Risk of colitis in immune checkpoint inhibitors and in chemotherapy/placebo for solid tumors: a systematic review and meta-analysis

BACKGROUND: We conducted a systematic review and meta-analysis in an attempt to evaluate the risk of colitis in immune checkpoint inhibitors (ICIs) and in chemotherapy/placebo for solid tumors. METHODS: Embase and PubMed were searched with specific keywords of our concern. Collected data were processed using Stata 14.0 and Review Manager 5.3. Odds ratios (ORs) of grade 1–5 and grade 3–5 colitis in treatment arms compared with control arms were pooled. RESULTS: A total of 11,226 patients from 20 phase 2/3 randomized controlled trials were included into this meta-analysis. Treatment strategies involving ICIs resulted in a significant increased risk of any grade colitis compared with chemotherapy/placebo (grade 1–5 colitis OR: 8.78, 95% CI: 5.88–13.12, P<0.001; grade 3–5 colitis OR: 10.82, 95% CI: 6.02–19.44, P<0.001). ICIs plus chemotherapy showed higher risk of colitis than placebo plus chemotherapy (grade 1–5 colitis OR: 12.85, 95% CI: 4.98–33.18, P<0.001; grade 3–5 colitis OR: 9.17, 95% CI: 3.31–25.41, P<0.001). ICIs monotherapy showed higher risk of colitis than placebo (grade 1–5 colitis OR: 11.98, 95% CI: 6.789–21.13, P<0.001; grade 3–5 colitis OR: 21.46, 95% CI: 7.80–59.04, P<0.001). When comparing risk of colitis among three ICIs, results suggested that CTLA-4 antibodies (grade 1–5 colitis OR: 13.43, 95% CI: 7.88–22.89, P<0.001; grade 3–5 colitis OR: 15.74, 95% CI: 7.34–33.78, P<0.001) tended to generate the highest risk of colitis and PD-1 antibodies (grade 1–5 colitis OR: 3.64, 95% CI: 1.87–7.06, P<0.001; grade 3–5 colitis OR: 4.56, 95% CI: 1.68–12.36, P=0.003) the lowest. Subgroup analyses between different tumor types showed that non-small-cell lung cancer (NSCLC) patients receiving ICIs treatment seemed to have the lowest risk of colitis (grade 1–5 colitis OR: 6.41, 95% CI: 2.26–18.21, P<0.001; grade 3–5 colitis OR: 5.64, 95% CI: 1.69–18.87, P=0.005). Publication bias was present in this study, but trim and fill analysis was done and confirmed the results were reliable. CONCLUSIONS: Among different treatment strategies for solid tumors, combination of ICIs and chemotherapy produces higher risk of colitis than ICIs monotherapy. CTLA-4 antibodies tended to generate highest risk of colitis, and PD-1 antibodies the lowest. Compared with melanoma and some other solid tumors, NSCLC patients receiving ICIs treatment were least likely to develop colitis of any grade.