Efficacy and safety of radiotherapy/chemoradiotherapy combined with immune checkpoint inhibitors for locally advanced stages of esophageal cancer: A systematic review and meta-analysis

Background: Radiotherapy (RT)/ Chemoradiotherapy (CRT) are important treatments for all stages of esophageal cancer (EC). The combination of immune checkpoint inhibitors (ICIs) with RT/CRT seems to be promising avenue for the treatment of EC. Therefore, a systematic review and metaanalysis was performed in order to assess the safety and efficacy of RT/CRT and ICI combination therapy for EC patients. Methods: PubMed and several other databases were searched (according to specific criteria) to find relevant studies published prior to the 31(st) of December 2021. Results: 1962 articles were identified for screening, and six trials containing 668 patients were identified and pooled to determine the one- and two-year overall survival (OS), which were 84.5% (95% confidence interval (CI): 69.9%-100%) and 68.3% (95% CI: 49.0%-95.1%), respectively. Additionally, the rate of pooled grade 3-5 adverse reactions was 41.0% (95% CI: 31.2%-51.2%). The rate of specific grade 3-5 adverse reactions are as follows: lymphopenia (36.8%-60%), esophagitis (20%), anastomotic leakage (18%), esophageal fistula (10%), pain (10%), leukopenia (5.3%-10%), esophageal hemorrhage (2.5%-5%), chyle leakage (3%), fatigue (5%), cough ( 2.7%-5%), diarrhea (2.7%), pulmonary embolism (2.5%) and allergic reaction (2.5%). The pooled rate of pneumonitis of grade 3-5 and grade 1-5 was 0.8% (95% CI: 0.1%-0.16%, I-2: 0%) and 5.4% (95% CI: 2.0%-14.2%, I-2: 82%). For thoracic complication, esophagitis was 63.6% (95% CI: 42.4%-80.6%), which appeared to be more frequent with the combination of ICIs to RT/CRT (12%-37.7%). Other thoracic complications include esophageal hemorrhage (2.5%-10%), esophageal fistula (6%-10%) and anastomotic leakage (6%-21%). Additionally, some of the trials did not report cardiac related adverse reactions. The subgroup analyses also revealed that the pooled rate patients with grade 3-5 pneumonitis was higher for CRT/RT with concurrent and sequential ICI treatment (1.9%) than other groups (0.8%). Conclusion: This study suggests that the addition of ICIs to RT/CRT for EC patients may be both safe and feasible. However, larger randomized studies are needed to confirm these results.

Automated summary

This study evaluated the safety and efficacy of combining ICIs with RT/CRT for EC patients, showing promising results in terms of one- and two-year overall survival rates but with a higher incidence of grade 3-5 adverse reactions. Additional large randomized studies are required to confirm these findings.