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Departments of Molecular and Clinical Endocrinology and Oncology and Neurological Sciences, Section of Neurosurgery (P.C., L.M.C.), University Federico II (A.C., R.P., G.L.), 80131 Naples, Italy; Division of Endocrinology, Hospital Niguarda Ca Granda (R.A., R.C.), 20162 Milan, Italy; and Division of Neurosurgery, Neurologic Institute Carlo Besta (G.L., A.L.), 20162 Milan, Italy
Address all correspondence and requests for reprints to: Dr. Annamaria Colao, 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.
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Abstract |
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 Top Abstract IntroductionSubjects and MethodsResultsDiscussionReferences |
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Objective: The objective of this study was to investigate whether partial surgical removal of GH-secreting pituitary tumors enhances the response rate to somatostatin analogs (SSA; sc octreotide, slow-release octreotide, and lanreotide).
Design: This was a multicenter, open, retrospective study.
Setting: The study was performed at university hospitals.
Subjects and Methods: Eighty-six patients (42 women and 44 men; age, 42 ± 14 yr) with acromegaly were studied.
Interventions: Patients underwent two courses of octreotide, lanreotide, or slow-release octreotide treatments before and after surgery of at least 6 months.
Main Outcome Measure: The main outcome measure was normal IGF-I levels for age.
Results: Presurgical SSA treatment significantly decreased GH and IGF-I levels in all patients. GH levels were less than 2.5 µg/liter in 12 patients (14%); IGF-I levels normalized in nine (10%). After surgery, GH and IGF-I levels further decreased in all patients; tumor removal was greater than 75% in 50 (58%), 50.1–75% in 21 (24%), 25.1–50% in 10 (12%), and less than 25% in five patients (6%). Preoperatively, pituitary function was impaired in 12 patients (14%). Postsurgical SSA treatment lowered GH levels to less than 2.5 µg/liter in 49 (56%) and normalized IGF-I levels in 48 patients (55%). The success rate was significantly increased compared with that before surgery (P < 0.0001). GH (r = –0.48; P < 0.0001) and IGF-I levels (r = –0.38; P = 0.0003) after postsurgery SSA treatment correlated with the amount of tumor surgically removed. After surgery, pituitary function was impaired in 28 patients (32.6%) and was improved in 12 patients (13.9%). The cumulative prevalence of pituitary deficiency did not change during the study (normal function from 40 to 42%; deficiency from 60 to 58%).
Conclusions: Surgical tumor removal (>75%) enhances the response to SSAs without impairing pituitary function. Our data indicate that surgical debulking has a significant place in the treatment algorithm of acromegaly.
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Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Surgery, radiotherapy, and medical therapy with dopamine agonists, somatostatin analogs (SSA), or GH receptor antagonist are variably used (8). Currently, it remains uncertain whether surgery should still be considered first-line treatment in all patients with GH-secreting pituitary tumors due to the limited success in large invasive tumors, which represent the majority of GH-secreting tumors (8, 9, 10). Medical therapy with slow release SSA formulations, i.e. octreotide-LAR (LAR) and lanreotide (LAN), is effective in more than 60% of patients, and it is considered to be the first line approach when cardiovascular and/or respiratory complications are so severe as to increase surgical risk (7, 8). Preoperative therapy with sc octreotide (OCT), LAR, or LAN improves soft tissue swelling, thus reducing the degree and/or incidence of hypertrophy of tongue and upper respiratory tract soft tissues, cardiac mass and dysfunction, arrhythmias, and sleep apnea, which all can increase the risks of a surgical approach (11, 12). Additionally, tumor shrinkage (between 20–30% of initial size) has been reported in a number of studies (13); an approximately 50% tumor decrease is achieved when SSAs are used exclusively or before surgery or radiotherapy (14). On this basis, presurgical treatment with SSA was suggested to improve surgical outcome for some tumors with limited invasiveness or to replace surgery as first-line treatment in selected patients (8, 9, 10).
In contrast, partial surgical removal, i.e. debulking, of GH-secreting pituitary tumors has not been proven to be successful; the outcome of SSA treatment in newly diagnosed patients is reported to be similar to that in patients who have undergone unsuccessful surgery (9, 15, 16, 17, 18). However, in a recent study consisting of 24 patients with acromegaly treated before and after surgery for at least 1 month, GH and IGF-I levels normalized in 29.2% and 45.8% of patients, respectively, before surgery and in 54.2% and 78.3%, respectively, after surgery (19). Major limitations of this study were the small series and the short duration of SSA treatment.
To explore whether surgical debulking of GH-secreting pituitary tumors enhances the response rate to OCT, LAR, and LAN in acromegaly, we performed this multicenter, retrospective cohort study. We report a significant increase in the rate of IGF-I normalization during postsurgical treatment with SSA and also observed that the postsurgical IGF-I decrease after SSA correlated with the extent of tumor debulking.
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Subjects and Methods |
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Patients with active acromegaly were treated with OCT, LAN, or LAR for at least 6 months before and 6 months after surgery for persistently active acromegaly and were operated on in our centers, which have a single pituitary surgeon dedicated to pituitary tumors to achieve the highest rate of surgical cure (20, 21).
Exclusion criteria
Patients treated with transcranic approach, primarily operated on or irradiated, treated with SSA after second surgery, or cured by surgery were excluded from the study (22).
Cure criteria
For the purpose of this study, patients were considered controlled/cured before and after surgery if their IGF-I levels were in the normal range for age.
Study design
This was a multicenter, retrospective study.
Patients
We reviewed all patients files undergoing neurosurgery for GH-secreting pituitary tumors from January 1, 1995 to December 31, 2003. Eighty-six patients [42 women aged 42 ± 14 yr (mean ± SD), and 44 men, aged 41 ± 14 yr] were included. The diagnosis of acromegaly was defined, as previously reported (23), by high serum GH levels during a 6-h time course, not suppressible below 1 µg/liter after a glucose load, and high plasma IGF-I levels for age (expressed as a fold increase compared with the upper limit of the normal range). The patients’ profiles at diagnosis are shown in Table 1
. Based on magnetic resonance imaging (MRI), five patients had microadenoma, 12 had enclosed macroadenoma, 51 had macroadenoma with extrasellar extension without clear-cut signs of invasion of surrounding structures, and 18 patients had invasive macroadenoma (Table 1). The presumed duration of acromegaly was assessed by comparing photographs taken over a period of 10–30 yr and by 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 diagnosis ranged from 12–360 months in women and from 12–240 months in men.
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In all patients fulfilling the inclusion criteria, GH and IGF-I results were considered at the following time points: T-1, at diagnosis; T-2, immediately before surgery during the first course of SSA treatment; T-3, after surgery and at least 3 months for OCT treatment or 4 months of LAR or LAN treatments [therefore, unaffected by previous SSA treatment (24)]; and T-4, after a second course of SSA treatment of similar duration to that administered before surgery.
At T-1 and T-3, GH levels were calculated as the mean value of samples drawn every 30 min over a period of 6 h; at T-2 and T-4, GH levels were calculated as the average of multiple blood samples, at least three in the morning preceding the next drug injection in the patients treated with depot SSA and at least six in 6 h in those treated with OCT. The average value was considered for statistical analysis. IGF-I levels were always assayed in a single sample drawn at the same time of GH assay. Results are shown in the entire series and according to tumor size (Table 2).
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To investigate each individual patient’s tolerability (25) before starting the first SSA course, all patients received an acute test with OCT at a dose of 0.1 mg in the morning after an overnight fast and at least 2 h of bed rest. Then 35 patients received OCT at a dose of 0.45–1.2 mg/d in three or four daily administrations, 27 received LAR im at a dose of 20–40 mg every 28 d, and 24 patients received LAN im at a dose of 60–120 mg every 28 d. Of the 18 patients (21%) showing concomitant hyperprolactinemia, only nine (10%) required combined treatment with cabergoline orally at a dose ranging from 1–3 mg/wk (Table 1
). In all patients, the dose was progressively increased to normalize GH and IGF-I levels. During the second SSA course, 56 patients (65%) were treated with the same drug as during the first course; OCT was replaced with LAN in 17 (20%) or with LAR in eight (9%) due to drug availability during the years of follow-up. Changes in LAN vs. LAR and LAR vs. LAN was performed in only two patients each, respectively. During the second course of treatment, cabergoline was no longer required; prolactin levels remained mildly elevated only in two cases.
MRI studies
MRI studies were performed on clinical 0.5T, 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 previously reported (15). The acquisitions were repeated before and after the administration of 0.1 mmol gadolinium chelate (diethylene-triamine pentacetate). MRI was performed at all time points. Based on previous results (15), the change in tumor volume after the two courses of SSA treatment was evaluated as the percent difference compared with baseline or postsurgical MRI, respectively, and was scored according to a semiquantitative scale as follows: no change, ±0–25%; mild shrinkage/growth, ±25.1–50%; moderate shrinkage/growth, ±50.1–75%; and considerable shrinkage/growth, >75%. On the MRI performed after surgery, surgical debulking was measured as the decrease in tumor size scored after a semiquantitative scale as: poor, 
25%; mild, 25.1–50%; moderate, 50.1–75%; and notable, >75%.
Diagnosis of hypopituitarism (26)
Gonadotropin deficiency was established on the basis of low testosterone levels (<3 µg/liter) in men or low 17ß-estradiol levels (<50 ng/liter) in premenopausal women and on low FSH and LH levels (<2 IU/liter) in postmenopausal women. TSH deficiency was established on the basis of low TSH levels (<0.5 mIU/liter) in the presence of free T3 and free T4 levels below or in the lower part of the normal range. ACTH deficiency was established on the basis of low morning cortisol levels (<50 µg/liter) or levels below 200 µg/liter after the administration of 250 µg synacthen, im. None of our patients had diabetes insipidus.
Assays
GH assays changed over time; initially RIAs were used and then replaced by immunoradiometric assays. Throughout the study, the same assay was used in the serial evaluation of each patient. Serum IGF-I was measured by RIA or immunoradiometric assay after ethanol extraction depending on assay availability. Because age reference ranges for IGF-I assays changed during the period of observation, data are shown as the fold increase compared with the upper limit of the normal range (normal, 1) calculated on normative IGF-I data in each laboratory.
Statistical analysis
The data were analyzed using SPSS software (SPSS, Inc., Cary, NC). A preliminary analysis showed a nonnormal distribution of most variables. Comparison among groups was made using the Kruskal-Wallis test, followed by Dunn’s test. Repeated measures were analyzed by the Friedman test. Correlation coefficients were calculated by measuring the Spearman coefficient. The 
2 test with Fisher correction was applied as appropriate. Data are reported as the mean ± SD unless otherwise specified.
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Results |
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The duration of the first course of SSA treatment was 12.5 ± 8.1 months (median, 12 months). OCT (40%), LAR (30%), and LAN (29%; P = 0.2) were equally employed. The median treatment duration was slightly shorter in patients with microadenomas and enclosed macroadenomas (6 months) than in those with extrasellar and invasive macroadenomas (12 months; P = 0.069). The median doses of OCT, LAR, and LAN were 0.9 mg/d, 30 mg every 28 d, and 90 mg every 28 d, respectively. Significant decreases in GH and IGF-I were observed in all patients (Table 2). Individual results of GH and IGF-I levels from T-1 to T-4 are shown in Fig. 1. The median percent GH decrease in patients receiving primarily LAR and LAN was higher than that in those receiving OCT (80% and 71% vs. 61%; P = 0.013). The median percent decrease in IGF-I was similar with OCT, LAR, and LAN (36%, 27%, and 30%, respectively; P = 0.44). Serum GH and IGF-I levels during the study in relation to the drug used are shown in Fig. 2. During the presurgical treatment, GH levels below 2.5 µg/liter and normalized IGF-I levels were found in 12 (14%) and nine (10%) patients, respectively. With MRI, tumor size did not change in 42 patients (49%); shrinkage was mild in 29 (34%) and moderate to notable in 11 patients (13%). Four patients (5%) had an increase in tumor size: mild (by 25–40%) in three with extrasellar macroadenomas and notable (by 75%) in one with invasive macroadenoma. Six patients (8%; one with enclosed macroadenoma, three with extrasellar macroadenoma, and two with invasive macroadenoma) had improvement of one deficit after treatment (Fig. 3).
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The postsurgery MRI, indicated that debulking was notable in 50 patients (58%); in 11 of them no tumor was visualized. Reduction was moderate in another 21 (24%), mild in 10 (12%), and poor in five patients (6%). An additional decrease in GH and IGF-I levels was observed in all patients (Table 2). Individual results of GH and IGF-I decrease are shown in Fig. 1. Thirteen patients (two microadenomas, four enclosed macroadenomas, five extrasellar macroadenomas, and one invasive macroadenoma) had a postoperative IGF-I level within the normal range for age and gender (Fig. 1). Twelve patients (two microadenomas, four enclosed macroadenomas, five extrasellar macroadenomas, and one invasive macroadenoma) had a postoperative IGF-I level within the normal range for age and gender (Fig. 1). In these patients, restarting somatostatin treatment immediately after surgery was decided with GH levels above 2.5 µg/liter in two patients with microadenoma and two patients with extrasellar macroadenoma, persistent tumor mass in six patients (two enclosed, three extrasellar, and one invasive macroadenomas), and increase in GH and IGF-I levels in the 3 months after the first postsurgery follow-up in the remaining two patients with enclosed macroadenomas. Impairment of pituitary function after surgery was found in 28 patients (32.6%): deficit in one axis occurred in 17 and of two axes in 11 patients (Fig. 3). Thus, overall, the prevalence of deficit in one axis increased from 34% to 37%, in two axes from 19% to 22%, and in three axes from 1% to 8% (Fig. 3). Twelve patients (13.9%) improved their pituitary function: one deficit recovered in eight and two deficits in four patients (Fig. 3). Radiotherapy was performed within 12 months after surgery in two patients with enclosed macroadenomas, 17 with extrasellar macroadenomas and seven patients with invasive macroadenomas. Radiation was administered with a conventional fractionated technique in 20 and with single fraction radiosurgery in six patients.
Outcome of postsurgical somatostatin analogs treatment
The duration of the second course of SSA treatment was 18.7 ± 14.3 months (median, 12 months). SSA doses remained stable during the two courses of treatment; the OCT doses were 1.03 ± 0.4 (range, 4.5–18) and 1.03 ± 0.4 mg/d (n = 10; range, 4.5–18), the LAR doses were 30.8 ± 6.5 (range, 20–40) and 29.2 ± 8.3 mg every 28 d (n = 24; range, 10–40), and the LAN doses were 88.2 ± 27 (range, 60–120) and 97.3 ± 41 mg every 28 d (n = 22; range, 60–240), respectively. In all patients, GH and IGF-I levels further decreased significantly (Table 2 and Fig. 1). IGF-I normalized in 47 patients without any relationship to tumor size (Fig. 4), in the nine patients with normal IGF-I levels during the presurgical SSA treatment and in an additional 38 patients. The success rate of SSA thus increased from 10% to 55% (P < 0.0001). GH levels below 2.5 µg/liter were found in 48 patients (56%). The increase in success rate of postsurgical SSA treatment remained significant even after excluding from the analysis the irradiated patients (from 16% to 62%; P < 0.001) or the patients treated after surgery with depot SSA and before surgery with OCT (from 11% to 52%; P < 0.001). Among the patients with invasive adenomas, GH and IGF-I levels were similar in the patients with prevalent invasion of one or both cavernous sinuses (no. 13) and in the patients with prevalent invasion of other structures such as the frontal lobe (no. 1), the third ventricle (no. 1), or the sphenoid sinus (no. 3; data not shown).
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); according with the extent of the debulk, greater than 75%, 50.1–75%, 25.1–50%, or less than 25% normal IGF-I levels were achieved in 38, 10, two, and zero patients, respectively. By grouping the patients into those having tumor debulking more or less than 75% of initial size, both GH (2.9 ± 3.4 vs. 12.2 ± 13.7 µg/liter; P < 0.0001) and IGF-I levels (1.08 ± 0.68 vs. 1.45 ± 0.69 upper limit of the normal range; P = 0.001) were lower in the former; normal IGF-I levels were achieved in 72% and 36%, respectively (P = 0.003). Percent decrements in GH and IGF-I levels after the second SSA course compared with the postsurgery levels (40 ± 9% and 27 ± 4%, respectively) were similar to those obtained after the first SSA course compared with baseline levels [52 ± 13% (P = 0.42) and 27 ± 3% (P = 0.83), respectively]. On MRI, residual tumors further decreased by moderate to notable in 14 patients (16%) and mild in 10 patients (12%); residual tumor did not change in 59 patients (67%). A mild to moderate increase in residual tumor mass was observed in three patients (3%). Two patients were nonresponsive to both treatment courses, and one was nonresponsive to the first and responsive to the second course. The pituitary function remained stable in 74% of the patients (Fig. 3). Impairment of pituitary function after the second course of SSA was found in seven patients (8.1%); deficit in one axis occurred in five and of two axes in two patients (Fig. 3). Improvement of pituitary function was observed in 15 patients (17.4%); recovery of one deficit was observed in 10 patients and of two deficits in five patients (Fig. 3). The cumulative prevalence of pituitary deficiency did not change during the study [from diagnosis to end of postsurgical treatment; normal pituitary function, 40% vs. 42%; pituitary deficiency(ies). 60% vs. 58%].
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Discussion |
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Worldwide, the primary therapy of acromegaly is based on the surgical removal of the pituitary tumor (8, 23). Surgery is successful in the majority of microadenomas and enclosed macroadenomas, disappointing in large and invasive tumors (23). By using stringent criteria for cure (22), overall surgical cure is achieved in 57.3% of 688 patients (27), 61% of 100 patients (28), 63% of 90 patients (29), 70.2 of 57% (30), and 42% of 100 patients (31). Additionally, results are better when surgery is performed only in experienced centers, preferably by one operator (20, 21). The evidence that surgical outcome is related to preoperative GH level, tumor size, and dural invasion (30, 31) suggested that a short preoperative course of medical therapy might improve surgical outcome, but results are controversial (12).
It is a matter of fact that SSA suppress GH levels in about 50% of patients in different series (16), improve clinical signs and symptoms even when IGF-I levels are not normalized (14), reduce cardiovascular morbidity and sleep apnea (7), thus reducing the anesthetic risk (11), and induce tumor shrinkage (12, 14). A recent analysis of 15 studies examining tumor shrinkage after primary SSA treatment (14) showed a decrease of about 50% in tumor mass. Major drawbacks of life-long primary treatment with SSA are the high costs of the drugs, evidence of limited compliance (even if improved with depot formulation), and side effects. In general, side effects do not limit therapy, but a number of studies reported 3–5% dropout rates, in one study up to 25% (32). SSA treatment was also reported to be the major factor responsible for the costs of management of acromegaly (33). As expected, costs of nonresponsive patients (including management of comorbidities) were higher than those reported for SSA-responsive patients (33). Currently, therefore, surgery is considered as first-line treatment in all patients with acromegaly except in those patients with an unacceptable anesthetic risk or who have refused surgery (8). Treatment with SSA is indicated as adjunctive treatment after unsuccessful surgery with an overall success rate of 50% (16, 23). Radiotherapy, second surgery, and GH receptor antagonist therapy are the treatment choices in patients unsuccessfully operated on and resistant to SSA (8).
Whether surgical debulking can improve subsequent response to SSA has been poorly investigated. In 24 patients with acromegaly treated before and after surgery for at least 1 month with SSA, Petrossians et al. (19) reported normalized GH and IGF-I levels in 29% and 46%, respectively, before surgery and in 54% and 78%, respectively, after surgery. Even if the series of patients is small, these results are clinically relevant. To investigate the place of surgical debulking in the treatment algorithm of acromegaly, we carried out this retrospective study. The strengths of our study are the large number of cases, the duration of the presurgical course of SSA being long enough to gain information about individual patient sensitivity to the drug, the policy in our centers that only one neurosurgeon operates on our patients, and the long clinical experience in following acromegaly, so that our treatment and follow-up protocols coincide. Another advantage is that two thirds of our patients received the same drug during the first and the second course of treatment; the remaining patients received depot formulation during the second course of treatment due to drug availability that evolved over time. The major drawback of our study is its retrospective design; considering, however, that clinical protocols for diagnosis and follow-up did not change significantly in these last 10 yr our results are of value.
The most important implication of our study is that surgical debulking in acromegalic patients resistant (at least partially) to SSA induces a significant increase in the prevalence of normal IGF-I levels during subsequent postoperative SSA treatment. Because we did not change the drug used, except in a subset of patients whose results did not alter the overall conclusions, nor was the drug dose altered and considering the durations of SSA treatment pre- and postoperatively were comparable, the reduction of tumor mass is the most likely explanation for the normalization of IGF-I levels. In fact, the percent hormonal decrease during the second SSA course compared with postsurgery levels was comparable to that obtained during the first SSA course compared with baseline levels. Clearly, hormonal levels before the second course were significantly lower than those before the first course as result of neurosurgery. Additional support of our conclusion is provided by the observation that the extent of tumor debulking significantly correlated with subsequent response to SSA. Tumor debulking is an approved treatment approach to malignancies, but it is only empirically applied to pituitary tumors. Pituitary surgery only rarely causes complications such as cerebrospinal fluid leakage, arachnoiditis, and temporary or permanent diabetes insipidus (8, 23). The most frequent complication of surgery is considered to be pituitary failure, which develops after surgery in only 20–30% of patients with macroadenomas (8, 23). Thus, surgery is considered a safe procedure. Indeed, in our series we observed slight changes in the degree of pituitary deficiency during the study; no significant impairment was found overall, except for the prevalence of three pituitary axis deficits that increased from 1% to 9%. Radiotherapy was performed in the year after surgery only in a subset of 26 patients (30%). The possibility that radiotherapy could be responsible for the outcome of the second course of SSA treatment is unlikely because of both the short period of observation and the small number of treated cases. Even though the overall efficacy of radiotherapy remains contentious (8), there is a large consensus that the results of radiotherapy are delayed for years, either when employing the conventional fractionated technique, or radiosurgery by 
-knife (34). However, the improvement in the success rate of SSA after surgical debulking was still present even after excluding previously irradiated patients from the analysis.
Previous results comparing the efficacy of SSA treatment as primary treatment and as adjuvant treatment after unsuccessful surgery showed no difference in suppressing GH levels below 2.5 µg/liter and in normalizing IGF-I levels for age (9, 15, 16, 17, 18). Thus, our present finding of significantly better results after unsuccessful surgery could be considered rather unexpected. Two important aspects should be pointed out. First, all previous studies, except that by Petrossians et al. (19), compared different series of patients, whereas our study compared the therapeutic response in individual patients. Furthermore, the vast majority of the patients included in our study were nonresponsive or poorly responsive to primary SSA treatment. In fact, compared with literature data reporting an overall efficacy of SSA in about 50% of patients with acromegaly (16), we found a successful response in only 12.8%. Our cohort is, thus, representative of the poorly SSA-responsive subset of patients with acromegaly. In this light, our results indicate a potentially new contribution of surgery: not necessarily to achieve cure of the disease, which is difficult when dural or bony invasion is present, but to remove at least 75% of the tumor volume. In fact, normal IGF-I levels were achieved in 71.7% of the patients with more than 75% tumor debulking on surgery and in 36.4% of those with less than 75% tumor debulking.
In conclusion, in patients treated primarily with SSAs and poorly responsive to these drugs, surgical debulking of at least 75% of the tumor volume significantly enhances the success rate of OCT, LAR, and LAN independently of which SSA drug is used. The beneficial effect in terms of age-adjusted IGF-I normalization was not accompanied by any significant additional impairment of residual pituitary function. Our data clearly indicate a place for surgical debulking in the treatment algorithm of acromegaly.
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Footnotes |
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First Published Online November 1, 2005
Abbreviations: LAN, Lanreotide; LAR, slow-release octreotide; MRI, magnetic resonance imaging; OCT, octreotide; SSA, somatostatin analog.
Received May 31, 2005.
Accepted October 20, 2005.
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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-Knife radiosurgery in acromegaly: a 4-year-follow-up study. J Clin Endocrinol Metab 88:3105–3131This article has been cited by other articles:
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  S. Melmed, A. Colao, A. Barkan, M. Molitch, A. B. Grossman, D. Kleinberg, D. Clemmons, P. Chanson, E. Laws, J. Schlechte, et al. Guidelines for Acromegaly Management: An Update J. Clin. Endocrinol. Metab., May 1, 2009; 94(5): 1509 - 1517. [Abstract] [Full Text] [PDF]
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C. L Ronchi, E. Rizzo, A. G Lania, R. Pivonello, S. Grottoli, A. Colao, E. Ghigo, A. Spada, M. Arosio, and P. Beck-Peccoz Preliminary data on biochemical remission of acromegaly after somatostatin analogs withdrawal Eur. J. Endocrinol., January 1, 2008; 158(1): 19 - 25. [Abstract] [Full Text] [PDF]
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) and second (
) courses of SSA treatment in relation to tumor size.