Upfront or deferred radiotherapy combined with chemoimmunotherapy for inoperable oesophageal squamous cell carcinoma:...

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.

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).

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.

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.

National Natural Science Foundation of China, Anhui Provincial Health Science and Technology Project, Health Research Project of Anhui Province.