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 decompensating events impact on the prognosis of patients with HCC more profoundly than tumour progression. This observation is particularly relevant in the new era of highly effective immunotherapy, that can also be administered to patients with impaired hepatic function (i.e., higher albumin-bilirubin (ALBI) grade) and/or with clinical signs of portal hypertension that both indicate a high risk of hepatic decompensation. Thus, it is of utmost clinical importance in HCC patients to develop practical strategies for prevention and management of decompensation that including a rigorous diagnostic workup and treatment of the underlying liver disease etiology – which may allow for cirrhosis recompensation and to ensure the use of non-selective beta-blockers in those with portal hypertension. We propose that future trials should incorporate hepatic decompensation as a clinically meaningful and prognostically relevant intermediate endpoint to investigate 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 and multifaceted treatment approach that addresses both the underlying liver disease and the superimposed cancer to optimise overall patient outcomes in the context of expanding therapeutic options.