Role of Octreotide in Cancer and Therapy-Related Complications

September 1, 2002

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.

Octreotide (Sandostatin), a somatostatin analog, has a wide range of uses inthe management of cancer patients. It is a unique molecule that specifically binds to somatostatin receptor subtype 2. This property of activating thereceptor can result in a multitude of physiologic actions (for example,inhibition of synthesis and release of peptides in endocrine and neoplasticcells, antiangiogenesis, antisecretory effect in the gastrointestinal mucosa,anticholecystokinin activity retarding gallbladder motility, and reduction insplanchnic blood flow). In addition, in vitro experiments confirm thatoctreotide has cytostatic activity against a variety of malignancies. Octreotideis now widely used in the treatment of hormonal syndromes that result from avariety of neuroendocrine and endocrine neoplasms. Its dramatic effect incontrolling malignant carcinoid syndrome and hormone-induced diarrhea (forexample, from gastrinoma and VIPoma) has been well documented. However, thechronic 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 fortargeted radiotherapy. It is also an effective agent for the control oftherapy-induced diarrhea refractory to oral therapy. Could this molecule have anexpanded role in cancer research? A 2-day meeting of investigators familiar withoctreotide research was held in April 2002 to discuss this question. This was afrank, interactive forum reviewing new data on octreotide and the long-actingrelease (LAR) formulation, octreotide LAR depot, to determine its future inresearch.

There were four main areas of discussion: (1) neuroendocrineneoplasms, (2) therapy-induced diarrhea (chemotherapy and radiotherapy), (3)review of potential research in pancreatic, hepatocellular, and prostatecancers, and (4) exploitation of novel properties of this molecule (antiangiogenicproperty).

In this supplement, Irvin Modlin and Lowell Anthony review thecurrent status of neuroendocrine tumors; both emphasize the emerging role ofradiolabeled octreotide in therapy for these neoplasms. Dr. Anthony discussesthe possibility of additional new targets in the treatment of thesemalignancies. He feels that survival time of patients with these indolentneoplasms can be prolonged substantially, making these neoplasms even morechronic conditions than they are now. This would be a highly desirable strategyfor future research.

Scott Wadler and Babu Zachariah discuss potential researchavenues 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 oftherapy. This lack of awareness is further amplified by the lack ofinfrastructure and skills of many practices in the management of diarrhea. Healso characterizes the high-risk patient with "gastrointestinalsyndrome." He states that diarrhea can no longer be treated and dealt within isolation. Associated "risk factors" must be considered as well. Henotes the value of octreotide in the treatment of National Cancer Institute(NCI) Common Toxicity Criteria grade 3 and 4 diarrheas but elaborates on theemerging role of prophylactic octreotide (particularly the use and research onoctreotide LAR depot).

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

Jordan Berlin, LewisRoberts, and Larry Kvols and Viktor Boerlindiscuss various tumor types and potential avenues of research for octreotide.Dr. Berlin reviews the current status of various therapies in the treatment ofpancreatic carcinoma. He notes that octreotide has limited activity in thisextremely malignant process and is not likely to play a role in its management.Dr. Roberts discusses data from several published studies and emphasizes theneed for further research to ascertain the role of octreotide LAR depot in thetreatment of advanced hepatocellular carcinoma. Drs. Kvols and Boerlin note thatdifferentiation of the neuroendocrine neoplastic cell population in prostatecancer is frequent and has been underestimated. Preliminary data suggest somebiologic activity of octreotide but further research is necessary.

Finally, Eugene Woltering explains the antiangiogenic propertiesof octreotide and discusses methods to exploit these properties in futureprojects.

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