Sorafenib for the treatment of unresectable hepatocellular carcinoma

Abstract

Raf kinases and vascular endothelial growth factor receptor (VEGFR) and platelet-derived growth factor receptor (PDGFR) tyrosine kinases are potential molecular targets for obtaining both anti-tumor cell progression and anti-angiogenesis effects in cancers, including hepatocellular carcinoma (HCC). Sorafenib is an oral multi-kinase inhibitor that mainly targets Raf kinases and receptor tyrosine kinases associated with angiogenesis (VEGFR-2/-3, PDGFR-beta). A global randomized controlled trial (RCT) of sorafenib versus placebo conducted in patients with advanced HCC demonstrated the beneficial effects of the drug on the time-to-progression and overall survival. Furthermore, a RCT with a similar design to that of the global trial conducted in the Asia-Pacific region also demonstrated the efficacy of the drug. The most common treatment-related adverse events of sorafenib were found to be diarrhea, fatigue, and skin toxicity, namely, hand-foot syndromes and rash. Based on the results of the RCTs, sorafenib has been established as a standard agent for systemic chemotherapy in HCC patients with metastatic disease or transcatheter arterial chemoembolization (TACE)-refractory disease who are not suitable candidates for local treatments. The efficacy and safety of sorafenib in patients with moderate liver dysfunction have not been confirmed to date and more data are needed. Development of new therapeutic methods is needed for the treatment of advanced HCC in the future; clinical trials of sorafenib-based combination therapy, second-line therapy after sorafenib failure, and adjuvant therapy after local treatments are warranted in HCC patients.

Keywords: hepatocellular carcinoma; platelet-derived growth factor receptor; raf kinase; sorafenib; vascular endothelial growth factor receptor.

Figure 1

Chemical structural formulas of compounds inhibiting Raf1 and sorafenib. Adapted by permission from Macmillan Publishers Ltd: Nat Rev Drug Discov, 5:835–44. © 2006.

Figure 2

Mechanism of action of sorafenib. Sorafenib exerts a dual anticancer effect on the tumor and tumor vasculature by inhibiting Raf kinases including Raf-1 as well as the receptor tyrosine kinases vascular endothelial growth factor receptor 2 (VEGFR2), VEGFR3, platelet-derived growth factor receptor (PDGFR), etc. Reproduced with permission from Gollob JA, Wilhelm S, Carter C, et al 2006. Role of Raf kinase in cancer: therapeutic potential of targeting the Raf/MEK/ERK signal transduction pathway. Semin Oncol, 33:392–406. Copyright © 2006 Elsevier. Abbreviation: Sf, sorafenib.

Figure 3

Survival benefit was confirmed in the SHARP trial; the median overall survival was 10.7 months in the sorafenib group as compared with 7.9 months in the placebo group (hazard ratio for death in the sorafenib group, 0.69; 95% CI: 0.55–0.87). Reproduced with permission from Llovet JM, Ricci S, Mazzaferro V, et al 2008. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med, 359:378–90. Copyright © Massachusetts Medical Society. All rights reserved.

Figure 4

Median time to progression (TTP) was 5.5 months in the sorafenib group as compared with 2.8 months in the placebo group (hazard ratio for progression in the sorafenib group, 0.58; 95% CI: 0.45–0.74) in the SHARP trial. There was a statistically significant difference in the TTP between the two groups. Reproduced with permission from Llovet JM, Ricci S, Mazzaferro V, et al 2008. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med, 359:378–90. Copyright © Massachusetts Medical Society. All rights reserved.