Diagnosis and management of toxicities of immune checkpoint inhibitors in hepatocellular carcinoma

Abstract

Immune checkpoint inhibitors (ICIs) have reshaped cancer therapy. ICIs enhance T cell activation through various mechanisms and may help reverse the exhausted phenotype of tumour-infiltrating lymphocytes. However, disrupting the key role that checkpoint molecules play in immune homeostasis may result in autoimmune complications. A broad range of immune-related adverse events (irAEs) involve almost every organ but mostly affect the skin, digestive system, lung, endocrine glands, nervous system, kidney, blood cells, and musculoskeletal system. They are usually manageable but can be life-threatening. The incidence of irAEs is not very different in patients with hepatocellular carcinoma (HCC) compared to other tumour types, although there is a trend towards a higher incidence of hepatic irAEs. HCC usually develops on a background of cirrhosis with associated systemic manifestations. Extrahepatic organ dysfunction in cirrhosis may cause signs and symptoms that overlap with irAEs or increase their severity. Available guidelines for the management of irAEs have not specifically considered the assessment of toxicities in the context of patients with liver cancer and cirrhosis. This review addresses the toxicity profile of ICIs in patients with HCC, focusing on the challenges that the underlying liver disease poses to their diagnosis and management. Challenges include late recognition, inadequate work-up and delayed treatment, overdiagnosis and inappropriate interruption of ICIs, complications caused by immunosuppressive therapy, and increased cost. A specific algorithm for the management of hepatic irAEs is provided.

Keywords: Durvalumab; Hepatotoxicity; Immunotherapy; Ipilimumab; Nivolumab; Pembrolizumab; Tremelimumab.

Fig. 1.. Most common organ comorbidities associated with chronic liver diseases.

*ASH: alcoholic steatohepatitis; HCC: hepatocellular carcinoma; NASH: non-alcoholic steatohepatitis.

Fig. 2.. Management of hepatitis induced by ICI in patients with hepatocellular carcinoma.

ALT, alanine aminotransferase; AST, aspartate aminotransferase; CMV, cytomegalovirus; GGT, gamma glutamyltransferase; ICI, immune checkpoint inhibitor; Tbil, total bilirubin; ULN, upper limit of normal.