Neoadjuvant Chemoradiotherapy Versus Neoadjuvant Immunochemotherapy for Resectable Esophageal Cancer: a Target Trial Emulation Study

Detailed Description This study is a target trial emulation (TTE) designed to compare thecausal effects of neoadjuvant immunochemotherapy (nICT) versus neoadjuvantchemoradiotherapy (nCRT) in patients with resectable locally advanced esophageal squamouscell carcinoma (ESCC). The TTE framework, as proposed by Hernán and Robins, is used toemulate a hypothetical randomized controlled trial using observational data.Data Source: Electronic health records (EHR) from Henan Cancer Hospital, includingmedical records, pathology reports, imaging reports, prescription systems, radiotherapyrecords, and follow‐up systems, covering the period from January 2013 to December 2025.Target Trial Specification: ‐ Eligibility: Age ≥18 years; histologically confirmed ESCC; clinical stage cT3‐4aN0‐2 M0 or cT2N+ M0 (AJCC 8th edition); ECOG PS 0‐1; no prior antitumor therapy foresophageal cancer; curative surgical intent at Time Zero. ‐ Treatment Strategies: Strategy A (nCRT): platinum‐based chemotherapy with concurrentradiotherapy (41.4‐50.4 Gy). Strategy B (nICT): PD‐1 inhibitor combined withplatinum‐based chemotherapy (2‐4 cycles). ‐ Assignment: In the target trial, patients are randomized 1:1. In the emulation,patients are assigned based on actual treatment received, with propensity scoreoverlap weighting to simulate randomization. ‐ Follow‐up: Time Zero is defined as the day before the first neoadjuvant treatmentorder. Follow‐up continues until death, loss to follow‐up, or administrative end ofstudy (December 31, 2026). A grace period of up to 180 days is allowed for treatmentinitiation (i.e., the order date must be within 180 days from Time Zero). Patientswho initiate treatment beyond this window are excluded from the primary analysis orevaluated separately in sensitivity analyses. ‐ Outcomes: Primary: Overall Survival (OS). Secondary: Event‐Free Survival (EFS),pathological complete response (pCR) rate, tumor regression grade (TRG), R0resection rate, and safety (≥grade 3 adverse events per CTCAE v5.0, postoperativecomplications per Clavien‐Dindo classification).Statistical Analysis: ‐ Primary Analysis: Overlap weighting using propensity scores to balance baselinecovariates; weighted Cox proportional hazards models to estimate hazard ratios (HR)with 95% confidence intervals for OS and EFS. ‐ Secondary Analysis: pCR, TRG, and R0 rates compared between groups in the surgicalsubgroup. ‐ Sensitivity Analyses: Per‐protocol analysis, clone‐censor‐weight method, E‐value forunmeasured confounding, different Time Zero definitions, different grace periods (4weeks, 12 weeks), complete‐case analysis vs multiple imputation. ‐ Sensitivity Analyses: Per‐protocol analysis, clone‐censor‐weight method, E‐value forunmeasured confounding, different Time Zero definitions, different grace periods (4weeks, 12 weeks), complete‐case analysis vs multiple imputation. ‐ Subgroup Analyses: By age, sex, tumor location, clinical stage, ECOG PS, anddiagnosis period (2013‐2019 vs 2020‐2025).Sample Size: Based on historical data, the target sample size is approximately 150‐200patients per group, with a total enrollment of approximately 400 patients (final samplesize determined after data extraction and pilot feasibility assessment).Ethics: Approved by the Medical Ethics Committee of Henan Cancer Hospital (Approval No.2026‐366‐001). A waiver of informed consent was granted for this retrospective study.