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Journal of Clinical Endocrinology & Metabolism , doi:10.1210/jc.2008-0424
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The Journal of Clinical Endocrinology & Metabolism Vol. 93, No. 9 3436-3442
Copyright © 2008 by The Endocrine Society

Growth Hormone-Secreting Tumor Shrinkage after 3 Months of Octreotide-Long-Acting Release Therapy Predicts the Response at 12 Months

Annamaria Colao, Rosario Pivonello, Renata S. Auriemma, Mariano Galdiero, Silvia Savastano, Ludovica F. S. Grasso and Gaetano Lombardi

Department of Molecular and Clinical Endocrinology and Oncology, Section of Endocrinology, University "Federico II" of Naples, 80131 Naples, Italy

Address all correspondence and requests for reprints to: Annamaria Colao, M.D., Ph.D., Department of Molecular and Clinical Endocrinology and Oncology, "Federico II" University of Naples, via S. Pansini 5, 80131 Naples, Italy. E-mail: colao{at}unina.it.


   Abstract
Top
 Abstract
Introduction
 Patients and Methods
 Results
 Discussion
 References
 
Objective: The objective of the study was to evaluate whether tumor shrinkage or GH and IGF-I levels achieved after 3 months predicted tumor shrinkage after 12 months of octreotide-long-acting release (LAR) treatment.

Patients: Patients included 67 patients with de novo acromegaly (33 women, 34 men; aged 20–82 yr) receiving LAR at a dose of 20 mg every 28 d for 3 months. Final LAR dose was 10 mg every 28 d in 4, 30 mg every 28 d in 39, 20 mg every 28 d in 24 patients.

Design: The design of the study was analytical, observational, open, and retrospective.

Outcome Measures: Percent change in GH and IGF-I levels and tumor volume after 3 and 12 months of therapy was measured. Stepwise regression and receiving-operator characteristics analysis were used to calculate the optimal cutoff to predict 12 months tumor shrinkage at 12 months.

Results: The percent tumor shrinkage after 12 months was significantly correlated with GH, IGF-I, and tumor volume at 3 months and with the dose of LAR administered between 3 and 12 months. There was no correlation with gender, age, baseline GH levels and tumor volume. In a stepwise regression analysis, percent tumor shrinkage after 3 months was the best predictor of tumor shrinkage after 12 months (t = 5.92; P < 0.0001), followed by GH levels after 3 months (t = 2.86; P = 0.0056). To predict 50% or greater tumor shrinkage after 12 months, the best cutoff point of tumor shrinkage at 3 months was 22.1% [sensitivity (95% confidence interval) = 85.5% (71.2–95.4); specificity = 83.3% (65.3–94.3)], whereas that of GH levels after 3 months was 7.8 µg/liter [sensitivity = 70.3% (53.0–84.1); specificity = 93.3% (79.0–99.0)].

Conclusion: Tumor shrinkage achieved after 3 months of LAR treatment at 20 mg/28 d predicted tumor shrinkage at 12 months, provided that dosages were changed according to individual patients requirement.


   Introduction
Top
 Abstract
 Introduction
Patients and Methods
 Results
 Discussion
 References
 
Somatostatin analogs are a cornerstone of medical therapy for acromegaly. The treatment with octreotide-long-acting release (LAR) for 12 months controls GH and IGF-I excess in 54 and 63% of unselected patients (1), respectively, with an increasing proportion of subjects achieving IGF-I normalization with treatment continuation (2). Clinically significant tumor shrinkage (20–30% vs. baseline) has also been reported (3, 4) in a greater proportion of patients who received first-line medical therapy [231 of 448 patients (52%)], compared with those treated after surgery and/or radiotherapy [52 of 248 patients (21%)] (3). The highest rate of clinically significant shrinkage (>20%) occurred in patients who received first-line therapy with LAR (80%), compared with the short-acting octreotide formulation (50%) or lanreotide slow-release formulation (35%) (3). The cohort of patients treated with lanreotide was, however, much smaller than those who received LAR and sc octreotide. In 99 de novo patients with acromegaly who received first-line therapy-with LAR (n = 60) or lanreotide slow release (n = 39) for 12 months, we reported control of GH in 57.6% of IGF-I levels in 45.5% and a greater than 50% tumor shrinkage in 44.4% (5). The duration of treatment, however, is relevant to the degree of tumor shrinkage. In a homogeneous cohort of 56 patients treated with LAR continuously for 24 months, tumor volume decreased by 68.1 ± 16.5% using dosages up to 40 mg every 28 d (6).

Despite these observations, there is still a debate on the role of first-line therapy with somatostatin analogs (7, 8, 9). Of paramount importance would be the ability to predict the results of treatment early in the course of therapy. Controversy exists as to the predictive value of initial tumor size, inhibition of GH and IGF-I levels during treatment, and dose or type of somatostatin analog used (4, 5, 6, 10, 11). In the study previously mentioned (5), the parameter that best correlated with tumor shrinkage at 1 yr was percent suppression of IGF-I period, but this study did not analyze the predictive ability of short-term factors in inducing tumor shrinkage.

This report evaluates the predictive value of tumor shrinkage along with GH and IGF-I suppression after 3 months of LAR on tumor size achieved after 1 yr. Data for this analysis were collected prospectively in 67 patients, and all but 12 were included in the report described elsewhere (5). As secondary parameters we also analyzed baseline parameters including age at diagnosis, gender, estimated disease duration, GH and IGF-I levels, and tumor size.


   Patients and Methods
Top
 Abstract
 Introduction
 Patients and Methods
Results
 Discussion
 References
 
Study design

This is an observational, analytical, open, retrospective study.

Inclusion criteria

Patients with active acromegaly coming to the Unit of Endocrinology of the "Federico II" University of Naples from January 1, 1995, to March 31, 2007, primarily treated with octreotide-LAR, and with a follow-up of 12 months were enrolled. The routine procedure in our clinic since 1997 (12), in agreement with our neurosurgeons, is to use depot somatostatin analogs as first-line therapy in all patients with: (1) macroadenomas with extrasellar extension and (2) patients with proven cardiomyopathy, hypertension, sleep apnea or other respiratory disorders, and/or other systemic complications potentially making anesthesia less safe than in other patients. This procedure is fully discussed with our patients who sign a written consent at the time of hospitalization agreeing with diagnostic procedures and treatment strategy.

Exclusion criteria

For the purposes of this study, patients treated after unsuccessful surgery, patients requiring combined dopamine-agonists and somatostatin analogs, patients treated with lanreotide, and patients with a follow-up shorter than 12 months were excluded.

Patients

Of 305 patients coming to our department for acromegaly, 89 patients with newly diagnosed active acromegaly who received first-line therapy with LAR were considered for this study. Two-hundred sixteen patients were excluded because of: 1) first-line surgery in 106, 2) concomitant hyperprolactinemia requiring combined somatostatin analogs and dopamine agonist treatment in 34; and 3) first-line treatment with lanreotide in 76 patients. Of the 89 patients, 22 (32.8%) were excluded either because of treatment duration less than 12 months (in five patients) or magnetic resonance imaging (MRI) examinations after 3 months were not available (in 17 patients). Data from 67 patients (33 women aged 20–82 yr and 34 men aged 20–76 yr) were included, and all but 12 patients have been included in previous studies (5, 6, 13). The diagnosis of acromegaly was defined in all of the patients as previously reported (14), by high serum GH levels, not suppressible less than 1 µg/liter after glucose load and high plasma IGF-I levels for age. Based on MRI, five patients had a microadenoma, 15 patients had an enclosed macroadenoma (noninvasive, intrasellar), 23 patients had a macroadenoma with extrasellar extension, and 18 patients had macroadenomas with clear-cut invasion of surrounding structures. For the purpose of this study and based on surgical outcome as reported by Nomikos et al. (15) showing no difference between patients with microadenomas and those with enclosed macroadenomas, we grouped patients with these tumors (group 1; n = 22), whereas those with extrasellar and invasive macroadenomas constituted a separate group (group 2; n = 45). Overall, the interval between assumed clinical onset and the time of treatment ranged from 12 to 360 months (median 60 months). Table 1Go shows the patients’ profile at study entry.


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  		TABLE 1. Patients’ profile at diagnosis and during treatment with LAR according to tumor classification

 
This study was conducted in accordance with the Helsinki II Declaration on human experimentation. This study takes advantage of data collected in a large, prospective database to investigate the effect of surgery or medical therapy (with somatostatin analogs and/or dopamine/agonists) on GH, IGF-I, tumor mass, cardiovascular risk markers, cardiomyopathy, hypertension, metabolic profile, and prostate disease in all the patients coming for a diagnosis of acromegaly in our department. The database was started in 1990 and approved by our Ethical Committee in 1997 (no. 60/97).

Cure criteria

The acromegaly was considered controlled if fasting mean GH levels were ≤2.5 µg/liter in the presence of normal IGF-I levels for sex and age (16).

Study protocol

This study investigated the predictive value of tumor shrinkage, GH and IGF-I suppression after 3 months of LAR treatment on tumor shrinkage obtained after 12 months. The main outcome measures were GH and IGF-I age-normalized levels, percent GH and IGF-I suppression and percent tumor shrinkage after 3 months. Secondary outcome measures were baseline age, gender, estimated disease duration, GH and IGF-I levels, and tumor size.

Treatment protocol

Before starting pharmacotherapy, all patients received an acute test with scoctreotide at a dose of 0.1 mg in the morning after an overnight fast and at least 2 h of bed rest to investigate tolerability to somatostatin analogs (17). Then all patients received im LAR at an initial dose of 20 mg every 28 d. After 3 months, the dose was increased to 30 mg every 28 d, if GH was above 10 µg/liter and IGF-I levels were not normalized (n = 39), was maintained at 20 mg every 28 d if GH levels fell less than 10 µg/liter (n = 20) or was reduced to 10 mg every 28 days if GH levels were less than 1 µg/liter (n = 4).

MRI studies

MRI studies were performed on clinical 1T and 1.5T scanners, using T1 weighted gradient recalled-echo (repetition time 200–300 msec; echo time 10–12 msec; flip angle 90°, four signal averages) in the sagittal and coronal planes, as already reported (5, 6, 13). In each measurement seven to 11 slices were obtained, with a slice thickness of 2–3 mm and an in-plane spatial resolution of 0.7–0.97 mm (the matrix was 192–256 x 256 on a field of view of 24–25 cm on the sagittal plane and 160–256 x 256 on a field of view of 18–20 cm in the coronal plane). The acquisitions were repeated before and after the administration of 0.1 mmol of gadolinium chelate (diethylene-triamine pentacetate). In all patients MRI was performed at diagnosis and after 3, 6, and 12 months of treatment. In this study we considered results of the 3 and 12 months follow-up. The sagittal, axial, and coronal diameters were measured by MRI, and then we calculated tumor volume by the De Chiro and Nelson formula: (volume = sagittalcoronalaxial diameters){pi}/6. As in our previous study (5) on the posttreatment MRI, tumor change was assessed primarily as percent decrease or increase of volume compared with the baseline. The percent changes were scored by a semiquantitative scale as follows: no change = ± 0–25%; mild shrinkage or growth = ± 25.1–50%; moderate shrinkage or growth = ± 50.1–75%; notable shrinkage or growth = ± greater than 75%.

Assays

From January 1, 1995, to December 31, 2001, serum GH levels were measured by immunoradiometric assay (IRMA; Sorin, Saluggia, Italy); the sensitivity of the assay was 0.2 µg/liter, and the intra- and interassay variation coefficients (CVs) were, respectively, 4.5 and 7.9%. From January 1, 2002, up to today, serum GH levels were measured by IRMA, using commercially available kits (HGH-CTK-IRMA; Sorin). The sensitivity of the assay was 0.05 µg/liter. The intra- and interassay CVs were 4.3 and 8.5%, respectively. Serum IGF-I was measured by IRMA after ethanol extraction, using Diagnostic System Laboratories Inc. (Webster, TX). The normal range in men aged 20 or less, 21–30, 31–40, 41–50, 51–60, 61–70, and older than 70 yr was 180–625, 118–475, 102–400, 100–306, 95–270, 88–250, and 78–200 µg/liter, respectively, whereas in women it was 151–530, 118–450, 100–390, 96–288, 90–250, 82–200, and 68–188 µg/liter, respectively. The sensitivity of the assay was 0.8 µg/liter. The intraassay CVs were 3.4, 3.0, and 1.5% for low, medium, and high points of the standard curve, respectively. The interassay CVs were 8.2, 1.5, and 3.7% for low, medium, and high points of the standard curve. IGF-I data are shown as ratio vs. the upper limit of normal range (ULN; normal = ≤1).

Statistical analysis

The data were statistically analyzed using MedCalc Software for Windows (MedCalc, Mariakerke, Belgium). Data are reported as mean ± SD unless otherwise specified. A preliminary analysis by the Shapiro and Wilk test showed a nonnormal distribution of most parameters. The comparisons were performed by using the Mann-Whitney test or Wilcoxon signed rank test for unpaired or paired comparison, respectively, or the Kruskal-Wallis test followed by the Dunn’s test for more than two comparisons (18). Categorical variables were compared with the {chi}2 test.

To predict tumor shrinkage after 12 months, we used the following procedure. First, we calculated the correlation coefficients between percent tumor changes after 12 months and all primary and secondary outcome measures by calculating the Spearman coefficients. Then we used the stepwise multiple linear regression to assess which parameter better predicted tumor shrinkage after 12 months. In this analysis, we entered only those variables that had a P < 0.01 in the univariate analysis. Finally, based on the results of the stepwise correlation analysis, we calculated the cutoff thresholds for those parameters best predictors of tumor shrinkage after 12 months. They were analyzed by a receiving-operator characteristics (ROC) curves calculated using MedCalc Software for Windows. The cutoff values selected to best discriminate between the subjects with or without a greater than 50% tumor shrinkage after 12 months were those values with the largest positive likelihood ratio (ratio of the true positive rate to the false positive rate).


   Results
Top
 Abstract
 Introduction
 Patients and Methods
 Results
Discussion
 References
 
Patients’ profile at study entry and response to LAR after 3 and 12 months according with initial tumor volume is reported in Table 1Go.

Three months after LAR treatment at a dose of 20 mg every 28 d, in both groups GH and IGF-I levels decreased significantly, but IGF-I levels decreased at a higher magnitude in group 1 than group 2 patients (Table 1Go). The prevalence of GH control and IGF-I normalization was higher in group 1 than group 2 (Table 1Go). Overall, tumor volume decreased by 25.9 ± 18.5% [median 22.4%, 95% coefficient of interval (CI) 21.5–30.4%], greater in group 1 than group 2 (Table 1Go and Fig. 1Go). The prevalence of greater than 25% tumor shrinkage was higher in group 1 than group 2 patients (Table 1Go).


Figure 1
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  		FIG. 1. Individual changes in tumor volumes (median ± interquartile range) after 3 and 12 months of octreotide-LAR treatment. Group 1 included patients with microadenomas and enclosed macroadenomas; group 2 included patients with extrasellar and invasive macroadenomas.

 
After 12 months, GH and IGF-I progressively decreased and tumor volume further reduced (Table 1Go and Fig. 1Go). The LAR dosage was increased to 30 mg every 28 d in seven patients of group 1 (31.8%) and 32 patients of group 2 (71.1%, P < 0.0001); in four other patients of group 1 (18.2%), the dose was reduced to 10 mg every 28 d. The final outcome of LAR treatment in this series was: GH control in 52.2% (significantly higher in group 1, P = 0.037), and IGF-I normalized in 58.2% (similar in the two groups, P = 0.37). Tumor shrinkage was similar in groups 1 and 2; the prevalence of clinically significant shrinkage was similar in the two groups (Fig. 1Go).

Correlation analysis

Tumor shrinkage after 12 months was significantly correlated with GH (Fig. 2Go) and IGF-I levels (Table 2Go) after 3 months of LAR treatment and with tumor shrinkage after 3 months (Fig. 2Go), the dose used during 3–12 months treatment, and only modestly, baseline IGF-I levels (Table 2Go). No correlation was found between gender, patients’ age, disease duration, baseline IGF-I levels (age normalized), and tumor volume with percent shrinkage after 12 months (Table 2Go). At the stepwise linear regression analysis, the best predictor of the amount of tumor shrinkage after 12 months was the percent tumor shrinkage after 3 months (t = 3,28; P = 0.0021) followed by GH levels after 3 months (t = 2.58; P = 0.014). Percent tumor shrinkage after 12 months could be predicted according with the following model: –39.3 + 0.433 month GH levels + 0.71% 3 month tumor changes (95% CI –52.5 to –42.8; 95% prediction interval –80.5 to –14.8).


Figure 2
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  		FIG. 2. Correlation analysis between percent tumor shrinkage after 3 months (top panel) and GH levels after 3 months (bottom panel) with percent tumor shrinkage after 12 months. The graph shows the distribution of individual patients, the regression line, and the 95% CI.

 

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  		TABLE 2. Correlation coefficients between 12 months shrinkage vs. 3 months treatment response and baseline data

 
Prediction model

To assess which level of GH and percent tumor shrinkage after 3 months was able to predict 50% or greater tumor shrinkage at 12 months, we used a ROC analysis. The best cutoff point of tumor shrinkage after 3 months was 22.1% [sensitivity (95% CI) = 85.5 (71.2–95.4); specificity = 83.3 (65.3–94.3)], whereas that of GH levels after 3 months was 7.8 µg/liter [sensitivity = 70.3 (53.0–84,1); specificity = 93.3 (79.0–99.0)] (Fig. 3Go). There was no difference in comparing the two ROC curves (difference between areas = 0.003; SE = 0.051; 95% CI –0.097 to 0.103; P = 0,951). The probability of a 50% or greater tumor shrinkage after 12 months of treatment with LAR was 96% in patients having 22.1% or greater shrinkage with GH levels 7.8 µg/liter or less after 3 months (24 of 25 patients) and 11.1% in those not fulfilling these criteria (three of 27 patients) (P < 0.0001). The patients with tumor shrinkage less than 22.1% in presence of GH levels 7.8 µg/liter or less after 3 months (eight of 12 patients) as well as those with tumor shrinkage 22.1% or greater in presence of GH levels greater than 7.8 µg/liter after 3 months (two of three patients) had a 66.6% probability to obtain a tumor shrinkage by greater than 50% after 12 months.


Figure 3
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  		FIG. 3. Results of the ROC curves to establish the cutoffs for GH levels (top panel) and percent tumor shrinkage (bottom panel) after 3 months of treatment with LAR to predict a 50% or greater tumor shrinkage after 12 months.

 

   Discussion
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
References
 
The ability to predict the magnitude of tumor shrinkage after 12 months of treatment with somatostatin analogs, such as LAR, is of paramount clinical importance. Surgical outcome is better in patients with lower preoperative GH levels, small tumors and no dural invasion (19, 20) and when surgery is performed in centers with a dedicated experienced neurosurgeon (21, 22). In one of the largest series of patients undergoing transsphenoidal surgery in a single center, Nomikos et al. (15) reported an approximately 75% cure rate in patients with microadenomas and enclosed macroadenomas, compared with 40% in those with larger tumors. Based on this information, surgical outcome would be expected to be better in patients achieving a suppressed GH along with clinically significant tumor shrinkage after first-line therapy with somatostatin analogs (23). However, only a few reports support this hypothesis (12, 24, 25).

So far no data were available to predict the amount of tumor shrinkage after a 12-month course of first-line therapy with somatostatin analogs. The results of the current study demonstrate that the magnitude of tumor shrinkage and the level of GH achieved after 3 months of treatment with LAR at a dosage of 20 mg every 28 d predicted the amount of tumor shrinkage after 12 months of treatment at individualized dosages. Moreover, patients obtaining a greater than 22.1% tumor shrinkage together with GH levels less than 7.8 µg/liter after 3 months had a higher than 90% chance of having a greater than 50% tumor shrinkage after 12 months. These results can be of help in the treatment decision for acromegaly.

The primary objective of therapy in acromegaly is to reverse symptoms and signs of the disease, treat the underlying cause, prevent disease recurrence, and improve long-term survival (26). Surgery via the transsphenoidal route with or without adjuvant radiotherapy is still considered the treatment of choice, but despite recent advances, the overall surgical cure rate remains around 50% and radiotherapy may take 5–10 yr to lower GH to safe levels (8). Radiotherapy has the additional disadvantage of inducing a high incidence of hypopituitarism, which is associated with excess mortality (27, 28). These concerns have prompted a reappraisal of somatostatin analog therapy for acromegaly, not just as an adjunct to surgery and radiotherapy but as first-line therapy (7, 8, 9). In this scenario, LAR is effective and safe as noted by control of GH and IGF-I secretion in 57 and 67%, respectively, after a median of 12 months of treatment (1). The cure rate increased to 80.3% in our series when treatment was continued for 24 months increasing the dose to 40 mg every 28 d (6). LAR treatment applied as first-line therapy is also associated with significant tumor shrinkage. We first reported a mean tumor volume reduction of 53% in 15 newly diagnosed patients treated with LAR every 28 d for 12 months (13), confirming data from Lundin et al. (29) who found a mean tumor volume reduction of 51% in 11 newly diagnosed patients treated with sc octreotide for up to 70 months. Subsequently Bevan et al. (30) reported a mean tumor volume reduction of 49% in seven newly diagnosed patients with microadenomas and of 43% in 20 newly diagnosed patients with macroadenomas treated with the sc octreotide for 24 wk and then Octreotide-LAR for another 24 weeks. In another multicenter study, median tumor volume was reduced by 54% in microadenomas and 49% in macroadenomas after 6 months of LAR treatment (31). Similar experience was reported by Jallad et al. (32) and Mercado et al. (33) in two large cohorts: tumor shrinkage greater than 20–25% was observed in 76% of 80 (32) and in 75% of 68 patients (33), respectively.

Some studies have attempted to predict tumor shrinkage after somatostatin analogs. The initial tumor size was predictive in some studies (11, 30, 34, 35, 36) but not in others (5, 28, 37). Posttreatment IGF-I levels were predictive of tumor shrinkage in our series (5) and in that of Jallad et al. (32). Generally, control of acromegaly is associated with a higher degree of tumor shrinkage (3), but notable shrinkage was observed also in nonresponsive patients (5, 30). Poor disease control was observed in the only two patients in our series having tumor growth during treatment (5). The dosages of somatostatin analogs used have been widely variable and poorly associated with the magnitude of tumor shrinkage (5). The short-term response to LAR treatment has not been compared with the long-term response in any of the previous studies. Thus, the results of the current study are original and clinically relevant, demonstrating that the amount of tumor shrinkage observed after the first 3 months of treatment along with the level of GH obtained at the same time point can predict with a high sensitivity and accuracy the amount of tumor shrinkage seen after 1 yr of therapy. A greater than 50% tumor shrinkage can be accepted as a clinically significant reduction of tumor volume; even in very large tumors, this decrease may be insufficient to improve surgical resection. If these data are confirmed in larger series of patients, the results after 3 months treatment may be able to anticipate surgical debulking, which was shown to improve subsequent treatment with somatostatin analogs (38, 39), in the patients without clinically significant cardiovascular or respiratory complications. The patients showing a poor response to a 3-month LAR treatment, in terms of a lower than 22.1% shrinkage and a GH level above 7.8 µg/liter had a minimal chance of obtaining a greater than 50% tumor shrinkage after 12 months. In the current series, two patients had a slight, but not significant, increase of tumor volume by 10 and 19.1% after 3 months of treatment with LAR at a dose of 20 mg every 28 d. Both patients were nonresponsive to the treatment in terms of GH and IGF-I control. Whereas the former patient with a microadenoma subsequently showed tumor shrinkage with a dose of 30 mg every 28 d by 32.4% after 12 months, the latter with an enclosed macroadenoma had a nonsignificant change during the treatment, showing a 4.1% increase, compared with baseline. Clearly even a greater than 50% tumor shrinkage does not ensure surgical cure because invasiveness is known to be minimally influenced by somatostatin analog pretreatment. In patients with invasive adenomas, achieving control of acromegaly with somatostatin analogs can be considered a life-long approach.

Our study has two important drawbacks. The first is the retrospective design: 25% of the patients were excluded from the analysis because the 3-month MRI was not available. The second drawback is related to changes in the sensitivity of GH assays used during the study. The GH cutoff required to predict tumor shrinkage should be considered cautiously because it would likely not be the same using different assays. The 7.8 µg/liter value should be considered a rough estimate of GH suppression after beginning treatment rather than an absolute number to calculate tumor shrinkage after 12 months of therapy.

Conclusions

The magnitude of tumor shrinkage after 12 months of LAR treatment can be predicted by tumor shrinkage and GH levels after 3 months at a fixed dose of 20 mg every 28 d. A high predictive value was conferred to the association of a greater than 22.1% tumor shrinkage and a GH level <7.8 µg/liter after 3 months. These data should prompt further analyses to verify the predictive power of this model that could be used to better program strategies of treatment for individual patients with acromegaly.


   Acknowledgments
 
We thank Alfonso Gruosso for kindly revising the study.


   Footnotes
 
This work was supported by unrestricted grants from Ipsen, Italfarmaco, and Novartis (to A.C. and G.L.) to the Department of Molecular and Clinical Endocrinology (University Federico II, Naples) to support research projects in the field of neuroendocrinology. This study did not receive any support from pharmaceutical industries. The study has been registered in the www.clinicaltrials.gov database with the ID NCT00616408.

Authors Disclosure: A.C. received lecture fees by Ipsen and Novartis. R.P., R.S.A., M.G., S.S., L.F.S.G., and G.L. have nothing to disclose.

First Published Online July 1, 2008

Abbreviations: CI, Coefficient of interval; CV, coefficients of variation; IRMA, immunoradiometric assay; LAR, long-acting release; MRI, magnetic resonance imaging; ROC, receiving-operator characteristics; ULN, upper limit of normal range.

Received February 22, 2008.

Accepted June 25, 2008.


   References
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
 References
 

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A. Colao, R. S. Auriemma, M. Galdiero, G. Lombardi, and R. Pivonello
Effects of Initial Therapy for Five Years with Somatostatin Analogs for Acromegaly on Growth Hormone and Insulin-Like Growth Factor-I Levels, Tumor Shrinkage, and Cardiovascular Disease: A Prospective Study
J. Clin. Endocrinol. Metab., October 1, 2009; 94(10): 3746 - 3756.
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