The survival impact of upfront or sequential chemoradiotherapy in locally advanced esophageal squamous cell carcinoma

The treatment of locally advanced unresectable esophageal squamous cell carcinoma (ESCC) is a clinical challenge with limited therapeutic consensus. The immune checkpoint inhibitor (ICI)-based conversion therapies emerged as an option besides definitive chemoradiotherapy (DCRT). Especially for those returned to DCRT after unsuccessful conversion therapy (salvage), the clinical outcome remained overlooked when compared with upfront DCRT.

This study retrospectively analyzed the clinical data of patients with locally advanced ESCC who had received DCRT either as upfront or salvage therapy from 2018 to 2024. Overall survival (OS), event-free survival (EFS), progression-free survival (PFS) and objective remission rate (ORR) were assessed.

Totally 848 patients from 3 medical centers were screened, and 91 patients were included. The overall objective remission rate (ORR) was achieved in 28 cases (68.29%) in the salvage group, higher than the upfront group (26.00%, P < 0.001). Following conversion therapy, 11 patients achieved an ORR of 26.83%. After completing salvage DCRT, CR was observed in 2 patients (4.88%) and PR in 26 patients (63.41%). PFS was 20.3 months (95% CI: 11.6-28.9 months) and 6.4 months in the salvage and upfront group (HR 0.36, 95%CI: 0.19-0.66; P = 0.001). The median OS for the entire cohort was 24.6 months (95% CI 19.5-29.8 months), with a median OS of 42.2 months in the salvage group compared with 15.9 months in the upfront group (HR 0.39, 95% CI: 0.22-0.69; P = 0.001). The salvage group showed significantly longer OS than the upfront group, with 1-year OS rates of 95.1% and 56.9%, and 2-year OS rates of 68.8% and 36.6%, respectively.

The salvage DCRT significantly improved the survival outcomes of patients with locally advanced unresectable ESCC over upfront DCRT. These findings support the clinical feasibility of this strategy and underscore the need for prospective randomized trials to validate its role as a new treatment paradigm.