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

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.

Sex

All

Minimum age

18 Years

Inclusion Criteria:

1. Age ≥ 18 years at the time of diagnosis.
2. Histologically confirmed esophageal squamous cell carcinoma (ESCC).
3. Clinical stage cT3-4a N0-2 M0 or cT2N+ M0 (AJCC 8th edition), with no distant metastasis (M1), based on clinical staging records available at Time Zero.
4. ECOG performance status 0-1 (or proxy: total hospitalization days ≤14 days in the past year if ECOG PS is missing).
5. No prior antitumor therapy for esophageal cancer (surgery, radiotherapy, chemotherapy, targeted therapy, or immunotherapy).
6. Curative surgical intent documented at Time Zero.

Exclusion Criteria:

1. Distant metastasis (M1) or clinically determined unresectable disease.
2. Active concurrent malignancy within 5 years prior to diagnosis (excluding basal cell carcinoma of the skin or carcinoma in situ).
3. Severe comorbidities significantly limiting life expectancy or precluding neoadjuvant therapy (proxy: total hospitalization days \>30 days in the past year).
4. Pregnancy or lactation.
5. Known contraindications or hypersensitivity to the study drugs.