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

Advanced Hepatocellular Carcinoma Clinical Trial

Official title: Treatment of Advanced Hepatocellular Carcinoma With Depot Somatostatin Analogues: a Pilot Prospective Study Based on Somatostatin Receptors Tumors Expression

Status Completed

Clinical Trial 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.

Clinical Trial Description

Study objectives

1. To evaluate relationships between GH/IGF-I and IGF-II axis and development and progression of HCC;

2. To evaluate the expression of somatostatin receptor expression in biopsies of HCC by quantitative RT-PCR and immunohistochemistry and in vivo by octreoscan;

3. To evaluate the efficacy of octreotide-LAR or lanreotide-autogel as compared to placebo on clinical symptoms, liver function, biological markers and tumor dimensions by ultrasonography in advanced HCC patients;

4. To correlate the response to somatostatin analogues to somatostatin receptor expression in vitro and in vivo and suppression of the IGF-I and -II axis.

Study design

This is a pilot, open, prospective, monocentric study addressed to:

1. patients with liver cirrhosis and multifocal HCC with or without portal vein invasion;

2. patients with liver cirrhosis and single HCC nodule of >6 cm in size with or without portal vein invasion [principal branch, right branch (one or more segmentary arms), left branch (one or more segmentary arms)];

3. patients with liver cirrhosis and more than 3 HCC nodules of > 3 cm in size with or without portal vein invasion [principal branch, right branch (one or more segmentary arms), left branch (one or more segmentary arms)];

4. patients with cirrhosis without HCC.

Study protocol All enrolled subjects will be subjects to a baseline evaluation and a post-treatment evaluation according with the treatment protocol (see below).

A) Clinical study in vivo diagnostic routine analysis (clinical evaluation, ECG, chest X-ray, blood chemistry, analysis of liver function, α-FP assay, CEA, liver ultrasonography and angio-ultrasonography, abdominal CT scan or MRI); blood sampling for GH, IGF-I, IGF-II, IGFBP-3, ALS, insulin, IGFBP-1 and IGFBP-2; whole body scintigraphy with radiolabeled octreotide (octreoscan) liver biopsy in patients in good clinical condition according with good clinical practice procedures. Biopsy will be performed under ultrasonography guidance with a 19G or 21G needle after local subcutaneous anesthesia (lidocaine 2%). Abdominal ultrasonography will followed biopsy to exclude hemorrage. The tissue sample will be stores at -80° until analysis.

B) Morphological in vitro study the expression of somatostatin receptors will be performed by immunohistochemistry in sequential sections as well as by RT-PCR using specific primers for all receptors; the study includes an analysis of classical histology and immunohistochemical markers. The study includes positive and negative controls for an appropriate analysis of the results.

Study duration

The first study is a pilot study which expected number of patients fulfilling the inclusion criteria is 15 to address the issue of liver cirrhosis with HCC. The enrollment period will be of 12 months or shorter if the 15 patients are enrolled in a shorter time. The observational period is expected to be 3-12 months, according with previous studies. Treatment will be continued in all survivors even if the study will end after 12 months, according with previous studies. Subsequently, the study will proceed with a placebo-controlled randomized study according with the results obtained in the pilot study and will enroll 30-60 in case of patients with HCC without cirrhosis and 20-40 for patients with liver cirrhosis and HCC. All patients will be registered in dedicated CRF and data will be collected by investigators not involved in data analysis.

Withdrawal from the study

The causes of early study withdrawal will be recorded according with:

1. adverse events;

2. no treatment response or patients' clinical condition deterioration according with the investigator judgment;

3. major protocol violation;

4. patient's withdrawal of the consent.

Concomitant therapies All patients will continue all treatments as per investigator judgment. In case some therapy will be withdrawn this will be recorded in the CRF and analyzed as a potential beneficial effect of somatostatin analogues therapy.

Main outcome measures A) Efficacy parameters

For cirrhosis:

Stabilization or improvement of live function parameters Reduction of biological markers of disease (if elevated before starting the treatment) Improvement of quality of life according with SF36 questionnaire

For HCC:

Prolongation of the survival curve (>6 months) Stabilization or reduction of tumor size Reduction or disappearance of portal vein thrombosis Stabilization or improvement of live function parameters Reduction of biological markers of disease (if elevated before starting the treatment) Improvement of quality of life according with SF36 questionnaire

Expected results

The expected results are:

1. Both cirrhotic and normal liver express somatostatin receptors. The different receptor pattern can suggest a role of this receptor subtype in HCC development. The correlation study can also give insight into any role of somatostatin receptors in differentiation, staging and prognosis of HCC.

2. Treatment with somatostatin analogues will prolong survival in advanced HCC patients. This should occur according with liver function before starting the treatment. We expect that patients having tumors with high expression of SS-2 receptors on their HCC will have the longest survival. ;

Study Design

Allocation: Non-Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Advanced Hepatocellular Carcinoma
• Carcinoma
• Carcinoma, Hepatocellular

• NCT number: NCT00495846
• Study type: Interventional
• Source: Federico II University
• Status: Completed
• Phase: Phase 2/Phase 3
• Start date: April 2007
• Completion date: December 2008