Targeted therapy of hepatocellular cancer

Expert Opinion on Investigational Drugs

Volumn 19, Issue 2, 2010, Pages 265-274

  Wysocki, Piotr Jan ^a  

^a POZNAN UNIVERSITY OF MEDICAL SCIENCES   (Poland)

Author keywords

Angiogenesis; Hepatocellular cancer; MTOR inhibitors; Receptor tyrosine kinase inhibitors; Signaling pathways; Targeted therapy

Indexed keywords

ABT 100; ANTINEOPLASTIC AGENT; BEVACIZUMAB; BRIVANIB; CEDIRANIB; CETUXIMAB; EPIDERMAL GROWTH FACTOR RECEPTOR; ERLOTINIB; GEFITINIB; GEMCITABINE; LAPATINIB; MAMMALIAN TARGET OF RAPAMYCIN; MITOGEN ACTIVATED PROTEIN KINASE; MONOCLONAL ANTIBODY; MONOCLONAL ANTIBODY IMC A12; OXALIPLATIN; PAZOPANIB; PHOSPHATIDYLINOSITOL 3 KINASE; PLACEBO; PROTEIN KINASE B; RAF PROTEIN; RAPAMYCIN; RAS PROTEIN; SOMATOMEDIN C RECEPTOR; SORAFENIB; UNCLASSIFIED DRUG; VANDETANIB; VASCULOTROPIN; VASCULOTROPIN RECEPTOR;

ADVANCED CANCER; ANGIOGENESIS; CANCER GROWTH; CANCER SURVIVAL; CARCINOGENESIS; CLINICAL TRIAL; DIARRHEA; DRUG EFFICACY; DRUG SAFETY; HAND FOOT SYNDROME; HUMAN; HYPOPHOSPHATEMIA; LIVER CELL CARCINOMA; NONHUMAN; REVIEW; SIDE EFFECT; WEIGHT REDUCTION;

ANGIOGENESIS INHIBITORS; ANTINEOPLASTIC AGENTS; ANTINEOPLASTIC COMBINED CHEMOTHERAPY PROTOCOLS; CARCINOMA, HEPATOCELLULAR; DRUG DELIVERY SYSTEMS; HUMANS; INTRACELLULAR SIGNALING PEPTIDES AND PROTEINS; LIVER NEOPLASMS; NEOVASCULARIZATION, PATHOLOGIC; PROTEIN-SERINE-THREONINE KINASES; RECEPTOR PROTEIN-TYROSINE KINASES; SIGNAL TRANSDUCTION;

EID: 74549130088     PISSN: 13543784     EISSN: None     Source Type: Journal    
DOI: 10.1517/13543780903514110     Document Type: Review

References (109)

1. Bosch FX, Ribes J, Diaz M, Cleries R. Primary liver cancer: worldwide incidence and trends. Gastroenterology 2004;127(5 Suppl 1):S5-16
2. Parkin DM, Bray F, Ferlay J, Pisani P. Estimating the world cancer burden: Globocan 2000. Int J Cancer 2001;94(2):153-156 (Pubitemid 32911406)
3. Pisani P, Bray F, Parkin DM. Estimates of the world-wide prevalence of cancer for 25 sites in the adult population. Int J Cancer 2002;97(1):72-81
4. Fattovich G, Stroffolini T, Zagni I, Donato F. Hepatocellular carcinoma in cirrhosis: incidence and risk factors. Gastroenterology 2004;127(5 Suppl 1):S35-50
5. Farazi PA, DePinho RA. Hepatocellular carcinoma pathogenesis: from genes to environment. Nat Rev Cancer 2006;6(9):674-687
6. Thorgeirsson SS, Grisham JW. Molecular pathogenesis of human hepatocellular carcinoma. Nat Genet 2002;31(4):339-346
7. Villanueva A, Newell P, Chiang DY, et al. Genomics and signaling pathways in hepatocellular carcinoma. Semin Liver Dis 2007;27(1):55-76
8. Brechot C, Pourcel C, Louise A, et al. Presence of integrated hepatitis B virus DNA sequences in cellular DNA of human hepatocellular carcinoma. Nature 1980;286(5772):533-535
9. Murakami Y, Saigo K, Takashima H, et al. Large scaled analysis of hepatitis B virus (HBV) DNA integration in HBV related hepatocellular carcinomas. Gut 2005;54(8):1162-1168
10. Minami M, Daimon Y, Mori K, et al. Hepatitis B virus-related insertional mutagenesis in chronic hepatitis B patients as an early drastic genetic change leading to hepatocarcinogenesis. Oncogene 2005;24(27):4340-4348
11. Wang J, Chenivesse X, Henglein B, Brechot C. Hepatitis B virus integration in a cyclin A gene in a hepatocellular carcinoma. Nature 1990;343(6258):555-557
12. Feitelson MA, Duan LX. Hepatitis B virus X antigen in the pathogenesis of chronic infections and the development of hepatocellular carcinoma. Am J Pathol 1997;150(4):1141-1157
13. Balsano C, Avantaggiati ML, Natoli G, et al. Full-length and truncated versions of the hepatitis B virus (HBV) X protein (pX) transactivate the cmyc protooncogene at the transcriptional level. Biochem Biophys Res Commun 1991;176(3):985-992
14. Twu JS, Lai MY, Chen DS, Robinson WS. Activation of protooncogene c-jun by the X protein of hepatitis B virus. Virology 1993;192(1):346-350
15. Chirillo P, Falco M, Puri PL, et al. Hepatitis B virus pX activates NF-kappa B-dependent transcription through a Raf-independent pathway. J Virol 1996;70(1):641-646
16. Seto E, Mitchell PJ, Yen TS. Transactivation by the hepatitis B virus X protein depends on AP-2 and other transcription factors. Nature 1990;344(6261):72-74
17. Andrisani OM, Barnabas S. The transcriptional function of the hepatitis B virus X protein and its role in hepatocarcinogenesis (Review). Int J Oncol 1999;15(2):373-379
18. Lee YH, Yun Y. HBx protein of hepatitis B virus activates Jak1-STAT signaling. J Biol Chem 1998;273(39):25510-25515
19. Benn J, Schneider RJ. Hepatitis B virus HBx protein activates Ras-GTP complex formation and establishes a Ras, Raf, MAP kinase signaling cascade. Proc Natl Acad Sci USA 1994;91(22):10350-10354
20. Cha MY, Kim CM, Park YM, Ryu WS. Hepatitis B virus X protein is essential for the activation of Wnt/beta-catenin signaling in hepatoma cells. Hepatology 2004;39(6):1683-1693
21. Ueda H, Ullrich SJ, Gangemi JD, et al. Functional inactivation but not structural mutation of p53 causes liver cancer. Nat Genet 1995;9(1):41-47
22. Lee SW, Lee YM, Bae SK, et al. Human hepatitis B virus X protein is a possible mediator of hypoxia-induced angiogenesis in hepatocarcinogenesis. Biochem Biophys Res Commun 2000;268(2):456-461
23. Yamanaka T, Kodama T, Doi T. Subcellular localization of HCV core protein regulates its ability for p53 activation and p21 suppression. Biochem Biophys Res Commun 2002;294(3):528-534
24. Fukutomi T, Zhou Y, Kawai S, et al. Hepatitis C virus core protein stimulates hepatocyte growth: correlation with upregulation of wnt-1 expression. Hepatology 2005;41(5):1096-1105
25. Florese RH, Nagano-Fujii M, Iwanaga Y, et al. Inhibition of protein synthesis by the nonstructural proteins NS4A and NS4B of hepatitis C virus. Virus Res 2002;90(1-2):119-131
26. Ozturk M. p53 mutation in hepatocellular carcinoma after aflatoxin exposure. Lancet 1991;338(8779):1356-1359
27. Terasaki S, Kaneko S, Kobayashi K, et al. Histological features predicting malignant transformation of nonmalignant hepatocellular nodules: a prospective study. Gastroenterology 1998;115(5):1216-1222
28. Watanabe S, Horie Y, Kataoka E, et al. Non-alcoholic steatohepatitis and hepatocellular carcinoma: lessons from hepatocyte-specific phosphatase and tensin homolog (PTEN)-deficient mice. J Gastroenterol Hepatol 2007;22(Suppl 1):S96-S100
29. Caldwell S, Park SH. The epidemiology of hepatocellular cancer: from the perspectives of public health problem to tumor biology. J Gastroenterol 2009;44(Suppl 19):96-101
30. Taub R. Liver regeneration: from myth to mechanism. Nat Rev Mol Cell Biol 2004;5(10):836-847
31. Harada K, Shiota G, Kawasaki H. Transforming growth factor-alpha and epidermal growth factor receptor in chronic liver disease and hepatocellular carcinoma. Liver 1999;19(4):318-325
32. Hisaka T, Yano H, Haramaki M, et al. Expressions of epidermal growth factor family and its receptor in hepatocellular carcinoma cell lines: relationship to cell proliferation. Int J Oncol 1999;14(3):453-460
33. Ito Y, Takeda T, Higashiyama S, et al. Expression of heparin binding epidermal growth factor-like growth factor in hepatocellular carcinoma: an immunohistochemical study. Oncol Rep 2001;8(4):903-907
34. Huether A, Hopfner M, Baradari V, et al. EGFR blockade by cetuximab alone or as combination therapy for growth control of hepatocellular cancer. Biochem Pharmacol 2005;70(11):1568-1578
35. Hopfner M, Sutter AP, Huether A, et al. Targeting the epidermal growth factor receptor by gefitinib for treatment of hepatocellular carcinoma. J Hepatol 2004;41(6):1008-1016
36. Philip PA, Mahoney MR, Allmer C, et al. Phase II study of erlotinib (OSI-774) in patients with advanced hepatocellular cancer. J Clin Oncol 2005;23(27):6657-6663
37. Thomas MB, Chadha R, Glover K, et al. Phase 2 study of erlotinib in patients with unresectable hepatocellular carcinoma. Cancer 2007;110(5):1059- 1067
38. Ramanathan RK, Belani CP, Singh DA, et al. A phase II study of lapatinib in patients with advanced biliary tree and hepatocellular cancer. Cancer Chemother Pharmacol 2009;64(4):777-783
39. O'Dwyer PJ, Giantonio BJ, Levy DE, et al. Gefitinib in advanced unresectable hepatocellular carcinoma: results from the Eastern Cooperative Oncology Group's Study E1203. J Clin Oncol (Meeting Abstracts) 2006;24(18 Suppl):4143
40. Zhu AX, Stuart K, Blaszkowsky LS, et al. Phase 2 study of cetuximab in patients with advanced hepatocellular carcinoma. Cancer 2007;110(3):581-589
41. Gruenwald V, Wilkens L, Gebel M, et al. A phase II open-label study of cetuximab in unresectable hepatocellular carcinoma: final results. J Clin Oncol (Meeting Abstracts) 2007;25(18 Suppl):4598
42. Louafi S, Hebbar M, Rosmorduc O, et al. Gemcitabine, oxaliplatin (GEMOX) and cetuximab for treatment of hepatocellular carcinoma (HCC): results of the phase II study ERGO. J Clin Oncol (Meeting Abstracts) 2007;25(18 Suppl):4594
43. Breuhahn K, Longerich T, Schirmacher P. Dysregulation of growth factor signaling in human hepatocellular carcinoma. Oncogene 2006;25(27):3787-3800
44. Rowinsky EK, Youssoufian H, Tonra JR, et al. IMC-A12, a human IgG1 monoclonal antibody to the insulin-like growth factor I receptor. Clin Cancer Res 2007;13(18 Pt 2):5549s-55s
45. Higano CS, Yu EY, Whiting SH, et al. A phase I, first in man study of weekly IMC-A12, a fully human insulin like growth factor-I receptor IgG1 monoclonal antibody, in patients with advanced solid tumors. J Clin Oncol (Meeting Abstracts) 2007;25(18 Suppl):3505
46. Vivanco I, Sawyers CL. The phosphatidylinositol 3-Kinase AKT pathway in human cancer. Nat Rev Cancer 2002;2(7):489-501
47. Fang JY, Richardson BC. The MAPK signalling pathways and colorectal cancer. Lancet Oncol 2005;6(5):322-327
48. Giannelli G, Sgarra C, Porcelli L, et al. EGFR and VEGFR as potential target for biological therapies in HCC cells. Cancer Lett 2008;262(2):257-264
49. Oseini AM, Roberts LR. PDGFRalpha: a new therapeutic target in the treatment of hepatocellular carcinoma? Expert Opin Ther Targets 2009;13(4):443-454
50. Franovic A, Gunaratnam L, Smith K, et al. Translational up-regulation of the EGFR by tumor hypoxia provides a nonmutational explanation for its overexpression in human cancer. Proc Natl Acad Sci USA 2007;104(32):13092-13097
51. Xiao GH, Jeffers M, Bellacosa A, et al. Anti-apoptotic signaling by hepatocyte growth factor/Met via the phosphatidylinositol 3-kinase/Akt and mitogen-activated protein kinase pathways. Proc Natl Acad Sci USA 2001;98(1):247-252
52. Wang L, Wang WL, Zhang Y, et al. Epigenetic and genetic alterations of PTEN in hepatocellular carcinoma. Hepatol Res 2007;37(5):389-396 (Pubitemid 46605424)
53. Villanueva A, Chiang DY, Newell P, et al. Pivotal role of mTOR signaling in hepatocellular carcinoma. Gastroenterology 2008;135(6):1972-1983, 83 e1-11
54. Rogers R, Ouellet G, Brown C, et al. Cross-talk between the Akt and NF-kappaB signaling pathways inhibits MEHP-induced germ cell apoptosis. Toxicol Sci 2008;106(2):497-508
55. Bellacosa A, Chan TO, Ahmed NN, et al. Akt activation by growth factors is a multiple-step process: the role of the PH domain. Oncogene 1998;17(3):313-325
56. Schmitz KJ, Wohlschlaeger J, Lang H, et al. Activation of the ERK and AKT signalling pathway predicts poor prognosis in hepatocellular carcinoma and ERK activation in cancer tissue is associated with hepatitis C virus infection. J Hepatol 2008;48(1):83-90
57. Sahin F, Kannangai R, Adegbola O, et al. mTOR and P70 S6 kinase expression in primary liver neoplasms. Clin Cancer Res 2004;10(24):8421-8425
58. Faivre S, Kroemer G, Raymond E. Current development of mTOR inhibitors as anticancer agents. Nat Rev Drug Discov 2006;5(8):671-688
59. Liu H, Pan Z, Li A, et al. Roles of chemokine receptor 4 (CXCR4) and chemokine ligand 12 (CXCL12) in metastasis of hepatocellular carcinoma cells. Cell Mol Immunol 2008;5(5):373-378
60. Xiang ZL, Zeng ZC, Tang ZY, et al. Chemokine receptor CXCR4 expression in hepatocellular carcinoma patients increases the risk of bone metastases and poor survival. BMC Cancer 2009;9:176
61. Leufgen H, Bihl MP, Rudiger JJ, et al. Collagenase expression and activity is modulated by the interaction of collagen types, hypoxia, and nutrition in human lung cells. J Cell Physiol 2005;204(1):146-154
62. Erler JT, Bennewith KL, Nicolau M, et al. Lysyl oxidase is essential for hypoxia-induced metastasis. Nature 2006;440(7088):1222-1226
63. Covello KL, Kehler J, Yu H, et al. HIF-2alpha regulates Oct-4: effects of hypoxia on stem cell function, embryonic development, and tumor growth. Genes Dev 2006;20(5):557-570
64. Gordan JD, Simon MC. Hypoxia-inducible factors: central regulators of the tumor phenotype. Curr Opin Genet Dev 2007;17(1):71-77
65. Levitzki A. PDGF receptor kinase inhibitors for the treatment of PDGF driven diseases. Cytokine Growth Factor Rev 2004;15(4):229-235
66. Semenza GL. Targeting HIF-1 for cancer therapy. Nat Rev Cancer 2003;3(10):721-732
67. Amaravadi R, Thompson CB. The survival kinases Akt and Pim as potential pharmacological targets. J Clin Invest 2005;115(10):2618-2624
68. Lee TK, Man K, Ho JW, et al. FTY720 induces apoptosis of human hepatoma cell lines through PI3-K-mediated Akt dephosphorylation. Carcinogenesis 2004;25(12):2397-2405
69. Crul M, Rosing H, de Klerk GJ, et al. Phase I and pharmacological study of daily oral administration of perifosine (D-21266) in patients with advanced solid tumours. Eur J Cancer 2002;38(12):1615-1621
70. Van Ummersen L, Binger K, Volkman J, et al. A phase I trial of perifosine (NSC 639966) on a loading dose/maintenance dose schedule in patients with advanced cancer. Clin Cancer Res 2004;10(22):7450-7456
71. Liu F, Wang P, Jiang X, et al. Antisense hypoxia-inducible factor 1alpha gene therapy enhances the therapeutic efficacy of doxorubicin to combat hepatocellular carcinoma. Cancer Sci 2008;99(10):2055-2061
72. Semela D, Piguet AC, Kolev M, et al. Vascular remodeling and antitumoral effects of mTOR inhibition in a rat model of hepatocellular carcinoma. J Hepatol 2007;46(5):840-848
73. Huynh H, Chow KH, Soo KC, et al. RAD001 (everolimus) inhibits tumour growth in xenograft models of human hepatocellular carcinoma. J Cell Mol Med 2009;13(7):1371-1380
74. Pang RW, Poon RT. From molecular biology to targeted therapies for hepatocellular carcinoma: the future is now. Oncology 2007;72(Suppl 1):30-44
75. Rizell M, Andersson M, Cahlin C, et al. Effects of the mTOR inhibitor sirolimus in patients with hepatocellular and cholangiocellular cancer. Int J Clin Oncol 2008;13(1):66-70
76. Lev S, Moreno H, Martinez R, et al. Protein tyrosine kinase PYK2 involved in Ca(2+)-induced regulation of ion channel and MAP kinase functions. Nature 1995;376(6543):737-745
77. Dhillon AS, Hagan S, Rath O, Kolch W. MAP kinase signalling pathways in cancer. Oncogene 2007;26(22):3279-3290
78. McKillop IH, Schmidt CM, Cahill PA, Sitzmann JV. Altered expression of mitogen-activated protein kinases in a rat model of experimental hepatocellular carcinoma. Hepatology 1997;26(6):1484-1491
79. Schmidt CM, McKillop IH, Cahill PA, Sitzmann JV. Increased MAPK expression and activity in primary human hepatocellular carcinoma. Biochem Biophys Res Commun 1997;236(1):54-58
80. Giambartolomei S, Covone F, Levrero M, Balsano C. 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(20):2606-2610
81. Lee HC, Tian B, Sedivy JM, et al. Loss of Raf kinase inhibitor protein promotes cell proliferation and migration of human hepatoma cells. Gastroenterology 2006;131(4):1208-1217
82. Coleman WB. Mechanisms of human hepatocarcinogenesis. Curr Mol Med 2003;3(6):573-588
83. Carloni V, Vizzutti F, Pantaleo P. Farnesyltransferase inhibitor, ABT-100, is a potent liver cancer chemopreventive agent. Clin Cancer Res 2005;11(11):4266-4274
84. Wentz SC, Wu H, Yip-Schneider MT, et al. Targeting MEK is effective chemoprevention of hepatocellular carcinoma in TGF-alpha-transgenic mice. J Gastrointest Surg 2008;12(1):30-37
85. Huynh H, Soo KC, Chow PK, Tran E. Targeted inhibition of the extracellular signal-regulated kinase kinase pathway with AZD6244 (ARRY-142886) in the treatment of hepatocellular carcinoma. Mol Cancer Ther 2007;6(1):138-146
86. Llovet JM, Ricci S, Mazzaferro V, et al. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med 2008;359(4):378-390
87. 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(1):25-34
88. Poon RT, Ng IO, Lau C, et al. Tumor microvessel density as a predictor of recurrence after resection of hepatocellular carcinoma: a prospective study. J Clin Oncol 2002;20(7):1775-1785
89. Yao DF, Wu XH, Zhu Y, et al. Quantitative analysis of vascular endothelial growth factor, microvascular density and their clinicopathologic features in human hepatocellular carcinoma. Hepatobiliary Pancreat Dis Int 2005;4(2):220-226
90. Yoshiji H, Kuriyama S, Yoshii J, et al. Vascular endothelial growth factor tightly regulates in vivo development of murine hepatocellular carcinoma cells. Hepatology 1998;28(6):1489-1496
91. Park YN, Kim YB, Yang KM, Park C. Increased expression of vascular endothelial growth factor and angiogenesis in the early stage of multistep hepatocarcinogenesis. Arch Pathol Lab Med 2000;124(7):1061-1065
92. Zhao J, Hu J, Cai J, et al. Vascular endothelial growth factor expression in serum of patients with hepatocellular carcinoma. Chin Med J (Engl) 2003;116(5):772-776
93. Huang GW, Yang LY, Lu WQ. Expression of hypoxia-inducible factor 1alpha and vascular endothelial growth factor in hepatocellular carcinoma: impact on neovascularization and survival. World J Gastroenterol 2005;11(11):1705-1708
94. Imura S, Miyake H, Izumi K, et al. Correlation of vascular endothelial cell proliferation with microvessel density and expression of vascular endothelial growth factor and basic fibroblast growth factor in hepatocellular carcinoma. J Med Invest 2004;51(3-4):202-209
95. Moon WS, Rhyu KH, Kang MJ, et al. Overexpression of VEGF and angiopoietin 2: a key to high vascularity of hepatocellular carcinoma? Mod Pathol 2003;16(6):552-557
96. Liu Y, Poon RT, Li Q, et al. Both antiangiogenesis-and angiogenesis-independent effects are responsible for hepatocellular carcinoma growth arrest by tyrosine kinase inhibitor PTK787/ZK222584. Cancer Res 2005;65(9):3691-3699
97. Finn RS, Bentley G, Britten CD, et al. Targeting vascular endothelial growth factor with the monoclonal antibody bevacizumab inhibits human hepatocellular carcinoma cells growing in an orthotopic mouse model. Liver Int 2009;29(2):284-290
98. Siegel AB, Cohen EI, Ocean A, et al. Phase II trial evaluating the clinical and biologic effects of bevacizumab in unresectable hepatocellular carcinoma. J Clin Oncol 2008;26(18):2992-2998
99. Boige V, Baey C, Dromain C, et al. Circulating endothelial cells (CEC) and angiogenic proteins monitoring in patients (pts) with advanced hepatocellular carcinoma (HCC) treated with bevacizumab. J Clin Oncol (Meeting Abstracts) 2009;27(15S):4597
100. Thomas MB, Morris JS, Chadha R, et al. Phase II trial of the combination of bevacizumab and erlotinib in patients who have advanced hepatocellular carcinoma. J Clin Oncol 2009;27(6):843-850
101. Zhu AX, Blaszkowsky LS, Ryan DP, et al. Phase II study of gemcitabine and oxaliplatin in combination with bevacizumab in patients with advanced hepatocellular carcinoma. J Clin Oncol 2006;24(12):1898-1903
102. Sun W, Haller DG, Mykulowycz K, et al. Combination of capecitabine, oxaliplatin with bevacizumab in treatment of advanced hepatocellular carcinoma (HCC): a phase II study. J Clin Oncol (Meeting Abstracts) 2007;25(18 Suppl):4574
103. Hsu C, Yang T, Toh H, et al. Modified-dose capecitabine + bevacizumab for the treatment of advanced/metastatic hepatocellular carcinoma (HCC): a phase II, single-arm study. J Clin Oncol (Meeting Abstracts) 2007;25(18 Suppl):15190
104. Wysocki PJ, Zolnierek J, Szczylik C, Mackiewicz A. Targeted therapy of renal cell cancer. Curr Opin Investig Drugs 2008;9(6):570-575
105. Koeberle D, Montemurro M, Samaras P, et al. Continuous sunitinib treatment in patients with unresectable hepatocellular carcinoma (HCC): a multicenter phase II trial (SAKK 77/06 and SASL 23). J Clin Oncol (Meeting Abstracts) 2009;27(15S):4591
106. Zhu AX, Sahani DV, Duda DG, et al. Efficacy, safety, and potential biomarkers of sunitinib monotherapy in advanced hepatocellular carcinoma: a phase II study. J Clin Oncol 2009;27(18):3027-3035
107. Raoul JL, Finn RS, Kang YK, et al. An open-label phase II study of first-and second-line treatment with brivanib in patients with hepatocellular carcinoma (HCC). J Clin Oncol (Meeting Abstracts) 2009;27(15S):4577
108. 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(26):4293-4300
109. Strebel BM, Dufour JF. Combined approach to hepatocellular carcinoma: a new treatment concept for nonresectable disease. Expert Rev Anticancer Ther 2008;8(11):1743-1749