Hepatocellular carcinoma: Systemic therapies and future perspectives

Expert Review of Anticancer Therapy

Volumn 14, Issue 10, 2014, Pages 1205-1218

  Mikhail, Sameh ^a   Cosgrove, David ^b   Zeidan, Amer ^c  

^a THE OHIO STATE UNIVERSITY WEXNER MEDICAL CENTER   (United States)

^b JOHNS HOPKINS UNIVERSITY   (United States)

^c YALE CANCER CENTER   (United States)

Author keywords

biomarkers; hepatocellular carcinoma; immune therapy; liver transplantation; locoregional therapy; partial hepatectomy; sorafenib

Indexed keywords

ALPHA FETOPROTEIN; B7 ANTIGEN; BEVACIZUMAB; BRIVANIB; CD86 ANTIGEN; CETUXIMAB; CYTOTOXIC T LYMPHOCYTE ANTIGEN 4; DOXORUBICIN; EPIDERMAL GROWTH FACTOR RECEPTOR; ERLOTINIB; EVEROLIMUS; FLUORODEOXYGLUCOSE F 18; GEMCITABINE; GLYPICAN 3; LAPATINIB; MELANOMA ANTIGEN 1; MITOGEN ACTIVATED PROTEIN KINASE; MITOGEN ACTIVATED PROTEIN KINASE INHIBITOR; NY ESO 1 ANTIGEN; OXALIPLATIN; PERIFOSINE; PLACEBO; PROGRAMMED DEATH 1 RECEPTOR; RAF PROTEIN; RAPAMYCIN; RDEA 119; SELUMETINIB; SORAFENIB; SUNITINIB; UNCLASSIFIED DRUG; UNINDEXED DRUG;

ANGIOGENESIS; ANTINEOPLASTIC ACTIVITY; ASTHENIA; CANCER CHEMOTHERAPY; DIARRHEA; DRUG APPROVAL; DRUG EFFICACY; DRUG SAFETY; EGFR GENE; ENZYME ACTIVATION; FATIGUE; GASTROINTESTINAL HEMORRHAGE; HAND FOOT SYNDROME; HEPATITIS C; HEPATITIS C VIRUS; HUMAN; HYPERTENSION; HYPERTRANSAMINASEMIA; IN VITRO STUDY; INCIDENCE; LIVER CELL CARCINOMA; LIVER CIRRHOSIS; LIVER TRANSPLANTATION; LOW DRUG DOSE; MOLECULAR PATHOLOGY; MOLECULARLY TARGETED THERAPY; MULTIPLE CYCLE TREATMENT; NEOVASCULARIZATION (PATHOLOGY); NEUTROPENIA; OBESITY; ONCOGENE K RAS; OVERALL SURVIVAL; PHASE 2 CLINICAL TRIAL (TOPIC); POSITRON EMISSION TOMOGRAPHY; PROGRESSION FREE SURVIVAL; PROSPECTIVE STUDY; RANDOMIZED CONTROLLED TRIAL (TOPIC); REVIEW; SIGNAL TRANSDUCTION; SYSTEMIC THERAPY; THROMBOCYTOPENIA; TREATMENT RESPONSE; WNT SIGNALING PATHWAY; WOUND INFECTION; ADULT; CARCINOMA, HEPATOCELLULAR; COMPLICATION; IMMUNOTHERAPY; LIVER NEOPLASMS; PATHOLOGY; PROCEDURES; SURVIVAL RATE;

ADULT; CARCINOMA, HEPATOCELLULAR; HEPATITIS C; HUMANS; IMMUNOTHERAPY; LIVER CIRRHOSIS; LIVER NEOPLASMS; LIVER TRANSPLANTATION; MOLECULAR TARGETED THERAPY; OBESITY; SURVIVAL RATE;

EID: 84907513085     PISSN: 14737140     EISSN: 17448328     Source Type: Journal    
DOI: 10.1586/14737140.2014.949246     Document Type: Review

References (153)

1. Jemal A, Siegel R, Xu J, Ward E. Cancer statistics, 2010. CA Cancer J Clin 2010; 60(5):277-300
2. Bosch FX, Ribes J, Diaz M, Cleries R. Primary liver cancer: Worldwide incidence and trends. Gastroenterology 2004; 127(5 Suppl 1):S5-S16
3. Edwards BK, Ward E, Kohler BA, et al. Annual report to the nation on the status of cancer, 1975-2006, featuring colorectal cancer trends and impact of interventions (risk factors, screening, and treatment) to reduce future rates. Cancer 2010;116(3): 544-73
4. Altekruse SF, McGlynn KA, Reichman ME. Hepatocellular carcinoma incidence, mortality, and survival trends in the United States from 1975 to 2005. J Clin Oncol 2009;27(9):1485-91
5. Mor E, Kaspa RT, Sheiner P, Schwartz M. Treatment of hepatocellular carcinoma associated with cirrhosis in the era of liver transplantation. Ann Intern Med 1998; 129(8):643-53
6. Chang PE, Ong WC, Lui HF, Tan CK. Is the prognosis of young patients with hepatocellular carcinoma poorer than the prognosis of older patients?. A comparative analysis of clinical characteristics, prognostic features, and survival outcome. J Gastroenterol 2008;43(11):881-8
7. Zhong YD, Yang YF. Diabetes mellitus, chronic hepatitis C, and hepatocellular carcinoma. Hepatology 2008;48(4):1348
8. Jarnagin WR. Management of small hepatocellular carcinoma: A review of transplantation, resection, and ablation. Ann Surg Oncol 2010;17(5):1226-33
9. Nuzzo G, Giuliante F, Gauzolino R, et al. Liver resections for hepatocellular carcinoma in chronic liver disease: Experience in an Italian centre. Eur J Surg Oncol 2007; 33(8):1014-18
10. Llovet JM, Fuster J, Bruix J. Intention-To-Treat analysis of surgical treatment for early hepatocellular carcinoma: Resection versus transplantation. Hepatology 1999;30(6):1434-40
11. Poon RT, Fan ST, Lo CM, et al. Long-Term survival and pattern of recurrence after resection of small hepatocellular carcinoma in patients with preserved liver function: Implications for a strategy of salvage transplantation. Ann Surg 2002;235(3):373-82
12. Kianmanesh R, Regimbeau JM, Belghiti J. Selective approach to major hepatic resection for hepatocellular carcinoma in chronic liver disease. Surg Oncol Clin N Am 2003;12(1):51-63
13. Mazzaferro V, Regalia E, Doci R, et al. Liver transplantation for the treatment of small hepatocellular carcinomas in patients with cirrhosis. N Engl J Med 1996;334(11): 693-9
14. Yao FY, Ferrell L, Bass NM, et al. Liver transplantation for hepatocellular carcinoma: Expansion of the tumor size limits does not adversely impact survival. Hepatology 2001; 33(6):1394-403
15. Thomas MB, Jaffe D, Choti MM, et al. Hepatocellular carcinoma: Consensus recommendations of the National Cancer Institute Clinical Trials Planning Meeting. J Clin Oncol 2010;28(25):3994-4005
16. Benson AB. NCCN practive guidelines in Oncology-v.2.2020. 2010. Available from: Www.nccn.org/professionals/physician-gls/ PDF/hepatobiliary.pdf [Last accessed 11 December 2010]
17. Belghiti J, Carr BI, Greig PD, et al. Treatment before liver transplantation for HCC. Ann Surg Oncol 2008;15(4): 993-1000
18. Zimmerman MA, Ghobrial RM, Tong MJ, et al. Recurrence of hepatocellular carcinoma following liver transplantation: A review of preoperative and postoperative prognostic indicators. Arch Surg 2008; 143(2):182-8; discussion 188
19. Cheung TT, Poon RT, Jenkins CR, et al. Survival analysis of high-intensity focused ultrasound therapy vs. transarterial chemoembolization for unresectable hepatocellular carcinomas. Liver Int 2014; 34(6):e136-43
20. Lu DS, Yu NC, Raman SS, et al. Radiofrequency ablation of hepatocellular carcinoma: Treatment success as defined by histologic examination of the explanted liver. Radiology 2005;234(3):954-60
21. Ebara M, Okabe S, Kita K, et al. Percutaneous ethanol injection for small hepatocellular carcinoma: Therapeutic efficacy based on 20-year observation. J Hepatol 2005;43(3):458-64
22. Chen MS, Li JQ, Zheng Y, et al. A prospective randomized trial comparing percutaneous local ablative therapy and partial hepatectomy for small hepatocellular carcinoma. Ann Surg 2006;243(3):321-8
23. Llovet JM, Real MI, Montana X, et al. Arterial embolisation or chemoembolisation versus symptomatic treatment in patients with unresectable hepatocellular carcinoma: A randomised controlled trial. Lancet 2002; 359(9319):1734-9
24. Cheng BQ, Jia CQ, Liu CT, et al. Chemoembolization combined with radiofrequency ablation for patients with hepatocellular carcinoma larger than 3 cm: A randomized controlled trial. JAMA 2008; 299(14):1669-77
25. Chang YS, Adnane J, Trail PA, et al. Sorafenib (BAY 43-9006) inhibits tumor growth and vascularization and induces tumor apoptosis and hypoxia in RCC xenograft models. Cancer Chemother Pharmacol 2007;59(5):561-74
26. Llovet JM, Ricci S, Mazzaferro V, et al. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med 2008;359(4): 378-90
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(1):25-34
28. Marrero JA, Lencioni M, Kudo M, et al. Global investigation of therapeutic decisions in hepatocellular carcinoma and of its treatment with sorafenib (GIDEON) second interim analysis in more than 1,500 patients: Clinical findings in patients with liver dysfunction. J Clin Oncol 29: Abstract 4001
29. Cabibbo G, Tremosini S, Galati G, et al. Transarterial chemoembolization and sorafenib in hepatocellular carcinoma. Expert Rev Anticancer Ther 2014;14(7): 831-45
30. Zhang L, Hu P, Chen X, Bie P. Transarterial Chemoembolization (TACE) plus Sorafenib Versus TACE for Intermediate or Advanced Stage Hepatocellular Carcinoma: A Meta-Analysis. PLoS One 2014;9(6):e100305
31. 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(30): 3960-7
32. Llovet JM, Pena CE, Lathia CD, et al. Plasma biomarkers as predictors of outcome in patients with advanced hepatocellular carcinoma. Clin Cancer Res 2012;18(8): 2290-300
33. Miyahara K, Nouso K, Tomoda T, et al. Predicting the treatment effect of sorafenib using serum angiogenesis markers in patients with hepatocellular carcinoma. J Gastroenterol Hepatol 2011;26(11): 1604-11
34. Pinter M, Sieghart W, Hucke F, et al. Prognostic factors in patients with advanced hepatocellular carcinoma treated with sorafenib. Aliment Pharmacol Ther 2011; 34(8):949-59
35. Bolondi L, Caspary W, Bennouna J, et al. Clinical benefit of sorafenib in hepatitis C patients with hepatocellular carcinoma (HCC): Subgroup analysis of the SHARP trial. Gastrointestinal Cancers Symposium; 25 - 27 January 2008; Orlando, FL, USA
36. 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):2606-10
37. 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):4293-300
38. Yau T, Yao TJ, Chan P, et al. The significance of early alpha-fetoprotein level changes in predicting clinical and survival benefits in advanced hepatocellular carcinoma patients receiving sorafenib. Oncologist 2011;16(9):1270-9
39. Memon K, Kulik L, Lewandowski RJ, et al. Alpha-fetoprotein response correlates with EASL response and survival in solitary hepatocellular carcinoma treated with transarterial therapies: A subgroup analysis. J Hepatol 2012;56(5):1112-20
40. Chan SL, Mo FK, Johnson PJ, et al. New utility of an old marker: Serial alpha-fetoprotein measurement in predicting radiologic response and survival of patients with hepatocellular carcinoma undergoing systemic chemotherapy. J Clin Oncol 2009; 27(3):446-52
41. Bruix J, Raoul JL, Sherman M, et al. Efficacy and safety of sorafenib in patients with advanced hepatocellular carcinoma: Subanalyses of a phase III trial. J Hepatol 2012;57(4):821-9
42. Chen D, Zhao P, Li SQ, et al. Prognostic impact of pERK in advanced hepatocellular carcinoma patients treated with sorafenib. Eur J Surg Oncol 2013;39(9):974-80
43. Zhang Z, Zhou X, Shen H, et al. Phosphorylated ERK is a potential predictor of sensitivity to sorafenib when treating hepatocellular carcinoma: Evidence from an in vitro study. BMC Med 2009;7:41
44. Breous E, Thimme R. Potential of immunotherapy for hepatocellular carcinoma. J Hepatol 2011;54(4):830-4
45. Shi F, Shi M, Zeng Z, et al. PD-1 and PD-L1 upregulation promotes CD8(+) T-cell apoptosis and postoperative recurrence in hepatocellular carcinoma patients. Int J Cancer 2011;128(4):887-96
46. Gehring AJ, Ho ZZ, Tan AT, et al. Profile of tumor antigen-specific CD8 T cells in patients with hepatitis B virus-related hepatocellular carcinoma. Gastroenterology 2009;137(2):682-90
47. Cariani E, Pilli M, Zerbini A, et al. Immunological and molecular correlates of disease recurrence after liver resection for hepatocellular carcinoma. PLoS One 2012; 7(3):e32493
48. Dunn GP, Old LJ, Schreiber RD. The immunobiology of cancer immunosurveillance and immunoediting. Immunity 2004;21(2):137-48
49. Cao M, Cabrera R, Xu Y, et al. Hepatocellular carcinoma cell supernatants increase expansion and function of CD4(+) CD25(+) regulatory T cells. Lab Invest 2007;87(6):582-90
50. Zou W. Regulatory T cells, tumour immunity and immunotherapy. Nat Rev Immunol 2006;6(4):295-307
51. Mizukoshi E, Nakamoto Y, Arai K, et al. Comparative analysis of various tumorassociated antigen-specific t-cell responses in patients with hepatocellular carcinoma. Hepatology 2011;53(4):1206-16
52. Bricard G, Bouzourene H, Martinet O, et al. Naturally acquired MAGE-A10- And SSX-2-specific CD8+ T cell responses in patients with hepatocellular carcinoma. J Immunol 2005;174(3):1709-16
53. Tatsumi T, Takehara T, Katayama K, et al. Expression of costimulatory molecules B7-1 (CD80) and B7-2 (CD86) on human hepatocellular carcinoma. Hepatology 1997; 25(5):1108-14
54. Zang X, Allison JP. The B7 family and cancer therapy: Costimulation and coinhibition. Clin Cancer Res 2007; 13(18 Pt 1):5271-9
55. Palmer DH, Midgley RS, Mirza N, et al. A phase II study of adoptive immunotherapy using dendritic cells pulsed with tumor lysate in patients with hepatocellular carcinoma. Hepatology 2009; 49(1):124-32
56. Butterfield LH, Ribas A, Dissette VB, et al. A phase I/II trial testing immunization of hepatocellular carcinoma patients with dendritic cells pulsed with four alpha-fetoprotein peptides. Clin Cancer Res 2006;12(9):2817-25
57. Ali MY, Grimm CF, Ritter M, et al. Activation of dendritic cells by local ablation of hepatocellular carcinoma. J Hepatol 2005;43(5):817-22
58. Farazi PA, DePinho RA. The genetic and environmental basis of hepatocellular carcinoma. Discov Med 2006;6(35):182-6
59. Farazi PA, DePinho RA. Hepatocellular carcinoma pathogenesis: From genes to environment. Nat Rev Cancer 2006;6(9): 674-87
60. Llovet JM, Bruix J. Molecular targeted therapies in hepatocellular carcinoma. Hepatology 2008;48(4):1312-27
61. Minguez B, Tovar V, Chiang D, et al. Pathogenesis of hepatocellular carcinoma and molecular therapies. Curr Opin Gastroenterol 2009;25(3):186-94
62. Laurent-Puig P, Zucman-Rossi J. Genetics of hepatocellular tumors. Oncogene 2006; 25(27):3778-86
63. Kudo M. Current status of molecularly targeted therapy for hepatocellular carcinoma: Clinical practice. Int J Clin Oncol 2010;15(3):242-55
64. Kudo M. Hepatocellular carcinoma. 2009 and beyond: From the surveillance to molecular targeted therapy. Oncology 2008; 75(Suppl 1):1-12
65. Roberts PJ, Der CJ. Targeting the Raf-MEK-ERK mitogen-Activated protein kinase cascade for the treatment of cancer. Oncogene 2007;26(22):3291-310
66. 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):54-8
67. Huynh H, Nguyen TT, Chow KH, et al. Over-expression of the mitogen-Activated protein kinase (MAPK) kinase (MEK)-MAPK in hepatocellular carcinoma: Its role in tumor progression and apoptosis. BMC Gastroenterol 2003;3:19
68. Calvisi DF, Ladu S, Gorden A, et al. Ubiquitous activation of Ras and Jak/Stat pathways in human HCC. Gastroenterology 2006;130(4):1117-28
69. 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):318-25
70. Okano J, Shiota G, Kawasaki H. Expression of hepatocyte growth factor (HGF) and HGF receptor (c-met) proteins in liver diseases: An immunohistochemical study. Liver 1999;19(2):151-9
71. Yamaguchi R, Yano H, Iemura A, et al. Expression of vascular endothelial growth factor in human hepatocellular carcinoma. Hepatology 1998;28(1):68-77
72. Villanueva A, Newell P, Chiang DY, et al. Genomics and signaling pathways in hepatocellular carcinoma. Semin Liver Dis 2007;27(1):55-76
73. Bekaii-Saab T, Markowitz J, Prescott N, et al. A multi-institutional phase II study of the efficacy and tolerability of lapatinib in patients with advanced hepatocellular carcinomas. Clin Cancer Res 2009;15(18): 5895-901
74. Tannapfel A, Sommerer F, Benicke M, et al. Mutations of the BRAF gene in cholangiocarcinoma but not in hepatocellular carcinoma. Gut 2003;52(5): 706-12
75. 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
76. 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(19):2154-60
77. Abou-Alfa GK. Phase III randomized study of sorafenib plus doxorubicin versus sorafenib in patients with advanced hepatocellular carcinoma (HCC). 2010. Available from: Http://clinicaltrials.gov/ct2/ show/NCT01015833?term=sorafenib +doxorubicin+phase+III&rank=1 [Last accessed 27 December 2010]
78. 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):6657-63
79. Thomas MB, Chadha R, Glover K, et al. Phase 2 study of erlotinib in patients with unresectable hepatocellular carcinoma. Cancer 2007;110(5):1059-67
80. 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):843-50
81. A Phase III randomized, placebo controlled, double blind trial of sorafenib plus erlotinib vs. sorafenib plus placebo as first line systemic treatment for hepatocellular carcinoma (HCC). 2010. Available from: Http://clinicaltrials.gov/ct2/show/NCT00901901?term=SEARCH&rank=2 [Last accessed 27 December 2010]
82. Burris HA 3rd, Hurwitz HI, Dees EC, et al. Phase I safety, pharmacokinetics, and clinical activity study of lapatinib (GW572016), a reversible dual inhibitor of epidermal growth factor receptor tyrosine kinases, in heavily pretreated patients with metastatic carcinomas. J Clin Oncol 2005; 23(23):5305-13
83. Zhu AX, Stuart K, Blaszkowsky LS, et al. Phase 2 study of cetuximab in patients with advanced hepatocellular carcinoma. Cancer 2007;110(3):581-9
84. Asnacios A, Fartoux L, Romano O, et al. Gemcitabine plus oxaliplatin (GEMOX) combined with cetuximab in patients with progressive advanced stage hepatocellular carcinoma: Results of a multicenter phase 2 study. Cancer 2008;112(12):2733-9
85. Ou DL, Shen YC, Liang JD, et al. Induction of Bim expression contributes to the antitumor synergy between sorafenib and mitogen-Activated protein kinase/ extracellular signal-regulated kinase kinase inhibitor CI-1040 in hepatocellular carcinoma. Clin Cancer Res 2009;15(18): 5820-8
86. Hennig M, Yip-Schneider MT, Wentz S, et al. Targeting mitogen-Activated protein kinase kinase with the inhibitor PD0325901 decreases hepatocellular carcinoma growth in vitro and in mouse model systems. Hepatology 2010;51(4): 1218-25
87. 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):30-7
88. Huynh H. AZD6244 (ARRY-142886) enhances the antitumor activity of rapamycin in mouse models of human hepatocellular carcinoma. Cancer 2010; 116(5):1315-25
89. Huynh H, Ngo VC, Koong HN, et al. AZD6244 enhances the anti-Tumor activity of sorafenib in ectopic and orthotopic models of human hepatocellular carcinoma (HCC). J Hepatol 2010;52(1):79-87
90. Huynh H, Chow PK, Soo KC. AZD6244 and doxorubicin induce growth suppression and apoptosis in mouse models of hepatocellular carcinoma. Mol Cancer Ther 2007;6(9):2468-76
91. 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):138-46
92. Iverson C, Larson G, Lai C, et al. RDEA119/BAY 869766: A potent, selective, allosteric inhibitor of MEK1/2 for the treatment of cancer. Cancer Res 2009; 69(17):6839-47
93. Choo SP. AZD6244 and sorafenib in advanced hepatocellular carcinoma. 2010. Available from: Http://clinicaltrials.gov/ct2/ show/NCT01029418?. term=selumetinib&rank=14 [Last accessed 27 December 2010]
94. Clendeninn N. RDEA119 and sorafenib combination Dose escalation study. 2010. Available from: Http://clinicaltrials.gov/ct2/ show/NCT00785226?term=rdea +119&rank=1 [Last accessed 27 December 2010]
95. 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):2992-8
96. Huynh H, Ngo VC, Choo SP, et al. Sunitinib (SUTENT, SU11248) suppresses tumor growth and induces apoptosis in xenograft models of human hepatocellular carcinoma. Curr Cancer Drug Targets 2009;9(6):738-47
97. Zhu AX, Duda DG, Sahani DV, Jain RK. Development of sunitinib in hepatocellular carcinoma: Rationale, early clinical experience, and correlative studies. Cancer J 2009;15(4):263-8
98. Faivre S, Raymond E, Boucher E, et al. Safety and efficacy of sunitinib in patients with advanced hepatocellular carcinoma: An open-label, multicentre, phase II study. Lancet Oncol 2009;10(8):794-800
99. 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):3027-35
100. A multinational, randomized, open-label, phase 3 study of sunitinib malate versus sorafenib in patients with advanced hepatocellular carcinoma. 2010. Available from: Http://clinicaltrials.gov/ct2/show/NCT00699374?term=sunitinib+versus +sorafenib&rank=1 [Last accessed27 December 2010]
101. Dempke WC, Zippel R. Brivanib, a novel dual VEGF-R2/bFGF-R inhibitor. Anticancer Res 2010;30(11):4477-83
102. Raoul JL, Flinn 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 2009;27:4577
103. Johnson PJ, Qin S, Park JW, et al. Brivanib versus sorafenib as first-line therapy in patients with unresectable, advanced hepatocellular carcinoma: Results from the randomized phase III BRISK-FL study. J Clin Oncol 2013;31(28):3517-24
104. Brivanib in Hepatocellular Carcinoma. 2010. Available from: Http://clinicaltrials. gov/ct2/results?term=brivanib+HCC [Last accessed 27 December 2010]
105. Llovet JM, Decaens T, Raoul JL, et al. Brivanib in patients with advanced hepatocellular carcinoma who were intolerant to sorafenib or for whom sorafenib failed: Results from the randomized phase III BRISK-PS study. J Clin Oncol 2013;31(28):3509-16
106. Boyault S, Rickman DS, de Reynies A, et al. Transcriptome classification of HCC is related to gene alterations and to new therapeutic targets. Hepatology 2007;45(1): 42-52
107. Fujiwara Y, Hoon DS, Yamada T, et al. PTEN/MMAC1 mutation and frequent loss of heterozygosity identified in chromosome 10q in a subset of hepatocellular carcinomas. Jpn J Cancer Res 2000;91(3): 287-92
108. Nocera A, Andorno E, Tagliamacco A, et al. Sirolimus therapy in liver transplant patients: An initial experience at a single center. Transplant Proc 2008;40(6):1950-2
109. Toso C, Meeberg GA, Bigam DL, et al. De novo sirolimus-based immunosuppression after liver transplantation for hepatocellular carcinoma: Long-Term outcomes and side effects. Transplantation 2007;83(9):1162-8
110. Zhou J, Wang Z, Wu ZQ, et al. Sirolimus-based immunosuppression therapy in liver transplantation for patients with hepatocellular carcinoma exceeding the Milan criteria. Transplant Proc 2008; 40(10):3548-53
111. 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
112. 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):1371-80
113. Chen L, Shiah HS, Chen CY, et al. Randomized, phase I, and pharmacokinetic (PK) study of RAD001, an mTOR inhibitor, in patients (pts) with advanced hepatocellular carcinoma (HCC). J Clin Oncol 2009;2009:4587
114. Treiber G. Treatment of advanced or metastatic hepatocellular cancer (HCC): Interim analysis of a single-Arm phase II study of bevacizumab and RAD001. J Clin Oncol 2010;2010:4102
115. Zhu AX, Kudo M, Assenat E, et al. EVOLVE-1: Phase 3 study of everolimus for advanced HCC that progressed during or after sorafenib. J Clin Oncol 2014; 32(Suppl 3):abstract 172
116. Fei HR, Chen G, Wang JM, Wang FZ. Perifosine induces cell cycle arrest and apoptosis in human hepatocellular carcinoma cell lines by blockade of Akt phosphorylation. Cytotechnology 2010; 62(5):449-60
117. Campos LT, Nemunaitis J, Stephenson J, et al. Phase II study of single agent perifosine in patients with hepatocellular carcinoma (HCC). J Clin Oncol 2009; 27(15S):e15505
118. Huber AH, Weis WI. The structure of the beta-catenin/E-cadherin complex and the molecular basis of diverse ligand recognition by beta-catenin. Cell 2001;105(3):391-402
119. Taniguchi K, Roberts LR, Aderca IN, et al. Mutational spectrum of beta-catenin, AXIN1, and AXIN2 in hepatocellular carcinomas and hepatoblastomas. Oncogene 2002;21(31):4863-71
120. 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): 1683-93
121. 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):1096-105
122. Cabibbo G, Enea M, Attanasio M, et al. A meta-Analysis of survival rates of untreated patients in randomized clinical trials of hepatocellular carcinoma. Hepatology 2010; 51(4):1274-83
123. Combescure C, Foucher Y, Jackson D. Meta-Analysis of single-Arm survival studies: A distribution-free approach for estimating summary survival curves with random effects. Stat Med 2014;33(15):2521-37
124. Lee TK, Poon RT, Yuen AP, et al. Twist overexpression correlates with hepatocellular carcinoma metastasis through induction of epithelial-mesenchymal transition. Clin Cancer Res 2006;12(18):5369-76
125. Lygidakis NJ, Kosmidis P, Ziras N, et al. Combined transarterial targeting locoregional immunotherapy-chemotherapy for patients with unresectable hepatocellular carcinoma: A new alternative for an old problem. J Interferon Cytokine Res 1995; 15(5):467-72
126. Reinisch W, Holub M, Katz A, et al. Prospective pilot study of recombinant granulocyte-macrophage colony-stimulating factor and interferon-gamma in patients with inoperable hepatocellular carcinoma. J Immunother 2002:25(6):489-99
127. Sangro B, Mazzolini G, Ruiz J, et al. Phase I trial of intratumoral injection of an adenovirus encoding interleukin-12 for advanced digestive tumors. J Clin Oncol 2004;22(8):1389-97
128. Une Y, Kawata A, Uchino J. [Adopted immunochemotherapy using IL-2 and spleen LAK cell - randomized study]. Nihon Geka Gakkai zasshi 1991;92(9): 1330-3
129. Kawata A, Une Y, Hosokawa M, et al. Adjuvant chemoimmunotherapy for hepatocellular carcinoma patients. Adriamycin, interleukin-2, and lymphokine-Activated killer cells versus adriamycin alone. Am J Clin Oncol 1995; 18(3):257-62
130. Wang Y, Chen H, Wu M, et al. Postoperative immunotherapy for patients with hepatocarcinoma using tumor-infiltrating lymphocytes. Chin Med J (Engl) 1997;110(2):114-17
131. Takayama T, Sekine T, Makuuchi M, et al. Adoptive immunotherapy to lower postsurgical recurrence rates of hepatocellular carcinoma: A randomised trial. Lancet 2000;356(9232):802-7
132. Ladhams A, Schmidt C, Sing G, et al. Treatment of non-resectable hepatocellular carcinoma with autologous tumor-pulsed dendritic cells. J Gastroenterol Hepatol 2002;17(8):889-96
133. Mazzolini G, Alfaro C, Sangro B, et al. Intratumoral injection of dendritic cells engineered to secrete interleukin-12 by recombinant adenovirus in patients with metastatic gastrointestinal carcinomas. J Clin Oncol 2005;23(5):999-1010
134. Lee WC, Wang HC, Hung CF, et al. Vaccination of advanced hepatocellular carcinoma patients with tumor lysate-pulsed dendritic cells: A clinical trial. J Immunother 2005:28(5):496-504
135. Kuang M, Peng BG, Lu MD, et al. Phase II randomized trial of autologous formalin-fixed tumor vaccine for postsurgical recurrence of hepatocellular carcinoma. Clin Cancer Res 2004;10(5): 1574-9
136. Peng B, Liang L, Chen Z, et al. Autologous tumor vaccine lowering postsurgical recurrent rate of hepatocellular carcinoma. Hepatogastroenterology 2006;53(69):409-14
137. Butterfield LH, Ribas A, Meng WS, et al. T-cell responses to HLA-A. 0201 immunodominant peptides derived from alpha-fetoprotein in patients with hepatocellular cancer. Clin Cancer Res 2003;9(16 Pt 1):5902-8
138. Butterfield LH, Ribas A, Dissette VB, et al. A phase I/II trial testing immunization of hepatocellular carcinoma patients with dendritic cells pulsed with four alpha-fetoprotein peptides. Clin Cancer Res 2006;12(9):2817
139. Palmer DH, Midgley RS, Mirza N, et al. A phase II study of adoptive immunotherapy using dendritic cells pulsed with tumor lysate in patients with hepatocellular carcinoma. Hepatology 2009; 49(1):124
140. Petrini P, Lencioni M, Ricasoli M, et al. A phase II trial of sorafenib (S) in combination with 5-fluorouracil (5FU) continuous infusion in patients with advanced hepatocellular carcinoma: Preliminary data. J Clin Oncol 2009;2009:4592
141. Clinical study protocol phase 2, randomized study of cs-1008 in combination with sorafenib compared to sorafenib alone as first-line systemic therapy in subjects with advanced hepatocellular carcinoma. 2010. Available from: Http://clinicaltrials.gov/ct2/ show/NCT01033240?term=sorafenib+CS +1008&rank=1 [Last accessed 15 January 2011]
142. 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):1898-903
143. Thomas MB. Bevacizumab and erlotinib or sorafenib as first-line therapy in treating patients with advanced liver cancer. 2010. Available from: Http://clinicaltrials.gov/ct2/ show/NCT00881751?term=bevacizumab +hepatocellular+carcinoma&rank=13. [Last accessed 15 January 2011]
144. Abou-Alfa GK, Carvajal RD, Chung KY, et al. A non-randomized phase ii study of sequential irinotecan (cpt-11) and flavopiridol in patients with advanced hepatoma. J Clin Oncol 2006;24(18S):4148
145. A Phase 1b, open-label study of sorafenib with biib022 in subjects with advanced hepatocellular carcinoma. 2010. Available from: Http://clinicaltrials.gov/ct2/show/NCT00956436?term=BIIB022+and +hepatocellular+carcinoma&rank=1 [Last accessed 29 December 2010]
146. A multicenter, phase 2 study evaluating imc-A12 in combination with sorafenib as first-line therapy for patients with advanced hepatocellular carcinoma (HCC). 2010. Available from: Http://clinicaltrials.gov/ct2/ show/NCT00906373?term=IMC+A12 +AND+hepatocellular+carcinoma&rank=1 [Last accessed 29 December 2010]
147. Gogov S. A Randomized, placebo-controlled, double-blinded phase 2 study of second-line treatment with osi-906 in patients with advanced hepatocellular carcinoma (HCC) after failure of first-line treatment with sorafenib. 2011. Available from: Http://clinicaltrials. gov/ct2/show/NCT01101906?term=OSI-906&rank=7 [Last accessed 15 January 2011]
148. He A. Phase II study of ABT-888 and temozolomide in patients with advanced hepatocellular carcinoma (HCC) Progressing following sorafenib treatment or intolerant to sorafenib. 2010. Available from: Http:// clinicaltrials.gov/ct2/show/NCT01205828?. term=abt+888+AND+sorafenib&rank=1 [Last accessed 15 January 2011]
149. Louafi S, Boige V, Ducreux M, et al. Gemcitabine plus oxaliplatin (GEMOX) in patients with advanced hepatocellular carcinoma (HCC): Results of a phase II study. Cancer 2007;109(7):1384-90
150. Abou-Alfa GK, Gansukh B, Chou JF, et al. Phase II study of cixutumumab (IMC-A12, NSC742460; C) in hepatocellular carcinoma (HCC). J Clin Oncol 2011;29; abstr 4043
151. Borbath I, Santoro A, Van Laethem J, et al. A randomized, placebo-controlled phase II clinical trial evaluating the c-Met inhibitor, ARQ 197, in patients (pts) with hepatocellular carcinoma (HCC). J Clin Oncol 2010;28(15s):abstract TPS215
152. Carlson D. Efficacy and tolerability of ABT-869 versus sorafenib in advanced hepatocellular carcinoma (HCC). 2010. Available from: Http://clinicaltrials.gov/ct2/ show/NCT01009593?term=ABT+869+in +hepatocellular+carcinoma&rank=2 [Last accessed 15 January 2011]
153. A randomized, double-blind, multi-center Phase III study of brivanib versus sorafenib as first-line treatment in patients with advanced hepatocellular carcinoma. 2011. Available from: Http://clinicaltrials.gov/ct2/ show/NCT00858871?term=brivanib+AND +sorafenib&rank=1 [Last accessed 15 January 2011]