The antiangiogenic ceiling in hepatocellular carcinoma: does it exist and has it been reached?

The recommendation of sorafenib as standard of care in advanced hepatocellular carcinoma has lent support to the increased use of antiangiogenic therapies. However, in three phase 3 randomised trials that compared other antiangiogenics with sorafenib, results did not show superiority or non-inferiority of the new therapies. The 10-month median overall survival shown in these studies for patients given sorafenib might be a ceiling for single-agent antiangiogenic therapy. Strategies to increase survival time include combination therapies that pair antiangiogenic treatment with biological therapy or chemotherapy. The combination of sorafenib and erlotinib was not superior to sorafenib alone, which suggests no positive interaction between antiangiogenics and tyrosine kinase inhibitors in the treatment of advanced hepatocellular carcinoma. A combination of sorafenib and doxorubicin is being assessed in a randomised phase 3 trial. Differences in patient outcome with sorafenib because of disease cause and the ethnic origin of patients suggest that sorafenib's multitarget capacity, including RAF kinase inhibition, might be important. MET inhibitors cabozantinib and tivantinib are drugs that might also bypass the so-called antiangiogenic ceiling and have led to selective treatment of patients that overexpress MET with these drugs. Although this intense period of research activity has not yet resulted in significant improvements in survival for patients with advanced hepatocellular carcinoma, we are certainly closer to a customised treatment, which should increase the antiangiogenic survival ceiling.