The Risk of Diarrhea and Colitis in Patients With Advanced Melanoma Undergoing Immune Checkpoint Inhibitor Therapy: A Systematic Review and Meta-Analysis

Abstract

Checkpoint inhibitors are a first-line therapy for advanced melanoma, though their use is limited by diarrhea and colitis. The aim of our study was to determine the risk of these toxicities associated with immunotherapy in advanced melanoma. Electronic databases were searched through June 2017 for prospective studies reporting the risk of diarrhea and colitis in advanced melanoma treated with anti-programmed death-1 (PD-1) or anti-cytotoxic T-lymphocyte antigen-4 (CTLA-4) inhibitors. Standardized definitions assessed the grade of diarrhea and colitis. Pooled incidence and weighted relative risk estimates with 95% confidence intervals (CI) were estimated using random effects model. Eighteen studies were included: 6 studies (1537 patients) with PD-1 inhibitors and 15 studies (3116 patients) with CTLA-4 inhibitors. The incidence of all-grade diarrhea was 13.7% (95% CI, 10.1%-17.2%) for anti-PD-1 and 35.4% (95% CI, 30.4%-40.5%) for anti-CTLA-4. The incidence of all-grade colitis was 1.6% (95% CI, 0.7%-2.4%) for anti-PD-1, and 8.8% (95% CI, 6.1%-11.5%) for anti-CTLA-4. When PD-1 inhibitors were compared directly with CTLA-4 inhibitors, the relative risk of all-grade diarrhea was 0.58 (95% CI, 0.43-0.77), and the relative risk of all-grade colitis was 0.16 (95% CI, 0.05-0.51). The rate of therapy discontinuation was numerically higher for anti-CTLA-4 therapy compared with anti-PD-1 therapy. Finally, 2 studies compared combination immunotherapy with anti-CTLA-4 therapy alone. The relative risk of developing all-grade diarrhea and colitis with combination therapy was 1.31 (95% CI, 1.09-1.57) and 1.21 (95% CI, 0.73-1.99), respectively. Diarrhea and colitis are frequent toxicities associated with checkpoint inhibitors, and seem to be most common with CTLA-4 inhibitors.

Management of Immunotherapy-Related Toxicities, Version 1.2019, NCCN Clinical Practice Guidelines in Oncology

“…29,144 The highest rates of ICI-mediated GI irAEs have been seen with the addition of a PD-1/PD-L1 inhibitor to CTLA-4 blockade. [145][146][147] Retrospective case reviews suggest that symptom grade may not correlate with colitis severity as seen by endoscopy and histology. 66,148 Systematic reviews and meta-analyses have examined the incidence of specific GI irAEs in patients with solid tumors who received ICI therapy.…”

“…Rates of discontinuation were higher among patients taking anti-CTLA-4 agents. 146 Corticosteroids are typically the first line of treatment of GI irAEs. In retrospective reviews of patients with ICI-related enterocolitis, symptoms resolved with corticosteroid treatment in approximately 40% to 60% of individuals.…”

Immune checkpoint inhibitor‐induced diarrhea: Clinicopathological study of 11 patients

“…ICI-induced diarrhea occurs in 10-30% of patients and <10% of patients develop severe colitis. [3][4][5][6][7]9 In the present cases series, we carried out a retrospective analysis of patients with ICI-induced diarrhea to clarify the clinicopathological characteristics of the disease.…”

Tipping the balance: inhibitory checkpoints in intestinal homeostasis

“…133,134 The incidence of diarrhea and colitis is 35.4 and 8.8%, respectively with CTLA-4 inhibitors and 13.7 and 1.6%, respectively for PD-1 inhibitors. 135,136 Combining CTLA-4 and PD-1 inhibitors may increase the risk of diarrhea but not colitis. 135,136 Colonic bowel perforation is the most common cause of fatal immune-related adverse events in patients who develop immunotherapy-induced colitis, but the incidence of life-threatening colon perforation is low (<1% of patients).…”

“…135,136 Combining CTLA-4 and PD-1 inhibitors may increase the risk of diarrhea but not colitis. 135,136 Colonic bowel perforation is the most common cause of fatal immune-related adverse events in patients who develop immunotherapy-induced colitis, but the incidence of life-threatening colon perforation is low (<1% of patients). 20 Thus, although blockade of co-inhibitory receptors is a promising new approach to improve tumor control, it can cause severe life-threatening immune-related adverse events, most often through a dysregulation of intestinal homeostasis.…”