Advocating for Precision Neoadjuvant and Subsequent Adjuvant Therapies in Esophageal Squamous Cell Carcinoma: Evidence From a Real-World Multicenter Study.

Controversies persist regarding the optimal regimens of neoadjuvant and adjuvant therapies for locally advanced esophageal squamous cell carcinoma (ESCC). This real-world cohort study aimed to compare the efficacy of neoadjuvant chemotherapy (NCT), chemoradiotherapy (NCRT), and chemoimmunotherapy (NCIT), and to clarify the survival contributions of adjuvant strategies. We retrospectively enrolled 1818 ESCC patients across four high-volume Chinese medical centers. After propensity score matching, pathological tumor response and tumor downstaging followed the hierarchy NCRT > NCIT > NCT, yet no significant differences were detected in overall survival (OS) or progression-free survival (PFS). Subgroup analyses revealed superior OS benefits of NCIT in never‑smokers, nondrinkers, and patients with clinical N2-3 disease compared with NCT. While NCRT showed greater PFS benefit than NCIT as clinical T stage advanced, its OS advantage was restricted to obese individuals. Adjuvant immunotherapy extended PFS for patients receiving prior NCIT, whereas adjuvant chemotherapy delivered survival benefits to those with pathological lymph node metastasis. We constructed optimal treatment rule (OTR) decision trees with moderate-to-good predictive capacity to guide selection of neoadjuvant and adjuvant therapies based on survival benefit. These results highlight the necessity of precision perioperative therapy for ESCC. The established OTR decision trees can support individualized clinical decision-making.