Systemic treatment of advanced hepatocellular carcinoma: from disillusions to new horizons

Hepatocellular carcinoma (HCC) is an aggressive malignancy, which accounts for a third of all cancer deaths globally each year. The management of patients with HCC is complex, as both the tumour stage and any underlying liver disease must be considered conjointly. Since the approval of sorafenib in advanced HCC, several phase III clinical trials have failed to demonstrate any superiority over sorafenib in the frontline setting, and no agent has been shown to impact outcomes after sorafenib failure. This review will focus on the range of experimental therapeutics for patients with advanced HCC and highlight the successes and failures of these treatments as well as areas for future development. Specifics such as dose limiting toxicity and safety profile in patients with liver dysfunction related to the underlying chronic liver disease should be considered when developing therapies in HCC. Finally, robust validated and reproducible surrogate end-points as well as predictive biomarkers should be defined in future randomised trials.