GH, IGF-I and Somatostatin Analogues in Hepatocellular Carcinoma

Summary

The hepatocellular carcinoma (HCC) represents more than 5% of all human malignancies, with more than 500,000 deaths per year (1). In Campania region, mortality for HCC is 2 times higher than in the rest of Italy because of a higher locally prevalence of hepatitis-C virus infection. Development of HCC in liver cirrhosis is associated with increased DNA synthesis and regeneration of hepatocytes (2). Hepatocyte growth factor, the transforming growth factor-α, the fibroblast growth factor are well studied (3,4) while the insulin-like growth factor system (IGF-I, IGF-II and their binding proteins) has been less investigated. IGF-I and IGF-II modulate growth, metabolism and cell differentiation and have specific receptors in the liver (5). IGF-I levels in the upper normal range have been associated with an increased risk to develop prostate cancer (6), breast cancer (7) and colon cancer (8). Some data report increased expression of IGF-II in HCC (9,10) and others suggest a role of increased IGF-I bioavailability in HCC (11). We reported increased IGF-I/IGFBP-3 ratio in patients with HCC compared with those with cirrhosis with a similar liver function, so suggesting increased IGF-I bioavailability in HCC (12). There is no currently medical treatment for patients with advanced HCC which has a very poor prognosis (survival \<6 months). Because of limited liver function, classical chemotherapy cannot be applied (13). In patients with HCC without cirrhosis, surgery is possible only in 5% while in those with cirrhosis first-line treatment is still questioned as survival is \<50% three years after operation. Patients suitable for local resection of HCC are only those with Child-Pugh's "hyper A" liver function class, who are a minority (14-16). Percutaneous resection treatments may treat approximately 70%-90% of tumors with maximal diameters of \<3 cm (15,17-19). Somatostatin analogues are indicated in patients with neuroendocrine tumors expressing somatostatin receptors type 2 and 5 and has excellent safety profile. In advanced HCC, some studies demonstrated beneficial effects (20,21) while some others did not (22,23). Only a few data are available on somatostatin receptor expression in HCC (24,25). Somatostatin analogues have also a clear-cut inhibitory effect on circulating IGF-I levels with a potential additional effect in delaying HCC progression.

Timeline

Start

2007-04

Primary completion

2008-04

Completion

2008-12

Publications

• Results Llovet JM, Beaugrand M. Hepatocellular carcinoma: present status and future prospects. J Hepatol. 2003;38 Suppl 1:S136-49. doi: 10.1016/s0168-8278(02)00432-4. No abstract available.
• Results Blanc P, Desprez D, Fabre JM, Pageaux G, Daures JP, Larrey D, Saint-Aubert B, Michel H, Maurel P. Contribution of primary cultures of adult human hepatocytes to the pathophysiology of hepatocellular carcinoma. J Hepatol. 1996 Nov;25(5):663-9. doi: 10.1016/s0168-8278(96)80236-4.
• Results Burr AW, Hillan KJ, McLaughlin KE, Ferrier R, Chapman C, Mathew J, Burt AD. Hepatocyte growth factor levels in liver and serum increase during chemical hepatocarcinogenesis. Hepatology. 1996 Nov;24(5):1282-7. doi: 10.1002/hep.510240549.
• Results Tomiya T, Fujiwara K. Serum transforming growth factor alpha level as a marker of hepatocellular carcinoma complicating cirrhosis. Cancer. 1996 Mar 15;77(6):1056-60. doi: 10.1002/(sici)1097-0142(19960315)77:63.0.co;2-f.
• Results Jones JI, Clemmons DR. Insulin-like growth factors and their binding proteins: biological actions. Endocr Rev. 1995 Feb;16(1):3-34. doi: 10.1210/edrv-16-1-3. No abstract available.
• Results Chan JM, Stampfer MJ, Giovannucci E, Gann PH, Ma J, Wilkinson P, Hennekens CH, Pollak M. Plasma insulin-like growth factor-I and prostate cancer risk: a prospective study. Science. 1998 Jan 23;279(5350):563-6. doi: 10.1126/science.279.5350.563.
• Results Hankinson SE, Willett WC, Colditz GA, Hunter DJ, Michaud DS, Deroo B, Rosner B, Speizer FE, Pollak M. Circulating concentrations of insulin-like growth factor-I and risk of breast cancer. Lancet. 1998 May 9;351(9113):1393-6. doi: 10.1016/S0140-6736(97)10384-1.
• Results Giovannucci E, Pollak M, Platz EA, Willett WC, Stampfer MJ, Majeed N, Colditz GA, Speizer FE, Hankinson SE. Insulin-like growth factor I (IGF-I), IGF-binding protein-3 and the risk of colorectal adenoma and cancer in the Nurses' Health Study. Growth Horm IGF Res. 2000 Apr;10 Suppl A:S30-1. doi: 10.1016/s1096-6374(00)90014-5. No abstract available.
• Results Nardone G, Romano M, Calabro A, Pedone PV, de Sio I, Persico M, Budillon G, Bruni CB, Riccio A, Zarrilli R. Activation of fetal promoters of insulinlike growth factors II gene in hepatitis C virus-related chronic hepatitis, cirrhosis, and hepatocellular carcinoma. Hepatology. 1996 Jun;23(6):1304-12. doi: 10.1002/hep.510230602.
• Results Yang D, Faris R, Hixson D, Affigne S, Rogler CE. Insulin-like growth factor II blocks apoptosis of N-myc2-expressing woodchuck liver epithelial cells. J Virol. 1996 Sep;70(9):6260-8. doi: 10.1128/JVI.70.9.6260-6268.1996.
• Results Buzzelli G, Dattolo P, Pinzani M, Brocchi A, Romano S, Gentilini P. Circulating growth hormone and insulin-like growth factor-I in nonalcoholic liver cirrhosis with or without superimposed hepatocarcinoma: evidence of an altered circadian rhythm. Am J Gastroenterol. 1993 Oct;88(10):1744-8.
• Results Mattera D, Capuano G, Colao A, Pivonello R, Manguso F, Puzziello A, D'Agostino L. Increased IGF-I : IGFBP-3 ratio in patients with hepatocellular carcinoma. Clin Endocrinol (Oxf). 2003 Dec;59(6):699-706. doi: 10.1046/j.1365-2265.2003.01909.x.
• Results Llovet JM, Fuster J, Bruix J. Intention-to-treat analysis of surgical treatment for early hepatocellular carcinoma: resection versus transplantation. Hepatology. 1999 Dec;30(6):1434-40. doi: 10.1002/hep.510300629.
• Results Llovet JM, Fuster J, Bruix J; Barcelona-Clinic Liver Cancer Group. The Barcelona approach: diagnosis, staging, and treatment of hepatocellular carcinoma. Liver Transpl. 2004 Feb;10(2 Suppl 1):S115-20. doi: 10.1002/lt.20034.
• Results Livraghi T, Goldberg SN, Lazzaroni S, Meloni F, Solbiati L, Gazelle GS. Small hepatocellular carcinoma: treatment with radio-frequency ablation versus ethanol injection. Radiology. 1999 Mar;210(3):655-61. doi: 10.1148/radiology.210.3.r99fe40655.
• Results Livraghi T, Giorgio A, Marin G, Salmi A, de Sio I, Bolondi L, Pompili M, Brunello F, Lazzaroni S, Torzilli G, et al. Hepatocellular carcinoma and cirrhosis in 746 patients: long-term results of percutaneous ethanol injection. Radiology. 1995 Oct;197(1):101-8. doi: 10.1148/radiology.197.1.7568806.
• Results Lencioni RA, Allgaier HP, Cioni D, Olschewski M, Deibert P, Crocetti L, Frings H, Laubenberger J, Zuber I, Blum HE, Bartolozzi C. Small hepatocellular carcinoma in cirrhosis: randomized comparison of radio-frequency thermal ablation versus percutaneous ethanol injection. Radiology. 2003 Jul;228(1):235-40. doi: 10.1148/radiol.2281020718. Epub 2003 May 20.
• Results Kouroumalis E, Samonakis D, Skordilis P. Octreotide treatment of hepatocellular carcinoma. Hepatology. 2003 Feb;37(2):477. doi: 10.1053/jhep.2003.50026. No abstract available.
• Results Samonakis DN, Moschandreas J, Arnaoutis T, Skordilis P, Leontidis C, Vafiades I, Kouroumalis E. Treatment of hepatocellular carcinoma with long acting somatostatin analogues. Oncol Rep. 2002 Jul-Aug;9(4):903-7.
• Results Kapadia CR. Somatostatin and hepatocellular carcinoma. Gastroenterology. 1998 Nov;115(5):1298-9. doi: 10.1016/s0016-5085(98)70109-x. No abstract available.
• Results Raderer M, Hejna MH, Muller C, Kornek GV, Kurtaran A, Virgolini I, Fiebieger W, Hamilton G, Scheithauer W. Treatment of hepatocellular cancer with the long acting somatostatin analog lanreotide in vitro and in vivo. Int J Oncol. 2000 Jun;16(6):1197-201. doi: 10.3892/ijo.16.6.1197.
• Results Raderer M, Hejna MH, Kurtaran A, Kornek GV, Valencak JB, Oberhuber G, Vorbeck F, Virgolini I, Scheithauer W. Successful treatment of an advanced hepatocellular carcinoma with the long-acting somatostatin analog lanreotide. Am J Gastroenterol. 1999 Jan;94(1):278-9. doi: 10.1111/j.1572-0241.1999.00821.x.
• Results Yuen MF, Poon RT, Lai CL, Fan ST, Lo CM, Wong KW, Wong WM, Wong BC. A randomized placebo-controlled study of long-acting octreotide for the treatment of advanced hepatocellular carcinoma. Hepatology. 2002 Sep;36(3):687-91. doi: 10.1053/jhep.2002.35071.
• Results Reubi JC, Zimmermann A, Jonas S, Waser B, Neuhaus P, Laderach U, Wiedenmann B. Regulatory peptide receptors in human hepatocellular carcinomas. Gut. 1999 Nov;45(5):766-74. doi: 10.1136/gut.45.5.766.
• Results Blaker M, Schmitz M, Gocht A, Burghardt S, Schulz M, Broring DC, Pace A, Greten H, De Weerth A. Differential expression of somatostatin receptor subtypes in hepatocellular carcinomas. J Hepatol. 2004 Jul;41(1):112-8. doi: 10.1016/j.jhep.2004.03.018.
• Results Dimitroulopoulos D, Xinopoulos D, Tsamakidis K, Zisimopoulos A, Andriotis E, Panagiotakos D, Fotopoulou A, Chrysohoou C, Bazinis A, Daskalopoulou D, Paraskevas E. Long acting octreotide in the treatment of advanced hepatocellular cancer and overexpression of somatostatin receptors: randomized placebo-controlled trial. World J Gastroenterol. 2007 Jun 21;13(23):3164-70. doi: 10.3748/wjg.v13.i23.3164.
• Results Cebon J, Findlay M, Hargreaves C, Stockler M, Thompson P, Boyer M, Roberts S, Poon A, Scott AM, Kalff V, Garas G, Dowling A, Crawford D, Ring J, Basser R, Strickland A, Macdonald G, Green M, Nowak A, Dickman B, Dhillon H, Gebski V; Australasian Gastro-Intestinal Trials Group (AGITG) Ag0001H Investigators. Somatostatin receptor expression, tumour response, and quality of life in patients with advanced hepatocellular carcinoma treated with long-acting octreotide. Br J Cancer. 2006 Oct 9;95(7):853-61. doi: 10.1038/sj.bjc.6603325. Epub 2006 Sep 5.

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