Summing up 15 years of somatostatin analog therapy in neuroendocrine tumors: future outlook.

Neuroendocrine gastrointestinal tumors express somatostatin receptors (ssts) in 80%-90% of cases and somatostatin analogs have become increasingly important in the management of these patients. Most of the presently available somatostatin analogs (octreotide, RC-160, and lanreotide) bind to the sst2 and sst5, and in higher doses to sst3 of the ssts 1-5 described. Clinical improvement during somatostatin analog therapy is mainly mediated via a direct inhibitory effect on hormone production from the tumors, seen in 30%-70% of the patients. Also indirect non-tumor mediated effects on peripheral target organs contribute to the subjective improvement, achieved in 30%-70% of patients. Recently, significant improvement of quality of life has been demonstrated with long-acting depot formulations. There is little or no effect on tumor growth during octreotide therapy; tumor shrinkage has been reported in 10%-20% of patients, but stabilization of tumor growth can be achieved in about half of the patients with a duration of 8-16 months. Recently, induction of apoptosis has been described with high doses of lanreotide (12 mg/d). Eventually, however, all patients escape from somatostatin analog therapy with regard both to hormonal production and tumor growth, and the mechanism behind the tachyphylaxis is not yet known. Studies of optimal dosage and modes of administration, development of new slow release formulations, the potential value of high-dose somatostatin analog therapy and novel somatostatin receptor subtype specific analogs are important directions for the use of somatostatin analogs in the future. In addition, assessment of somatostatin receptor status for each patient and studies of tumor biology, e.g., inhibition of exocytosis, antiproliferative effects and induction of apoptosis during treatment will help to optimize treatment and provide new insights into mechanisms of action of somatostatin analogs.