Current systemic treatment of hepatocellular carcinoma: A review of the literature

World Journal of Hepatology

Volumn 7, Issue 10, 2015, Pages 1412-1420

  Chen, Kai Wen ^a,b   Ou, Tzu Ming ^b,c   Hsu, Chin Wen ^c   Horng, Chi Ting ^c   Lee, Ching Chang ^c   Tsai, Yuh Yuan ^c   Tsai, Chi Chang ^c   Liou, Yi Sheng ^d,e   Yang, Chen Chieh ^f   Hsueh, Chao Wen ^c   Kuo, Wu Hsien ^b,c  

^a HUALIEN ARMED FORCES GENERAL HOSPITAL   (Taiwan)

^b TRI SERVICE GENERAL HOSPITAL   (Taiwan)

^c KAOHSIUNG ARMED FORCES GENERAL HOSPITAL   (Taiwan)

^d TAICHUNG VETERANS GENERAL HOSPITAL   (Taiwan)

^e NATIONAL DEFENSE MEDICAL CENTER   (Taiwan)

^f Mennonite Christian Hospital   (Taiwan)

Author keywords

Hepatocellular carcinoma; Molecular target therapy; Sorafenib; Systemic treatment; Transarterial chemoembolization

Indexed keywords

EID: 84930392170     PISSN: None     EISSN: 19485182     Source Type: Journal    
DOI: 10.4254/wjh.v7.i10.1412     Document Type: Short Survey

References (86)

1. Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. CA Cancer J Clin 2011; 61: 69-90 [PMID: 21296855 DOI: 10.3322/caac.20107].
2. A new prognostic system for hepatocellular carcinoma: a retrospective study of 435 patients: the Cancer of the Liver Italian Program (CLIP) investigators. Hepatology 1998; 28: 751-755 [PMID: 9731568 DOI: 10.1002/hep.510280322].
3. Venook AP, Papandreou C, Furuse J, de Guevara LL. The incidence and epidemiology of hepatocellular carcinoma: a global and regional perspective. Oncologist 2010; 15 Suppl 4: 5-13 [PMID: 21115576 DOI: 10.1634/theoncologist.2010-S4-05].
4. Beasley RP. Hepatitis B virus. The major etiology of hepatocellular carcinoma. Cancer 1988; 61: 1942-1956 [PMID: 2834034 DOI: 10.1002/1097-0142(19880515)61:10<1942::AID-CNCR-2820611003>3.0.CO;2-J].
5. 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: 1485-1491 [PMID: 19224838 DOI: 10.1200/jco.2008.20.7753].
6. Llovet JM, Brú C, Bruix J. Prognosis of hepatocellular carcinoma: the BCLC staging classification. Semin Liver Dis 1999; 19: 329-338 [PMID: 10518312 DOI: 10.1055/s-2007-1007122].
7. Leung TW, Tang AM, Zee B, Lau WY, Lai PB, Leung KL, Lau JT, Yu SC, Johnson PJ. Construction of the Chinese University Prognostic Index for hepatocellular carcinoma and comparison with the TNM staging system, the Okuda staging system, and the Cancer of the Liver Italian Program staging system: a study based on 926 patients. Cancer 2002; 94: 1760-1769 [PMID: 11920539 DOI: 10.1002/cncr.10384].
8. Kudo M, Chung H, Osaki Y. Prognostic staging system for hepatocellular carcinoma (CLIP score): its value and limitations, and a proposal for a new staging system, the Japan Integrated Staging Score (JIS score). J Gastroenterol 2003; 38: 207-215 [PMID: 12673442 DOI: 10.1007/s005350300038].
9. Bolondi L, Burroughs A, Dufour JF, Galle PR, Mazzaferro V, Piscaglia F, Raoul JL, Sangro B. Heterogeneity of patients with intermediate (BCLC B) Hepatocellular Carcinoma: proposal for a subclassification to facilitate treatment decisions. Semin Liver Dis 2012; 32: 348-359 [PMID: 23397536 DOI: 10.1055/s-0032-1329906].
10. Lopez PM, Villanueva A, Llovet JM. Systematic review: evidencebased management of hepatocellular carcinoma-an updated analysis of randomized controlled trials. Aliment Pharmacol Ther 2006; 23: 1535-1547 [PMID: 16696801 DOI: 10.1111/j.1365-2036.2006.02932.x].
11. Huang C, Xu D, Xia Q, Wang P, Rong C, Su Y. Reversal of P-glycoprotein-mediated multidrug resistance of human hepatic cancer cells by Astragaloside II. J Pharm Pharmacol 2012; 64: 1741-1750 [PMID: 23146037 DOI: 10.1111/j. 2042-7158.2012.015 49.x].
12. Soini Y, Virkajärvi N, Raunio H, Pääkkö P. Expression of P-glycoprotein in hepatocellular carcinoma: a potential marker of prognosis. J Clin Pathol 1996; 49: 470-473 [PMID: 8763260 DOI: 10.1136/jcp.49.6.470].
13. Fardel O, Loyer P, Lecureur V, Glaise D, Guillouzo A. Constitutive expression of functional P-glycoprotein in rat hepatoma cells. Eur J Biochem 1994; 219: 521-528 [PMID: 7905826].
14. Li CG, Zhao ZM, Hu MG, Liu R. Predictive role of glutathione-S-transferase gene polymorphisms in risk and prognosis of hepatocellular carcinoma. Asian Pac J Cancer Prev 2012; 13: 3247-3252 [PMID: 22994742 DOI: 10.7314/APJCP. 2012.13.7.3247].
15. Lv LH, Wan YL, Lin Y, Zhang W, Yang M, Li GL, Lin HM, Shang CZ, Chen YJ, Min J. Anticancer drugs cause release of exosomes with heat shock proteins from human hepatocellular carcinoma cells that elicit effective natural killer cell antitumor responses in vitro. J Biol Chem 2012; 287: 15874-15885 [PMID: 22396543 DOI: 10.1074/jbc.M112.340588].
16. Chen MC, Chen CH, Chuang HC, Kulp SK, Teng CM, Chen CS. Novel mechanism by which histone deacetylase inhibitors facilitate topoisomerase IIα degradation in hepatocellular carcinoma cells. Hepatology 2011; 53: 148-159 [PMID: 21254166 DOI: 10.1002/hep.23964].
17. Chan KT, Lung ML. Mutant p53 expression enhances drug resistance in a hepatocellular carcinoma cell line. Cancer Chemother Pharmacol 2004; 53: 519-526 [PMID: 15004724 DOI: 10.1007/s00280-004-0767-4].
18. Nagahama H, Okada S, Okusaka T, Ishii H, Ikeda M, Nakasuka H, Yoshimori M. Predictive factors for tumor response to systemic chemotherapy in patients with hepatocellular carcinoma. Jpn J Clin Oncol 1997; 27: 321-324 [PMID: 9390209 DOI: 10.1093/jjco/27.5.321].
19. Nowak AK, Chow PK, Findlay M. Systemic therapy for advanced hepatocellular carcinoma: a review. Eur J Cancer 2004; 40: 1474-1484 [PMID: 15196530 DOI: 10.1016/j.ejca.2004.02.027].
20. Palmer DH, Hussain SA, Johnson PJ. Systemic therapies for hepatocellular carcinoma. Expert Opin Investig Drugs 2004; 13: 1555-1568 [PMID: 15566313 DOI: 10.1517/13543784.13.12.1555].
21. Thomas MB, O'Beirne JP, Furuse J, Chan AT, Abou-Alfa G, Johnson P. Systemic therapy for hepatocellular carcinoma: cytotoxic chemotherapy, targeted therapy and immunotherapy. Ann Surg Oncol 2008; 15: 1008-1014 [PMID: 18236117 DOI: 10.1245/s10434-007-9705-0].
22. National Comprehensive Cancer Network. National Comprehensive Cancer Network guidelines for hepatobiliary cancer. Version 2. [Accessed 2014]. Available from: URL: http://www.nccn.org/.
23. Raza A, Sood GK. Hepatocellular carcinoma review: current treatment, and evidence-based medicine. World J Gastroenterol 2014; 20: 4115-4127 [PMID: 24764650 DOI: 10.3748/wjg.v20. i15.4115].
24. Kudo M. Signaling pathway/molecular targets and new targeted agents under development in hepatocellular carcinoma. World J Gastroenterol 2012; 18: 6005-6017 [PMID: 23155330 DOI: 10.3748/wjg.v18.i42.6005].
25. Wilhelm S, Carter C, Lynch M, Lowinger T, Dumas J, Smith RA, Schwartz B, Simantov R, Kelley S. Discovery and development of sorafenib: a multikinase inhibitor for treating cancer. Nat Rev Drug Discov 2006; 5: 835-844 [PMID: 17016424].
26. Liu L, Cao Y, Chen C, Zhang X, McNabola A, Wilkie D, Wilhelm S, Lynch M, Carter C. 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 [PMID: 17178882 DOI: 10.1158/0008-5472. can-06-1377].
27. Llovet JM, Ricci S, Mazzaferro V, Hilgard P, Gane E, Blanc JF, de Oliveira AC, Santoro A, Raoul JL, Forner A, Schwartz M, Porta C, Zeuzem S, Bolondi L, Greten TF, Galle PR, Seitz JF, Borbath I, Häussinger D, Giannaris T, Shan M, Moscovici M, Voliotis D, Bruix J. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med 2008; 359: 378-390 [PMID: 18650514 DOI: 10.1056/NEJMoa0708857].
28. Cheng AL, Kang YK, Chen Z, Tsao CJ, Qin S, Kim JS, Luo R, Feng J, Ye S, Yang TS, Xu J, Sun Y, Liang H, Liu J, Wang J, Tak WY, Pan H, Burock K, Zou J, Voliotis D, Guan Z. 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 [PMID: 19095497 DOI: 10.1016/S1470-2045(08)70285-7].
29. Abou-Alfa GK, Johnson P, Knox JJ, Capanu M, Davidenko I, Lacava J, Leung T, Gansukh B, Saltz LB. Doxorubicin plus sorafenib vs doxorubicin alone in patients with advanced hepatocellular carcinoma: a randomized trial. JAMA 2010; 304: 2154-2160 [PMID: 21081728 DOI: 10.1001/jama.2010.1672].
30. Prete SD, Montella L, Caraglia M, Maiorino L, Cennamo G, Montesarchio V, Piai G, Febbraro A, Tarantino L, Capasso E, Palmieri G, Guarrasi R, Bianco M, Mamone R, Savastano C, Pisano A, Vincenzi B, Sabia A, D'Agostino A, Faiola V, Addeo R. Sorafenib plus octreotide is an effective and safe treatment in advanced hepatocellular carcinoma: multicenter phase II So.LAR. study. Cancer Chemother Pharmacol 2010; 66: 837-844 [PMID: 20041325 DOI: 10.1007/s00280-009-1226-z].
31. Zhai B, Sun XY. Mechanisms of resistance to sorafenib and the corresponding strategies in hepatocellular carcinoma. World J Hepatol 2013; 5: 345-352 [PMID: 23898367 DOI: 10.4254/wjh. v5.i7.345].
32. Faivre S, Raymond E, Boucher E, Douillard J, Lim HY, Kim JS, Zappa M, Lanzalone S, Lin X, Deprimo S, Harmon C, Ruiz-Garcia A, Lechuga MJ, Cheng AL. Safety and efficacy of sunitinib in patients with advanced hepatocellular carcinoma: an openlabel, multicentre, phase II study. Lancet Oncol 2009; 10: 794-800 [PMID: 19586800 DOI: 10.1016/S1470-2045(09)70171-8].
33. Cheng AL, Kang YK, Lin DY, Park JW, Kudo M, Qin S, Chung HC, Song X, Xu J, Poggi G, Omata M, Pitman Lowenthal S, Lanzalone S, Yang L, Lechuga MJ, Raymond E. Sunitinib versus sorafenib in advanced hepatocellular cancer: results of a randomized phase III trial. J Clin Oncol 2013; 31: 4067-4075 [PMID: 24081937 DOI: 10.1200/JCO.2012.45.8372].
34. Toh HC, Chen PJ, Carr BI, Knox JJ, Gill S, Ansell P, McKeegan EM, Dowell B, Pedersen M, Qin Q, Qian J, Scappaticci FA, Ricker JL, Carlson DM, Yong WP. Phase 2 trial of linifanib (ABT-869) in patients with unresectable or metastatic hepatocellular carcinoma. Cancer 2013; 119: 380-387 [PMID: 22833179 DOI: 10.1002/cncr.27758].
35. Cainap C, Qin S, Huang WT, Chung IJ, Pan H, Cheng Y, Kudo M, Kang YK, Chen PJ, Toh HC, Gorbunova V, Eskens F, Qian J, McKee MD, Ricker JL, Carlson DM, Nowiem SE. Phase III trial of linifanib versus sorafenib in patients with advanced hepatocellular carcinoma (HCC). J Clin Oncol 2013; 31 Suppl 4: abstr 249.
36. Finn RS, Kang YK, Mulcahy M, Polite BN, Lim HY, Walters I, Baudelet C, Manekas D, Park JW. Phase II, open-label study of brivanib as second-line therapy in patients with advanced hepatocellular carcinoma. Clin Cancer Res 2012; 18: 2090-2098 [PMID: 22238246 DOI: 10.1158/1078-0432.ccr-11-1991].
37. Park JW, Finn RS, Kim JS, Karwal M, Li RK, Ismail F, Thomas M, Harris R, Baudelet C, Walters I, Raoul JL. Phase II, open-label study of brivanib as first-line therapy in patients with advanced hepatocellular carcinoma. Clin Cancer Res 2011; 17: 1973-1983 [PMID: 21349999 DOI: 10.1158/1078-0432.ccr-10-2011].
38. Llovet JM, Decaens T, Raoul JL, Boucher E, Kudo M, Chang C, Kang YK, Assenat E, Lim HY, Boige V, Mathurin P, Fartoux L, Lin DY, Bruix J, Poon RT, Sherman M, Blanc JF, Finn RS, Tak WY, Chao Y, Ezzeddine R, Liu D, Walters I, Park JW. 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: 3509-3516 [PMID: 23980090 DOI: 10.1200/JCO.2012.47.3009].
39. Johnson PJ, Qin S, Park JW, Poon RT, Raoul JL, Philip PA, Hsu CH, Hu TH, Heo J, Xu J, Lu L, Chao Y, Boucher E, Han KH, Paik SW, Robles-Aviña J, Kudo M, Yan L, Sobhonslidsuk A, Komov D, Decaens T, Tak WY, Jeng LB, Liu D, Ezzeddine R, Walters I, Cheng 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: 3517-3524 [PMID: 23980084 DOI: 10.1200/JCO.2012.48.4410].
40. Zhu AX, Abrams TA, Miksad R, Blaszkowsky LS, Meyerhardt JA, Zheng H, Muzikansky A, Clark JW, Kwak EL, Schrag D, Jors KR, Fuchs CS, Iafrate AJ, Borger DR, Ryan DP. Phase 1/2 study of everolimus in advanced hepatocellular carcinoma. Cancer 2011; 117: 5094-5102 [PMID: 21538343 DOI: 10.1002/cncr.26165].
41. Shiah HS, Chen CY, Dai CY, Hsiao CF, Lin YJ, Su WC, Chang JY, Whang-Peng J, Lin PW, Huang JD, Chen LT. Randomised clinical trial: comparison of two everolimus dosing schedules in patients with advanced hepatocellular carcinoma. Aliment Pharmacol Ther 2013; 37: 62-73 [PMID: 23134470 DOI: 10.1111/apt.12132].
42. Santoro A, Rimassa L, Borbath I, Daniele B, Salvagni S, Van Laethem JL, Van Vlierberghe H, Trojan J, Kolligs FT, Weiss A, Miles S, Gasbarrini A, Lencioni M, Cicalese L, Sherman M, Gridelli C, Buggisch P, Gerken G, Schmid RM, Boni C, Personeni N, Hassoun Z, Abbadessa G, Schwartz B, Von Roemeling R, Lamar ME, Chen Y, Porta C. Tivantinib for second-line treatment of advanced hepatocellular carcinoma: a randomised, placebocontrolled phase 2 study. Lancet Oncol 2013; 14: 55-63 [PMID: 23182627 DOI: 10.1016/S1470-2045(12)70490-4].
43. Kim HC, Chung JW, Lee W, Jae HJ, Park JH. Recognizing extrahepatic collateral vessels that supply hepatocellular carcinoma to avoid complications of transcatheter arterial chemoembolization. Radiographics 2005; 25 Suppl 1: S25-S39 [PMID: 16227494 DOI: 10.1148/rg.25si055508].
44. 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 [PMID: 15334691].
45. Wang B, Xu H, Gao ZQ, Ning HF, Sun YQ, Cao GW. Increased expression of vascular endothelial growth factor in hepatocellular carcinoma after transcatheter arterial chemoembolization. Acta Radiol 2008; 49: 523-529 [PMID: 18568538 DOI: 10.1080/02841 850801958890].
46. Raoul JL, Sangro B, Forner A, Mazzaferro V, Piscaglia F, Bolondi L, Lencioni R. Evolving strategies for the management of intermediate-stage hepatocellular carcinoma: available evidence and expert opinion on the use of transarterial chemoembolization. Cancer Treat Rev 2011; 37: 212-220 [PMID: 20724077 DOI: 10.1016/j.ctrv.2010.07.006].
47. Park JW, Koh YH, Kim HB, Kim HY, An S, Choi JI, Woo SM, Nam BH. Phase II study of concurrent transarterial chemoembolization and sorafenib in patients with unresectable hepatocellular carcinoma. J Hepatol 2012; 56: 1336-1342 [PMID: 22314421 DOI: 10.1016/j.jhep.2012.01.006].
48. Dufour JF. TACE with or without systemic therapy?. J Hepatol 2012; 56: 1224-1225 [PMID: 22402292 DOI: 10.1016/j. jhep.2012.02.011].
49. Farinati F, Giacomin A, Vanin V, Giannini E, Trevisani F. TACE treatment in hepatocellular carcinoma: what should we do now?. J Hepatol 2012; 57: 221-222 [PMID: 22286000 DOI: 10.1016/j.jhep.2011.12.022].
50. 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: e100305 [PMID: 24945380 DOI: 10.1371/journal.pone.0100305].
51. Liu L, Chen H, Wang M, Zhao Y, Cai G, Qi X, Han G. Combination therapy of sorafenib and TACE for unresectable HCC: a systematic review and meta-analysis. PLoS One 2014; 9: e91124 [PMID: 24651044 DOI: 10.1371/journal.pone.0091124].
52. Kudo M, Imanaka K, Chida N, Nakachi K, Tak WY, Takayama T, Yoon JH, Hori T, Kumada H, Hayashi N, Kaneko S, Tsubouchi H, Suh DJ, Furuse J, Okusaka T, Tanaka K, Matsui O, Wada M, Yamaguchi I, Ohya T, Meinhardt G, Okita K. Phase III study of sorafenib after transarterial chemoembolisation in Japanese and Korean patients with unresectable hepatocellular carcinoma. Eur J Cancer 2011; 47: 2117-2127 [PMID: 21664811 DOI: 10.1016/j.ejca.2011.05.007].
53. Chen KF, Tai WT, Liu TH, Huang HP, Lin YC, Shiau CW, Li PK, Chen PJ, Cheng AL. Sorafenib overcomes TRAIL resistance of hepatocellular carcinoma cells through the inhibition of STAT3. Clin Cancer Res 2010; 16: 5189-5199 [PMID: 20884624 DOI: 10.1158/1078-0432.ccr-09-3389].
54. Tai WT, Cheng AL, Shiau CW, Huang HP, Huang JW, Chen PJ, Chen KF. Signal transducer and activator of transcription 3 is a major kinase-independent target of sorafenib in hepatocellular carcinoma. J Hepatol 2011; 55: 1041-1048 [PMID: 21354226 DOI: 10.1016/j.jhep.2011.01.047].
55. Rosmorduc O, Desbois-Mouthon C. Targeting STAT3 in hepatocellular carcinoma: sorafenib again. J Hepatol 2011; 55: 957-959 [PMID: 21718664 DOI: 10.1016/j.jhep.2011.06.005].
56. Yang SF, Wang SN, Wu CF, Yeh YT, Chai CY, Chunag SC, Sheen MC, Lee KT. Altered p-STAT3 (tyr705) expression is associated with histological grading and intratumour microvessel density in hepatocellular carcinoma. J Clin Pathol 2007; 60: 642-648 [PMID: 16901975 DOI: 10.1136/jcp.2006.036970].
57. Chen KF, Tai WT, Huang JW, Hsu CY, Chen WL, Cheng AL, Chen PJ, Shiau CW. Sorafenib derivatives induce apoptosis through inhibition of STAT3 independent of Raf. Eur J Med Chem 2011; 46: 2845-2851 [PMID: 21531053 DOI: 10.1016/j.ejmech.2011.04.007].
58. Chen KF, Tai WT, Hsu CY, Huang JW, Liu CY, Chen PJ, Kim I, Shiau CW. Blockade of STAT3 activation by sorafenib derivatives through enhancing SHP-1 phosphatase activity. Eur J Med Chem 2012; 55: 220-227 [PMID: 22871485 DOI: 10.1016/j.ejmech.2012.07.023].
59. Tai WT, Shiau CW, Chen PJ, Chu PY, Huang HP, Liu CY, Huang JW, Chen KF. Discovery of novel Src homology region 2 domaincontaining phosphatase 1 agonists from sorafenib for the treatment of hepatocellular carcinoma. Hepatology 2014; 59: 190-201 [PMID: 23908138 DOI: 10.1002/hep.26640].
60. Chen KF, Chen HL, Shiau CW, Liu CY, Chu PY, Tai WT, Ichikawa K, Chen PJ, Cheng AL. Sorafenib and its derivative SC-49 sensitize hepatocellular carcinoma cells to CS-1008, a humanized anti-TNFRSF10B (DR5) antibody. Br J Pharmacol 2013; 168: 658-672 [PMID: 22978563 DOI: 10.1111/j. 1476-5381. 2012.02212.x].
61. De Maria N, Manno M, Villa E. Sex hormones and liver cancer. Mol Cell Endocrinol 2002; 193: 59-63 [PMID: 12161002 DOI: 10.1016/S0303-7207(02)00096-5].
62. Tamoxifen in treatment of hepatocellular carcinoma: a randomised controlled trial. CLIP Group (Cancer of the Liver Italian Programme) Lancet 1998; 352: 17-20 [PMID: 9800740 DOI: 10.1016/S0140-673 6(98)01259-8].
63. Perrone F, Gallo C, Daniele B, Gaeta GB, Izzo F, Capuano G, Adinolfi LE, Mazzanti R, Farinati F, Elba S, Piai G, Calandra M, Stanzione M, Mattera D, Aiello A, De Sio I, Castiglione F, Russo M, Persico M, Felder M, Manghisi OG, De Maio E, Di Maio M, Pignata S. Tamoxifen in the treatment of hepatocellular carcinoma: 5-year results of the CLIP-1 multicentre randomised controlled trial. Curr Pharm Des 2002; 8: 1013-1019 [PMID: 11945148 DOI: 10.2174/1381612024607063].
64. Villa E, Ferretti I, Grottola A, Buttafoco P, Buono MG, Giannini F, Manno M, Bertani H, Dugani A, Manenti F. Hormonal therapy with megestrol in inoperable hepatocellular carcinoma characterized by variant oestrogen receptors. Br J Cancer 2001; 84: 881-885 [PMID: 11286465 DOI: 10.1054/bjoc.2000.1534].
65. Villa E, Dugani A, Fantoni E, Camellini L, Buttafoco P, Grottola A, Pompei G, De Santis M, Ferrari A, Manenti F. Type of estrogen receptor determines response to antiestrogen therapy. Cancer Res 1996; 56: 3883-3885 [PMID: 8752151].
66. Di Maio M, De Maio E, Morabito A, D'Aniello R, De Feo G, Gallo C, Perrone F. Hormonal treatment of human hepatocellular carcinoma. Ann N Y Acad Sci 2006; 1089: 252-261 [PMID: 17261772 DOI: 10.1196/annals.1386.007].
67. Farinati F, Gianni S, De Giorgio M, Fiorentini S. Megestrol treatment in patients with hepatocellular carcinoma. Br J Cancer 2001; 85: 1606-1608 [PMID: 11720452 DOI: 10.1054/bjoc. 2001.2092].
68. Chow PK, Machin D, Chen Y, Zhang X, Win KM, Hoang HH, Nguyen BD, Jin MY, Lobo R, Findlay M, Lim CH, Tan SB, Gandhi M, Soo KC. Randomised double-blind trial of megestrol acetate vs placebo in treatment-naive advanced hepatocellular carcinoma. Br J Cancer 2011; 105: 945-952 [PMID: 21863030 DOI: 10.1038/bjc.2011.333].
69. Liu HL, Huo L, Wang L. Octreotide inhibits proliferation and induces apoptosis of hepatocellular carcinoma cells. Acta Pharmacol Sin 2004; 25: 1380-1386 [PMID: 15456543].
70. Xidakis C, Kolios G, Valatas V, Notas G, Mouzas I, Kouroumalis E. Effect of octreotide on apoptosis-related proteins in rat Kupffer cells: a possible anti-tumour mechanism. Anticancer Res 2004; 24: 833-841 [PMID: 15161035].
71. Samonakis DN, Notas G, Christodoulakis N, Kouroumalis EA. Mechanisms of action and resistance of somatostatin analogues for the treatment of hepatocellular carcinoma: a message not well taken. Dig Dis Sci 2008; 53: 2359-2365 [PMID: 18273705 DOI: 10.1007/s10620-007-0175-9].
72. Barbare JC, Bouché O, Bonnetain F, Dahan L, Lombard-Bohas C, Faroux R, Raoul JL, Cattan S, Lemoine A, Blanc JF, Bronowicki JP, Zarski JP, Cazorla S, Gargot D, Thevenot T, Diaz E, Bastie A, Aparicio T, Bedenne L. Treatment of advanced hepatocellular carcinoma with long-acting octreotide: a phase III multicentre, randomised, double blind placebo-controlled study. Eur J Cancer 2009; 45: 1788-1797 [PMID: 19303768 DOI: 10.1016/j.ejca.2009.02.018].
73. Ji XQ, Ruan XJ, Chen H, Chen G, Li SY, Yu B. Somatostatin analogues in advanced hepatocellular carcinoma: an updated systematic review and meta-analysis of randomized controlled trials. Med Sci Monit 2011; 17: RA169-RA176 [PMID: 21804474 DOI: 10.12659/MSM.881892].
74. Topalian SL, Weiner GJ, Pardoll DM. Cancer immunotherapy comes of age. J Clin Oncol 2011; 29: 4828-4836 [PMID: 22042955 DOI: 10.1200/JCO.2011.38.0899].
75. Wu K, Kryczek I, Chen L, Zou W, Welling TH. Kupffer cell suppression of CD8+ T cells in human hepatocellular carcinoma is mediated by B7-H1/programmed death-1 interactions. Cancer Res 2009; 69: 8067-8075 [PMID: 19826049 DOI: 10.1158/0008-5472. can-09-0901].
76. Topalian SL, Hodi FS, Brahmer JR, Gettinger SN, Smith DC, McDermott DF, Powderly JD, Carvajal RD, Sosman JA, Atkins MB, Leming PD, Spigel DR, Antonia SJ, Horn L, Drake CG, Pardoll DM, Chen L, Sharfman WH, Anders RA, Taube JM, McMiller TL, Xu H, Korman AJ, Jure-Kunkel M, Agrawal S, McDonald D, Kollia GD, Gupta A, Wigginton JM, Sznol M. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med 2012; 366: 2443-2454 [PMID: 22658127 DOI: 10.1056/NEJMoa1200690].
77. Dong H, Strome SE, Salomao DR, Tamura H, Hirano F, Flies DB, Roche PC, Lu J, Zhu G, Tamada K, Lennon VA, Celis E, Chen L. Tumor-associated B7-H1 promotes T-cell apoptosis: a potential mechanism of immune evasion. Nat Med 2002; 8: 793-800 [PMID: 12091876 DOI: 10.1038/nm730].
78. Freeman GJ, Long AJ, Iwai Y, Bourque K, Chernova T, Nishimura H, Fitz LJ, Malenkovich N, Okazaki T, Byrne MC, Horton HF, Fouser L, Carter L, Ling V, Bowman MR, Carreno BM, Collins M, Wood CR, Honjo T. Engagement of the PD-1 immunoinhibitory receptor by a novel B7 family member leads to negative regulation of lymphocyte activation. J Exp Med 2000; 192: 1027-1034 [PMID: 11015443 DOI: 10.1084/jem.192.7.1027].
79. Bristol-Myers Squibb. Dose escalation study of nivolumab (Anti-PD-1; BMS-936558; ONO-4538) in patients (Pts) with advanced hepatocellular carcinoma (HCC) with or without chronic viral hepatitis (Anti-PD-1 HCC). [Updated 2015 Feb 16]. Available from: URL: http://clinicaltrials.gov/ct2/show/results/NCT01658878.
80. Boni C, Fisicaro P, Valdatta C, Amadei B, Di Vincenzo P, Giuberti T, Laccabue D, Zerbini A, Cavalli A, Missale G, Bertoletti A, Ferrari C. Characterization of hepatitis B virus (HBV)-specific T-cell dysfunction in chronic HBV infection. J Virol 2007; 81: 4215-4225 [PMID: 17287266 DOI: 10.1128/JVI.02844-06].
81. Penna A, Pilli M, Zerbini A, Orlandini A, Mezzadri S, Sacchelli L, Missale G, Ferrari C. Dysfunction and functional restoration of HCV-specific CD8 responses in chronic hepatitis C virus infection. Hepatology 2007; 45: 588-601 [PMID: 17326153 DOI: 10.1002/hep.21541].
82. Shi F, Shi M, Zeng Z, Qi RZ, Liu ZW, Zhang JY, Yang YP, Tien P, Wang FS. PD-1 and PD-L1 upregulation promotes CD8(+) T-cell apoptosis and postoperative recurrence in hepatocellular carcinoma patients. Int J Cancer 2011; 128: 887-896 [PMID: 20473887 DOI: 10.1002/ijc.25397].
83. Fujiwara T, Urata Y, Tanaka N. Telomerase-specific oncolytic virotherapy for human cancer with the hTERT promoter. Curr Cancer Drug Targets 2007; 7: 191-201 [PMID: 17346111 DOI: 10.2174/156800907780058835].
84. Kawakami Y, Kitamoto M, Nakanishi T, Yasui W, Tahara E, Nakayama J, Ishikawa F, Tahara H, Ide T, Kajiyama G. Immunohistochemical detection of human telomerase reverse transcriptase in human liver tissues. Oncogene 2000; 19: 3888-3893 [PMID: 10951582 DOI: 10.1038/sj.onc.1203733].
85. Li YM, Song ST, Jiang ZF, Zhang Q, Su CQ, Liao GQ, Qu YM, Xie GQ, Li MY, Ge FJ, Qian QJ. Telomerase-specific oncolytic virotherapy for human hepatocellular carcinoma. World J Gastroenterol 2008; 14: 1274-1279 [PMID: 18300357 DOI: 10.3748/wjg.14.1274].
86. Lin WH, Yeh SH, Yang WJ, Yeh KH, Fujiwara T, Nii A, Chang SS, Chen PJ. Telomerase-specific oncolytic adenoviral therapy for orthotopic hepatocellular carcinoma in HBx transgenic mice. Int J Cancer 2013; 132: 1451-1462 [PMID: 22886913 DOI: 10.1002/ijc.27770].