Efficacy and Safety of Neoadjuvant Chemotherapy with or without Immune Checkpoint Inhibitors for Resectable Esophageal Squamous Cell Carcinoma: a Meta-analysis of Randomized Controlled Trials.

Background: Recently, there has been significant attention focused on neoadjuvant immune checkpoint inhibitors combined with chemotherapy (NICT) for the treatment of resectable esophageal squamous cell carcinoma (ESCC). In order to assess the efficacy and safety of this innovative combination in relation to traditional neoadjuvant chemotherapy (NCT), we performed a systematic meta-analysis of randomized controlled trials (RCTs).

Methods: A comprehensive review of the literature was performed across Embase, Cochrane Library, Web of Science, and PubMed, covering the period from their inception to May 2, 2025, to identify appropriate RCTs. The primary outcomes included pathological complete response (pCR) and major pathological response (MPR), R0 resection rate, event-free survival (EFS), and overall survival (OS). The adverse events (AEs) was identified as the secondary outcome.

Results: A total of five RCTs involving 755 patients were included for the final analysis. The result showed that compared with the NCT group, the NICT group for resectable ESCC significantly improved pCR (RR = 2.51; 95% CI: 1.64-3.84; P < 0.01) and MPR (RR = 1.83; 95% CI: 1.16-2.88; P = 0.01). The pooled rates of pMR and MPR in the NICT group were significantly higher compared to the NCT group, with values of 23.2% versus 7.7% and 42.8% versus 25.8%. The R0 resection rate was comparable between the two groups (RR = 1.00; 95% CI: 0.99-1.02; P = 0.63) with pooled rates observed to be 100% for the NICT group and 98.2% for the NCT group. However, only one phase III RCT reported survival outcomes that demonstrated improved 1-year EFS rate (HR = 0.62, 95% CI: 0.39-1.00, P = 0.05) and 1-year OS rates (HR = 0.48, 95% CI: 0.24-0.97, P = 0.037) in the NICT group. Nevertheless, the analysis revealed no statistically significant differences in grade ≥ 3 TRAEs across the treatment strategies (RR = 1.03; 95% CI: 0.80-1.32; P = 0.82), with pooled rates recorded at 34.4% for the NICT group and 33.1% for the NCT group. The pooled rates were observed to be 24.7% for all grade immune-related adverse events (irAEs) and 3.1% for grade ≥ 3 irAEs.

Conclusions: Combining ICIs with chemotherapy as a neoadjuvant approach shows significant therapeutic promise in treating resectable ESCC, exhibiting favorable efficacy and acceptable safety profiles in the Chinese population. Nonetheless, more additional large-scale phase III RCTs are warranted for further validation of these preliminary outcomes.