GH, IGF-I and Somatostatin Analogues in Hepatocellular Carcinoma - Full Text View

Purpose

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.

Condition	Intervention	Phase
Advanced Hepatocellular Carcinoma	Drug: Octreotide-LAR, Lanreotide Autogel Other: Locoregional treatments	Phase 2 Phase 3


Study Type:	Interventional
Study Design:	Allocation: Non-Randomized Endpoint Classification: Safety/Efficacy Study Intervention Model: Single Group Assignment Masking: Open Label Primary Purpose: Treatment
Official Title:	Treatment of Advanced Hepatocellular Carcinoma With Depot Somatostatin Analogues: a Pilot Prospective Study Based on Somatostatin Receptors Tumors Expression

Resource links provided by NLM:

Drug Information available for: Somatostatin Octreotide acetate Octreotide Lanreotide Lanreotide acetate

Genetic and Rare Diseases Information Center resources: Liver Cancer

U.S. FDA Resources

Further study details as provided by Federico II University:

Primary Outcome Measures:

Prolongation of the survival curve (>6 months) [ Time Frame: 12 months ] [ Designated as safety issue: No ]

Secondary Outcome Measures:

Improvement of liver function, Reduction of biological markers of disease (if elevated before starting the treatment) [ Time Frame: 12 months ] [ Designated as safety issue: No ]
Improvement of quality of life according with SF36 questionnaire [ Time Frame: 12 months ] [ Designated as safety issue: No ]


Enrollment:	25
Study Start Date:	April 2007
Study Completion Date:	December 2008
Primary Completion Date:	April 2008 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
Experimental: A 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 trombosis 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	Drug: Octreotide-LAR, Lanreotide Autogel Octreotide-LAR intramuscular, dose of 30 mg every 28 days to increase up to 60 mg; lanreotide autogel 120 mg deep subcutaneous every 28 days for 3 months then uptitrated according with the protocol. Other Names: Sandostatin-LAR Ipstyl 120 mg Somatuline Depot
B Historical controls	Other: Locoregional treatments

Arms

Assigned Interventions

Experimental: A

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 trombosis 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

Drug: Octreotide-LAR, Lanreotide Autogel

Octreotide-LAR intramuscular, dose of 30 mg every 28 days to increase up to 60 mg; lanreotide autogel 120 mg deep subcutaneous every 28 days for 3 months then uptitrated according with the protocol.

Other Names:

Sandostatin-LAR
Ipstyl 120 mg
Somatuline Depot

B

Historical controls

Other: Locoregional treatments

Show Detailed Description

Eligibility


Ages Eligible for Study:	18 Years to 75 Years (Adult, Senior)
Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	No

Criteria

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.

Contacts and Locations

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00495846

Locations


Italy
D. Cotugno Hospital
Naples, Italy, 80131

Sponsors and Collaborators

Federico II University

Azienda Ospedaliera "D Cotugno" Hospital of Infectious Diseases

Investigators


Principal Investigator:	Annamaria Colao, MD, PhD	University Federico II of Naples

More Information

Publications:

Llovet JM, Beaugrand M. Hepatocellular carcinoma: present status and future prospects. J Hepatol. 2003;38 Suppl 1:S136-49. Review.

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.

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.

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.

Jones JI, Clemmons DR. Insulin-like growth factors and their binding proteins: biological actions. Endocr Rev. 1995 Feb;16(1):3-34. Review.

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.

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.

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.

Nardone G, Romano M, Calabrò 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.

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.

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.

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.

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.

Llovet JM, Fuster J, Bruix J; Barcelona-Clínic Liver Cancer Group. The Barcelona approach: diagnosis, staging, and treatment of hepatocellular carcinoma. Liver Transpl. 2004 Feb;10(2 Suppl 1):S115-20. Review.

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.

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.

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. Epub 2003 May 20.

Kouroumalis E, Samonakis D, Skordilis P. Octreotide treatment of hepatocellular carcinoma. Hepatology. 2003 Feb;37(2):477.

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.

Kapadia CR. Somatostatin and hepatocellular carcinoma. Gastroenterology. 1998 Nov;115(5):1298-9.

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.

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.

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. Erratum in: Hepatology. 2003 Feb;37(2):489.

Reubi JC, Zimmermann A, Jonas S, Waser B, Neuhaus P, Läderach U, Wiedenmann B. Regulatory peptide receptors in human hepatocellular carcinomas. Gut. 1999 Nov;45(5):766-74.

Bläker M, Schmitz M, Gocht A, Burghardt S, Schulz M, Bröring 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.

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.

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. Epub 2006 Sep 5. Erratum in: Br J Cancer. 2007 Apr 10;96(7):1154. Findlay, M [added]; Hargreaves, C [added]; Stockler, M [added]; Thompson, P [added]; Boyer, M [added]; Roberts, S [added]; Poon, A [added]; Scott, A M [added]; Kalff, V [added]; Garas, G [added]; Dowling, A [added]; Crawford, D [added]; Ring, J [added]; Basser, R [added]; Strickland, A [added]; Macdonald, G [added]; Green, M [added]; Nowak, A [added]; Dickman, B [added]; Dhillon, H [added]; Gebski, V [added].


Responsible Party:	Annamaria Colao, Federico II U
ClinicalTrials.gov Identifier:	NCT00495846 History of Changes
Other Study ID Numbers:	NeuroendoUnit-4
Study First Received:	July 2, 2007
Last Updated:	August 14, 2009
Health Authority:	Italy: Ministry of Health Italy: National Institute of Health

Keywords provided by Federico II University:


Hepatocellular carcinoma Somatostatin analogues Somatostatin receptors Octreotide	Lanreotide IGF-I IGF-II

Additional relevant MeSH terms:


Carcinoma Carcinoma, Hepatocellular Neoplasms, Glandular and Epithelial Neoplasms by Histologic Type Neoplasms Adenocarcinoma Liver Neoplasms Digestive System Neoplasms Neoplasms by Site Digestive System Diseases Liver Diseases	Octreotide Lanreotide Angiopeptin Somatostatin Gastrointestinal Agents Antineoplastic Agents, Hormonal Antineoplastic Agents Hormones Hormones, Hormone Substitutes, and Hormone Antagonists Physiological Effects of Drugs

ClinicalTrials.gov processed this record on September 26, 2016

GH, IGF-I and Somatostatin Analogues in Hepatocellular Carcinoma (SS-HCC)