The incidence of hepatocellular carcinoma (HCC) has increased over the past decade, with an estimated 1 million new cases per year worldwide. In 2010 in the United States alone, it was expected that over 24,000 new cases would be diagnosed, with approximately 19,000 deaths.1 The incidence of HCC in the Western world is expected to rise until 2020 because of the large population of patients infected with the hepatitis C virus. 2 Furthermore, epidemiologic data suggest that many patients with cryptogenic cirrhosis have nonalcoholic steatohepatitis (NASH) as the cause of their chronic liver disease.3 Due to the rise in obese patient populations, NASH could be an important risk factor for patients with cirrhosis.

Surgical resection and liver transplantation are the preferred treatments of HCC, because they both are potentially curative. Unfortunately, only 10%–15% of patients are candidates for either of these approaches.4 Patients with liver-limited disease who are not candidates for liver transplantation or resection may be managed by liver-directed therapies. Common treatment modalities include ablation (eg, microwave ablation, radiofrequency ablation, and cryoablation), chemoembolization, and radioembolization.

Systemic therapy for HCC

HCC is considered a chemotherapy-resistant malignancy. Systemic chemotherapy approaches have been ineffective in patients with HCC, with increased toxicities.5 However, the introduction of sorafenib (Nexavar) has changed the landscape of systemic therapy for HCC and opened up opportunities for development of new drug regimens and multidisciplinary approaches in the treatment of those patients. Sorafenib is a smallmolecule kinase inhibitor that blocks multiple intracellular and cell-surface kinases (KIT, FLT3, RET, VEGFR- 1, VEGFR-2, VEGFR-3, and PDGFR- b) involved in cell signaling, angiogenesis, and apoptosis.6

In two large international studies (SHARP and Asia-Pacific) in patients with advanced HCC, sorafenib showed improvement in time to tumor progression (TTP) as well as in overall survival compared with placebo.7,8 Patients in these two studies had a Child-Pugh classification of A and a favorable performance status. The hypervascularity of HCC and the predominant effect of sorafenib of vascular endothelial growth factor receptor (VEGFR)-related tyrosine kinase activity provided the proof of principle for targeting angiogenesis in this disease.

In the multicenter, phase III, double-blinded, placebo-controlled SHARP trial,7 602 patients with advanced HCC who had not received previous systemic treatment were given either sorafenib (400 mg twice daily) or placebo. At the second planned interim analysis, 321 deaths had occurred, and the study was stopped. The median overall survival was 10.7 months in the sorafenib group and 7.9 months in the placebo group.7 In 2007, sorafenib was granted US Food and Drug Administration approval for the treatment of patients with advanced HCC.

Overview of chemoembolization

Transarterial chemoembolization (TACE) is the most widely used approach in the palliative setting and in some patients considered for liver transplantation. Embolization of the hepatic artery and its branches causes ischemic necrosis in the tumor cells that derive their blood supply predominantly from the hepatic artery. In contrast, the normal liver parenchyma is fed primarily by the portal system. The additional mechanism of action of chemoembolization is the trapping of cytotoxic agents within the embolized tissue. This process occurs because the lipiodol, which is used in most regimens, flows through the malignant tissues and parenchyma to obstruct portal vein inflow and hepatic vein washout, whereas particulate material employed near the end of the embolization procedure acts by entrapping the agents through blocking the hepatic arterial supply inflow.