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Role of Octreotide in Cancer and Therapy-Related Complications

Role of Octreotide in Cancer and Therapy-Related Complications

Octreotide (Sandostatin), a somatostatin analog, has a wide range of uses in the management of cancer patients. It is a unique molecule that specifically binds to somatostatin receptor subtype 2. This property of activating the receptor can result in a multitude of physiologic actions (for example, inhibition of synthesis and release of peptides in endocrine and neoplastic cells, antiangiogenesis, antisecretory effect in the gastrointestinal mucosa, anticholecystokinin activity retarding gallbladder motility, and reduction in splanchnic blood flow). In addition, in vitro experiments confirm that octreotide has cytostatic activity against a variety of malignancies. Octreotide is now widely used in the treatment of hormonal syndromes that result from a variety of neuroendocrine and endocrine neoplasms. Its dramatic effect in controlling malignant carcinoid syndrome and hormone-induced diarrhea (for example, from gastrinoma and VIPoma) has been well documented. However, the chronic use of octreotide can result in steatorrhea and gallstone formation.

Radiolabeled octreotide has been used successfully for imaging (neuroendocrine, endocrine, breast, small-cell lung, and prostate cancers) and more recently for targeted radiotherapy. It is also an effective agent for the control of therapy-induced diarrhea refractory to oral therapy. Could this molecule have an expanded role in cancer research? A 2-day meeting of investigators familiar with octreotide research was held in April 2002 to discuss this question. This was a frank, interactive forum reviewing new data on octreotide and the long-acting release (LAR) formulation, octreotide LAR depot, to determine its future in research.

There were four main areas of discussion: (1) neuroendocrine neoplasms, (2) therapy-induced diarrhea (chemotherapy and radiotherapy), (3) review of potential research in pancreatic, hepatocellular, and prostate cancers, and (4) exploitation of novel properties of this molecule (antiangiogenic property).

In this supplement, Irvin Modlin and Lowell Anthony review the current status of neuroendocrine tumors; both emphasize the emerging role of radiolabeled octreotide in therapy for these neoplasms. Dr. Anthony discusses the possibility of additional new targets in the treatment of these malignancies. He feels that survival time of patients with these indolent neoplasms can be prolonged substantially, making these neoplasms even more chronic conditions than they are now. This would be a highly desirable strategy for future research.

Scott Wadler and Babu Zachariah discuss potential research avenues with octreotide LAR depot in the field of therapy-induced diarrhea. Dr. Wadler points out the lack of awareness of diarrhea as a serious toxic effect of therapy. This lack of awareness is further amplified by the lack of infrastructure and skills of many practices in the management of diarrhea. He also characterizes the high-risk patient with "gastrointestinal syndrome." He states that diarrhea can no longer be treated and dealt with in isolation. Associated "risk factors" must be considered as well. He notes the value of octreotide in the treatment of National Cancer Institute (NCI) Common Toxicity Criteria grade 3 and 4 diarrheas but elaborates on the emerging role of prophylactic octreotide (particularly the use and research on octreotide LAR depot).

Dr. Zachariah discusses the serious lack of awareness and research on radiotherapy-induced diarrhea. He notes that this toxic effect is very common (up to 40% of patients experience grade 3 or 4 diarrhea) in patients receiving pelvic chemoradiotherapy. He reports on two small studies that demonstrated potential benefit of therapy with octreotide but emphasizes and outlines two cooperative group studies (by the Radiation Therapy Oncology Group and the North Central Cancer Treatment Group) that would systematically evaluate the value of prophylactic octreotide LAR depot.

Jordan Berlin, Lewis Roberts, and Larry Kvols and Viktor Boerlin discuss various tumor types and potential avenues of research for octreotide. Dr. Berlin reviews the current status of various therapies in the treatment of pancreatic carcinoma. He notes that octreotide has limited activity in this extremely malignant process and is not likely to play a role in its management. Dr. Roberts discusses data from several published studies and emphasizes the need for further research to ascertain the role of octreotide LAR depot in the treatment of advanced hepatocellular carcinoma. Drs. Kvols and Boerlin note that differentiation of the neuroendocrine neoplastic cell population in prostate cancer is frequent and has been underestimated. Preliminary data suggest some biologic activity of octreotide but further research is necessary.

Finally, Eugene Woltering explains the antiangiogenic properties of octreotide and discusses methods to exploit these properties in future projects.

In summary, the conference proved very productive in reviewing the current information on octreotide in cancer and therapy-induced complications. More importantly, we could determine and rank new research directions. Several potential study designs were reviewed and discussed frankly. We hope to revisit these and other topics annually.

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