GH, IGF-I and Somatostatin Analogues in Hepatocellular Carcinoma

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.

Sex

All

Minimum age

18 Years

Maximum age

75 Years

Inclusion Criteria:

* Patients with cirrhosis without HCC in all liver function classes already receiving specific therapy for cirrhosis who accept be subjected to liver biopsy and to sign the written informed consent to participate to the study
* Patients with cirrhosis with multifocal HCC and clinical and/or radiological signs of persistence or recurrence of HCC in presence or absence of thrombosis of the portal vein, with a single nodule of \> 6 cm in size or multiple nodules of \> 3 cm in size who accept be subjected to liver biopsy and to sign the written informed consent to participate to the study

Exclusion Criteria:

* Age \< 18 yrs or \> 75 yrs
* Pregnancy or lactation
* Intolerance to somatostatin analogues

Treatment protocol:

* In all patients fulfilling the inclusion criteria, treatment will begin with octreotide-LAR at a dose of 30 mg every 28 days or lanreotide autogel 120 mg every 28 days for 3 months.
* After 28, 56 and 74 days (immediately before the next injection) all patients will be admitted to the Day Hospital of the IX Division of Internal Medicine of the D. Cotugno Hospital for the clinical examination, blood chemistry, blood sampling for the IGF axis analysis, and abdominal ultrasound. After 74 days, abdominal CT or MRI will also be performed.
* Then, in all survivors the interval between injection will be reduced to 21 days and follow up for the next 3 months will be done as stated before the day immediately preceding the injection.
* Then, in the subsequent follow-up the interval between injection will be reduced to 14 days and all procedures will be repeated at monthly intervals.
* All the patients fulfilling the inclusion criteria but refusing to participate to the study will be followed with the same methodology of those receiving the somatostatin analogues treatment.

• RESULTLlovet 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. PMID 12591191
• RESULTBlanc 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. PMID 8938543
• RESULTBurr 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. PMID 8903411
• RESULTTomiya 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. PMID 8635123
• RESULTJones 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. PMID 7758431
• RESULTChan 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. PMID 9438850
• RESULTHankinson 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. PMID 9593409