**1. Introduction**

Hepatocellular carcinoma (HCC) is the most common primary cancer of the liver. HCC is the second leading cause of cancer-related mortality worldwide with a very poor 5-year survival. The incidence of HCC has been increasing over the past decades [1]. Risk factors for HCC include hepatitis B and C infection, alcohol use, non-alcoholic steatohepatitis, and aflatoxin.

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© 2016 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons

Treatment approaches for HCC depend on the stage and the hepatic function, and includes surgical therapies (liver transplantation, resection, and ablation) and nonsurgical therapies, which may be liver-directed (percutaneous ethanol injection, radiofrequency ablation, transarterial embolization, external beam radiation therapy) or systemic therapies.

patients have more advanced cirrhosis. FDA approval of sorafenib for HCC did not particularly specify the underlying cirrhosis state. Data regarding safety and efficacy of sorafenib in patients with Child-Turcotte-Pugh B or C cirrhosis are limited, and suggest that patients have poorer overall survival and overall worse side effect profile in comparison to patients with Child-Turcotte-Pugh A. Advanced progressive cirrhosis rather than sorafenib itself might be

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Sorafenib is associated with several side effects such as hypertension, cardiotoxicity, arterial thromboembolism, bleeding, renal toxicity, hand-foot skin reaction and others. Sorafenib has been associated with potentially fatal liver toxicity. Liver function tests should regularly be

In a phase II trial, the combination of six cycles of doxorubicin with sorafenib 400 mg twice daily was compared to sorafenib and placebo [8]. Combination therapy was associated significantly longer median time to tumor progression (6.4 vs. 2.8 months) and median overall survival duration (13.7 vs. 6.5 months). The side effect profile was not significantly worse with combined therapy. However those results were not reproduced in the randomized phase III trial, Cancer and Leukemia Group B [CALGB] trial 80,802 [9]. The study was stopped early by the data monitoring safety board after a planned interim analysis suggested futility for the combination. In a preliminary report presented at the 2016 American Society of Clinical Oncology (ASCO) Gastrointestinal Cancers Symposium, median overall survival was not significantly better for the combination (9.3 vs. 10.5 months), nor was median progression-free

Lenvatinib is a multi-kinase inhibitor of VEGFRs, fibroblast growth factor receptors (FGFR),

A randomized noninferiority trial, the REFLECT study, compared lenvatinib (12 mg once daily for body weight ≥60 kg, 8 mg daily for <60 kg) with sorafenib (400 mg daily for all patients) in 954 patients with unresectable HCC and no prior systemic therapy (99% Child-Turcotte-Pugh A) [11]. The predefined noninferiority margin (primary endpoint overall survival) was 1.08. Lenvatinib was noninferior to sorafenib (median overall survival 13.6 vs. 12.3 months, hazard ratio 0.92, 95% CI 0.79–1.06), the objective response rate was higher (24 vs. 9%), and median time to progression was longer (7.4 vs. 3.7 months, hazard ratio 0.66, 95% CI 0.57–0.77). Lenvatinib leads to higher grade 3 or 4 hypertension (23 vs. 14%), while

Lenvatinib was approved in Japan in March 2018 for unresectable HCC. Lenvatinib is not

Both sorafenib and lenvatinib can be used in the first-line treatment of advanced HCC. There are no data on second-line treatment after lenvatinib and whether lenvatinib is effective as a

sorafenib was associated with higher hand-foot skin reaction (11 vs. 3%).

an explanation for such differences [6, 7].

*2.1.1. Combining sorafenib with doxorubicin*

survival (3.6 vs. 3.2 months), but toxicity was worse.

(PDGFR), c-Kit, and the RET proto-oncogene [10].

monitored during treatment.

**2.2. Lenvatinib**

approved by FDA yet.

second line after sorafenib.

Until 2008, there was no effective systemic therapy for advanced HCC. Cytotoxic chemotherapy has not been used routinely as of low efficacy and poor functional status for patients with advanced HCC, who often have cirrhosis. Since the advent of sorafenib in 2008, there has been a surge of several targeted and immune therapies with various degree of effectiveness. In this chapter, systemic therapies for advanced HCC will be reviewed. Those include oral kinase inhibitors, antiangiogenic monoclonal antibodies, immune-therapeutic approaches and cytotoxic chemotherapies.
