Second-line treatment of hepatocellular carcinoma: from theory to practical issues

Hepatocellular carcinoma (HCC) is the most frequent primary liver cancer with unmet needs of effective medications. Lenvatinib – a new oral multikinase inhibitor (MKI) proved to be as effective as sorafenib in terms of survival has been added recently to standard first-line treatment of advanced HCC. Regorafenib, another MKI in the RESORCE trial, a phase 3 study evaluating regorafenib in HCC patients who experience disease progression after first-line treatment with sorafenib, have shown a 2.8-month median survival benefit over placebo (10.6 versus 7.8 months). Cabozantinib and ramucirumab have all been shown to extend overall patient survival in sorafenib-refractory HCC patients and appear to have a reasonable safety profile. Immune checkpoint inhibitors therapy with nivolumab or pembrolizumab – monoclonal antibody to PD1-receptor are effective in about 15–18% of HСС patients presenting with long-lasting objective responses. Immunotherapy was safe in terms of viral hepatitis activation, but in comparative trials in first and second-line settings failed to achieve statistical difference in overall survival other sorafenib and placebo, respectively. Due to less toxic profile HCC immunotherapy seems to be a reasonable option to Child-Pugh B patients. Multiple ongoing trials are studying immune checkpoint inhibition alone or in combination with TKIs. The results of these trials will help determine the optimal choice, timing, and sequence of agents. This article reviews current situation in the field of new therapies of HCC from the point of common medical practice in searching for optimal second-line treatment decision in different clinical situations.