Immune Checkpoint Inhibitor–associated Diarrhea and Colitis: A Systematic Review and Meta-analysis of Observational Studies

Abstract

Immune checkpoint inhibitors (ICIs) have transformed the management of advanced malignancies but are associated with diarrhea and colitis. The objective of our systematic review and metaanalysis was to determine the incidence and outcomes of ICIassociated diarrhea and colitis. Bibliographic databases were searched through August 13, 2019, for observational studies of ICI therapy reporting the incidence and/or treatment of diarrhea or colitis. The primary outcome was ICI-associated diarrhea and colitis. Meta-analyses were performed with random-effects models. Twentyfive studies (N = 12,661) were included. All studies had a high risk of bias in at least 1 domain. The overall incidence of diarrhea/colitis was 12.8% [95% confidence interval (CI), 8.8-18.2, I 2 = 96.5]. The incidence was lower in patients treated with anti-programmed cell death 1/programmed death-ligand 1 (4.1%, 95% CI, 2.6-6.5) than in those treated with anti-cytotoxic T-cell lymphocyte-associated antigen 4 (20.1%, 95% CI, 15.9-25.1). The remission of diarrhea and/or colitis was higher in patients treated with corticosteroids plus biologics (88.4%, 95% CI, 79.4-93.8) than in those treated with corticosteroids alone (58.3%, 95% CI, 49.3-66.7, Q = 18.7, P < 0.001). ICI were permanently discontinued in 48.1% of patients (95% CI, 17.8-79.1). ICI were restarted after temporary interruption in 48.6% of patients (95% CI, 18.2-79.4) of whom 17.0% (95% CI, 6.4-30.0) experienced recurrence. Real-world incidence of ICI-associated diarrhea/colitis exceeds 10%. These events lead to permanent ICI discontinuation in just over 50% of patients, while <20% have recurrence of symptoms if ICI are resumed. Further studies are needed to identify patients who would benefit from early treatment with biologics as well as appropriate patients to resume ICI therapy.

Severe immune checkpoint inhibitor-associated gastritis: A case series and literature review

“…Our study included three patients who developed irAE gastritis with ICI monotherapy. Incidence of irAE colitis was shown to be higher in the com-bination therapy group than in the monotherapy group [21]. In our study, three patients developed irAE gastritis with ICI monotherapy, while one patient developed it with ICI combination therapy.…”

The multifaceted roles of common gut microbiota in immune checkpoint inhibitor-mediated colitis: From mechanism to clinical application

“…IMC is a common irAE and mortality rate of about 5%which sometimes terminates the treatment process of cancer patients ( 2 ). Meta-analysis of 629 patients from 26 studies showed that ICIs was permanently discontinued in 52.4% of patients with IMC ( 34 ). Colitis accounts for 37% of deaths caused by irAEs ( 35 ).…”

Moderate Colitis Not Requiring Intravenous Steroids Is Associated with Improved Survival in Stage IV Melanoma after Anti-CTLA4 Monotherapy, But Not Combination Therapy

“… 21 A recent meta-analysis of immune-related diarrhea/colitis after ICI found that ICI was terminated permanently in about 50% of patients, and that in those who resumed, about 20% had a recurrence of symptoms, but oncologic outcomes were not analyzed. 22 Given the paucity of prognostic information available to help guide decision-making regarding ICI termination and resumption after irAE development, we analyzed patients with stage IV melanoma treated consecutively at our institution with dual checkpoint blockade or single-agent anti-CTLA4 to determine the impact of both moderate and severe colitis on survival.…”