Background Concurrent chemoradiotherapy (CCRT) remains the standard treatment for unresectable esophageal cancer (EC). However, the clinical benefits of combining immunotherapy with CCRT for unresectable EC remain controversial. Therefore, we conducted a systematic review and meta-analysis to evaluate the potential benefits of different immunotherapy strategies added to CCRT in patients with unresectable EC. Methods We employed single-arm, pairwise and network meta-analysis (NMA) methods to analyze the overall survival (OS), progression-free survival (PFS), objective response rate (ORR) and safety of several combined treatment strategies based on CCRT. Results 30 single-arm trials and 39 controlled trials involving a total of 9648 participants were included. Compared with CCRT alone, both induction immunochemotherapy plus CCRT (ICT-CCRT) and CCRT plus consolidation immunotherapy (CCRT-IO) significantly improved OS in pairwise meta-analyses (HR 0.52, 95% CI 0.39–0.71, I²= 0.0%; HR 0.77, 95% CI 0.65–0.90, I²= 0.0%, respectively). In the NMA, only ICT-CCRT showed a significant OS benefit (HR 0.75, 95% CI 0.64–0.88), whereas CCRT-IO did not. For PFS, CCRT-IO consistently prolonged PFS compared with CCRT alone in both pairwise meta-analyses (HR 0.74, 95% CI 0.64-0.85, I²=0.0%) and NMA (HR 0.78, 95% CI 0.76–0.99). In contrast, ICT-CCRT demonstrated a significant PFS benefit only in the NMA (HR 0.84, 95% CI 0.71–0.99), but not in the pairwise analysis. Notably, ICT-CCRT ranked first in the NMA for both OS and PFS. Conclusions In conclusion, compared with CCRT alone, ICT-CCRT significantly improves OS and shows a potential PFS benefit. CCRT-IO improves OS only in pairwise analyses but consistently improves PFS across analyses. Currently, sufficient randomized controlled trials are lacking to validate the efficacy and determine the optimal timing and sequence. Systematic review registration https://www.crd.york.ac.uk/prospero/ , identifier CRD420261364669.
Fan et al. (2026) studied this question.