with significance set at p < 0.05 (*). Results Of 1004 esophagectomies in the database, 453 received docetaxel-based NAT resulting in pathological response of TRG0/1 (n = 92, 20.3%), TRG2 (n = 149, 32.9%), and TRG3 (n = 147, 32.5%). OS differed significantly between categories: 3-year OS for TRG 0/1 was 45% compared to 31% for TRG2 and 26% for TRG3 (*) with overlapping survival curves between the TRG2 group and entire cohort. When controlling for TRG, the absence of endoscopic response doubled the risk of death compared to complete response (*). Lack of dysphagia score improvement strongly trends towards correlation with worse survival (p = 0.07), while CT/PET response showed no significant survival impact. Conclusion Pathological response grading after NAT in EAC fails to predict oncological outcome in those with moderate response (TRG2). Clinical response criteria, especially the absence of improved endoscopic response or dysphagia scores, was associated with poor survival in TRG2 patients. By incorporating clinical response in addition to pathological response we can better predict survival in EAC patients undergoing NAT and surgery.