Comparative outcomes of neoadjuvant immunochemotherapy versus neoadjuvant chemoradiotherapy in locally advanced thoracic esophageal squamous cell carcinoma: a target trial emulation.

Background: Neoadjuvant chemoradiotherapy (NCRT) is standard for locally advanced esophageal squamous cell carcinoma (ESCC), while neoadjuvant immune-chemotherapy (NICT) is a promising alternative. This study compared pathological response and long-term survival between NICT and NCRT followed by surgery using a target trial emulation framework. Methods: We emulated a target trial in 288 consecutive patients with locally advanced thoracic ESCC who underwent neoadjuvant therapy and esophagectomy between March 2018 and December 2022. Eligible patients were aged 18-80 years and had clinical stage cT1N+M0 or cT2-4aN0-3M0 disease. The primary endpoints were overall survival (OS) and disease-free survival (DFS), with cancer-specific survival (CSS) and recurrence-free survival (RFS) as additional endpoints. Baseline characteristics were balanced after inverse probability of treatment weighting (IPTW). Bootstrap-weighted Cox models were applied to small subgroups for exploratory analyses. Results: Median follow-up was 49.3 months. Both pre- and post-IPTW, the NCRT group experienced a significantly higher incidence of severe (grade 3-4) myelosuppression compared with NICT (P < 0.001), whereas no significant differences were observed between the two cohorts in surgery-related outcomes. In the unadjusted cohort, patients receiving NCRT achieved superior pathological responses, with higher rates of pathological complete response (pCR) and tumor regression grade (TRG). After IPTW, all pathologic endpoints were well balanced except for TRG 0, which remained marginally different (P = 0.051, SMD = 0.376). Before IPTW, there were no significant differences between NCRT and NICT in OS or DFS (OS: HR = 1.08, 95% CI 0.72-1.63, P = 0.701; DFS: HR = 1.02, 95% CI 0.70-1.48, P = 0.915). Although the KM curves for CSS and RFS showed a separation trend, the differences were not significant (CSS: HR = 0.74, 95% CI 0.44-1.23, P = 0.245; RFS: HR = 0.72, 95% CI 0.46-1.14, P = 0.163). After IPTW weighting, OS and DFS remained comparable between the two groups, whereas NICT demonstrated advantages in RFS (HR = 0.47, 95% CI 0.27-0.82, P = 0.008) and CSS (HR = 0.49, 95% CI 0.26-0.89, P = 0.020). Multivariable analysis identified higher ypN stage as independent predictors of worse OS and DFS. Lower ypN stage and receipt of NICT were associated with better CSS and RFS. Conclusions: Among patients with locally advanced ESCC receiving neoadjuvant therapy, NCRT was associated with superior pathological response but also a higher risk of severe myelosuppression. After IPTW adjustment, NICT and NCRT showed comparable OS and DFS, while NICT was associated with significantly better RFS and CSS. These findings suggest that NICT may be a feasible alternative to NCRT in this population.