Beyond chemotherapy: systemic treatment options for hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is a major worldwide problem. Multiple chemotherapeutic agents have been used both as single agents and in combination to treat advanced HCC, but until recently none have been shown to improve overall survival. Sorafenib is a multitargeted tyrosine kinase inhibitor (TKI) that was the first systemic therapy to demonstrate improved overall survival among patients with advanced HCC in a phase III trial. Although sorafenib shifted the focus of HCC therapeutics to targeted agents, it produced differential outcomes among HCC patients according to etiology [i.e., hepatitis C virus (HCV) versus hepatitis B virus (HBV)] reflecting the difficulty of treating a heterogenous malignancy like HCC. A large number of additional targeted agents have subsequently been evaluated in HCC, such as sunitinib, regorafenib, and brivanib, and have proven inferior to sorafenib. However, several new agents that target c-MET and VEGF have shown promise in the phase II setting and are now being evaluated in randomized trials. This review will review the failures and recent successes reported in the HCC literature with a focus on targeted agents.