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The Journal of Clinical Endocrinology & Metabolism Vol. 83, No. 9 3034-3040
Copyright © 1998 by The Endocrine Society

Original Studies

Octreotide as Primary Therapy for Acromegaly1

Connie B. Newman, Shlomo Melmed, Ajax George, Drew Torigian, Michael Duhaney, Peter Snyder, William Young, Anne Klibanski, Mark E. Molitch, Robert Gagel, Leslie Sheeler, David Cook, William Malarkey, Ivor Jackson, Mary Lee Vance, Ariel Barkan, Lawrence Frohman and David L. Kleinberg

Department of Medicine, New York University and Veterans Administration Medical Center (C.B.N., D.L.K.), New York, New York 10010; the Division of Endocrinology and Metabolism, B-131 Cedars-Sinai Medical Center (S.M.), Los Angeles, California 90048; the Department of Radiology, New York University Medical Center (A.G., M.D.), New York, New York 10016; the Department of Radiology, Hospital of the University of Pennsylvania (D.T.), Philadelphia, Pennsylvania 19104; Endocrinology Division, University of Pennsylvania School of Medicine (P.S.), Philadelphia, Pennsylvania 19104-6149; the Department of Medicine, Mayo Clinic (W.Y.), Rochester, Minnesota 55905; the Neuroendocrine Unit, Massachusetts General Hospital (A.K.), Boston, Massachusetts 02114; the Center for Endocrinology, Metabolism, and Molecular Medicine, Northwestern University Medical School (M.E.M.), Chicago, Illinois 60611; the Section of Endocrinology, University of Texas M. D. Anderson Cancer Center (R.G.), Houston, Texas 77030; Innova Medical Services (L.S.), Brooklyn, Ohio 44144; the Division of Endocrinology, Diabetes and Clinical Nutrition, Oregon Health Sciences University (D.C.), Portland, Oregon 97201; the Department of Medicine, Ohio State University Medical Center (W.M.), Columbus, Ohio 43210; the Department of Medicine, Brown University-Rhode Island Hospital (I.J.), Providence, Rhode Island 02903; the Department of Medicine, University of Virginia Medical Center (M.L.V.), Charlottesville, Virginia 22908; the Department of Medicine, University of Michigan Medical Center (A.B.), Ann Arbor, Michigan 48109-0354; and the Department of Medicine, University of Illinois (L.F.), Chicago, Illinois 60612

Address all correspondence and requests for reprints to: David L. Kleinberg, M.D., Department of Medicine, New York University and Veterans Affairs Medical Center, 423 East 23rd Street, 16043 West, New York, New York 10010.

The effects of octreotide (up to 5 yr) as primary treatment in 26 patients with acromegaly were compared with those in 81 patients with acromegaly who received octreotide as secondary or adjunctive therapy after previous surgery and/or pituitary radiation. These patients were part of a multicenter study that took place between 1989–1995. The study was divided into 3 phases beginning with a 1-month placebo-controlled treatment period followed by a 1-month washout period. In the second phase, patients were randomized to treatment with either 100 or 250 µg octreotide, sc, every 8 h for 6 months. Octreotide was then discontinued for 1 month and reinitiated at the lower dose for a total mean treatment duration of 39 months. The dose was titrated by each investigator to improve each patient’s individual response, which included improvement in symptoms and signs of acromegaly as well as reduction of GH and insulin-like growth factor I (IGF-I) into the normal range.

In the second phase of the study, in which patients were randomized to either 100 or 250 µg octreotide, three times daily, mean integrated GH and IGF-I concentrations after 3 and 6 months were equivalent in the primary and secondary treatment groups. During long term open label treatment, mean GH fell from 32.7 ± 5.2 to 6.0 ± 1.7 µg/L 2 h after octreotide injection in the primary therapy group and remained suppressed for a mean period of 24 months (range, 3–60 months). The mean final daily dose was 777 µg. In the patients receiving secondary treatment, mean GH fell from 30.2 ± 7.6 to 5.6 ± 1.1 µg/L after 3 months and remained suppressed for the remainder of the study (average dose, 635 µg daily). Mean IGF-I concentrations fell from 5.2 ± 0.5 x 103 U/L (primary treatment group) and 4.7 ± 0.4 x 103 U/L (secondary treatment group) to a mean of 2.2 ± 0.3 x 103 U/L in both groups after 3 months of open label treatment and remained suppressed. IGF-I was reduced into the normal range during at least half of the study visits in 68% of the primary treatment group and in 62% of the secondary treatment group.

Patients whose GH levels fell to at least 2 SD below the baseline mean GH were considered responders. There was no significant difference in the percentage of responders in the primary and secondary treatment groups (70% vs. 61%), nor was there a statistical difference in the mean GH concentrations between the groups.

Symptoms of headache, increased perspiration, fatigue, and joint pain were reported at baseline by 46%, 73%, 69%, and 85%, respectively, of patients in the primary therapy group and improved during 3 yr of octreotide treatment in 50–100%. Similarly, these acromegaly-related symptoms were reported by 62%, 58%, 78%, and 60% of patients in the secondary therapy group, and improvement was noted in 62–88%.

Pituitary magnetic resonance imaging scans were available in 13 of 26 patients in the primary treatment group before and after 6 months of octreotide treatment. Tumor shrinkage was observed in 6 of 13 patients, with reduction in tumor volume greater than 25% in only 3. Of 6 patients with documented tumor shrinkage, IGF-I was reduced into the normal range in 4 patients. Of the 7 remaining patients in whom tumor shrinkage was less than 10%, IGF-I was reduced into the normal range in 5 patients. The degree of tumor shrinkage did not correlate with the percent reduction in IGF-I or GH.

In summary, octreotide was equally effective in 26 previously untreated acromegalic patients (primary treatment group) and 81 patients previously treated with either surgery or pituitary radiation (secondary treatment group). These observations call into question the current practice of surgical resection of all newly diagnosed GH-secreting pituitary adenomas regardless of the likelihood of cure. Although surgery is the treatment of choice in patients with tumors likely to be completely resected, our results suggest that if the possibility of surgical cure is low, as in patients with large or invasive tumors, then octreotide may be a reasonable primary therapeutic modality provided that the tumor does not threaten vision or neurological function.




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