Immune-checkpoint inhibitor-induced diarrhea and colitis in patients with advanced malignancies: retrospective review at MD Anderson

Abstract

BackgroundImmune checkpoint inhibitors (ICPIs) are gaining increasing popularity as an efficacious treatment for advanced malignancies. ICPI treatment can be complicated by diarrhea and colitis. Systemic steroids are the first line treatment. Infliximab is reserved for severe refractory cases. We aimed to assess the impact of ICPI-induced diarrhea and colitis and their immunosuppressive treatment on patients’ outcomes.MethodsThis retrospective analysis was conducted in 327 cancer patients who received ICPIs between 2011 and 2017. Patients with ICPI-induced toxicities in other organs were excluded. We collected data about patient demographics, clinical variables, and overall survival. We used descriptive analysis to compare different groups based on the occurrence and the treatment of diarrhea and colitis. Kaplan-Meier and log-rank test were used to estimate and compare overall survival durations between groups.ResultsDiarrhea was recorded in 117 (36%) patients; 79 (24%) of them required immunosuppressive treatment of either systemic corticosteroid without infliximab (n = 44) or with infliximab (n = 35). Caucasian ethnicity, melanoma, stage 3 cancer, and ipilimumab were predictors of colitis that requires immunosuppression. Patients who required immunosuppressants had better overall survival than those who did not require treatment for colitis or diarrhea (P < 0.001). Immunosuppression for diarrhea or colitis did not affect the overall survival significantly (P = 0.232), nor did the choice of treatment (corticosteroids with vs. without infliximab; P = 0.768). Diarrhea was an independent predictor of a favorable overall survival (P < 0.001), irrespective of treatment need (P = 0.003). We confirmed the same results in a subgroup analysis for patients with stage IV malignancies only. Patients who received long duration of steroid treatment (> 30 days) had numerically higher infection rate than those who received steroid for shorter duration (40.4 vs. 25.8%, P = 0.160). Likewise, long duration of steroid without infliximab was associated with increased risk of infection compared to short duration of steroid with infliximab (42.9% vs. 14.3%, P = 0.089).ConclusionsPatients with ICPI-induced diarrhea or colitis have improved survival outcomes. Diarrhea is an independent predictor of an improved survival regardless of treatment requirement. Immunosuppressive treatment for diarrhea did not significantly affect overall survival, however, infection rates were numerically higher among patients who received steroids for a long duration. Therefore, early non-steroid immunosuppressive therapy may ensure a more favorable overall outcome.

Three‐year follow‐up results from phase II studies of nivolumab in Japanese patients with previously treated advanced non‐small cell lung cancer: Pooled analysis of ONO‐4538‐05 and ONO‐4538‐06 studies

“…When the relationship between the occurrence of nivolumab‐induced irAEs and nivolumab efficacy was analyzed by irAE category, the occurrence of rash, endocrine disorders, and gastrointestinal toxicity was correlated with the ORR to nivolumab. The occurrence of these three toxicities has previously been correlated with the efficacy of anti‐PD‐1 antibodies, and the present data appear to support these findings.…”

A review of cancer immunotherapy toxicity

“…In a retrospective series that included 75 patients who had immune‐related enterocolitis, infliximab use was associated with a shorter time to symptom resolution and shorter duration of steroid use, and there was no decrease in overall survival . In another retrospective series, which included 117 patients treated with ICI who developed diarrhea, a steroid duration >30 days was associated with higher rates of infection compared with a shorter duration of steroid use with or without infliximab . In a retrospective series of the endoscopic and histologic features of ICI‐induced colitis, patients with ulcerations on colonoscopy were more likely to have steroid‐refractory colitis …”

“…43 In another retrospective series, which included 117 patients treated with ICI who developed diarrhea, a steroid duration >30 days was associated with higher rates of infection compared with a shorter duration of steroid use with or without infliximab. 44 In a retrospective series of the endoscopic and histologic features of ICI-induced colitis, patients with ulcerations on colonoscopy were more likely to have steroid-refractory colitis. 45 Vedolizumab, an anti-integrin α4β7 antibody with gut-specific effects, has been investigated for patients with steroid-dependent or refractory ICI-induced colitis.…”

Clinical diagnosis and treatment of immune checkpoint inhibitor‐associated adverse events in the digestive system

“…In patients with inadequate or no response to corticosteroids, dose escalation of steroids in time, and upgrading treatment to infliximab (IFX) or vedolizumab when necessary is recommended. Studies have shown that compared with long‐term steroid treatment, the therapy of short‐term steroids plus IFX reduces the risk of various opportunistic infections . Fecal microbiota transplant is reported to be valid in cases with GI irAEs refractory to steroids, IFX or vedolizumab …”

“…Studies have shown that compared with long-term steroid treatment, the therapy of short-term steroids plus IFX reduces the risk of various opportunistic infections. 17 Fecal microbiota transplant is reported to be valid in cases with GI irAEs refractory to steroids, IFX or vedolizumab. 18…”