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 lifethreatening. 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.

Surveillance and Monitoring of Hepatocellular Carcinoma During the COVID-19 Pandemic

“…[74][75][76] Safety monitoring on immune checkpoint inhibitors requires vigilance for immunerelated adverse events, which can range from more common events of mild rashes and arthralgias, to rare but potentially life-threatening events such as encephalitis, hypophysitis, myocarditis, pneumonitis, hepatitis, and colitis. 77 Immune-mediated adverse events can evolve and progress rapidly and may require high doses of steroids, other immunosuppressive therapies, and hospitalization in severe cases.…”

“…Patients and caregivers require education on the risks and warning symptoms of immunerelated adverse events, which can require urgent medical evaluation. 77…”

Milestones in the pathogenesis and management of primary liver cancer

“…Sangro et al review the available information, summarise the challenges that cirrhosis poses to diagnosis and management, and provide specific recommendations for liver toxicities. 76 This will be a useful aid for hepatologists, medical oncologists and any other specialist involved in the care of patients with HCC.…”

Immunotherapy with Checkpoint Inhibitors for Hepatocellular Carcinoma: Where Are We Now?

“…This trial is the natural continuation of the Cohort 4 of the CheckMate-040 study, which provided interesting results on dual checkpoint blockade (albeit in the second-line setting) [30]. In this cohort, 148 sorafenib-experienced patients received the combination of nivolumab + ipilimumab according to three different schedules: Nivolumab 1 mg/kg Q2W and ipilimumab 3 mg/Kg Q3W for the first three months, followed by nivolumab 1 mg/Kg Q2W (Group A); nivolumab 3 mg/kg Q2W and ipilimumab 1 mg/Kg Q3W for the first three months, followed by nivolumab 3 mg/Kg Q2W (Group B); or nivolumab 1 mg/kg Q2W and ipilimumab 3 mg/Kg Q6W (Group C) (29). Efficacy data showed an unprecedented OS of 22.8 months in Group A, 12.5 months in Group B, and 12.8 months in Group C [30].…”

“…The ORR was impressively high in all groups (32%, 31% and 31%, respectively) [30]. It is worth noting that Group A also had the higher rate of AEs, and the proportion of patients permanently discontinuing the treatment for toxicity was 18%, 6% and 2% in the three groups (29). The frequency of AST and ALT increases reached the maximum in Group A (20% and 16%, respectively), similarly to that of "hepatitis" (20%).…”