Digestive Diseases and Sciences

, Volume 57, Issue 5, pp 1122–1129 | Cite as

Sorafenib for Treatment of Hepatocellular Carcinoma: A Systematic Review

  • Bingru XieEmail author
  • David H. Wang
  • Stuart Jon Spechler



Sorafenib, a drug that inhibits Raf serine/threonine kinases mediating cell proliferation and receptor tyrosine kinases involved in angiogenesis, is approved for treatment of advanced hepatocellular carcinoma.


To explore the efficacy and safety of sorafenib for treating advanced HCC, and to identify clinical factors that might affect that efficacy and safety.


We conducted a systematic review using the PRISMA guidelines to identify prospective studies on sorafenib used alone or in combination with systemic and/or loco regional anti-tumor therapy for treating advanced HCC.


We identified 21 prospective trials of sorafenib treatment alone (7) or combined with other treatment (14). In randomized, placebo-controlled trials, sorafenib prolonged overall survival by 2.3–2.8 months, extended the time to tumor progression by 1.4–2.7 months, and increased disease control by 11–19 %. OS and DCRs were lowest for studies with the highest percentage of hepatitis B patients. Most studies reported major side effects (diarrhea, fatigue, and hand–foot syndrome) in <15 % of patients, with greater incidence in patients with advanced cirrhosis and those treated with sorafenib in combination with 5-FU drugs.


Treatment with sorafenib results in statistically significant, but clinically modest, improvements in OS, TTP, and DCR. For patients with hepatitis B, response seems to be poorer than for those with hepatitis C. The frequency of hand–foot syndrome seems to be higher when sorafenib is used in advanced cirrhosis and is combined with 5-FU drugs. It is not clear that sorafenib combined with other treatments is more effective than sorafenib alone.


Sorafenib Hepatocellular carcinoma Cirrhosis Transarterial chemoembolization Systematic review 



This work was supported by the Office of Medical Research, Department of Veterans Affairs, and the National Institutes of Health (R01-CA134571).

Conflict of interest

There is no financial or personal interest to report.


  1. 1.
    Parkin DM, Bray F, Ferlay J, et al. Global cancer statistics, 2002. CA Cancer J Clin. 2005;55:74–108.PubMedCrossRefGoogle Scholar
  2. 2.
    Pons-Renedo F, Llovet JM. Hepatocellular carcinoma: a clinical update. Med Gen Med. 2003;5:11.Google Scholar
  3. 3.
    American Cancer Society. Cancer Facts and Figures 2010. Atlanta: American Cancer Society; 2010.Google Scholar
  4. 4.
    El-Serag HB. Epidemiology of hepatocellular carcinoma in USA. Hepatol Res. 2007;37:S88–S94.PubMedCrossRefGoogle Scholar
  5. 5.
    El-Serag HB, Davila JA, Petersen NJ, et al. The continuing increase in the incidence of hepatocellular carcinoma in the United States: an update. Ann Intern Med. 2003;139:817–823.PubMedGoogle Scholar
  6. 6.
    El-Serag HB, Mason AC. Rising incidence of hepatocellular carcinoma in the United States. N Engl J Med. 1999;340:745–750.PubMedCrossRefGoogle Scholar
  7. 7.
  8. 8.
    Calvisi DF, Ladu S, Gorden A, et al. Ubiquitous activation of Ras and Jak/stat pathways in human HCC. Gastroenterology. 2006;130:1117–1128.PubMedCrossRefGoogle Scholar
  9. 9.
    Marotta F, Vangieri B, Cecere A, et al. The pathogenesis of hepatocellular carcinoma is multifactorial event. Novel immunological treatment in prospect. Clin Ter. 2004;155:187–199.PubMedGoogle Scholar
  10. 10.
    Avila MA, Berasain C, Sangro B, et al. New therapies for hepatocellular carcinoma. Oncogene. 2006;25:3866–3884.PubMedCrossRefGoogle Scholar
  11. 11.
    Goodsell DS. The molecular perspective: the Ras oncogene. Oncologist. 1999;4:263–264.PubMedGoogle Scholar
  12. 12.
    Stockl L, Berting A, Malkowski B, et al. Integrity of c-Raf-1/MEK signal transduction cascade is essential for hepatitis B virus gene expression. Oncogene. 2003;22:2604–2610.PubMedCrossRefGoogle Scholar
  13. 13.
    Giambartolomei S, Covone F, Levrero M, et al. Sustained activation of the Raf/MEK/Erk pathway in response to EGF in stable cell lines expressing the hepatitis C virus (HCV) core protein. Oncogene. 2001;20:2606–2610.PubMedCrossRefGoogle Scholar
  14. 14.
    Shimotohno K, Watashi K, Tsuchihara K, et al. Hepatitis C virus and its roles in cell proliferation. J Gastroenterol. 2002;37:50–54.PubMedCrossRefGoogle Scholar
  15. 15.
    Gollob JA, Wilhelm S, Carter C, et al. Role of Raf kinase in cancer: therapeutic potential of targeting the Raf/MEK/ERK signal transduction pathway. Semin Oncol. 2006;33:392–406.PubMedCrossRefGoogle Scholar
  16. 16.
    Wilhelm SM, Carter C, Tang L, et al. BAY 43-9006 exhibits broad spectrum oral antitumor activity and targets the RAF/MEK/ERK pathway and receptor tyrosine kinases involved in tumor progression and angiogenesis. Cancer Res. 2004;64:7099–7109.PubMedCrossRefGoogle Scholar
  17. 17.
    Wilhelm SM, Adnane L, Newell P, et al. Preclinical overview of sorafenib, a multikinase inhibitor that targets both Raf and VEGF and PDGF receptor tyrosine kinase signaling. Mol Cancer Ther. 2008;7:3129–3140.PubMedCrossRefGoogle Scholar
  18. 18.
    Rahmani M, Davis EM, Bauer C, et al. Apoptosis induced by the kinase inhibitor BAY 43-9006 in human leukemia cells involves down-regulation of Mcl-1 through inhibition of translation. J Biol Chem. 2005;280:35217–35227.PubMedCrossRefGoogle Scholar
  19. 19.
    Yu C, Bruzek LM, Meng XW, et al. The role of Mcl-1 downregulation in the proapoptotic activity of the multikinase inhibitor BAY 43-9006. Oncogene. 2005;24:6861–6869.PubMedCrossRefGoogle Scholar
  20. 20.
    Molhoek KR, Griesemann H, Shu J, et al. Human melanoma cytolysis by combined inhibition of mammalian target of rapamycin and vascular endothelial growth factor/vascular endothelial growth factor receptor-2. Cancer Res. 2008;68:4392–4397.PubMedCrossRefGoogle Scholar
  21. 21.
    Takimoto CH, Awada A. Safety and anti-tumor activity of sorafenib (Nexavar®) in combination with other anti-cancer agents: a review of clinical trials. Cancer Chemother Pharmacol. 2008;61:535–548.PubMedCrossRefGoogle Scholar
  22. 22.
    Moher D, Liberati A, Tetzlaff J, et al. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. PLoS Med. 2009;6:e1000097.PubMedCrossRefGoogle Scholar
  23. 23.
  24. 24.
  25. 25.
  26. 26.
    Llovet JM, Ricci S, Mazzaferro V, et al. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med. 2008;359:378–390.PubMedCrossRefGoogle Scholar
  27. 27.
    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, double-blind, placebo-controlled trial. Lancet Oncol. 2009;10:25–34.PubMedCrossRefGoogle Scholar
  28. 28.
    Abou-Alfa GK, Schwartz L, Ricci S, et al. Phase II study of sorafenib in patients with advanced hepatocellular carcinoma. J Clin Oncol. 2006;24:4293–4300.PubMedCrossRefGoogle Scholar
  29. 29.
    Massa E, Stadier C, et al. Efficacy, safety and impact on quality of life of a treatment with sorafenib in elderly cancer patients with advanced hepatocellular carcinoma. Result of a phase II study. Ann Oncol. 2009;20:s65.Google Scholar
  30. 30.
    Yau T, Chan P, Ng KK, et al. Phase 2 open-label study of single-agent sorafenib in treating advanced hepatocellular carcinoma in a hepatitis B-endemic Asian population: presence of lung metastasis predicts poor response. Cancer. 2009;115:428–436.PubMedCrossRefGoogle Scholar
  31. 31.
    Furuse J, Ishii H, Nakachi K, et al. Phase I study of sorafenib in Japanese patients with hepatocellular carcinoma. Cancer Sci. 2008;99:159–165.PubMedGoogle Scholar
  32. 32.
    Castroagudin JF, Molina E, et al. Short-term efficacy and safety of treatment of advanced hepatocellular carcinoma with sorafenib. J Hepatol. 2008;48:s141–s142.Google Scholar
  33. 33.
    Prete SD, Montella L, Caraglia M, et al. Sorafenib plus octreotide is an effective and safe treatment in advanced hepatocellular carcinoma: multicenter phase II So Cancer Chemother Pharmacol. 2010;66:837–844.PubMedCrossRefGoogle Scholar
  34. 34.
    Petrini I, Muul LM, et al. A phase II trial of sorafenib in combination with 5-fluorouracil continuous infusion in patients with advanced hepatocellular carcinoma: preliminary data. J Clin Oncol. 2009;27:4592.Google Scholar
  35. 35.
    Gianluca D, Muul LM, et al. Prospective phase II study of combination sorafenib plus mitomycin-c in the treatment of advanced hepatocellular carcinoma. Ann Oncol. 2009;20:8.Google Scholar
  36. 36.
    Yau T, Chan P, et al. Phase II trial of sorafenib with capecitabine and oxaliplatin (SECOX) in patients with locally advanced or metastatic hepatocellular carcinoma. EJC Suppl. 2009;7:20–21.CrossRefGoogle Scholar
  37. 37.
    Abou-Alfa GK, Johnson P, Knox JJ, et al. Doxorubicin plus sorafenib vs doxorubicin alone in patients with advanced hepatocellular carcinoma: a randomized trial. JAMA. 2010;304:2154–2160.PubMedCrossRefGoogle Scholar
  38. 38.
    Hsu CH, Shen YC, Lin ZZ, et al. Phase II study of combining sorafenib with metronomic tegafur/uracil for advanced hepatocellular carcinoma. J Hepatol. 2010;53:126–131.PubMedCrossRefGoogle Scholar
  39. 39.
    Giuliana F, Rosenberg A, et al. Sorafenib plus cisplatin and gemcitabine in the treatment of advanced hepatocellular carcinoma: a phase II study by the Grupo Oncologico Dell’Italia Meridonale (PROT. GOIM 2705). Cancer Treat Rev. 2010;36:S96.Google Scholar
  40. 40.
    Erhardt A, Kollings F, et al. First-in-men demonstration of sorafenib plus TACE for the treatment of advanced hepatocellular carcinoma (SOCRATES trial). Hepatology. 2009;50:1080A.Google Scholar
  41. 41.
    Reyes DK, Azad N, et al. Phase II trial of sorafenib wit doxirubicin eluting bead-transarterial chemoembolization (DEB–TACE) for patients with hepatocellular carcinoma: interim safety and efficacy analysis. Hepatology. 2009;50:6A–7A.Google Scholar
  42. 42.
    Richly H, Schultheis B, Adamietz IA, et al. Combination of sorafenib and doxorubicin in patients with advanced hepatocellular carcinoma: results from a phase I extension trial. Eur J Cancer. 2009;45:579–587.PubMedCrossRefGoogle Scholar
  43. 43.
    Faivre S, Feng L, et al. Phase I safety, pharmacokinetic, and pharmacodynamic study of AVE 1642, a human monoclonal antibody inhibiting the insulin-like grouth factor-1 receptor (IGF-1R/CD221), administered as single agent and in combination with sorafinib as first line therapy in patients with advanced hepatocellular carcinoma. Hepatology. 2010;52:S 466A–288.Google Scholar
  44. 44.
    Dufour JF, Hoppe H, Heim MH, et al. Continuous administration of sorafenib in combination with transarterial chemoembolization in patients with hepatocellular carcinoma: results of a phase I study. Oncologist. 2010;15:1198–1204.PubMedCrossRefGoogle Scholar
  45. 45.
    Pinter M, Smith W, et al. An interim safety analysis of sorafenib plus transarterial chemoembolization in hepatocellular carcinoma—a phase I/II pilot study (SORATACE-1 trial). Hepatology. 2010;52:1157A–1759.Google Scholar
  46. 46.
    Pawlik TM, Reyes DK, Cosgrove D, et al. Phase II trial of sorafenib combined with concurrent transarterial chemoembolization with drug-eluting beads for hepatocellular carcinoma. J Clin Oncol. 2011;29:3960–3967.PubMedCrossRefGoogle Scholar
  47. 47.
    Yang CH, Lin WC, Chuang CK, et al. Hand–foot skin reaction in patients treated with sorafenib: a clinicopathological study of cutaneous manifestations due to multitargeted kinase inhibitor therapy. Br J Dermatol. 2008;158:592–596.PubMedCrossRefGoogle Scholar
  48. 48.
    Chan AO, Yuen MF, Hui CK, et al. A prospective study regarding the complications of transcatheter intraarterial lipiodol chemoembolization in patients with hepatocellular carcinoma. Cancer. 2002;94:1747–1752.PubMedCrossRefGoogle Scholar
  49. 49.
    Shweiki D, Itin A, Soffer D, et al. Vascular endothelial growth factor induced by hypoxic may mediate hypoxic-initiated angiogenesis. Nature. 1992;359:843–845.PubMedCrossRefGoogle Scholar
  50. 50.
    Li X, Feng GS, Zheng CS, et al. Influence of transarterial chemoembolization on angiogenesis and expression of vascular endothelial growth factor and basic fibroblast growth factor in rat with Walker-256 transplanted hepatoma: an experimental study. World J Gastroenterol. 2003;9:2445–2449.PubMedGoogle Scholar
  51. 51.
    Lee JK, Chung YH, et al. Recurrences of hepatocellular carcinoma following initial remission by transcatheter arterial chemoembolization. J Gastroenterol Hepatol. 2002;17:52–58.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC (Outside the USA) 2012

Authors and Affiliations

  • Bingru Xie
    • 1
    • 2
    Email author
  • David H. Wang
    • 1
  • Stuart Jon Spechler
    • 1
  1. 1.Department of MedicineVA North Texas Healthcare System, and the University of Texas Southwestern Medical Center at DallasDallasUSA
  2. 2.Division of Gastroenterology (111B1)Dallas VA Medical CenterDallasUSA

Personalised recommendations