Systemic therapy for hepatocellular carcinoma (HCC) has changed markedly since 
the introduction of the molecular targeted agent sorafenib in 2007. Sorafenib 
increased the available treatment options for patients with extrahepatic spread 
and vascular invasion and improved survival in patients with advanced HCC; 
however, various shortcomings such as low response rates and relatively high 
toxicity (e.g., hand-foot skin reaction) prompted concerted efforts aimed at 
developing new molecular targeted agents to provide more treatment options and 
second-line agents for patients with disease progression or intolerance to 
sorafenib. Despite many attempts to develop new drugs between 2007 and 2016, all 
first-line and second-line clinical trials conducted during this period failed. 
However, between 2017 and 2019, 4 drugs (lenvatinib as a first-line agent and 
regorafenib, cabozantinib, and ramucirumab as second-line agents) emerged in 
quick succession from clinical trials and became available for clinical use. In 
addition, nivolumab and pembrolizumab were approved as second-line agents after 
sorafenib. A recent phase III trial (IMbrave150) showed that combination 
immunotherapy with atezolizumab plus bevacizumab increases overall survival 
compared with sorafenib therapy; Food and Drug Agency already approved this 
combination therapy, and worldwide approval is expected soon. This review 
describes the recent advances in systemic therapy and the use of tyrosine kinase 
inhibitors (sorafenib, lenvatinib, regorafenib, and cabozantinib), monoclonal 
antibodies (ramucirumab and bevacizumab), and immune checkpoint inhibitors 
(nivolumab, pembrolizumab, and atezolizumab) in elderly patients and the 
similarity of their efficacy and safety profiles to those in the general 
population.