GH, IGF-I and Somatostatin Analogues in Hepatocellular Carcinoma
Condition: Advanced Hepatocellular Carcinoma
MeSH terms: Carcinoma; Carcinoma, Hepatocellular
Study type: Interventional
Phase: Phase 2/Phase 3

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.
    

Detailed 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.
    

Intervention name(s): Octreotide-LAR, Lanreotide Autogel; Locoregional treatments
Intervention type(s): Drug; Other
Intervention description(s): 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 intervention name(s): Sandostatin-LAR; Ipstyl 120 mg; Somatuline Depot
Intervention MeSH terms: Octreotide; Lanreotide
Allocation: Non-Randomized
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Hepatocellular carcinoma; Somatostatin analogues; Somatostatin receptors; Octreotide; Lanreotide; IGF-I; IGF-II