Upfront or deferred radiotherapy combined with chemoimmunotherapy for inoperable oesophageal squamous cell carcinoma: a target trial emulation in China.

Background: Radiotherapy (RT) is a curative treatment modality for inoperable oesophageal squamous cell carcinoma (ESCC). However, for patients with ESCC receiving first-line chemoimmunotherapy (CIT), the appropriate sequence of RT relative to CIT remains unclear. Methods: This multicentre retrospective cohort study adopted a target trial emulation framework to compare survival outcomes between groups. Time zero was defined as the start date of the initial treatment. Simulated randomisation, treatment initiation, and follow-up commenced concurrently at time zero. Patients with inoperable ESCC (including locally advanced disease and supraclavicular lymph node metastasis) who received first-line CIT between June 2018 and December 2023 were enrolled from eight large-scale hospitals across China. Stabilised inverse probability of treatment weighting was applied to minimise baseline imbalances. Prespecified grace periods were introduced to classify participants into two groups: Upfront-RT and Deferred-RT. Immortal time bias was addressed using the clone-censor-weight method. Effect sizes were estimated using the absolute rate difference (RD) in overall survival (OS) and progression-free survival (PFS), as well as the cumulative risk ratio (RR) for death or disease progression. This study was registered with the Chinese Clinical Trial Registry (Identifier: ChiCTR2500111871). Findings: A total of 1242 participants (median [IQR] age, 69 [62-75] years; 1004 [80.8%] male) were included in the study. With a grace period of 42 days in the primary analysis, the Deferred-RT group had improved median OS (44.1 months vs 33.4 months; adjusted HR, 0.699 [95% CI, 0.580-0.843]), and longer median PFS (21.1 months vs 16.0 months; adjusted HR, 0.760 [95% CI, 0.645-0.895]) compared with the Upfront-RT group. After correcting baseline imbalances and immortal time bias, patients in the Upfront-RT group exhibited a reduction in the 3-year OS rate (41.9% vs 57.5%; RD, -15.6%; 95% CI, -26.3% to -5.6%) and PFS rate (22.4% vs 33.8%; RD, -11.4%; 95% CI, -19.2% to -4.2%), along with an increase in 3-year cumulative risk ratios for death (RR, 1.368; 95% CI, 1.108-1.637) and disease progression (RR, 1.172; 95% CI, 1.056-1.295), compared with those in the Deferred-RT group. Sensitivity and subgroup analyses corroborated these findings. The median RT dose was 60.0 (IQR, 50.4-60.0) Gy in the Upfront-RT group and 50.4 (IQR, 0-60.0) Gy in the Deferred-RT group. The incidence of severe treatment-related oesophageal fistula was 9.0% (36 cases) and 4.8% (40 cases), respectively. Interpretation: In this retrospective study with target trial emulation, first-line CIT plus deferred RT was associated with improved survival outcomes compared with upfront RT plus first-line CIT for patients with inoperable ESCC. However, given the inherent limitations of observational data and the lack of adjustment for time-varying covariates, the observed associations should be interpreted with caution as exploratory findings. Future prospective randomised controlled trials are needed to confirm these results. Funding: National Natural Science Foundation of China, Anhui Provincial Health Science and Technology Project, Health Research Project of Anhui Province.