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Divisions of Endocrinology (R.C., R.A.) and Neuroradiology (P.D.), Ospedale Niguarda, I-20162 Milan, Italy; Department of Neurosurgery (G.L., S.L.), Neurological Institute Carlo Besta, I-20133 Milan, Italy; and Division of Endocrinology (R.A., M.M., M.A., L.C., G.P.), Ospedali Riuniti, I-24100 Bergamo, Italy
Address all correspondence and requests for reprints to: Dr. R. Cozzi, Viale Ezio 5, I-20149 Milano, Italy. E-mail: renatocozzi{at}tiscali.it.
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Abstract |
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 Top Abstract IntroductionPatients and MethodsResultsDiscussionReferences |
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Objective: Our objective was to evaluate primary pharmacological treatment in acromegaly.
Design and Setting: We conducted an open prospective study at two Italian tertiary level centers.
Patients: We studied 67 consecutive patients (36 women; age, 54.9 ± 14.2 yr; 72% bearing macroadenoma).
Intervention: Individually tailored octreotide LAR (OCLAR) was administered.
Main Outcome Measures: Outcomes included safe GH (<2.5 µg/liter), normal age-matched IGF-I levels, and tumor shrinkage.
Results: After a median follow-up of 48 months (range, 6–108 months), safe GH levels and normal age-matched IGF-I values were obtained by 68.7 and 70.1% of patients, respectively. Hormonal endpoints were achieved regardless of basal levels, and early results were predictive of outcome. Tumor shrank in 82.1% of patients by 62 ± 31% (range, 0–100%), decreasing from 2101 ± 2912 to 1010 ± 2196 mm3 (P < 0.0001). The higher the basal GH values and the greater the GH/IGF-I changes on treatment, the greater the tumor shrinkage. Tumor disappeared in three patients and was progressively reduced to empty sella in five patients; apparent magnetic resonance imaging cavernous sinus invasion disappeared in three. In males, testosterone increased, restoring eugonadism in 64% of hypogonadal patients.
Conclusions: The efficacy on GH/IGF-I levels in unselected patients and the outstanding volumetric control indicate that treatment with OCLAR may be the first therapeutic approach to all acromegalic patients not amenable to surgical cure. Tumor shrinkage might also encourage the evaluation of primary OCLAR adoption in patients with initial visual field defects.
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Introduction |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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We evaluated prospectively the effects of primary octreotide LAR (OCLAR) treatment on GH/IGF-I hypersecretion and tumor size in 67 consecutive naive acromegalic patients, mainly with macroadenoma.
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Patients and Methods |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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Inclusion criteria were as follows: consecutive patients with active acromegaly, according to clinical picture, elevated GH levels not suppressible below 1 µg/liter after oral glucose tolerance test (OGTT), and high age-adjusted IGF-I levels; macroadenoma or invasive microadenoma at magnetic resonance imaging (MRI) scans; and no previous neurosurgery or radiotherapy.
Exclusion criteria were as follows: intrasellar microadenoma (except in patients refusing or unable to undergo neurosurgery); ophthalmological or neurological involvement; and liver or renal disease.
Sixty-seven consecutive naive acromegalic patients entered this prospective open study between January 1996 and December 2004. Demographic and clinical data are depicted in Table 1
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Each patient gave informed consent after full explanation of the purpose of the study, and the procedures followed were in accordance with the Helsinki Declaration of 1975 as revised in 1983.
Protocol
The endpoints were the achievement of safe GH levels (<2.5 µg/liter) and normal age-matched IGF-I, in agreement with consensus guidelines (15), and tumor shrinkage, as defined below.
After the baseline evaluation, OCLAR was started at the dose of 20 mg administered im every 28 d. The drug dosage was then individualized at 3- to 6-month intervals; it was escalated to 30 mg if GH or IGF-I levels remained pathological or decreased to 10 mg if IGF-I levels fell to less than 50% of the upper limit of the normal range.
Dopamine agonist administration was not allowed throughout the study.
Patients not reaching hormonal targets within 12 months were offered alternative treatments (neurosurgery or lanreotide or dopamine agonist addition). Those accepting alternative treatment were dropped from the study (and values obtained at that time were regarded as the last follow-up evaluation).
Testosterone or estroprogestinic replacement treatment was not administered to hypogonadal patients in the first 6–12 months to allow the evaluation of treatment-induced recovery from hypogonadism.
Patients were checked at regular intervals (3–6 months during the first year and yearly thereafter). Clinical (addressing menstrual history in premenopausal females and scoring in all patients headache, perspiration, swelling, arthralgia, and fatigue) and biochemical evaluations of hormonal, metabolic, and safety parameters were performed on an outpatient basis before the start of treatment and at every follow-up visit. Ophthalmological evaluation (in patients bearing macroadenoma) and MRI were performed before the start of treatment, at 6 and 12 months, and yearly thereafter. Ultrasound abdominal scan was performed before the start of treatment, and at 12- to 24-month intervals thereafter.
Blood samples were collected in the morning hourly for at least 3 h after an overnight fast and rest, while the patients were supine and awake, with an indwelling needle inserted in an antecubital vein, kept patent by slow infusion of saline. GH concentrations were assayed on each sample (the value reported is the mean of all samples); IGF-I, other hormones, and metabolic and safety parameters were assayed on the first sample.
Methods
Serum GH levels were measured by immunometric assay (Diagnostic Products Corp., Los Angeles, CA) with standards calibrated against World Health Organization First International Standard 80/505 (1 µg/liter = 2.6 mU/liter). The sensitivity is 0.01 µg/liter, the intra- and interassay coefficients of variation (CV) are 2.9–4.6 and 4.2–6.6%, respectively.
Serum IGF-I was measured after acid-ethanol extraction by a chemiluminescence assay (Nichols Institute Diagnostics, San Juan Capistrano, CA). The calibration with regard to the World Health Organization International Standard, National Institute for Biological Standards and Control 87/518, yields a conversion factor of 1.66. The intra- and interassay CV are 3.7 and 7.2%, respectively. Normal values for IGF-I are 182–780, 114–492, 90–360, and 71–290 µg/liter in patients aged 16–24, 25–39, 40–54 yr, and older than 55 yr, respectively.
Total testosterone was assayed by chemiluminescence (Roche, Milan, Italy), with intra- and interassay CV of 1.1–4.6 and 1.7–7.4%, respectively, and normal values ranging from 2.8–11 µg/liter.
Serum levels of prolactin, free T4, and urinary free cortisol (after extraction), glucose (fasting and at 120 min after OGTT), glycated hemoglobin (HbA1c), cholesterol (total as well as high-density lipoprotein and low-density lipoprotein), triglycerides, and safety parameters (blood count, liver, and kidney tests) were assayed by commercial methods.
Ophthalmological evaluation was performed by Goldmann or computerized perimetry and visual acuity testing.
MRI was performed by Philips Gyroscan (Philips, Eindhoven, The Netherlands) (ACS-NT) 1.5 T. A neuroradiologist unaware of the ongoing treatment blindly evaluated the images. For the purpose of this study, all images of a patient were reevaluated in a single session. On each scan, the largest diameter of the tumor was measured on coronal (vertical diameter and transverse) and sagittal (anteroposterior) sections. After correction for magnification factor, the approximate volume of the adenoma was calculated as the volume of a rotating ellipsoid, with the formula previously described (16): volume = 
(vertical diameter x anteroposterior x transverse)/6. The shrinkage of the tumor was arbitrarily considered significant when its volume was reduced by at least 25%.
Statistical analysis
Values are expressed as mean ± SD, unless otherwise stated.
Analyses were performed by GB-Stat 6.5.4 PPC.
Data were analyzed by parametric or nonparametric tests, depending, respectively, on whether or not they passed preliminary Kolmogorov-Smirnov test for normality. Continuous variables with normal distribution were analyzed by t test for paired or unpaired data, completely randomized ANOVA followed by Newman-Keuls test, ANOVA for repeated measures followed by Dunn test, and Pearson correlation test. Continuous variables with uneven distribution were analyzed by Wilcoxon test, Mann-Whitney test, Kruskall-Wallis test, and Spearman correlation test. Multiple regression analysis and logistic regression analysis were performed only on data that were significantly correlated in pairwise analysis. Categorical variables were analyzed by 
2 test or Fisher exact test, as appropriate. Longitudinal evaluations were performed by Kaplan-Meier method, and differences between subgroups were evaluated by log-rank test.
To evaluate the predictivity of basal levels and early results on final outcome at multiple levels without the bias of predetermined criteria, we constructed receiver operating characteristic curves by plotting the sensitivity against (1 – specificity) at each level using dedicated software.
All statistical tests were two-tailed, and values of P < 0.05 were considered significant.
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Results |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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At the last follow-up evaluation, six (9%), 10 (14.9%), and 44 (65.7%) patients were treated with 10, 20, and 30 mg every 28 d, respectively.
Clinical score improved in all responsive patients (data not shown).
GH/IGF-I levels
GH fell from 29.3 ± 27.8 to 3.2 ± 4.7 µg/liter at the last follow-up evaluation (P < 0.0001), reaching levels less than 2.5 µg/liter in 46 patients (68.7%). IGF-I decreased from 886 ± 332 to 329 ± 210 µg/liter (P < 0.0001) (274 ± 119 and 99 ± 63% of the upper limit of the normal range, respectively), reaching normal levels in 47 patients (70.1%). The percentage decreases were 81.5 ± 21.7% (median, 90%; range, 0–99%), and 59 ± 27% (median, 66%; range, +29 to –90%) for GH and IGF-I, respectively.
Both safe GH and normal IGF-I levels were achieved in 38 patients (56.7%). In the patients not achieving hormonal targets, GH and IGF-I decreased by 64 ± 28% (median, 70%; range, 0–97%) and 31 ± 29% (median, 33%; range, +29 to –74%), respectively.
Three patients (4.5%) were quite unresponsive to treatment (arbitrarily defined as a less than 10% change in GH/IGF-I levels within 6 months).
GH/IGF-I decreased mostly within 6–12 months, IGF-I levels further decreased (P < 0.01 for last time points vs. 6 months), and the number of patients achieving hormonal targets progressively increased (Fig. 1). Patients reaching hormonal endpoints did not have different basal hormonal levels vs. those who did not (28.5 ± 24.6 vs. 30.6 ± 32.3 µg/liter for GH, 863 ± 315 vs. 919 ± 358 µg/liter for IGF-I; P = 0.78 and 0.51, respectively). Patients starting from higher basal GH levels (vs. the median value of the series, i.e. 24 µg/liter) reached hormonal endpoints in the same percentage of those starting from lower ones (67.6 vs. 69.7% for GH, 70.6 vs. 66.7% for IGF-I; P = 0.86 and 0.73, respectively) and within the same time course (P = 0.99 and 0.72, respectively, by log-rank) (Fig. 2).
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No difference in the achievement of hormonal endpoints was observed between patients bearing macro- and micro- adenoma (62.5 vs. 84.2% for safe GH, 64.6 vs. 78.9% for normal IGF-I; P = 0.0842 and 0.2533, respectively).
At multivariate analysis, the best predictors of final hormonal values were the respective values obtained at 6 months. By receiver operating characteristic analysis, the best predictor for the final attainment of safe GH values was the achievement of GH levels less than 5 µg/liter (area under the curve, 0.9118 ± 0.05; P < 0.0001; sensitivity, 87%; specificity, 94%; accuracy, 84%). IGF-I normalization was predicted by the achievement of IGF-I levels less than 500 µg/liter (area under the curve, 0.8057 ± 0.0834; P < 0.0001; sensitivity, 86%; specificity, 75%; accuracy, 81%).
Tumor size
Semiquantitative evaluation. None of the patients experienced progression of tumor growth.
Tumor shrank in 55 patients (82.1%). Shrinkage was evident at the first evaluation in 80% of them, but in a few other cases the tumor shrank after 24 months. Shrinkage was progressive in 46% of patients (in 93% of patients with the more prolonged follow-up). In three patients (two bearing micro- and one macroadenoma), the adenoma disappeared. In five patients, a progressive (up to 30–96 months) reduction from macroadenoma with extrasellar extension to empty sella occurred. In three other patients, in whom basal MRI suggested the initial invasion of the cavernous sinus, follow-up imaging showed the clear visualization of the lateral border of the tumor, outside of the sinus itself.
Basal hormonal values in patients whose tumor shrank were higher than in patients whose tumor did not (35 ± 33 vs. 15 ± 7 µg/liter for GH, 1000 ± 356 vs. 765 ± 187 µg/liter for IGF-I; P = 0.0095 and 0.0351, respectively), and IGF-I normalization occurred more frequently (75 vs. 20%; P = 0.0067).
Tumor shrank more often in the younger than in the elderly patients (87 vs. 56%; P = 0.0202, using as cutoff the median age of the series, i.e. 56 yr).
The achievement of both hormonal and volumetric endpoints was obtained in 44.8% of patients. In most patients, tumor shrinkage occurred before hormonal normalization. In 35%, tumor shrank but GH did not reach a safe value. In 3%, no shrinkage occurred notwithstanding GH normalization. Neither safe GH nor tumor shrinkage was obtained in 15% of patients. Tumor shrank in 94 and 71% of patients achieving or not, respectively, safe GH values.
Quantitative evaluation
Tumor volume decreased from 2101 ± 2912 to 1010 ± 2196 mm3 (P < 0.0001). Percent decrease vs. baseline was 62 ± 31% (median, 67%; range, 0–99%). Tumor size decreased less than 25% of basal volume in 18% of patients, by 26–50% in 12%, and by more than 50% in 70%. In particular, tumor shrank more than 75% in 44%. Volumetric decrease was progressive: 28 ± 19, 53 ± 26, 69 ± 14, and 91 ± 7% at 6, 12, 24, and 36 months, respectively (P < 0.0001).
Basal GH/IGF-I levels and tumor size were not correlated, but basal GH values were significantly correlated with volumetric changes (r = 0.38; P = 0.0247); i.e. the greater the basal GH values, the greater the shrinkage. During treatment, there was a correlation between volumetric and hormonal changes (r = 0.54 and 0.43; P = 0.0009 and 0.0107 for GH and IGF-I, respectively); i.e. the greater GH/IGF-I suppression, the greater the shrinkage. Final tumor volume was inversely correlated to follow-up length (r = –0.32; P = 0.0354); i.e. the longer the follow-up, the lower the final tumor volume.
Volumetric decrease in patients achieving hormonal targets was slightly higher than that obtained in patients who did not (71 ± 23 vs. 46 ± 38%; P = 0.0554).
Patients with macroadenoma showed tumor shrinkage more frequently than patients bearing microadenoma (81 vs. 53%; P = 0.0196). The absolute quantitative reduction was far greater in the former group (1353 ± 1555 vs. 240 ± 182 mm3; P = 0.05), and percent decrease in tumor volume vs. baseline was similar (64 ± 30 vs. 56 ± 34%; P = 0.6053).
Figure 3 shows quantitative reduction in tumor size according to basal MRI characteristic of the adenoma.
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Prolactin, free T4, and urinary free cortisol levels did not change throughout treatment (data not shown).
Normal gonadal function was resumed in the only amenorrheic female in fertile age, and in seven of 11 hypogonadal males, in whom treatment increased testosterone from 2.9 ± 1.3 to 3.9 ± 1.6 µg/liter (P = 0.0166), restoring eugonadism within 6 months. This result was not related to tumor size or to its change during treatment or to GH/IGF-I changes.
Metabolic effects (Table 2)
Mean fasting glucose, HbA1c, and cholesterol levels did not change. Triglycerides decreased significantly (P = 0.01).
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Adverse effects
Gallstones or biliary sludge appeared in 12% of patients. One patient, who had transiently stopped OCLAR treatment, required urgent surgical treatment for acute cholecystitis.
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Discussion |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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-Knife radiosurgery does not seem to obtain better results (23). The role of pharmacotherapy has instead increased, mainly after the development of SA, octreotide (24), and its long-acting formulation OCLAR (25, 26, 27, 28). Following a pioneering study (14), which showed that primary medical treatment of acromegaly with sc octreotide was as effective as in patients previously unsuccessfully operated on, a few other reports strengthened the possibility of treating selected patients with SA only. In this prospective long-lasting open study in 67 consecutive naive nonselected acromegalic patients mainly affected by macroadenoma, OCLAR normalized GH and IGF-I values in 68.7 and 70.1%, respectively. These figures are similar to those reported both in a few small series of PT patients (29, 30), and in mixed series (adjuvant and PT) (26, 31). In contrast with a meta-analysis (28) showing that the likelihood of achieving hormonal endpoints is greater in patients starting from lower basal GH levels, we show that our patients with initial higher basal GH values achieve hormonal targets as patients with basal lower levels and with the same time course. In agreement with our previous report (27), we thus confirm that the achievement of hormonal endpoints is quite independent from basal hormonal values. The reason for the discrepancy with data reported in the meta-analysis (28) is unclear.
Another interesting finding in agreement with our previous work (27) is the ability to predict the final outcome of PT with OCLAR on the basis of early results (with 86% sensitivity and 75% specificity for IGF-I value < 500 µg/liter at 6 months in predicting IGF-I normalization).
We observed tumor size shrinkage in 82.1% of patients, more frequently in macro- than in microadenoma, as already reported (27, 29, 32), and quantitatively greater in macroadenoma, as in the initial reports on this topic (30, 31). Quantitative tumor size reduction in this series was impressive, being greater than 50% in 70.6% and greater than 75% in 44.1% of cases. Moreover, shrinkage was progressive in many patients, the adenoma disappeared in three (as once reported) (33), and empty sella occurred in other five. This finding, which is in contrast with a recent review (34), confirms that the fraction of patients whose tumor shrinks while on treatment with OCLAR is far higher among primarily treated cases, as already reported (32). The progressive shrinkage of the adenoma, up to empty sella in a few cases, contrasts with the previous knowledge about the effects of SA on tumor volume in acromegaly. Although the early reported results on this topic were variable (35), present data strongly point out that the antitumor effect exerted by SA in primarily treated acromegalic patients resembles what happens in macroprolactinoma patients treated by dopamine agonist drugs (36).
Tumor shrank also in patients who did not reach safe GH levels, as already reported (reviewed in Ref. 32); this discrepancy might be explained by the different molecular mechanisms involved in inhibition of GH secretion and induction of tumor shrinkage (37). Hormonal normalization was correlated to volumetric changes; i.e. the greater the shrinkage, the greater the hormonal decrease, and the higher the basal GH values, the greater the shrinkage. Moreover, IGF-I normalization was much more frequent in patients whose tumor shrank. So the main features (GH levels and adenoma size) universally known to be limiting factors to the success rate of neurosurgery (12) seem to play a favoring role for OCLAR therapy in this series.
OCLAR shrank the tumor also in patients with clearly invasive adenoma, but invasiveness did not revert. In contrast, in some cases with doubtful invasion of the medial wall of the cavernous sinus at the first MRI, shrinkage clearly allowed us to better distinguish the lateral limit of the adenoma. So the pretreatment neuroradiological finding of invasiveness might sometimes be misleading, and the control MRI, showing a better definition of tumor limits, could change the final therapeutic strategy.
In our series, OCLAR was interrupted in the three patients whose adenoma disappeared during treatment only. In one of them with a microadenoma, GH/IGF-I levels remained normal even 18 months after drug withdrawal, and MRI control did not show any change. In the other two patients, GH/IGF-I levels increased again slowly and treatment was restarted soon, before MRI control could show any regrowth of the adenoma.
The safety treatment profile was excellent. Thyroid and adrenal function were not impaired; gonadal function improved significantly, allowing restoration of eugonadism in most hypogonadal patients. This finding is analogous to the recovery of hypogonadism during dopaminergic treatment of macroprolactinoma (36).
Glucose metabolism was not impaired in the whole group; glucose balance improved in 45% and worsened in 45% of diabetic patients as well as in 33% of nondiabetics. The worsening of glucose metabolism during OCLAR treatment has been considered a serious side effect of SA treatment, in contrast to the improvement observed during GH-antagonist treatment (38). Whereas most studies did not report any significant change (reviewed in Ref. 39), others found increased fasting glucose levels in previously euglycemic patients, whereas glucose response in diabetic patients was unpredictable (40). Cholesterol was unaffected by treatment, whereas triglycerides decreased. The improvement of lipid profile during treatment with octreotide was already reported (41).
Biliary function was unaffected in most patients of this series, but a single patient required urgent surgery for acute cholecystitis. The low rate of biliary dysfunction in this series may depend on the diet assumed in our country as well as on the mechanism of action of the depot formulation of octreotide. The patient who required acute surgery had stopped the drug for a short period of time. In this situation, gallbladder contractility might be restored, thus causing acute impaction of stones on biliary tracts (42).
In conclusion, PT with OCLAR normalizes GH/IGF-I levels and reduces tumor volume in a very high percentage of patients; shrinkage is most impressive in the patients with the highest GH levels and the largest tumors. These data, coupled to the improvement of gonadic function and safety profile, point out that in selected acromegalic patients (huge and/or invasive adenoma with high GH levels, poor candidates to surgical cure), OCLAR should be the first treatment of the disease, as in the patients at high surgical risk due to disease-related comorbidities. The high prevalence and the impressive degree of tumor shrinkage obtained with OCLAR treatment might encourage us to evaluate primary OCLAR adoption for improving surgical prognosis and even in patients with initial visual field defects. Moreover, the shrinkage of tumor, initially regarded as invasive, could change the final therapeutic strategy in some patients.
In a contemporary patient-oriented approach to acromegalic disease, surgical and medical therapy should not be mutually exclusive, but rather they should be complementary. When primary SA treatment in patients that are not amenable to surgical cure does not achieve hormonal targets, surgical debulking may improve subsequent response to a new challenge with SA, according to recent data obtained in a selected series of patients partially sensitive to SA (43, 44).
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Footnotes |
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First Published Online January 31, 2006
Abbreviations: CV, Coefficient of variation; HbA1c, glycated hemoglobin; MRI, magnetic resonance imaging; OCLAR, octreotide LAR; OGTT, oral glucose tolerance test; PT, primary treatment; SA, somatostatin analogs.
Received October 26, 2005.
Accepted January 25, 2006.
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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