Chemotherapy is one of the most important treatment modalities for advanced 
hepatocellular carcinoma (HCC). On the basis of the results of two pivotal Phase 
III placebo-controlled studies, sorafenib is currently acknowledged worldwide as 
the standard therapeutic agent for advanced HCC. Following the introduction of 
sorafenib for the treatment of HCC, Phase III trials of numerous other agents as 
first-line or second-line chemotherapy have been conducted to determine if any 
of these agents might offer superior survival benefit to sorafenib. In 2016, a 
clear survival benefit of regorafenib over placebo was demonstrated in HCC 
patients showing disease progression after sorafenib treatment. A year later, in 
2017, lenvatinib has been shown to be non-inferior to sorafenib, in terms of the 
overall survival, in chemo-naïve patients with advanced HCC. More recently, 
promising outcomes have also been reported with new agents, such as nivolumab 
and cabozantinib. At present, various novel combination regimens including these 
agents are currently under development. Hepatic arterial infusion chemotherapy 
(HAIC) is frequently adopted for the treatment of locally advanced HCC in Japan, 
based on reports of high response rates and favorable long-term outcomes. 
Although some randomized controlled trials of HAIC plus sorafenib vs. sorafenib 
alone as first-line therapy have been conducted in patients with advanced HCC, 
no firm evidence of the superiority of one over the other has been established 
yet. In the future, demonstration of the survival advantage of HAIC and the 
recognition of HAIC as one of the standard treatments for patients with advanced 
HCC are expected.