6 and 4.1 months in the sorafenib- and placebo-treated patients (hazard ratio = 0.75; 95% CI, 0.54–1.05). However, a wide difference was seen in the overall survival according to the presence or absence of MVI and/or EHS in both trials. Among the sorafenib-treated patients in the SHARP trial, median overall survival was 14.5 months for patients without MVI and/or EHS versus 8.9 months for patients with MVI and/or EHS. In the Asia–Pacific trial, median overall survival was 14.3 and FLT3 inhibitor 5.6 months, respectively. Therefore, the survival benefit of sorafenib monotherapy in advanced HCC patients with PVT or extrahepatic metastasis is still not

satisfactory, especially in Asian patients. To overcome these limited therapeutic responses, the development of more effective therapy is urgently needed. When monotherapy is not enough to control tumor progression, combined therapy or a multidisciplinary DAPT research buy approach can be considered. In our previous study, localized concurrent intra-arterial

chemoradiation therapy plus repeated HAIC combination treatment achieved favorable results in patients with localized advanced HCC with PVT.21 The efficacy of sorafenib in advanced HCC has been examined in combination with conventional systemic chemotherapy, such as doxorubicin, tegafur/uracil, 5-FU, and mitomycin.22 In spite of the positive results in combining sorafenib with chemotherapeutic agents, these clinical trials were non-randomized and conducted on a small number of patients. Combining other agents with different mechanisms of action is theoretically a reasonable therapeutic approach in the treatment of advanced HCC. Also, combining molecularly-targeted therapies that block different pathways compared with sorafenib monotherapy is an attractive approach. Non-specific serine/threonine protein kinase Future studies should evaluate the efficacy and safety of combination therapy of sorafenib plus conventional chemotherapeutic

agents or other targeted agents. Moreover, the use of sorafenib in combination with other therapeutic options, such as transcatheter arterial chemoembolization, internal, or external radiotherapy in advanced HCC is also a topic of interest, and further studies on this topic are warranted. In conclusion, the management of patients with advanced HCC with conventional cytotoxic systemic monotherapy or combined therapy has not been satisfactory over the last decades. At present, sorafenib is the only approved therapy for advanced HCC. However, to improve the survival benefit of sorafenib by maximizing the therapeutic efficacy, a major challenge is how to refine treatment strategies and select proper patients. In addition, we should consider not only therapeutic efficacy, but also practical issues, such as medical cost in Asia. Based on these efforts, it is expected that advanced HCC will be considered a treatable and increasingly curable disease in the near future.