Esophageal squamous cell carcinoma (ESCC) is highly prevalent in China, with most patients presenting with locally advanced disease. Neoadjuvant chemoradiotherapy (nCRT) is the current standard of care, while neoadjuvant immunochemotherapy (nICT) has emerged as a promising alternative. However, no large-scale randomized controlled trial has directly compared nICT versus nCRT for long-term overall survival (OS) in this population. This study aims to compare the causal effects of nICT versus nCRT on OS and other key outcomes in patients with resectable locally advanced ESCC using target trial emulation (TTE) methodology. This is a single-center, retrospective, observational cohort study using TTE. Data are derived from electronic health records (EHR) of esophageal cancer patients hospitalized at Henan Cancer Hospital between January 2013 and December 2025. Patients meeting eligibility criteria (age ≥18 years; histologically confirmed ESCC; clinical stage cT3-4a N0-2 M0 or cT2N+ M0; ECOG PS 0-1; no prior antitumor therapy) are assigned to nICT or nCRT groups based on actual treatment initiation. Propensity score overlap weighting is used to balance baseline covariates. The primary outcome is overall survival (OS). Secondary outcomes include event-free survival (EFS), pathological complete response (pCR) rate, tumor regression grade (TRG), R0 resection rate, and safety. This study will provide real-world causal evidence on the comparative effectiveness of nICT versus nCRT in the Chinese ESCC population.
Detailed Description This study is a target trial emulation (TTE) designed to compare the causal effects of neoadjuvant immunochemotherapy (nICT) versus neoadjuvant chemoradiotherapy (nCRT) in patients with resectable locally advanced esophageal squamous cell carcinoma (ESCC). The TTE framework, as proposed by Hernán and Robins, is used to emulate a hypothetical randomized controlled trial using observational data. Data Source: Electronic health records (EHR) from Henan Cancer Hospital, including medical records, pathology reports, imaging reports, prescription systems, radiotherapy records, 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 cT3-4a N0-2 M0 or cT2N+ M0 (AJCC 8th edition); ECOG PS 0-1; no prior antitumor therapy for esophageal cancer; curative surgical intent at Time Zero. * Treatment Strategies: Strategy A (nCRT): platinum-based chemotherapy with concurrent radiotherapy (41.4-50.4 Gy). Strategy B (nICT): PD-1 inhibitor combined with platinum-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 score overlap weighting to simulate randomization. * Follow-up: Time Zero is defined as the day before the first neoadjuvant treatment order. Follow-up continues until death, loss to follow-up, or administrative end of study (December 31, 2026). A grace period of up to 180 days is allowed for treatment initiation (i.e., the order date must be within 180 days from Time Zero). Patients who initiate treatment beyond this window are excluded from the primary analysis or evaluated separately in sensitivity analyses. * Outcomes: Primary: Overall Survival (OS). Secondary: Event-Free Survival (EFS), pathological complete response (pCR) rate, tumor regression grade (TRG), R0 resection rate, and safety (≥grade 3 adverse events per CTCAE v5.0, postoperative complications per Clavien-Dindo classification). Statistical Analysis: * Primary Analysis: Overlap weighting using propensity scores to balance baseline covariates; 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 surgical subgroup. * Sensitivity Analyses: Per-protocol analysis, clone-censor-weight method, E-value for unmeasured confounding, different Time Zero definitions, different grace periods (4 weeks, 12 weeks), complete-case analysis vs multiple imputation. * Sensitivity Analyses: Per-protocol analysis, clone-censor-weight method, E-value for unmeasured confounding, different Time Zero definitions, different grace periods (4 weeks, 12 weeks), complete-case analysis vs multiple imputation. * Subgroup Analyses: By age, sex, tumor location, clinical stage, ECOG PS, and diagnosis period (2013-2019 vs 2020-2025). Sample Size: Based on historical data, the target sample size is approximately 150-200 patients per group, with a total enrollment of approximately 400 patients (final sample size 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.
Study Type
OBSERVATIONAL
Enrollment
400
Concurrent radiotherapy administered as part of neoadjuvant chemoradiotherapy, typically 41.4-50.4 Gy in fractionated doses, combined with platinum-based chemotherapy.
Platinum-based chemotherapy administered as part of neoadjuvant treatment, combined with either concurrent radiotherapy (nCRT) or PD-1 inhibitors (nICT).
PD-1 inhibitors administered as part of neoadjuvant immunochemotherapy, combined with platinum-based chemotherapy for 2-4 cycles.
Overall Survival (OS)
Overall Survival (OS) is defined as the time from Time Zero (the day before the first neoadjuvant treatment order) to death from any cause. Patients alive at the time of analysis are censored at the date of last known contact.
Time frame: From Time Zero up to 10 years
Event-Free Survival (EFS)
Event-Free Survival (EFS) is defined as the time from Time Zero to the first occurrence of death, disease progression, local recurrence, distant metastasis, or inoperability, whichever occurs first.
Time frame: From Time Zero up to 10 years
Pathological Complete Response (pCR) Rate
Pathological complete response (pCR) is defined as the absence of viable tumor cells in the primary tumor and all resected lymph nodes (ypT0 ypN0) on postoperative pathological examination.
Time frame: At the time of surgery
Tumor Regression Grade (TRG)
Tumor regression grade assessed according to Mandard criteria or Chinese standard (TRG 0-3) on postoperative pathological examination.
Time frame: At the time of surgery
R0 Resection Rate
R0 resection rate is defined as the proportion of patients achieving microscopically margin-negative resection on postoperative pathological examination.
Time frame: At the time of surgery
Incidence of Treatment-Related Adverse Events
Incidence and severity of treatment-related adverse events (≥grade 3), graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 5.0.
Time frame: From treatment initiation through 90 days after treatment completion
Incidence of Postoperative Complications
Incidence and severity of postoperative complications graded according to the Clavien-Dindo classification (≥grade III) and Esophagectomy Complications Consensus Group (ECCG) criteria.
Time frame: From surgery through 90 days postoperatively
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