Dose Escalation of Octreotide-LAR as First-Line Therapy in Resistant Acromegaly
Dose Escalation of Octreotide-LAR as First-Line Therapy in Resistant Acromegaly
Epidemiological data indicate that patients with active acromegaly have reduced life
 expectancy because of cardiovascular (60%) and respiratory diseases (25%) mainly (1-10). A
 post-treatment GH value <5 mU/liter (equal to <2.5 μg/liter) and IGF-I in the normal range
 for age are recognized as the most predictive survival indices.

 Since their introduction into clinical use approximately two decades ago, somatostatin
 analogs have been considered a cornerstone of medical therapy for acromegaly. After 12 months
 of treatment with octreotide-LAR, control of GH and IGF-I excess, is achieved in 54% and 63%
 of unselected patients (11). The proportion of subjects achieving IGF-I normalization
 increases significantly with time (12). Significant tumor shrinkage has also been reported in
 a number of studies (13,14): an average 50% tumor decrease is achieved when the drug is used
 exclusively, or before surgery or radiotherapy (14). In 99 unselected newly diagnosed
 patients after 12 months of treatment with somatostatin analogues we reported control of GH
 levels in 57.6% and IGF-I levels in 45.5% and a greater than 50% tumor shrinkage in 44.4%
 (15).

 The dose of LAR in different studies ranged from 10-40 mg every 28 days (q28d): high doses
 are generally administered in patients who do not control GH and IGF-I excess with lower
 doses. As reported in the meta-analysis (11) the rate of IGF-I normalization tended to be
 lower as octreotide-LAR dose was raised: 90% in patients treated with 10 mg, 61% with 20 mg
 and 53% with 30 mg. However, some further benefit by increasing the dose of octreotide-LAR
 was reported in some studies (16-18).

 Data on dose escalation of octreotide-LAR given as first-line therapy in newly diagnosed
 patients with acromegaly are lacking.
This is an analytical, interventional, 24-month, open, prospective study to investigate the
 effect of progressive increase of octreotide-LAR doses in newly diagnosed patients with
 acromegaly. Primary outcome measures were GH and IGF-I control and tumor shrinkage; secondary
 outcome measure was glucose tolerance.

 At diagnosis and every six months, 24-48 hours before changes in treatment doses was applied,
 were measured:

 1. Serum IGF-I levels twice in a single sample at the time 0 of the GH profile; GH levels
 calculated as the mean value of 3-6 samples drawn every 30 min; the average value was
 considered for the statistical analysis;

 2. Tumor volume on MRI studies performed on clinical 1T and 1.5T scanners, using T1
 weighted gradient recalled-echo in the sagittal and coronal planes, as already reported
 (15,21,22). The acquisitions were repeated before and after the administration of 0.1
 mmoles of gadolinium chelate (diethylene-triamine pentacetate). In all patients MRI was
 performed at diagnosis and after 6, 12, and 24 months of treatment. The maximal
 sagittal, axial and coronal diameters were measured, then tumor volume was calculated by
 the De Chiro and Nelson formula [(volume= sagittal*coronal*axial diameters)*π/6].
 According with previous studies (13,21) on post-treatment MRI, tumor shrinkage was
 assessed as percent decrease of tumor volume compared with baseline.

 3. Glucose tolerance by assaying glucose and insulin levels at fasting. Only at diagnosis
 glucose and insulin were also measured every 30 minutes for 2 hours after the oral
 administration of 75 g of glucose diluted in 250 ml of saline solution. In four patients
 the glucose load was not performed because of overt diabetes (fasting glucose was above
 7 mmol/L at two consecutive measurements) (25). Diabetes mellitus was diagnosed in
 another eight patients when 2 hours after the oGTT glucose was >11 mmol/L (25). Impaired
 glucose tolerance (IGT) when glucose level was between >7.8 mmol/L and <11 mmol/L 2
 hours after the oGTT and/or impaired fasting glucose (IFG) when glucose level was
 between 5.6 and 6.9 mmol/L at fasting were diagnosed in 20 patients (25). Glucose
 tolerance was normal (below 5.6 mmol/L at fasting) in 24 patients. To predict insulin
 resistance [HOMA-R (%)] and ß-cell function [HOMA-β (%)] was used the HOMA (homeostatic
 model assessment) according with Matthews et al. (24). By assuming that normal-weight
 healthy subjects aged <35 years have a HOMA-β of 100% and a HOMA-R of 1, the values for
 individual patients can be assessed from the insulin and glucose concentrations by the
 formulae: HOMA-R = [insulin (mU/L)*fasting glucose (mmol/L)] / 22.5; HOMA-β (%) =
 [20*insulin (mU/L)] / [glucose (mmol/L)-3.5].

 Treatment protocol Before starting therapy, all patients received an acute test with s.c.
 octreotide at a dose of 0.1 mg in the morning after an overnight fast and at least 2 hrs of
 bedrest, to investigate each patient's tolerability to somatostatin analogues (25). Then, all
 patients were treated with octreotide-LAR i.m. at an initial dose of 20 mg every 28 days for
 three months. Subsequently, LAR treatment was maintained at the same dose in patients
 achieving GH levels ≤2.5 μg/liter and IGF-I levels in the normal range (Group A), or
 increased up to 30 mg every 28 days in patients with GH levels >2.5 μg/liter and/or IGF-I
 levels above the normal range. After another 9 months of treatment with 30 mg/q28d, the dose
 was maintained in 15 patients achieving GH levels ≤2.5 μg/liter and IGF-I levels in the
 normal range (Group B) while it was further increased to 40 mg/q28 days if fasting GH levels
 were still >2.5 μg/liter and/or IGF-I levels were above the normal range (Group C).
Inclusion Criteria:

 -  patients with newly diagnosed acromegaly

 -  age above 18 years

 -  no previous treatments for acromegaly

 Exclusion Criteria:

 -  primary surgery

 -  concomitant hyperprolactinemia if requiring combined treatment with dopamine-agonist

 -  primary treatment with lanreotide

 -  treatment duration less than 24 months