The Efficacy of Immune-checkpoint Inhibitors in Combination with Definitive Chemoradiotherapy in Non-metastatic Esophageal SCC: A Systematic Review and Meta-analysis.

Background

Inoperable esophageal squamous cell carcinoma (ESCC) remains a challenging malignancy. Immune checkpoint inhibitors (ICIs) have shown activity in esophageal cancer. This systematic review evaluated the efficacy and safety of adding immune checkpoint inhibitors to definitive chemoradiotherapy (dCRT) in this setting.

Methods

A systematic search of PubMed, Scopus, and Embase was performed from database inception to February 10, 2026. Original studies enrolling adults with histologically confirmed ESCC treated with ICIs plus dCRT or definitive radiotherapy were eligible. Risk of bias was assessed using MINORS, and pooled analyses were performed using random-effects models.

Results

Seventeen studies including 4,800 patients met the inclusion criteria, of whom 1,659 patients received ICI as part of their definitive treatment. In comparative analyses, adding ICIs was associated with improved overall survival (OS) and progression-free survival (PFS) versus no ICI, with pooled hazard ratios of 0.61 (95% CI 0.49-0.76, p=0.003) and 0.62 (95% CI 0.50-0.77, p=0.003), respectively. Among patients receiving ICI-based treatment, at 2 years, pooled OS was 68% and pooled PFS was 48%. The pooled objective response rate was 75%.

Conclusions

The addition of ICIs to definitive radiotherapy-based treatment was associated with improved survival and antitumor activity in patients with inoperable ESCC, although toxicity remains clinically relevant. These findings support a promising role for this strategy, but the current evidence is limited by non-randomized study designs, heterogeneity, and geographic concentration. Prospective randomized studies are needed to define the optimal sequencing, patient selection, and safety profile of this approach.