Sequential therapy with sunitinib and sorafenib in metastatic hepatocellular carcinoma

Abstract

Hepatocellular carcinoma (HCC) is the sixth most common cancer worldwide and the third most common cause of cancer-related death [1]. More than 75% of cases occur in the Asian-Pacific region, largely in association with chronic hepatitis B virus (HBV) infection, and 360,000 patients in Eastern Asia die from this disease each year [1]. Diagnosed at early stages, it is potentially curable by surgery and by locoregional procedures. However, disease that is diagnosed at an advanced stage or continues to progress after locoregional therapy has a dismal prognosis because of underlying liver cirrhosis and lack of effective alternative treatments. Sorafenib (Nexavar; Bayer, West Haven, CT, USA and Onyx, Emeryville, CA, USA) is an oral multitargeted tyrosine kinase inhibitor (TKI) and the first agent shown to improve overall survival (OS) in advanced HCC [2, 3]. Sorafenib inhibits angiogenesis by targeting receptors for VEGF (VEGFR2 and VEGFR3) and blocks tumor cell proliferation by inhibiting RAF/MEK/ERK signaling [4]. This combined inhibition of VEGF and PDGF pathways decreases tumor vascularization and endothelial cell proliferation and thus retards tumor progression. Sunitinib malate (Sutent; Pfizer, New York, NY, USA) is another oral, multitargeted TKI that acts on VEGFR-1, VEGFR-2, and VEGFR-3, PDGFR-α and PDGFR-β, and partially overlaps with sorafenib in its target inhibition profile [5]. Sunitinib is approved for the treatment of renal cell carcinoma (RCC) and imatinib-resistant gastrointestinal stromal tumors (GIST) [6]. Observational phase II studies suggest that sunitinib has antitumor activity in patients with advanced HCC, and a multicenter phase III clinical trial to compare its effectiveness with that of sorafenib in advanced HCC is in progress. Improving treatment outcomes for patients with advanced HCC requires development of alternative agents and regimens that are active, tolerable and safe. Further knowledge of drug mechanisms, and of biomarkers to predict tumor response and/or resistance are also needed. At present we have no standardized second-line regimen in HCC patients after progression on first line sorafenib. In metastatic RCC patients, sorafenib and sunitinib are currently used in sequence. Observational studies on the efficacy and cross-resistance of these drugs in RCC patients failed to define optimal strategy of sequential treatment [7– 13], however data for sequential treatment with these two TKIs in advanced HCC patients are lacking. We performed this retrospective study to evaluate the efficacy and safety of sequential administration of sunitinib following failure of sorafenib in advanced HCC patients.