Establishing hepatic decompensation as a meaningful clinical outcome during systemic therapy for hepatocellular carcinoma.

Unlike other solid tumours, the prognosis of patients with advanced hepatocellular carcinoma (HCC) is dually influenced by tumour progression and liver dysfunction. Accumulating evidence suggests that clinically evident hepatic decompensation events exert an even stronger impact on the prognosis of patients with HCC than tumour progression. This observation is particularly relevant in the new era of highly effective immunotherapy, that can also be administered to patients with worse hepatic function (i.e., higher albumin-bilirubin (ALBI) grade) and indicators of portal hypertension are most likely to experience a high risk of hepatic decompensation. Thus, there is an unmet need to identify in patients with HCC, practical strategies for preventing and managing decompensation including a proper diagnostic process to identify underlying liver disease, its aetiology and risk factors, implementing use of non-selective beta-blockers for portal hypertension and achieving cirrhosis recompensation through aetiologic cure. We propose that future trials should incorporate hepatic decompensation as a clinically meaningful and prognostically relevant intermediate secondary endpoint to uncouple the competing effects of decompensation and tumour progression on overall survival -the gold standard endpoint for the regulatory approval of systemic HCC therapy. Clinical practice should adopt an integrated a multifaceted treatment approach that addresses both the underlying liver disease and the superimposed cancer disease to optimize overall patients' outcomes throughout the expanding therapeutic landscape.