Gastrointestinal and Hepatic Complications of Immunotherapy: Current Management and Future Perspectives

Checkpoint inhibitor (CPI) immunotherapy has transformed the treatment of multiple cancers over the past decade, leading to durable remissions, but also to severe inflammatory toxicities. These toxicities, termed immune-related adverse events (irAEs), can affect any organ system in the body, but commonly induce inflammation in barrier organs. Gastrointestinal (GI) and hepatic irAEs are among the most frequent and most severe from contemporary immunotherapies, with inflammation in the colon and or small intestines (entero)colitis as the single most common GI irAE. The aim of this review is to describe the evidence supporting our current understanding of CPI enterocolitis and hepatitis, as well as the management of these entities.

Although most patients who develop enterocolitis recover without long-term GI sequelae, enterocolitis is still an important reason for treatment discontinuation, which, in patients with metastatic cancer, can be a life-threatening outcome. At present, we have almost no prospective, randomized data regarding the management of CPI enterocolitis, and current management algorithms are based on expert opinion and small retrospective studies with a high likelihood of bias. Retrospective studies have defined colonic ulceration as a predictor of colitis responsiveness to corticosteroids, and have defined microscopic colitis as a subtype of CPI enterocolitis with a distinct treatment response. Corticosteroids appear to be effective for 60-70% of patients with CPI enterocolitis, with about a third of patients requiring escalation to a biologic agent such as infliximab or vedolizumab. Yet proper sequencing of these treatments to minimize risk and maximize treatment benefit has not been established, and we do not know how treatment of colitis influences cancer outcomes. CPI enterocolitis and hepatitis are important causes of treatment interruption and discontinue, and significant morbidity in patients undergoing immunotherapy. As guidelines for diagnosis and management rely heavily on expert opinion, we have an urgent need for randomized and prospective trials that use both colitis and cancer outcomes to determine optimal management strategies.