Edward M. Wolin, M.D.
Co-Director Carcinoid/Neuroendocrine Center
Samuel Oschin Comprehensive Cancer Institute
Cedars-Sinai Medical Center
Los Angeles, CA
Somatostatin is a natural hormone, which works to stop the growth and hormone-secretion of neuroendocrine cells. However, it is destroyed in the body within minutes, making it highly impractical to use it as drug. To overcome this problem, modifications of the somatostatin molecule have been made, allowing it to survive and remain functional for long periods of time. These modifications of somatostatin are called somatostatin analogs. Octreotide (Sandostatin®) and octreotide LAR have long been the only somatostatin analogs available for the therapy of carcinoid syndrome. They are highly effective in the management of diarrhea and flushing associated with metastatic carcinoid tumors.
In an exciting new development, there is now proof that somatostatin analogs can stop the growth of neuroendocrine cells, thus paving the way for their use as anti-cancer drugs (low toxicity “chemotherapy”). In the PROMID study, 85 patients with midgut carcinoids were randomized to octreotide LAR 30mg/month vs. placebo. The average progression-free survival period was 14.3 mo. with octreotide vs. 6 months with placebo. At 6 months, 64% of the octreotide-treated patients remained without cancer progression vs. 37.2% of the placebo-treated patients.(1) This study establishes octreotide as standard therapy for all patients with metastatic carcinoid, whether or not a syndrome of diarrhea and flushing is present.
Another important advance has been the development of new highly effective somatostatin analogs. One, known as lanreotide, can be combined with water to form stable molecular aggregates that dissemble over a period of four weeks, continuously releasing lanreotide into the circulation after a single subcutaneous injection. This product, lanreotide autogel, can thus be administered as a single subcutaneous injection every four weeks. In addition to being less painful than deep IM injection of octreotide LAR, subcutaneous injection of lanreotide autogel allows for the administration of higher and potentially more effective doses in a smaller volume. It provides for reliable blood levels in obese people, when octreotide LAR doses intended for IM use can end up in fat instead of muscle, impairing absorption. Lanreotide autogel can also be easily administered to thin individuals who do not have adequate muscle mass for repeated deep IM injections. Randomized clinical trials exploring lanreotide in carcinoid/neuroendocrine tumors, with or without carcinoid syndrome are ongoing.
The third exciting somatostatin analog being used is called pasireotide (SOM-230). Pasireotide binds to more types of somatostatin receptors on carcinoid/NET cells, and binds more tightly than either octreotide or lanreotide. The long acting formulation which is given every four weeks is called pasireotide LAR. In 27% of patients whose carcinoid syndrome could not be controlled with octreotide or lanreotide, the syndrome could be controlled with pasireotide. Side effects are very similar for all three of these somatostatin analogs, except pasireotide caused elevated blood sugar in 12% of patients and type 2 diabetes mellitus in 7%. (2). Studies are currently under way to compare symptom control and tumor control with pasireotide LAR vs. octreotide LAR.
References:
1) Placebo-Controlled, Double-Blind, Prospective, Randomized Study on the Effect of Octreotide LAR in the Control of Tumor Growth in Patients With Metastatic Neuroendocrine Midgut Tumors: A Report From the PROMID Study Group
Rinke, A et al, JCO Oct 1 2009: 4656-4663.
2) Pasireotide LAR In Patients With Metastatic Carcinoid Tumors: Interim Safety Results From A Randomized, Multicenter Phase I Study. Edward Wolin, Larry Kvols, Shereen Ezzat, Walter Kocha, Eric Van Cutsem, Ulrike Schönherr and Abderrahim Fandi. 2009 Am Soc Clin Oncol Gastrointestinal Cancers Symposium, Abstr. 122
Friday, October 9, 2009
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