118 does not adversely impact survival [J]. Hepatology, 2001, 33 (6):139-103. [23] Duffy JP, Vardanian A, Benjamin E, et al. Liver transplantation criteria for hepatocellular carcinoma should be expanded: a 22- year experience with 67 patients at UCLA[J]. Ann Surg, 2007, 26(3):502-511. [2] Toso C, Asthana S, Bigam DL, et al. Reassessing selection criteria prior to liver transplantation for hepatocellular carcinoma utilizing the scientific registry of transplant recipients database[j]. Hepatology, 2008, 9(3):832-838. [25] 2008 23 8-86. [26] Heckman JT, Devera MB, Marsh JW, et al. Bridging locoregional therapy for hepatocellular carcinoma prior to liver transplantation[j]. Ann Surg Oncol, 2008, 15(11):3169-3177. [27] 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[j]. Ann Surg, 2002, 235(3):373-382. [28] Adam R, Azoulay D. Is primary resection and salvage transplantation for hepatocellular carcinoma a reasonable strategy? [J]. Ann Surg, 2005, 21():671-672. [29] Gogia S, Befeler AS. Treating hepatocellular carcinoma without liver transplantation[j]. Curr Gastroenterol Rep, 2009, 11 (1):69-75. [30] Llovet JM.Updated treatment approach to hepatocellular carcinoma[j]. J Gastroenterol, 2005, 0(3):225-235. [31] Valle JW Dangoor A Beech J et al. Treatment of inoperable hepatocellular carcinoma with pegylated liposomal doxorubicin (PLD): results of a phase II study[j]. Br J Cancer, 2005, 92():628-630. [32] Bronowicki JP, Vetter D, Dumas F, et al. Transcatheter oily. chemoembolization for hepatocellular carcinoma. A - year [J]. study of 127 French patients[j]. Cancer, 199, 7(1):16-2. [33] Simonetti RG, Liberati A, Angiolini C, et al. Treatment of hepatocellular carcinoma: a systematic review of randomized controlled trials[j]. Ann Oncol, 1997, 8(2):117-136. [3] Nowak AK, Chow PK, Findlay M. Systemic therapy for advanced hepatocellular carcinoma: a review[j]. Eur J Cancer, 200, 0(10):17-18. [35] Pollock R. UICC manual of clinical oncology[m]. 7th eds. New York: Wiley- Liss, 1999:07-2. [36]. [M]. 2001 573-592. 2009-02- 08 2009-03- 01 510515 10 HCC HCC HCC R735.7 A 1007-813(2009)02-0118- 05 Molecular targeted therapy for hepatocellular carcinoma Luo Rongcheng, Li Aimin South Hospital Affiliated to South Medical University,Guangzhou 510515,China Abstract In recent decade, molecular targeted therapy, as an important breakthrough in tumor therapies, has achieved success in the treatment of lung carcinoma, maligant gastrointestinal stromal tumors, maligant lymphadenoma, intestinal neoplasms and breast cancer. Great progress has been made in small molecular targeted therapy for HCC and sorafenib has been approved as a standard agent for molecular targeted therapy for HCC. Key words hepatocellular carcinoma;molecular targeted therapy; sorafenib HCC
2009 22 2 119 73% 7 HCC 2.3% 2 0.7% PR HCC complete remission CR HCC HCC Eastern Cooperative Oncology Group ECOG 1 1.1 - Onyx 80% 1 2-3 - Raf- 1 B- Raf 8% - vascular endothelial growth factor receptor 8% 2% VEGFR 1 2 3 β [1-2] Raf- 1 HCC vascular endothelial growth factor VEGF HCC [3- ] HCC 137 [7] HCC 3 2.2% partial remission PR 8 5.8% minor response MR HCC III Oriental study 1189 2 1 6 33.6% stable disease SD HCC 16.2 150 [5] overall survival OS 9.2 76 2007 10 11 FDA OS 6.5.2 HCC 0.68 2.8 1. 2008 7 SFDA 3% 1 1% HCC HCC PR CR SHARP SHARP ORIENTAL SHARP ORIENTAL SHARP [6] HCC OS 21 HCC 602 HCC HCC 00 mg [ 2/d OS transcatheter arterial chemoembolization TACE TACE [8] OS 10.7 7.9 ] Global 1156 0.69 OS HCC % 2.1.9 1.2 sunitinib sutent 5.5 2.8
120 FR1 VEGFR2 VEGFR3 KIT FMS 3 EGFR FMS- like tyrosinekinase 3 FLT3 [ 1 RET ] [9-11] 2006 1 FDA 2007 11 [15-17] SFDA platelet derived growth factor PDGF - α PDGF- β VEG- Zhu [12] HCC 37.5 mg 2.1 IMC- C225 1/d 2 6 1 EGFR progression- free survival PFS 19 HCC 3~ Asnacios [18] II 3 3 5 00 mg/m 2 2 2 2 1 250 mg/m 2 1/ GEMOX PR 8 SD 12 Faivre [13] 1 000 mg/m 2 100 mg/m 2 2 23% HCC ECOG 0~1 Child A B PFS.7 OS 9.5 50 mg/d 2 6 2% 20% 37 62 3~82 % 11% 3 92% 2 1~7 3~ 16% 3 3% 2% 2.2 erlotinib EGFR 2% 1% 1~2 ATP 68% HCC Philip [16] 25% < 38 HCC 50% 6% 50% 150 mg/d 3 8% 1 PR PR 12 32% 6 13 SD 59% HCC 13 Thomas [17] 2 epidermal growth factor receptor EGFR IMC- C225 ABX- EGF EGFR EGFR HCC PR 6% SD 69% 0 HCC 150 mg/d CR PR 17 16 EGFR EGFR 3 - α HCC [1] EGFR [19] VEGF VEGF HCC
2009 22 2 121 HCC VEGF 20 endostatin ES 90 3.1 VEGF HCC VEGF Flt- 1 131 I HCC CD17 [20-21] HCC CD17 2005 2008 HCC CD17 [22-25] 5 mg/m 2 10 mg/m 2 1/2 HCC 12.5%~ [28-29] CD17 15.% disease control rate DCR 65%~ 80% PFS 6.5~6.9 HCC [30] Seldinger 2006 Zhu [26] 131 I GEMOX- B HCC HCC 0.75 mci/kg 36 HCC 6 12 18 2 33 HCC 30 83.3% 58.3% 53.0%.% 20% DCR 89% PFS 5.3 19 OS 9.6 3.2 ES ES [1] Wilhelm SM Carter C Tang L et al. BAY 3-9006 exhibits broad spectrum oral antitumor activity and targets the RAF/ MEK/ERK pathway and receptor tyrosine kinases involved in tumor progression and angiogenesis[j]. Cancer Res 200 6(19):7099-7109. [2] Chang YS Adnane J Trail PA et al. Sorafenib (BAY3-9006) 2006 7 NP inhibits tumor growth and vascularization and induces tumor apoptosis and hypoxia in RCC xenograft models[j]. Cancer Chemother Pharmacol 2007 59(5):561-57. [3] Villanueva A Newell P ChiangDY et al. Genomics and signaling pathways in hepatocellular carcinoma[j]. Semin Liver [27] ES Dis 2007 27(1):55-76. [] Calvisi DF Ladu S Gorden A et al. Ubiquitous activation of Ras and Jak/Stat pathways in human HCC[J]. Gastroenterology 2006 130():1117-1128. ES 75.9 53.3% [5] Abou- Alfa GK Schwartz L Ricci S et al. Phase II study of sorafenib in patients with advanced hepatocellular carcinoma AFP 2 [J]. J Clin Oncol 2006 2(26):293-300. [6] Llovet JM Ricci S Mazzaferro V et al. Sorafenib in advanced
122 hepatocellular carcinoma[j]. N Engl J Med 2008 359 (): 378-390. [7] Cheng AL Kang YK Chen Z, et al. Efficacy and safety of sorafenib in patients in the Asia- Pacific region with advanced hepatocellular carcinoma: a phase III randomised, doubleblind, placebo- controlled trial[j]. Lancet Oncol 2009 10(1): 25-3. [8] Abou- Alfa G Johnson P Knox J et al. Preliminary results from a phase, randomized, double blind study of sorafenib plus doxorubicin versus placebo plus doxorubicin in patients with advanced hepatocellular carcinoma[eb/ol]. [2009-01- 20].http://professional.cancerconsultants.com/cme_2007_ecco.aspx?id=0650#_ednref5. [9] Mendel DB Laird AD Xin X et al. In vivo antitumor activity of SU1128, a novel tyrosine kinase inhibitor targeting vascular endothelial growth factor and platelet- derived growth factor receptors: determination of a pharmacokinetic/pharmacodynamic relationship[j]. Clin Cancer Res 2003 9 (1):327-337. [10] Abrams TJ Lee LB Murray LJ et al. SU1128 inhibits KIT and platelet- derived growth factor receptor beta in preclinical models of human small cell lung cancer[j]. Mol Cancer Ther 2003 2 (5):71-78. [11] ChowLQ Eckhardt SG. Sunitinib: from rational design to clinical efficacy[j]. J Clin Oncol 2007 25(7):88-896. [12] Zhu X Sahani DV di Tomaso E et al. A phase study of sunitinib in patients with advanced hepatocellular carcinoma [EB/OL]. [2009-01- 20]. http://www.asco.org/asco/abstracts +%26+Virtual+Me- el+meeting/abstracts?&vmview=abst_ detail_view&confid=7&abstractid=3306. [13] Faivre SJ Raymond E Douillard J et al. Assessment of safety and drug- induced tumor necrosis with sunitinib in patients (pts) with unresectable hepatocellular carcinoma (HCC) [EB/ OL]. [2009-01- 20]. http://www.asco.org/asco/abstracts+% 26+Virtual+Meeting/Abstracts?&vmview=abst_detail_view& confid=7&abstractid=32225. [1] Cerea G, Ricotta R, Schiavetto I et al. Cetuximab for treatment of metastatic colorectal cancer[j]. Ann Oncol 2006 17 (Suppl 7): S66- S67. [15] O'Dwyer PJ Giantonio BJ Levy DE et al. Gefitinib in advanced unresectable hepatocellular carcinoma: results from the Eastern Cooperative Oncology Groups Study E1203[EB/ OL]. [2009-01- 20]. http://www.asco.org/asco/abstracts+% 26+Virtual+Meeting/Abstracts?&vmview=abst_detail_view& confid=0&abstractid=3532. [16] Philip PA Mahoney MR Allmer C et al. Phase II study of erlotinib (OSI- 77) in patients with advanced hepatocellular cancer[j]. J Clin Oncol 2005 23(27):6657-6663. [17] Thomas MB Chadha R Glover K et al. Phase 2 study of erlotinib in patients with unresectable hepatocellular carcinoma [J]. Cancer 2007 110(5):1059-1067. [18] 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[j]. Cancer 2008 112 (12):2733-2739. [19] Kraizer Y Mawasi N, Seagal J et al. Vascular endothelial growth factor and angiopoietin in liver regeneration[j]. Biochem Biophys Res Commun 2001 287(1):209-215. [20] Ferrara N Hillan KJ Gerber HP et al. Discovery and development of bevacizumab, an anti- VEGF antibody for treating cancer[j]. Nat Rev Drug Discov 200 3(5):391-00. [21] Kim KJ Li B Winer J et al. Inhibition of vascular endothelial growth factor- induced angiogenesis suppresses tumour growth in vivo[j]. Nature 1993 362(623):81-8. [22] Schwartz JD Schwartz M Lehrer D et al. Bevacizumab in hepatocellular carcinoma (HCC) in patients without metastasis and without invasion of the portal vein[eb/ol]. [2009-01- 20].http://www.asco.org/ASCO/Abstracts+%26+Virtual+Meeting/Abstracts?&vmview=abst_detail_view&confID=3&abstractID=3033. [23] Schwartz JD Schwartz M Lehrer D et al. Bevacizumab in unresectable hepatocellular carcinoma (HCC) for patients without metastasis and without invasion of the portal vein [EB/OL]. [2009-01- 20]. http://www.asco.org/asco/abstracts+%26+virtual+meeting/abstracts?&vmview=abst_detail_ view&confid=0&abstractid=31126. [2] Malka D Dromain C Farace F et al. Bevacizumab in patients (pts) with advanced hepatocellular carcinoma (HCC): preliminary results of a phase II study with circulating endothelial cell(cec) monitoring[eb/ol]. [2009-01- 20]. http: //www.asco.org/asco/abstracts+% 26+Virtual+Meeting/Abstracts?&vmview=abst_detail_view&confID=7&abstractID= 381. [25] Siegel AB Cohen EI Ocean A et al. Phase II trial evaluating the clinical and biologic effects of bevacizumab in unresectable hepatocellular carcinoma[j]. J Clin Oncol 2008 26 (18):2992-2998. [26] 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]. J Clin Oncol 2006 2(12):1898-1903. [27]. [J]. 2008 35(1):5-7. [28]. [M]. : 2002:102-103. [29] Yang LJ Sui YF Chen ZN. Preparation and activity of conjugate of monoclonal antibody HAb18 against hepatoma F (ab')(2) fragment and staphylococcal enterotoxin A[J]. World J Gastroenterol 2001 7(2):216-221. [30]. 131 I HAb18F (ab)2 [J]. 2005(6):596-598. 2009-01- 22 2009-02- 10