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Predictors of Tumor Shrinkage after Primary Therapy with Somatostatin Analogs in Acromegaly: A Prospective Study in 99 Patients

Department of Molecular and Clinical Endocrinology and Oncology (A.C., R.P., R.S.A., M.G., G.L.), Section of Endocrinology, and Departments of Neurological Sciences (F.B., F.T.) and Radiology (F.C., S.C.), Section of Neuroradiology, 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

 
Context: Primary treatment with depot octreotide and lanreotide induces tumor shrinkage in newly diagnosed patients with acromegaly.

Objective: The objective of the study was to evaluate clinical predictors of tumor shrinkage.

Design: This was an analytical, observational, open, prospective study.

Subjects: The study included 99 patients: 13 with microadenoma and 86 with macroadenoma (25 enclosed, 32 extrasellar, 29 invasive).

Main Outcome Measures: Age, gender, estimated disease duration, body mass index, GH and IGF-I levels, and tumor volume at diagnosis and after 12 months of treatment were measured. Percentage of GH, IGF-I, and tumor size changes from baseline were also analyzed. Tumor changes were scored as absent (± 0–25%), mild (± 25.1–50%), moderate (± 50.1–75%), or notable (75%).

Interventions: Sixty patients (60.6%) received depot octreotide im (20–30 mg every 28 d), and 39 patients (39.4%) received lanreotide im (60–90 mg every 28 d).

Results: Basal tumor volume and maximal tumor diameter correlated with age, disease duration, and GH levels. After 12 months, GH levels were controlled (2.5 µg/liter) in 57.6%, IGF-I levels in 45.5%, and both in 42.4%. Shrinkage was absent in 22 patients (22.2%), mild in 31 (31.1%), moderate in 30 (30.3%), and notable in 14 patients (14.1%). Two patients (not responding to treatment) had a mild tumor increase (by 34 and 31.2%, respectively). Basal and posttreatment tumor volumes were highly correlated (r = 0.79, P < 0.0001). At the multistep regression analysis, the percent IGF-I decrease (t = 2.6; P = 0.011) was the best predictor of posttreatment tumor volume, followed by patients’ age (t = 2.1; P = 0.042) and percent GH decrease (t = 2.0; P = 0.044).

Conclusions: Most patients with acromegaly (75.5%) had 25% or greater tumor shrinkage after 12 months of primary somatostatin analog therapy: significant increase of tumor mass occurred in only 2.1% of patients (uncontrolled during treatment). Best predictor of tumor shrinkage was posttreatment IGF-I.

	Introduction

Top Abstract Introduction Patients and Methods Results Discussion References

 
SOMATOSTATIN ANALOGS ARE a cornerstone of medical therapy for acromegaly. The control of GH and IGF-I excess and the improvement of the symptoms and the cardiomyopathy are all established benefits of the therapy (1, 2, 3). Moreover, clinically significant tumor shrinkage of about 20–30% has been reported in a number of studies (4). Two recent analyses of the literature revealed that for patients who experienced significant shrinkage, an approximate 50% decrease in pituitary mass is achieved when a somatostatin analog is used exclusively or before surgery or radiotherapy (5), i.e. 231 of 448 patients (52%) vs. 52 of 248 patients (21%) (4).

The patient’s status regarding prior therapy appears to be the major predictor of whether tumor shrinkage will be observed (4). Controversy has been reported on the predictive value of initial tumor size and the inhibition of GH and IGF-I levels during treatment (4). The dose of the somatostatin analog used during treatment has been investigated in only two studies (6, 7), with opposite results.

Previous studies were limited by having a small sample of patients, preventing successful statistical analysis; the use of short-acting analogs that are overcome by the slow release formulations; and the duration of treatment in some patients not being long enough to provide adequate data on the efficacy of the treatment of tumor volume.

This observational, analytical, open, prospective study was designed to assess tumor shrinkage in newly diagnosed patients with active acromegaly who had undergone primary treatment for 12 months exclusively with slow-release formulation of octreotide (LAR) or lanreotide (LAN). Clinical predictors of tumor shrinkage were investigated.

	Patients and Methods

Top Abstract Introduction Patients and Methods Results Discussion References

 
Inclusion criteria

Patients with active acromegaly coming to the Unit of Endocrinology of the "Federico II" University of Naples from January 1, 1995, to December 31, 2004, primarily treated with LAR or LAN only in a random fashion and with a follow-up of 12 months. Data from 15 patients (8) and 47 patients (9) were included in previous studies. The standard routine procedure in our clinic since 1997 (10), and in agreement with our neurosurgeons, is to perform primary therapy with depot somatostatin analogs in all the patients with macroadenomas with extrasellar extension and patients with proven cardiomyopathy, hypertension, sleep apnea or other respiratory disorders, and/or other systemic complications that can make the anesthesiological procedures less safe than in other patients. This procedure is fully discussed with our patients who sign a written consent at the time of hospitalization and at the moment of deciding the treatment.

Exclusion criteria

Patients treated with LAR or LAN after unsuccessful surgery, patients requiring combined dopamine-agonists and somatostatin analogs, and patients with a follow-up shorter than 12 months or treated with sc LAR for longer than 30 d before receiving LAR or LAN were excluded from the study.

Cure criteria

For Giustina et al. (11), the patients were considered controlled/cured if fasting mean GH levels were 2.5 µg/liter or less or nadir GH after oral glucose load (oral glucose tolerance test) was 1 µg/liter or less in the presence of normal IGF-I levels for sex and age.

Patients

Of the 256 patients admitted to our department for acromegaly, 95 were excluded because of primary surgery, 33 were treated for less than 12 months, and 29 had concomitant hyperprolactinemia and were treated with combined somatostatin analogs and dopamine-agonist treatment. Ninety-nine patients (47 women and 52 men, aged 45.6 ± 17.9 yr) fulfilled the inclusion criteria. The diagnosis of acromegaly was defined in all of the patients as previously reported (12) by high serum GH levels during a 6-h time course, not suppressible less than 1 µg/liter after glucose load and high plasma IGF-I levels for age (expressed as the upper limit value of normal range). Based on magnetic resonance imaging (MRI), 13 patients had a microadenoma, 25 patients had an enclosed macroadenoma, 32 patients had a macroadenoma with extrasellar extension, and 29 patients had macroadenomas with clear-cut signs of invasion of surrounding structures (Table 1). The presumed duration of acromegaly was assessed by comparing photographs taken over a period of 10–30 yr and interviewing the patients as to the date of onset of acral enlargement and facial disfigurement. The interval between assumed clinical onset and the time of treatment ranged from 24 to 360 months (125 ± 89 months).

Study design and protocol

This is a prospective study aimed at investigating tumor shrinkage in acromegaly primarily treated with LAR and LAN for 12 months and finding predictors of tumor shrinkage. The following parameters were collected:

1. At diagnosis: age, gender, estimated disease duration, height, weight and body mass index (BMI), GH and IGF-I levels, and tumor size.

2. After 12 months of treatment: GH and IGF-I levels, tumor size, and percentage of GH and IGF-I and tumor size decrease.

Tumor size was measured as sagittal, axial and coronal diameters, maximal diameter, and calculation of volume.

Treatment protocol

Before starting pharmacotherapy, all patients received an acute test with sc LAR at a dose of 0.1 mg in the morning after an overnight fast and at least 2 h of bed rest to investigate each patient’s tolerability to somatostatin analogs (13). Then 60 patients (60.6%) received LAR im at an initial dose of 20 mg every 28 d, and 39 patients (39.4%) received LAN im at an initial dose of 30 mg every 14 d or 60 mg every 28 d according to the formulation used. Since 2000, two different LAN formulations were available in Italy: the 30-mg and the 60-mg microparticular formulations for im injection every 14 or 28 d. The dose of LAR and LAN was subsequently increased to 30 mg every 28 d, 30 mg every 10 d, or 60 mg every 21 d, respectively, if GH and IGF-I levels were not normalized. To analyze the potential effect of the drug dosage on tumor shrinkage, we uniformed the doses of LAR and LAN by assigning arbitrary values as: 1) to the dose of LAR 10 mg every 28 d; 2) to the dose of LAR 20 mg every 28 d and the dose of LAN 30 mg every 14 d or LAN 60 mg every 28 d; and 3) to the dose of LAR 30 mg every 28 d and the dose of LAN 30 mg every 10 d or LAN 60 mg every 21 d.

We assigned these values according to the current clinical practice that is based on the use of the initial dose of LAR 20 mg and LAN 30 mg every 14 d or 60 mg every 28 d that can be modified according to individual patient response. None of the patients enrolled in the current study was treated with the new formulation of LAN-autogel.

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 degrees, four signal averages) in the sagittal and coronal planes, as already reported (8, 9). In each measurement 7–11 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 gadolinium chelate (diethylene-triamine pentacetate). In all patients MRI was performed at diagnosis and after 12 months of treatment. The sagittal, axial, and coronal diameters were measured by MRI, and then we considered the maximal tumor diameter and calculated tumor volume by the De Chiro and Nelson formula [(volume = sagittal _* coronal _* axial diameters) _* /6]. According to previous studies (8, 9), on the posttreatment MRI, tumor change was assessed primarily as percentage decrease or increase of tumor volume and, secondarily, of maximal tumor diameter, compared with the baseline. The percent changes were scored by a semiquantitative scale (Table 2).

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, 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 20-yr-old or younger, 21- to 30-, 31- to 40-, 41- to 50-, 51- to 60-, 61- to 70-yr-old, and older than 70-yr-old men 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 the upper limit of normal range (ULN; normal = 1 or less).

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 disease duration, baseline and posttreatment GH and percent GH suppression, dose of the drugs, posttreatment IGF-I, and tumor volume. Correlation coefficients were calculated by measuring the Pearson or the Spearman coefficients for the variables normally or not normally distributed. The stepwise multiple linear regression was performed to assess the relative importance of: 1) age, BMI, and basal GH and IGF-I levels (as actual data and ULN), on basal volume and maximal diameter; 2) age, BMI, and basal and posttreatment GH and IGF-I levels (as actual data and ULN), basal volume and maximal diameter on posttreatment tumor volume and maximal diameter; and 3) percent changes of GH and IGF-I levels on the percent changes of tumor volume and maximal diameter. In this analysis, we entered only those variables that had a P < 0.01 in the univariate analysis. Of note, the maximal tumor diameter was excluded from the model to predict tumor volume and vice versa. To analyze the correlation between the dosage of the drugs, as arbitrarily scored in three groups, and the percent decrements of GH, IGF-I, and tumor volume in the entire series, we calculated the Sperman’s rho with the 95% confidence interval (CI). The comparison among the groups treated with different dosages was performed by using the Kruskal-Wallis test followed by the Dunn’s test.

	Results

Top Abstract Introduction Patients and Methods Results Discussion References

 
Table 1 summarizes the patients’ characteristics at baseline according to their tumor classification. Tumor volume and maximal tumor diameter were inversely correlated with patients’ age and disease duration and directly correlated with GH but not IGF-I levels (Table 3). Serum GH levels and IGF-I levels, both expressed as micrograms per liter or expressed as ULN (r = 0.52; P < 0.0001; r = 0.24; P = 0.014, respectively), were significantly correlated.

View larger version (18K): [in this window] [in a new window]   FIG. 1. Tumor volumes (mean ± SEM) at baseline and 12 months after receiving primary LAR or LAN treatment in the 99 patients. Results are shown by dividing the patients in two groups: 42 patients who achieved GH and IGF-I control (controlled) and 57 patients who did not (noncontrolled). A, P < 0.049 vs. baseline values of noncontrolled patients. B, P = 0.0002 vs. 12-month values of noncontrolled patients. The superscript graph shows the percent tumor volume change after treatment in individual patients grouped as above.

View larger version (16K): [in this window] [in a new window]   FIG. 2. Correlation analysis between percent decrease of tumor volume and percent decrease of IGF-I levels in the 99 patients 12 months after receiving primary LAR or LAN treatment. The graph shows the distribution of individual patients, regression line, and 95% CI.

	Discussion

Top Abstract Introduction Patients and Methods Results Discussion References

This observational, analytical, open, prospective study, conducted in a large series of patients with acromegaly with clear inclusion and exclusion criteria for the analysis, and in particular receiving exclusively LAR or LAN for 12 months, demonstrated that: 1) 75.5% of the patients had a mild to notable tumor shrinkage and only two patients (2.1%) had a mild tumor increase during treatment; 2) disease control (GH 2.5 µg/liter and normal IGF-I levels) was associated with a greater decrease of tumor mass; and 3) posttreatment IGF-I levels were the best predictors of tumor shrinkage.

Baseline tumor size as a predictor of shrinkage

The predictive value of initial tumor size was considered in some previous studies: Bevan et al. (15) reported a more than 60% tumor shrinkage in 71% of microadenomas and in only 35% of macroadenomas, whereas Ezzat et al. (7), Amato et al. (16), and Cozzi et al. (6) found a greater tumor shrinkage in macroadenomas than microadenomas; we (8) did not previously find any difference between micro- and macroadenomas. Pretreatment tumor volume was found to be correlated positively with shrinkage by Plöckinger et al. (17) but not by Lucas et al. (18) and Lundin et al. (19). In the current study, we did not find any correlation between baseline tumor size and posttreatment tumor shrinkage. The percent tumor shrinkage was similar in the 13 patients with microadenomas (37.2 ± 30.4%, 95% CI 18.9–55.9) and the 86 patients with macroadenomas (45.4 ± 28.3%, 95% CI 39.3–51.4, P = 0.34). Clearly the small number of patients with microadenomas, compared with those with macroadenomas in our series, does not permit firm conclusions on the role of baseline tumor dimension on tumor shrinkage. However, our results suggest that baseline tumor volume is unlikely to have a predictive role on tumor shrinkage because the higher the baseline tumor volume, the higher the posttreatment tumor volume.

Control of GH and IGF-I excess as a predictor of shrinkage

No significant effect of posttreatment GH and IGF-I levels on tumor shrinkage were reported in several studies (6, 9, 15, 16, 17, 19, 20, 21). In some other studies, however, biochemical parameters were associated with tumor shrinkage. Abe and Lüdecke (22) reported tumor growth during treatment with LAR only in patients with no significant biochemical response. In another study, Arosio et al. (23) found a 58% tumor shrinkage in patients with a decrease of GH level with LAR of more than 50% and a 29% tumor shrinkage in the patients with a decrease of GH levels less than 50%, but this was not statistically significant. Similarly, Ezzat et al. (7) found that tumor shrinkage occurred only in patients with GH and IGF-I reductions, and Lucas et al. (18) reported that a positive biochemical response to LAN predicted tumor shrinkage. Patients with tumor shrinkage were reported to have a greater suppression of IGF-I levels than those without tumor shrinkage by Verhelst et al. (24). In analogy with these latter studies, we found that disease control predicts tumor shrinkage. In fact, the amount of tumor shrinkage was invariably and significantly higher in patients achieving either GH or IGF-I control, or both, than in those who did not. Moreover, IGF-I levels were the best predictors of shrinkage of both tumor volume and maximal tumor diameter. GH levels were also highly correlated with shrinkage but with a less predictive value than IGF-I.

The dose of LAR and LAN as a predictor of shrinkage

The predictive effect of somatostatin analog doses on tumor shrinkage has been scarcely examined. Tumor shrinkage was reported by Ezzat et al. (7) to occur in 19% of patients on LAR sc 100 µg three times a day and in 37% of those on 250 µg three times a day. Cozzi et al. (6) found no relationship between tumor shrinkage and the dose of LAR. In the current study, we found a significant positive correlation between the dosages of LAR and LAN with both basal and posttreatment GH and IGF-I levels, tumor volume, and maximal tumor diameter and the posttreatment percentage decrease of IGF-I, tumor volume, and maximal tumor diameter. Therefore, patients showing higher baseline hormone levels and larger tumors at diagnosis required higher doses of LAR and LAN and had smaller decreases both in IGF-I and tumor size (evaluated both as volume and maximal diameter). This finding indicates that the doses of LAR and LAN did not directly correlate with the entity of hormone suppression and tumor shrinkage but rather with the expression of each patient’s sensitivity. This finding seems to be in contrast with the previous study by Ezzat et al. (7). It should be stated, however, that the current study was not designed to investigate the possibility of a dose-dependent effect of LAR or LAN on hormone suppression and tumor size. Therefore, our results rather reflect the current clinical use of somatostatin analogs: higher doses are used to control GH and IGF-I levels in the patients having at diagnosis higher GH and IGF-I levels. As also clearly shown in the current study, GH levels correlate with tumor size at diagnosis. Therefore, it is expected that patients having more severe disease at diagnosis (i.e. high GH and IGF-I levels and large tumors) could require higher doses than those having milder disease. In this respect, the higher the dosages used, the higher the hormone levels and tumor size after treatment.

Conclusions

In summary, primary therapy with depot somatostatin analogs is associated with different degrees of tumor shrinkage in 75.5% of patients with acromegaly. Only a small minority of the patients (2.1%) partially responding to the treatment, as far as GH and IGF-I suppression is concerned, had a significant increase of tumor mass during treatment. IGF-I levels after treatment were the best predictors of tumor shrinkage, followed by GH levels and age. Control of GH and IGF-I excess is, therefore, crucial to have significant shrinkage of tumor mass in newly diagnosed patients with acromegaly.

	Acknowledgments

 
We thank Alfonso Gruosso for the linguistic revision of the manuscript.

	Footnotes

 
This study did not receive any specific financial support. The Department of Molecular and Clinical Endocrinology and Oncology, Section of Endocrinology, University "Federico II" of Naples, receives unrestricted grants from Ipsen, Italfarmaco, Novartis, Pfizer, and Serono for research studies in neuroendocrinology.

A.C. received lecture fees from Ipsen, Novartis, and Pfizer; R.P., R.S.A., F.B., M.G., F.T., F.C., and S.C. have nothing to declare; G.L. received lecture fees from Ipsen and Novartis.

First Published Online March 14, 2006

Abbreviations: BMI, Body mass index; CI, confidence interval; CV, coefficient of variation; IRMA, immunoradiometric assay; LAN, lanreotide; LAR, octreotide; MRI, magnetic resonance imaging; ULN, upper limit of normal range.

Received September 21, 2005.

Accepted March 7, 2006.

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				A. Colao, R. Pivonello, R. S Auriemma, M. Galdiero, S. Savastano, and G. Lombardi Beneficial effect of dose escalation of Octreotide-LAR as first-line therapy in patients with acromegaly Eur. J. Endocrinol., November 1, 2007; 157(5): 579 - 587. [Abstract] [Full Text] [PDF]

				M. Bex, R. Abs, G. T'Sjoen, J. Mockel, B. Velkeniers, K. Muermans, and D. Maiter AcroBel the Belgian registry on acromegaly: a survey of the 'real-life' outcome in 418 acromegalic subjects Eur. J. Endocrinol., October 1, 2007; 157(4): 399 - 409. [Abstract] [Full Text] [PDF]

				S. Melmed Acromegaly N. Engl. J. Med., December 14, 2006; 355(24): 2558 - 2573. [Full Text] [PDF]

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