Primary Medical Therapy for Acromegaly: An Open, Prospective, Multicenter Study of the Effects of Subcutaneous and Intramuscular Slow-Release Octreotide on Growth Hormone, Insulin-Like Growth Factor-I, and Tumor Size

Abstract

Conventional surgery and radiotherapy for acromegaly have limitations. There are few data on the use of the somatostatin analog octreotide (Oct) as primary medical therapy. An open prospective study of 27 patients with newly diagnosed acromegaly was conducted in nine endocrine centers in the United Kingdom. Twenty patients had macroadenomas, and 7 had microadenomas. For the first 24 wk (phase 1), patients received sc Oct in an initial dose of 100 microg, 3 times daily, increased to 200 micro g three times daily after 4 wk in the 13 patients whose mean serum GH remained greater than 5 mU/liter (2 microg/liter). Five-point GH profiles were performed at 0, 4, 12, and 24 wk, and high resolution pituitary imaging using a standard protocol was performed at 0, 12, and 24 wk (magnetic resonance imaging in 25 patients and computed tomography in 2). Tumor dimensions and volumes were calculated by a central, reporting neuroradiologist, and the results were audited by a second, independent neuroradiologist. After 24 wk, 15 patients proceeded to phase 2 of the study with a direct switch to monthly injections of the depot formulation of Oct, Sandostatin long-acting release (Oct-LAR). Further GH profiles were performed at 36 and 48 wk, and pituitary imaging was performed at 48 wk. The median pretreatment serum GH concentration was 30.7 mU/liter (range, 6.7-141.4). During sc Oct, serum GH fell to less than 5 mU/liter in 9 patients (38%), and IGF-I fell to normal in 8 patients (33%). All 27 tumors shrank during sc Oct; for microadenomas the median tumor volume reduction was 49% (range, 12-73), and for macroadenomas it was 43% (range, 6-92). After 24 wk of Oct-LAR (end of phase 2), the GH level was less than 5 mU/liter in 11 of 14 patients (79%), and IGF-I was normal in 8 of 15 patients (53%). In the 15 patients given Oct-LAR (10 macroadenomas), wk 48 scans showed a further overall median tumor volume reduction of 24%. At the end of the study 79% of patients had mean serum GH levels below 5 mU/liter, 53% had normal IGF-I levels, and 73% showed greater than 30% tumor shrinkage. Twenty-nine percent of patients achieved all 3 targets, but no patient with pretreatment GH levels above 50 mU/liter did so at any stage of the study. Primary medical therapy with Oct offers the prospect of normalization of GH/IGF-I levels together with substantial tumor shrinkage in a significant subset of acromegalic patients. This is most likely to occur in patients with pretreatment GH levels less than 50 mU/liter (20 microg/liter).

Gross total resection or debulking of pituitary adenomas improves hormonal control of acromegaly by somatostatin analogs

“…We hypothesized that by reducing tumor mass and decreasing basal GH secretion, the subsequent control of GH and IGF-I levels with SSAs could be improved. This hypothesis is consistent with longterm trials that show a better control of GH and IGF-I with SSAs when initial GH levels are lower (12). Patient inclusion for our study was facilitated by the fact that most acromegalic patients who undergo surgery at our centers are pretreated with SSAs for a period of at least 3 months to improve general health and facilitate surgical adenoma resection (18).…”

“…As long-term treatment by SSAs permits the normalization of GH and IGF-I in a substantial Table 2 Individual GH and IGF-1 values for all patients at the four study time points. number of cases (40 -60%) (12), some physicians may opt to treat patients suffering from extrasellar macroadenomas with SSAs when compression of adjoining structures is not present (12)(13)(14)(15)(16)(17). Whether or not surgery improves the outcome of medical therapy with SSAs has not been studied previously.…”

Somatostatin agonists for treatment of acromegaly

“…Several papers in recent years report the efficacy of primary pharmacotherapy in achieving biochemical disease control. Similar rates of patient control were achieved in the primary and adjuvant groups, with GH plasma levels ≤2.5 μg/L (64%) and/or normalization of IGF-1 (64%) Ayuk et al, 2002Ayuk et al, , 2004Bevan et al, 2002;Colao et al, 2001Colao et al, , 2006cCozzi et al, 2003Cozzi et al, , 2006. Even though de novo patients had higher pre-treatment GH or IGF-1 levels or both, than those already treated with surgery and/or radiotherapy, patients achieved the same ultimate level of biochemical control by the end of the study Cozzi et al, 2003).…”

The ongoing challenge of discrepant growth hormone and insulin‐like growth factor I results in the evaluation of treated acromegalic patients: a systematic review and meta‐analysis

“…Finally, data from four studies were retrieved in the setting of an intervention trial regarding the administration of SSAs in acromegalic patients. [12][13][14][15] The studies were published from 1987 to 2013 and contained records of patients from 1964 to 2011 (follow-up range 12-552 months), totalling 7071 patients. For 5626 of the above patients, concomitant data for both IGF-I and GH were available, allowing the estimation of discordance between the two criteria.…”