Chronic Immune-Mediated Diarrhea and Colitis Associated With Prolonged Survival in Patients Treated With ICIs

Use of proton pump inhibitors (PPIs) is a risk factor for chronic immune-mediated diarrhea and colitis (IMDC) in patients with cancer treated with immune checkpoint inhibitors (ICIs), according to results of a retrospective analysis reported in the Journal of the National Comprehensive Cancer Network.

Immune-mediated diarrhea and colitis is a common adverse effect of ICI therapy. The severity of this immune-related adverse effect can range from mild diarrhea that is self-limiting to a condition characterized by life-threatening complications, including perforation of the bowel. In addition, IMDC can have a limited course (acute IMDC) or may exist for long-term periods (chronic IMDC).

Although previous studies identified an association between the occurrence of IMDC and prolonged survival in patients with cancer treated with ICI therapy, less is known about the impact of chronic IMDC on survival or its risk factors.

This study included consecutive, adult patients with cancer who developed grade 2 or higher diarrhea/colitis while undergoing treatment with ICIs at the University of Texas MD Anderson Cancer Center in Houston, Texas, between January 2018 and October 2019. Another inclusion criterion was immunosuppressive therapy with steroids, infliximab, or vedolizumab as part of the management of IMDC. Exclusion criteria included presence of inflammatory bowel disease, as well as other concurrent gastrointestinal disorders.

Patient categorization was according to whether they experienced acute or chronic IMDC. Presence of the condition for an overall duration of more than 3 months distinguished chronic IMDC from acute IMDC. In addition, chronic IMDC was further characterized as persistent symptomatic, recurrent (recurrence of symptoms following a symptom-free period of 1 month or longer), and persistent histologic IMDC, with the absence of clinical symptoms a characteristic of the latter category.

Of the 88 patients included in the study, 43 had chronic IMDC and 45 patients had acute IMDC. At baseline, the median age was 66 years for patients with chronic IMDC and 65 years for those with acute IMDC. Most patients had solid tumor cancers, with genitourinary cancer and melanoma representing the most common malignancies in both patient subgroups.

Risk factors for chronic IMDC identified on univariate analysis included use of PPI (odds ratio [OR], 3.96; P =.026), duration of IMDC symptoms (OR, 1.05; P <.001), duration of hospitalization from initial episode (OR, 1.07; P =.043), histologic features of chronic active colitis (OR, 4.8; P =.025) or microscopic colitis (OR, 5.0; P =.045), and a delay in selective immunosuppressive therapy administration for IMDC (OR, 1.06; P =.047). On multivariate analysis adjusting for a range of confounding factors, histologic evidence of chronic active or microscopic colitis was independently associated with chronic IMDC (OR, 4.54; P =.031).

Regarding use of PPIs as a risk factor for chronic IMDC, the study investigators hypothesized, “Our findings resulted from the known influence of this class of routinely used medications on the gut microbiota: specifically, the increased risk of enteric infections, bacterial translocation, and the pathogenesis of microscopic colitis (one of the histologic variants of IMDC).”

Another key of finding this study was that the percentage of patients with evidence of cancer progression at the time that IMDC developed was significantly lower in those with chronic (14%) compared with acute IMDC (33%; P =.019), and this difference was maintained at last follow-up (30% vs 51%; P =.002). For patients with chronic IMDC, multivariate analysis showed use of infliximab-based therapy compared with vedolizumab (OR, 5.10; P =.004) was independently associated with cancer progression.

Regarding the latter finding, the study investigators noted, “Vedolizumab treatment constituted the bulk of the [selective immunosuppressive therapies] used in our study, which may serve as a protective factor because it mitigates the antitumor effect of ICIs to a lesser extent than infliximab without increasing the risk of secondary malignancies in vulnerable patients.”

At a median clinical follow-up of 11 months, overall survival was significantly longer for patients with chronic vs acute IMDC (P =.035), those who received 3 or more vs 2 or fewer doses of selective immunosuppressive therapy (P =.018), patients with recurrent vs persistent symptomatic chronic IMDC (P =.036), and those with persistent histologic vs persistent symptomatic chronic IMDC (P =.041).

In their concluding remarks, the study investigators commented that chronic IMDC “likely reflects a prolonged immune checkpoint inhibitor effect and is associated with better cancer outcome and overall survival.”

However, “future larger-scale studies are warranted to clarify the predictive value of histologic features in chronic IMDC and outcomes related to cancer treatment,” they added.

Disclosures: One author declared affiliation with and receipt of research funding from the pharmaceutical industry. Please refer to the original article for a full list of disclosures.

Reference

Zou F, Abu-Sbeih H, Ma W, et al. Association of chronic immune-mediated diarrhea and colitis with favorable cancer response. J Natl Compr Canc Netwk. Published online December 14, 2020.  doi:10.6004/jnccn.2020.7647