Esophageal Squamous Cell Carcinoma (ESCC)
Conditions
Keywords
Esophageal Cancer, Squamous Cell Carcinoma, Neoadjuvant Immunochemotherapy, Neoadjuvant Chemoradiotherapy, Target Trial Emulation, Real-World Data
Brief summary
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
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.
Interventions
RADIATIONRadiotherapy
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).
DRUGPD-1 Inhibitor
PD-1 inhibitors administered as part of neoadjuvant immunochemotherapy, combined with platinum-based chemotherapy for 2-4 cycles.
Sponsors
Henan Cancer Hospital
Study design
Observational model
COHORT
Time perspective
RETROSPECTIVE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival (OS) | From Time Zero up to 10 years | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Event-Free Survival (EFS) | From Time Zero up to 10 years | 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. |
| Pathological Complete Response (pCR) Rate | At the time of surgery | 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. |
| Tumor Regression Grade (TRG) | At the time of surgery | Tumor regression grade assessed according to Mandard criteria or Chinese standard (TRG 0-3) on postoperative pathological examination. |
| R0 Resection Rate | At the time of surgery | R0 resection rate is defined as the proportion of patients achieving microscopically margin-negative resection on postoperative pathological examination. |
| Incidence of Treatment-Related Adverse Events | From treatment initiation through 90 days after treatment completion | 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. |
| Incidence of Postoperative Complications | From surgery through 90 days postoperatively | Incidence and severity of postoperative complications graded according to the Clavien-Dindo classification (≥grade III) and Esophagectomy Complications Consensus Group (ECCG) criteria. |
Contacts
CONTACTYan Zheng, M.D./Ph.D
CONTACTMing Song
Outcome results
None listed