Treatment of Advanced Hepatocellular Carcinoma With Depot Somatostatin Analogues: a Pilot Prospective Study Based on Somatostatin Receptors Tumors Expression
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.
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.
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
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
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
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
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.
Allocation: Non-Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
Prolongation of the survival curve (>6 months)
Annamaria Colao, MD, PhD
University Federico II of Naples
Italy: Ministry of Health