Risk of immune-related diarrhea with PD-1/PD-L1 inhibitors in different cancer types and treatment regimens

Objective: To compare the incidence and severity of diarrhea among different tumor types and treatment regimens, and also compared with CTLA-4 inhibitors in randomized controlled trials. Methods: MEDLINE, PMC database and EMBASE were retrieved until December 2018. Studies were eligible if they were randomized controlled trials and included participants undergoing PD-1/PD-L1 inhibitors for cancer, measured a treatment side effect of diarrhea, and reported quantitative data. The risks of diarrhea in PD-1/PD-L1 inhibitors were compared among different treatment regimens. Results: Totally 21 studies involving 11554 patients were included for meta-analysis. For all-grade diarrhea, the risk after the PD-1/PD-L1 inhibitors plus CTLA-4 inhibitor combination was 1.90 times significantly higher than that of monotherapy, and the risk was 0.69 and 0.60 times significantly lower than that of monotherapy compared with chemotherapy and ipilimumab. The incidence of diarrhea was not significantly different between PD-1/PD-L1 inhibitor monotherapy versus placebo or between low-doses versus high-doses. For high-grade (grade ≥ 3) diarrhea, the risk after the PD-1/PD-L1 inhibitors plus CTLA-4 inhibitor combination was 3.29 times significantly higher than that of monotherapy, the risk in PD-1/PD-L1 inhibitors monotherapy was 0.50 and 0.38 times significantly lower than chemotherapy and ipilimumab respectively. No significant difference was found in the incidence of diarrhea between PD-1/PD-L1 inhibitor monotherapy versus placebo or between low-doses versus high-doses whether in all-grade or high-grade group. Conclusions: PD-1/PD-L1 inhibitors have a lower risk of developing diarrhea than chemotherapy and CTLA-4 inhibitor. There is no direct relationship between the dose of PD-1/PD-L1 inhibitors and the risk of developing diarrhea.