High-dose treatment with lanreotide of patients with advanced neuroendocrine gastrointestinal tumors: Clinical and biological effects

Background. Neuroendocrine tumors usually present with inoperable metastatic disease and severe hormonal symtoms. Specific chemotherapy, alpha-interferon and the somatostatin analog octreotide are established therapies in these patients but all of them eventually fail. Other somatostatin analogs, e.g., RC-160 and lanreotide, are currently being studied in different doses and modes of administration. Patients and methods: Nineteen patients with advanced neuroendocrine gastrointestinal tumors [13 carcinoids and six endocrine pancreatic tumors (EPT)], liver metastases being present in 18, most of them heavily pretreated, were included. Seventeen out of 18 patients had somatostatin receptors demonstrated by octreotide scintigraphy. Lanreotide was given as four daily subcutaneous injections, starting with 750 mu g/d, then increasing every week up to 12,000 mu g/d after six weeks, a dose which was maintained, if tolerated, for 12 months, or until progression. Results. There was a significant tumor size response (> 50%) in one patient (5%), whereas 12 patients (70%) had tumor stabilization for 12 months. Biochemical tumor markers were significantly reduced at six months (urinary 5-hydroxyindoleacetic acid and plasma chromogranin) and 12 months (chromogranin) and the overall biochemical response rate was 58% with this high dose of lanreotide. Adverse events were observed and four patients stopped the treatment due to adverse events. Studies of tumor biopsies before and during treatment indicated induction of apoptosis in patients with tumor stabilization and biochemical response. Conclusion. High-dose treatment with lanreotide (12,000 mu g/d) produced tumor size response in 5%, stabilization in 70% and a biochemical response in 58% of patients, These results should be related to the advanced stage of the disease as indicated by the mean duration of disease of more than four years, but they do not appear to be better than those achieved with standard doses of somatostatin analogs. However, in responding patients we observed induction of apoptosis in the tumors, a phenomenon not seen with regular doses of somatostatin analogs, but often produced by chemotherapeutic agents.