| Systemic therapy is one of the most important treatment modalities for advanced hepatocellular carcinoma (HCC), and, in recent years, it has made rapid progress. On the basis of the results of two pivotal phase III placebo-controlled studies, sorafenib has been 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 have been conducted as first-line or second-line treatment. Until now, lenvatinib and atezolizumab plus bevacizumab demonstrated positive results in first-line treatment, and regorafenib, ramucirumab (patients only with 400 ng/ml or over of α-fetoprotein), and cabozantinib in second-line treatment. In Japan, use of sorafenib, regorafenib, lenvatinib, ramucirumab and atezolizumab plus bevacizumab for patients with advanced HCC became eligible for coverage by the national health insurance in 2009, 2017 2018, 2019, and 2020, respectively, and cabozantinib will be reimbursed in second or third line treatment until the end of this year. Especially, atezolizumab plus bevacizumab has been reported to be clinically meaningful improvement in overall survival in patients with advanced HCC, and is expected as a practice-changing treatment. Thus, promising outcomes have also been reported in advanced HCC with combination therapy of immune-oncologic agent plus VEGF inhibitor, and various combination therapy such as ipilimumab plus nivolumab, tremelimumab plus durvalumab, lenvatinib plus pembrolizumab, bezacizumab plus durvalumab and cabozantinib plus atezolizumab are underway in global phase III trials. In the near future, triplet or quarto regimen may be developed. These combination regimens have been reported to be higher objective response rate, around 30-50%, which was comparable to those of transarterial chemoembolization (TACE). In 2015, the criteria of “TACE refractory” was presented as a good indication for systemic therapy. Then, in Apple Consensus Meeting 2019, the concept of “TACE unsuitable” has been proposed. The indications for systemic therapy has been expanded to the intermediate stage, which is a good indication for TACE. In the future, the advent of favorable systemic regimens that offer superior survival benefit to TACE are expected in patients with intermediate stage HCC. |
