Hepatocellular carcinoma (HCC) is the most common primary liver tumor and is often diagnosed at an unresectable advanced stage. Systemic chemotherapy as well as transarterial chemoembolization (TACE) and hepatic arterial infusion chemotherapy (HAIC) are used to treat advanced HCC. TACE and HAIC have long been the standard of care for patients with unresectable HCC but are limited to the treatment of intrahepatic lesions. Systemic chemotherapy with doxorubicin or chemohormonal therapy with tamoxifen have also been considered, but neither has demonstrated survival benefits. In the treatment of unresectable advanced HCC, cisplatin is administered transhepatic arterially for local treatment. Subsequently, for cisplatin-refractory cases due to drug resistance, a shift to systemic therapy with a different mechanism of action is expected to produce new antitumor effects. Cisplatin is also used for the treatment of liver tumors other than HCC. This review summarizes the action and resistance mechanism of cisplatin and describes the treatment of the major hepatobiliary cancers for which cisplatin is used as an anticancer agent, with a focus on HCC.

Primary liver cancer is the sixth most common cancer and the third most common cause of cancer-related deaths worldwide. Hepatocellular carcinoma (HCC) is a major histologic type with a poor prognosis owing to the difficulty in early detection, the chemotherapy resistance, and the high recurrence rate of the disease. Despite recent advancements in HCC prevention and diagnosis, over 50% of patients are diagnosed at Barcelona Clinic Liver Cancer Stage B or C. Systemic therapies are recommended for unresectable HCC (uHCC) with major vascular invasion, extrahepatic metastases, or intrahepatic lesions that have a limited response to transcatheter arterial chemoembolization, but the treatment outcome tends to be unsatisfactory due to acquired drug resistance. Elucidation of the mechanisms underlying the resistance to systemic therapies and the appropriate response strategies to solve this issue will contribute to improved outcomes in the multidisciplinary treatment of uHCC. In this review, we summarize recent findings on the mechanisms of resistance to drugs such as sorafenib, regorafenib, and lenvatinib in molecularly targeted therapy, with a focus on epigenetic regulation and the tumor microenvironment and outline the approaches to improve the therapeutic outcome for patients with advanced HCC.