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Sorafenib has been the only approved systemic treatment of hepatocellular carcinoma (HCC) for almost a decade. Recently, two new drugs showed positive results in two Phase III studies. The RESORCE trial identified regorafenib as a valid second-line treatment for patients progressing to sorafenib, the REFLECT trial showed that lenvatinib is noninferior to sorafenib as front-line treatment. Following these trials, the therapeutic scenario will be dominated by anti-VEGFR drugs, with three different molecules showing a proven anticancer activity. Some open problems still remain and different immunotherapy trials are underway, following promising preliminary results. In this review we analyze: the most recent advancements about patients treated with sorafenib; the results of RESORCE and REFLECT trials; and the ongoing Phase III clinical trials. Finally, we discuss how they could address the current problems and possibly reshape the future of the systemic treatments for HCC., Competing Interests: Financial & competing interests disclosure A Granito is a consultant for Bayer. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript.

Hepatocellular carcinoma is one of the most common malignancies and represents a unique challenge for physicians and patients. Treatment patterns are not uniform between areas despite efforts to promote a common protocol. Even if most hepatologists worldwide adopt the Barcelona Clinic Liver Cancer staging system, Asian and North American physicians are also independently making an effort to expand the indications of each treatment, combining therapies for better outcomes. Also, new therapeutic techniques have emerged and an increasing number of studies are trying to include these paradigm shifts into newer treatment guidelines. Controversial and diverging points in the current international guidelines are emphasized and discussed. Unanswered questions are also analyzed to identify the most needed and promising future perspectives., Competing Interests: Financial & competing interests disclosure L Bolondi in the last 2 years has received honoraria for lectures and/or participation to advisory boards by the following companies: Bayer, Bristol Myers Squibb, Syrtex, MSD. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript.