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Gastrointestinal Cancer Editorial Making Sense of the Advances in the Treatment of Hepatocellular Carcinoma Imane El-Dika, MD 1 and Ghassan K Abou-Alfa, MD 2,3 1. American University of Beirut Medical Center, Beirut, Lebanon; 2. Memorial Sloan Kettering Cancer Center, New York, NY, US; 3. Weill Medical College, Cornell University, New York, NY, US Abstract Recent advances in the understanding and management of hepatocellular carcinoma are promising and may usher in a new era in cancer therapy. Here we discuss the latest improvement in hepatitis C antiviral therapy, loco-regional tumor control, c-met inhibitors, and immune therapy. Genetic testing in hepatocellular carcinoma could be a turning point in the treatment development of this fatal disease. Keywords Hepatocellular carcinoma, hepatitis C virus, NS3/4A protease inhibitors, trans-arterial chemoembolization, sorafenib, tivantinib, cabozantinib, tremelimumab, nivolumab Disclosure: Imane El-Dika, MD, and Ghassan K Abou-Alfa, MD, have no conflicts of interests to declare. No funding was received in the publication of this article. Open Access: This article is published under the Creative Commons Attribution Noncommercial License, which permits any noncommercial use, distribution, adaptation, and reproduction provided the original author(s) and source are given appropriate credit. Received: September 16, 2015 Published Online: November 10, 2015 Citation: Oncology & Hematology Review, 2015;11(2):141–2 Correspondence: Ghassan K Abou-Alfa, MD, Memorial Sloan Kettering Cancer Center, 300 East 66th Street, New York, NY 10065, US. E: abou-alg@mskcc.org Hepatocellular carcinoma (HCC) is a leading cause of cancer-related death, with a rising global incidence. 1 The majority of HCC occurs in the setting of liver cirrhosis, mainly due to hepatitis C virus (HCV) infection, hepatitis B viral infection, alcohol consumption, or nonalcoholic fatty liver disease. The most important development in HCC is the advent of novel curative therapies for HCV. Treatment for HCV infection early in the disease process includes a more than 70 % reduction in the risk for HCC. 2 Earlier therapy consisted of the poorly tolerated injectable interferon (IFN), with low efficacy and a high toxicity profile. Recent advances in the treatment of chronic hepatitis C have been achieved through the development of direct-acting antiviral agents that target the nonstructural protein NS3/4A serine protease, which processes the nascent viral poly-protein, allowing for HCV replication. 3 Next-generation HCV NS3/4A protease inhibitors inhibit the NS5A replication scaffold, also known as the membranous web, and the NS5B ribonucleic acid (RNA)-dependent RNA polymerase. Among several clinical trials, more than 90 % of patients achieved sustained viral response (SVR) with sofosbuvir, 4,5 simeprevir, 6 or ledipasvir. 7 High efficacy was shown among all subgroups, except for genotypes 1 and 4. While still unclear, the curative effect of these new therapies will probably affect the incidence of HCC. Management of HCC remains a multidisciplinary approach, especially in the presence of curative treatments in early stage. Screening, risk stratification, Tou ch MEd ica l MEdia and management of liver decompensation are crucial in patient care. Surgery, liver transplant, and radiofrequency ablation remain the standard of care for the curative treatment of early-stage HCC. 8 Transarterial chemoembolization (TACE) is the most widely used modality for nonresectable tumors. 9 Recently, transarterial embolization (TAE) has shown similar outcome and safety profiles, 10 questioning the role of adding doxorubicin. Radioembolization with Y90 is challenging the current paradigm of HCC treatment, despite the lack of any randomized clinical trial data to date. 11 Enhancing the treatment effect of antiangiogenic therapy by preventing the angiogenic flare of sorafenib has failed so far. 12,13 The advent of sorafenib as a standard of care with an improvement in survival to 10.7 months compared with 7.9 months for placebo (0.69; 95  % confidence interval [CI] 0.55–0.87; p=0.001) opened the door into ample opportunities for the evaluation of other therapeutic options. 14 A randomized phase II study of sorafenib plus doxorubicin in first- line treatment of HCC showed improvement in overall survival (OS) of 13.7 months compared with 6.5 months for doxorubicin plus placebo (p=0.0049). 15 A large randomized phase III trial followed that. 16 However, the study was halted in view of an interim analysis that showed that “it is very unlikely that significant differences in overall survival and progression-free survival will be shown between the treatment arms”, 5 based on CALGB 80802 communication. 141