The HeiLivCa study,20 ECOG 1208, and the TACE-2 study are also addressing similar questions with slightly different patient populations. For example, the open ECOG 1208 study randomizes patients to receive sorafenib or placebo in conjunction with TACE and allows the interventionalist to choose one of a few different chemoembolization methods. Liver-directed therapy can take the form of conventional TACE, using the mixture of doxorubicin, mitomycin, and cisplatin described previously. However, embolization may also be completed by employing conventional Ethiodol (ethiodized oil) TACE, using only doxorubicin or doxorubicin-loaded beads. This varied approach may provide an analytic advantage, because the design better mirrors what is happening at institutions around the world.
The optimal scheduling of sorafenib in relation to TACE has yet to be determined, but with these trials, the elucidation of combination therapy will be discovered. For instance, the TACE-2 trial is not only comparing drug-eluting beads with and without sorafenib but is also additionally randomizing patients into two arms. One arm starts sorafenib or placebo at day 0, whereas the other arm begins with sorafenib or placebo at day 7 after TACE (2–5 weeks post randomization). This study will help to clarify the timing of combination therapy for HCC.
Conclusion
With increased angiogenic factors following embolization and the emergence of specific agents to target those factors, a potential benefit of targeting angiogenesis as an adjunct to TACE may be expected. Although the rationale is sound and safety has been demonstrated in preliminary studies,21,22 using sorafenib in patients with HCC receiving chemoembolization is not yet recommended outside the clinical trial setting. Over the coming years, efficacy data from ongoing randomized studies will be available. It is best to support the current ongoing clinical trials so we may reach a definitive answer. With the increasing awareness among community oncologists and their participation in clinical trials, we should be able to optimize the use of sorafenib in combination with TACE and extend its use in conjunction with other locoregional therapies.
References
1. Jemal A, Siegel R, Xu J, Ward E. Cancer statistics, 2010. CA Cancer J Clin 2010;60:277–300.
2. El-Serag HB, Mason AC. Risk factors for the rising rates of primary liver cancer in the United States. Arch Intern Med 2000;160:3227–3230.
3. Caldwell SH, Oelsner DH, Iezzoni JC, et al. Cryptogenic cirrhosis: clinical characterization and risk factors for underlying disease. Hepatology 1999;29:664–669.
4. Llovet JM. Treatment of hepatocellular carcinoma. Curr Treat Options Gastroenterol 2004;7:431–441.
5. Llovet JM, Burroughs A, Bruix J. Hepatocellular carcinoma. Lancet 2003;362:1907– 1917.
6. Liu L, Cao Y, Chen C, et al. Sorafenib blocks the RAF/MEK/ERK pathway, inhibits tumor angiogenesis, and induces tumor cell apoptosis in hepatocellular carcinoma model PLC/ PRF/5. Cancer Res 2006;66:11851–11858.
7. Llovet JM, Ricci S, Mazzaferro V, et al. Sorafenib in advanced hepatocellular carcinomacarcinoma. N Engl J Med 2008;359:378–390.
8. Cheng AL, Kang YK, Chen Z, et al. Efficacy and safety of sorafenib in patients in the Asia-Pacific region with advanced hepatocellular carcinoma: a phase III randomised, doubleblind, placebo-controlled trial. Lancet Oncol 2009;10:25–34.
9. Llovet JM, Bruix J. Systematic review of randomized trials for unresectable hepatocellular carcinoma: chemoembolization improves survival. Hepatology 2003;37:429–442.
10. Camma C, Schepis F, Orlando A, et al. Transarterial chemoembolization for unresectable hepatocellular carcinoma: meta-analysis of randomized controlled trials. Radiology 2002;224:47–54.
11. Leung DA, Goin JE, Sickles C, Raskay BJ, Soulen MC. Determinants of postembolization syndrome after hepatic chemoembolization. J Vasc Interv Radiol 2001;12:321–326.
12. Sergio A, Cristofori C, Cardin R, et al. Transcatheter arterial chemoembolization (TACE) in hepatocellular carcinoma (HCC): the role of angiogenesis and invasiveness. Am J Gastroenterol 2008;103:914–921.
13. Li X, Feng GS, Zheng CS, Zhuo CK, Liu X. Expression of plasma vascular endothelial growth factor in patients with hepatocellular carcinoma and effect of transcatheter arterial chemoembolization therapy on plasma vascular endothelial growth factor level. World J Gastroenterol 2004;10:2878–2882.
14. Yang XR, Xu Y, Yu B, et al. High expression levels of putative hepatic stem/progenitor cell biomarkers related to tumour angiogenesis and poor prognosis of hepatocellular carcinoma. Gut 2010;59:953–962.
15. Hu J, Xu Y, Shen ZZ, et al. High expressions of vascular endothelial growth factor and platelet-derived endothelial cell growth factor predict poor prognosis in alpha-fetoprotein- negative hepatocellular carcinoma patients after curative resection. J Cancer Res Clin Oncol 2009;135:1359–1367.
16. Xiong ZP, Yang SR, Liang ZY, et al. Association between vascular endothelial growth factor and metastasis after transcatheter arterial chemoembolization in patients with hepatocellular carcinoma. Hepatobiliary Pancreat Dis Int 2004;3:386–390.
17. Chung Y, Kim B, Chen C, et al. Study in Asia of the combination of transarterial chemoembolization (TACE) with sorafenib in patients with hepatocellular carcinoma trial (START): second interim safety and efficacy analysis. J Clin Oncol 2010;28[15S]:4026.
18. Erhardt A, Kolligs FT, Dollinger MM, et al. First-in-men demonstration of sorafenib plus TACE for the treatment of advanced hepatocellular carcinoma (SOCRATES trial). Presented at the 60th Annual Meeting of the American Association for the Study of Liver Diseases; October 30–November 3, 2009; Boston, MA.
19. Okita K, Imanaka K, Chida N, et al. Phase III study of sorafenib in patients in Japan and South Korea with advanced hepatocellular carcinoma (HCC) treated after transarterial chemoembolization (TACE). Presented at the 2010 Gastrointestinal Cancers Symposium; January 22–24, 2010; Orlando, FL. Abstract LBA128.
20. Hoffmann K, Glimm H, Radeleff B, et al. Prospective, randomized, double-blind, multi-center, phase III clinical study on transarterial chemoembolization (TACE) combined with sorafenib versus TACE plus placebo in patients with hepatocellular cancer before liver transplantation–HeiLivCa [ISRCTN24081794]. BMC Cancer 2008;8:349.
21. Reyes DK, Azad NS, Koteish A, et al. Phase II trial of sorafenib combined with doxorubicin-eluting bead transarterial chemoembolization (DEB-TACE) for patients with unresectable hepatocellular carcinoma (HCC): interim safety and efficacy analysis. Presented at the 2010 Gastrointestinal Cancers Symposium; January 22–24, 2010; Orlando, FL. Abstract 254.
22. Valenti DA, Cabrera T, Khankan A, et al. Combined sorafenib and yttrium-90 radioembolization in the treatment of advanced HCC: preliminary results. J Vasc Interv Radiol 2009;20(suppl):S65–S66. Abstract 169.