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Neoadjuvant Chemoradiotherapy Versus Neoadjuvant Immunochemotherapy for Resectable Esophageal Cancer: A Target Trial Emulation Study (TTE-ESCC)

17 augustus 2026 bijgewerkt door: YanZheng,MD, Henan Cancer Hospital

A Virtual Randomized Controlled Trial Comparing Neoadjuvant Chemoradiotherapy Versus Neoadjuvant Immunochemotherapy for Resectable Esophageal Cancer Based on Real-World Data: A Target Trial Emulation Study Protocol

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.

Studie Overzicht

Toestand

Nog niet aan het werven

Conditie

Interventie / Behandeling

Gedetailleerde beschrijving

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.

Studietype

Observationeel

Inschrijving (Geschat)

400

Contacten en locaties

In dit gedeelte vindt u de contactgegevens van degenen die het onderzoek uitvoeren en informatie over waar dit onderzoek wordt uitgevoerd.

Studiecontact

Studie Contact Back-up

Deelname Criteria

Onderzoekers zoeken naar mensen die aan een bepaalde beschrijving voldoen, de zogenaamde geschiktheidscriteria. Enkele voorbeelden van deze criteria zijn iemands algemene gezondheidstoestand of eerdere behandelingen.

Geschiktheidscriteria

Leeftijden die in aanmerking komen voor studie

  • Volwassen
  • Oudere volwassene

Accepteert gezonde vrijwilligers

Nee

Bemonsteringsmethode

Niet-waarschijnlijkheidssteekproef

Studie Bevolking

The study population consists of patients with locally advanced esophageal squamous cell carcinoma (ESCC) diagnosed at Henan Cancer Hospital between January 2013 and December 2025. Eligible patients are those who meet the inclusion criteria and initiated either neoadjuvant chemoradiotherapy (nCRT) or neoadjuvant immunochemotherapy (nICT) within 180 days after Time Zero. Patients are identified from electronic health records (EHR) including medical records, pathology reports, imaging reports, and prescription systems.

Beschrijving

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.

Studie plan

Dit gedeelte bevat details van het studieplan, inclusief hoe de studie is opgezet en wat de studie meet.

Hoe is de studie opgezet?

Ontwerpdetails

Cohorten en interventies

Groep / Cohort
Interventie / Behandeling
Neoadjuvant Immunochemotherapy (nICT) Group
Patients who initiated neoadjuvant immunochemotherapy (PD-1 inhibitor combined with platinum-based chemotherapy) within 180 days after Time Zero. Treatment includes PD-1 inhibitors (e.g., camrelizumab, sintilimab, toripalimab, tislelizumab) combined with paclitaxel/nab-paclitaxel and cisplatin/carboplatin, planned for 2-4 cycles, followed by surgery when feasible.
Straling: Radiotherapy
Concurrent radiotherapy administered as part of neoadjuvant chemoradiotherapy, typically 41.4-50.4 Gy in fractionated doses, combined with platinum-based chemotherapy.
Geneesmiddel: Platinum-based Chemotherapy
Platinum-based chemotherapy administered as part of neoadjuvant treatment, combined with either concurrent radiotherapy (nCRT) or PD-1 inhibitors (nICT).
Neoadjuvant Chemoradiotherapy (nCRT) Group
Patients who initiated neoadjuvant chemoradiotherapy (platinum-based chemotherapy with concurrent radiotherapy) within 180 days after Time Zero. Radiotherapy is typically administered at 41.4-50.4 Gy in fractionated doses, with concurrent platinum-based chemotherapy, followed by surgery when feasible.
Geneesmiddel: Platinum-based Chemotherapy
Platinum-based chemotherapy administered as part of neoadjuvant treatment, combined with either concurrent radiotherapy (nCRT) or PD-1 inhibitors (nICT).
Geneesmiddel: PD-1 Inhibitor
PD-1 inhibitors administered as part of neoadjuvant immunochemotherapy, combined with platinum-based chemotherapy for 2-4 cycles.

Wat meet het onderzoek?

Primaire uitkomstmaten

Uitkomstmaat
Maatregel Beschrijving
Tijdsspanne
Overall Survival (OS)
Tijdsspanne: 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.
From Time Zero up to 10 years

Secundaire uitkomstmaten

Uitkomstmaat
Maatregel Beschrijving
Tijdsspanne
Event-Free Survival (EFS)
Tijdsspanne: 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.
From Time Zero up to 10 years
Pathological Complete Response (pCR) Rate
Tijdsspanne: 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.
At the time of surgery
Tumor Regression Grade (TRG)
Tijdsspanne: At the time of surgery
Tumor regression grade assessed according to Mandard criteria or Chinese standard (TRG 0-3) on postoperative pathological examination.
At the time of surgery
R0 Resection Rate
Tijdsspanne: At the time of surgery
R0 resection rate is defined as the proportion of patients achieving microscopically margin-negative resection on postoperative pathological examination.
At the time of surgery
Incidence of Treatment-Related Adverse Events
Tijdsspanne: 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.
From treatment initiation through 90 days after treatment completion
Incidence of Postoperative Complications
Tijdsspanne: 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.
From surgery through 90 days postoperatively

Medewerkers en onderzoekers

Hier vindt u mensen en organisaties die betrokken zijn bij dit onderzoek.

Sponsor

Henan Cancer Hospital

Studie record data

Deze datums volgen de voortgang van het onderzoeksdossier en de samenvatting van de ingediende resultaten bij ClinicalTrials.gov. Studieverslagen en gerapporteerde resultaten worden beoordeeld door de National Library of Medicine (NLM) om er zeker van te zijn dat ze voldoen aan specifieke kwaliteitscontrolenormen voordat ze op de openbare website worden geplaatst.

Bestudeer belangrijke data

Studie start (Geschat)

20 augustus 2026

Primaire voltooiing (Geschat)

31 december 2027

Studie voltooiing (Geschat)

20 augustus 2028

Studieregistratiedata

Eerst ingediend

17 augustus 2026

Eerst ingediend dat voldeed aan de QC-criteria

17 augustus 2026

Eerst geplaatst (Werkelijk)

21 augustus 2026

Updates van studierecords

Laatste update geplaatst (Werkelijk)

21 augustus 2026

Laatste update ingediend die voldeed aan QC-criteria

17 augustus 2026

Laatst geverifieerd

1 augustus 2026

Meer informatie

Termen gerelateerd aan deze studie

Trefwoorden

Aanvullende relevante MeSH-voorwaarden

Andere studie-ID-nummers

  • 2026-366

Plan Individuele Deelnemersgegevens (IPD)

Bent u van plan om gegevens van individuele deelnemers (IPD) te delen?

NEE

Informatie over medicijnen en apparaten, studiedocumenten

Bestudeert een door de Amerikaanse FDA gereguleerd geneesmiddel

Nee

Bestudeert een door de Amerikaanse FDA gereguleerd apparaatproduct

Nee

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