Preoperative Lanreotide Treatment Improves Outcome in Patients with Acromegaly Resulting from Invasive Pituitary Macroadenoma

The Journal of International Medical Research 2012; 40: 517 524 Preoperative Lanreotide Treatment Improves Outcome in Patients with Acromegaly Resulting from Invasive Pituitary Macroadenoma Z-Q LI 1,3,a, Z QUAN 1,3,a, H-L TIAN 4 AND M CHENG 2 1 Department of Neurosurgery, and 2 Department of Radiography, Fengxian Branch of Shanghai Sixth People s Hospital, Shanghai Jiao Tong University, Shanghai, China; 3 Shanghai Neurological Research Institute of Anhui University of Science and Technology, Shanghai, China; 4 Department of Neurosurgery, Shanghai Sixth People s Hospital, Shanghai Jiao Tong University, Shanghai, China OBJECTIVE: To investigate whether 3 months preoperative treatment with lanreotide improved outcome in newly diagnosed patients with acromegaly resulting from invasive pituitary macroadenoma. METHODS: After baseline evaluation, untreated patients were randomized to undergo direct transsphenoidal surgery or lanreotide treatment (30 mg via intramuscular injection every 2 weeks, increased to 30 mg/week at week 8 if growth hormone nadir > 2.5 µg/l), for 3 months prior to surgery. Tumour shrinkage following lanreotide treatment was analysed. Cure was evaluated at 3 months postsurgery by measuring growth hormone and insulinlike growth factor-1 (IGF-1) levels. RESULTS: Preoperative lanreotide treatment significantly reduced mean tumour size. Growth hormone and IGF-1 levels were lower in the pretreatment group than in the direct surgery group at 3 months postsurgery. According to combined growth hormone and IGF-1 levels, significantly more patients were cured by trans-sphenoidal surgery in the pretreatment group compared with the direct surgery group (11 of 24 and five of 25 patients, respectively). CONCLUSIONS: Lanreotide treatment for 3 months before trans-sphenoidal surgery effectively reduced tumour size, and improved surgical cure rate, in newly diagnosed patients with acromegaly resulting from invasive pituitary macroadenoma. KEY WORDS: LANREOTIDE; PREOPERATIVE TREATMENT; ACROMEGALY; PITUITARY MACROADENOMA Introduction Pituitary adenomas are common benign neoplasms, with > 40% of pituitary tumours demonstrating microscopic evidence of local a Z-Q Li and Z Quan contributed equally to this work. invasion. 1,2 These invasive adenomas are often macroadenomas (> 10 mm in diameter 3 ) and may invade bone, dura or adjacent structures such as the cavernous or sphenoid sinuses. 4,5 Invasive pituitary adenomas are notoriously difficult to manage 517

because of their size, invasiveness, speed of growth and high frequency of recurrence. 6 Acromegaly is a rare disease caused by a growth hormone-secreting adenoma. The management of acromegaly includes transsphenoidal surgery, pharmacological therapy and radiotherapy all of which reverse excessive growth hormone secretion and reduce tumour size without compromising normal pituitary function. Trans-sphenoidal surgery allows removal of the pituitary tumour with minimal injury to the pituitary gland and has been accepted as first-line therapy for growth hormone-secreting pituitary adenoma. 7 Outcome predictors include tumour size, extrasellar extension, dural invasion and preoperative growth hormone levels. 8,9 The somatostatin analogues, lanreotide and octreotide, have been accepted as firstchoice medical therapies for acromegaly, especially for invasive tumours and macroadenomas. 10 Studies indicate that the use of somatostatin analogues reduces growth hormone levels, normalizes insulinlike growth factor (IGF)-1 levels and causes shrinkage of growth hormone-secreting adenomas, 11 which could improve the likelihood of a good outcome after radical resection. Maximal benefit is achieved after 10 years therapy, 12,13 although long-term use of somatostatin analogues is limited because of their cost. 14 Short-term preoperative treatment with these agents could prove to be cost-effective. 15 This study investigated whether treatment with lanreotide for 3 months before surgery improves the surgical cure rate for newly diagnosed patients with acromegaly resulting from invasive pituitary macroadenoma. Patients and methods STUDY POPULATION Patients newly diagnosed with acromegaly at the Department of Neurosurgery, Fengxian Branch of Shanghai Sixth People s Hospital or the Department of Neurosurgery, Shanghai Sixth People s Hospital, Shanghai Jiao Tong University, Shanghai, China between December 2006 and January 2010, were eligible for enrolment to the study. Diagnosis was based on clinical features of acromegaly including headache, carpal tunnel syndrome, acroparaesthesia, hyperhidrosis, debility, arthralgias, visual field defects, sleep apnoea, soft tissue swelling and lumbodorsal pain. 16 The inclusion criteria were: (i) newly diagnosed, previously untreated patients; (ii) growth hormone nadir > 2.5 µg/l during a standard 75 g oral glucose tolerance test measured over a 3-h period; (iii) IGF-1 levels 1.3 the upper limit of normal (ULN), adjusted for age and gender; (iv) pituitary macroadenoma verified by magnetic resonance imaging (MRI) scan, with bony destruction or erosion into the sphenoid sinus, suprasellar region or cavernous sinuses, according to Hardy criteria 17 ; (v) age 18 80 years. Exclusion criteria were: (i) history of prior surgery, radiotherapy or medical treatment for pituitary macroadenoma; (ii) immediate requirement for surgery as indicated by clinical criteria; (iii) pregnancy; (iv) contraindications for MRI scan; (v) patient judged not suitable to participate in the study for other reasons, such as personality disorder or alcohol abuse. The study was approved by the Committees for Medical Research of the Fengxian Branch of Shanghai Sixth People s Hospital and Shanghai Sixth People s Hospital. Written informed consent was obtained from each patient before study inclusion. ASSESSMENT OF ENDOCRINE FUNCTION All patients underwent endocrine examina - 518

tions immediately before and 3 months after surgery, with additional examinations conducted before lanreotide pretreatment, if appropriate. Blood was collected from all patients after an overnight fast, allowed to clot for 30 min at room temperature, centrifuged at 3000 g for 20 min at 4 C and stored at 70 C until analysis. IGF-1 was measured using the Quantikine human IGF-1 immunoassay kit (R&D Systems, Minneapolis, MN, USA). The IGF-1 concentration was adjusted for age and gender. 13 For evaluating growth hormone levels following oral glucose tolerance testing, blood samples were drawn at 0, 30, 60, 90, 120 and 180 min after ingestion of 75 g glucose. Serum was prepared and stored as described above. Growth hormone levels were measured using the DELFIA hgh kit (PerkinElmer Life and Analytical Sciences, Turku, Finland). IMAGING ASSESSMENTS All patients underwent pituitary MRI examinations with spin-echo sequence T1- weighted MRI at study entry, after lanreotide pretreatment/before surgery and immediately after surgery. All MRI scans were performed with a 3.0T whole body system (Sigma EXCITE HDx; GE Healthcare, Milwaukee, MI, USA). Image analysis was performed in consensus by two neuroradiologists who were blinded to the surgical outcome. Due to the irregular shape of the tumours, precise tumour size was measured using a Dextroscope workstation (Bracco AMT, Princeton, NJ, USA). TREATMENT After baseline endocrine evaluations and imaging assessments were performed, patients were randomized to one of two groups according to a computer-generated randomization schedule: (i) lanreotide (Somatuline LA; Ipsen, Paris, France) treatment for 3 months prior to transsphenoidal surgery (pre treatment group) or (ii) immediate trans-sphenoidal surgery (direct surgery group). To reduce the risk of adverse gastrointestinal events in the pretreatment group, lanreotide treatment was initiated at a dose of 30 mg, administered via intramuscular injection every 2 weeks; dosage was increased to 30 mg/week at week 8 if the growth hormone nadir was > 2.5 µg/l on a day curve (mean of five oral glucose tolerance growth hormone measurements, performed at 08.30, 11.00, 13.00, 17.00 and 19.00 h on 1 day). All patients underwent trans-sphenoidal adenomatectomy using standard micro - neurosurgical techniques to remove the pituitary tumour. The same two neuro - surgeons operated together on all patients. TUMOUR CONSISTENCY AND INVASION Tumour texture was classified as soft, soft firm or firm. The degree of tumour invasion was classified as none, local or extensive and scored as 0, 1 or 2, respectively. REMISSION CRITERIA The serum endocrine remission criteria for acromegaly were growth hormone nadir after oral glucose tolerance testing < 1.0 µg/l and IGF-1 levels within the normal range (matched for age and gender) 3 months after surgery. 18 Pituitary MRI examination was performed 3 months after surgery to check for tumour remnants. STATISTICAL ANALYSES Quantitative data were presented as mean ± SD, and qualitative data as absolute numbers and percentages. Comparisons among groups were performed using the Student s t- test or Wilcoxon signed-rank test for 519

quantitative data and the Pearson s χ 2 -test for qualitative variables. Statistical evaluation of the data was carried out using SPSS version 13.0 (SPSS Inc., Chicago, IL, USA) for Windows. A P-value < 0.05 was considered to be statistically significant. A power calculation verified that 19 patients per group would be needed to detect an increase in cure rate from 15% to 50% with an α-error level of 5% and a β-error level of 80%. Allowing for a follow-up loss rate of 10%, study enrolment was closed when 52 patients were included (n = 26 per group). Results The study enrolled 52 patients with acromegaly resulting from macroadenoma (n = 26 per group). Of these patients, three did not return for the 3-month follow-up visit (one in the direct surgery group and two in the pretreatment group), and the final analysis included 49 patients. There was no difference between the groups at baseline in gender distribution, age, growth hormone nadir, IGF-1 concentration or tumour volume (Table 1). The growth hormone nadir was > 2.5 µg/l and the IGF-1 was > 1.3 ageand sex-adjusted ULN in all patients. Treatment outcomes using growth hormone, IGF-1 and growth hormone + IGF- 1 criteria are given in Table 2. There were no statistically significant differences in the within-group cure rates when defined by these three outcome measures. Patients in the pretreatment group had a significantly higher cure rate (using growth hormone, IGF-1 or growth hormone + IGF-1 criteria) than those in the direct surgery group (P < 0.05 for all comparisons). Tumour volume was significantly reduced after lanreotide treatment (mean tumour volume 5.81 ± 3.67 ml before treatment versus 4.31 ± 3.32 ml after treatment; median percentage change 38.4% ± 32.3%; P < 0.05). Figure 1 illustrates a typical pattern of shrinkage in one of the study participants. There was no significant difference in initial tumour volume between those patients who were eventually cured and those not cured following surgery, in either study group. There was a significant difference in tumour volume reduction during pretreatment, between those patients TABLE 1: Baseline demographic and clinical characteristics of patients with acromegaly resulting from invasive pituitary macroadenomas, who underwent trans-sphenoidal surgery either immediately after diagnosis (direct surgery group) or after 3 months lanreotide treatment (30 mg via intramuscular injection every 2 weeks, increased to 30 mg/week at week 8 if growth hormone nadir > 2.5 µg/l; pretreatment group) Pretreatment group Direct surgery group Characteristic n = 24 n = 25 Gender, males/females 13/11 12/13 Age, years 49.2 ± 12.3 48.1 ± 11.7 Growth hormone nadir during oral glucose 22.4 ± 19.3 19.6 ± 14.6 tolerance testing, µg/l IGF-1, µg/l 879 ± 212 867 ± 279 Tumour volume, ml 5.81 ± 3.67 5.54 ± 3.32 Data presented as n (%) of patients or mean ± SD. IGF-1, insulin-like growth factor-1. No statistically significant between-group differences (P 0.05; Student s t-test [age, growth hormone nadir, IGF-1, tumour volume] or Pearson s χ 2 -test [gender]). 520

TABLE 2: Nadir serum growth hormone concentrations after oral glucose tolerance testing and serum insulin-like growth factor-1 (IGF-1) concentrations in patients with acromegaly resulting from invasive pituitary macroadenoma. Patients underwent trans-sphenoidal surgery either immediately after diagnosis (direct surgery group) or after 3 month s lanreotide treatment (30 mg via intramuscular injection every 2 weeks, increased to 30 mg/week at week 8 if growth hormone nadir > 2.5 µg/l; pretreatment group) Pretreatment group Direct surgery group n = 24 n = 25 At After lanreotide 3 months At 3 months Parameter diagnosis treatment postsurgery diagnosis postsurgery Growth hormone, 22.4 ± 19.3 12.5 ± 10.6 3.4 ± 2.6 b 19.6 ± 14.6 6.4 ± 5.0 b,c µg/l a IGF-1, µg/l 879 ± 212 861 ± 226 391 ± 162 b 867 ± 279 556 ± 187 b,c Growth hormone 11 (45.8) 6 (24.0) c 1.0 µg/l a Normal IGF-1 13 (54.2) 6 (24.0) c Growth hormone 11 (45.8) 5 (20.0) c 1.0 µg/l a + normal IGF-1 Data presented as n (%) of patients or mean ± SD. a Growth hormone nadir after oral glucose tolerance testing. b P < 0.05 for difference between diagnosis and 3 months postsurgery values in each group; Wilcoxon signedrank test. c P < 0.05 for difference between groups; Wilcoxon signed-rank test. IGF-1 levels were defined as normal based on the upper limit of the normal range, adjusted for patient age and gender. who were cured and those who were not cured following surgery ( 46 ± 21% and 19 ± 11%, respectively; P < 0.01). There was a significant between-group difference in tumour texture (P < 0.01). In the pretreatment group there were six firm, one soft firm and 17 soft tumours. In the direct surgery group there were no firm, three soft firm and 22 soft tumours. Tumours in the pretreatment group had significantly lower invasion scores than those in the direct surgery group (0.91 ± 0.61 versus 1.38 ± 0.69; P < 0.01). There were no operative or perioperative deaths. Surgical complications (mostly mild and causing no permanent disability) occurred in 10/49 patients (20.4%), and there was no significant difference between the pretreatment and direct surgery groups (five of 24 [20.8%] and five of 25 [20.0%] patients, respectively). The most frequent complications were diabetes insipidus in three patients (two in the pretreatment group and one in the direct surgery group) and cerebrospinal fluid rhinorrhoea in three patients (one in the pretreatment group and two in the direct surgery group). Persistent surgical complications were seen in two patients in the pretreatment group (minor bitemporal visual field defects) and two patients in the direct surgery group (one case of diabetes insipidus and one of olfactory nerve dysfunction). The differences between the groups were not significant. Discussion Invasive pituitary adenomas present major challenges to neurosurgeons because of their 521

A B C FIGURE 1: Enhanced magnetic resonance imaging scans demonstrating shrinkage of macroadenoma (arrows) in a 56-year-old female patient with acromegaly: (A) before lanreotide treatment; (B) after 3 months treatment with lanreotide; (C) 3 months after surgical resection local invasive behaviour, and total surgical resection is difficult with standard techniques. 19 Surgery is effective in controlling excess growth hormone and IGF- 1 secretion in 70 90% of patients with microadenomas, and approximately 50% of those with macroadenomas, when performed by dedicated and experienced neurosurgeons. 20 22 Surgical cure rates range from 15% to 30% for invasive macroadenomas. 23,24 Pretreatment of newly diagnosed acromegalic patients with somatostatin analogues before transsphenoidal surgery has been found to lead to an increased surgical cure rate in patients with invasive macroadenomas. 25 In acromegaly, somatostatin analogues are effective in controlling growth hormone and IGF-1 hypersecretion, 6 and lanreotide has been reported to induce tumour shrinkage in 40 50% of adenomas. 26 Further tumour shrinkage has been observed after surgical debulking in patients receiving lanreotide. 27 Cure rates (using growth hormone + IGF-1 criteria) in the present study were 45.8% in the pretreatment group and 20.0% in the direct surgery group. Preoperative lanreotide treatment increased the surgical cure rate in patients with macroadenoma. Pretreatment with lanreotide likely resulted in decreased tumour invasion and size, which made surgical removal easier. These findings are in agreement with a previous study in which the cure rate at 16 weeks postsurgery was 49% in lanreotide-pretreated patients versus 18.4% in direct surgery patients. 28 Pharmacokinetic studies indicate that the levels of somatostatin analogues are well below therapeutic concentrations at 12 weeks after the last injection, 29,30 and extensive studies indicate that their effects have disappeared by 3 months postsurgery in the majority of patients. 14,31 Evaluation of cure was performed at 3 months postsurgery in the present study, in agreement with the present clinical routine in China. Cure rate also reflects the criteria used to define cure itself. 32 The single criterion for cure in the study by Mao et al. 28 was IGF-1 ULN, but the persistence of growth-hormone hypersecretion is thought to promote increased IGF-1 in some patients. 33 The present study, therefore, included a growth hormone nadir of 1.0 µg/l, as well as IGF-1 ULN, in the criteria for cure. When the growth hormone nadir 1.0 µg/l criterion was added, three patients were no longer defined as cured. 522

Preoperative treatment with somatostatin analogues has been associated with improved results for trans-sphenoidal surgery, especially in macroadenoma. 22,25,28 It has also been suggested that short-term somatostatin analogue treatment may soften the tumour parenchyma and facilitate tumour removal. 25 Contrary to previous reports, the present study showed a significant increase in tumour firmness with lanreotide pretreatment. Increased firmness of the adenoma might negatively affect surgical outcome, 34 but there was no indication of an adverse effect of firm tumour consistency on surgical cure in the present study. Somatostatin analogue-induced changes in tumour consistency might assist in the discrimination between the adenoma and surrounding normal pituitary tissue, and thus facilitate surgical cure. Postoperative complications none of which was serious occurred in 10 patients in the present study. There was no difference in surgical complication rates between the two study groups. In conclusion, 3 months presurgical treatment with lanreotide effectively reduced tumour volume and invasion, decreased postoperative growth hormone and IGF-1 levels, and improved surgical cure rates, in patients with invasive macroadenoma. Acknowledgements We thank our colleagues in the Department of Neurosurgery, Fengxian Branch of The Sixth People s Hospital, Shanghai Jiao Tong University, Shanghai, China, for their help in conducting this study. Conflicts of interest The authors had no conflicts of interest to declare in relation to this article. Received for publication 13 October 2011 Accepted subject to revision 27 October 2011 Revised accepted 23 February 2012 Copyright 2012 Field House Publishing LLP References 1 Meij BP, Lopes MS, Ellegala DB, et al: The longterm significance of microscopic dural invasion in 354 patients with pituitary adenomas treated with transsphenoidal surgery. J Neurosurg 2002; 96: 195 208. 2 Gong J, Zhao Y, Abdel-Fattah R, et al: Matrix metalloproteinase-9, a potential biological marker in invasive pituitary adenomas. Pituitary 2008; 11: 37 48. 3 Lundin P, Pedersen F: Volume of pituitary macroadenomas: assessment by MRI. J Comput Assist Tomogr 1992; 16: 519 528. 4 Kaltsas GA, Grossman AB: Malignant pituitary tumours. Pituitary 1998; 1: 69 81. 5 Daly AF, Rixhon M, Adam C, et al: High prevalence of pituitary adenomas: a crosssectional study in the province of Liège, Belgium. J Clin Endocrinol Metab 2006; 91: 4769 4775. 6 Buchfelder M: Management of aggressive pituitary adenomas: current treatment strategies. Pituitary 2009; 12: 256 260. 7 Melmed S: Medical progress: acromegaly. N Engl J Med 2006; 355: 2558 2573. 8 Nomikos P, Buchfelder M, Fahlbusch R: The outcome of surgery in 668 patients with acromegaly using current criteria of biochemical cure. Eur J Endocrinol 2005; 152: 379 387. 9 Shou XF, Li SQ, Wang YF, et al: Treatment of pituitary adenomas with a transsphenoidal approach. Neurosurgery 2005; 56: 249 256. 10 Lamberts SW, Hofland LJ: Future treatment strategies of aggressive pituitary tumors. Pituitary 2009; 12: 261 264. 11 Melmed S, Sternberg R, Cook D, et al: A critical analysis of pituitary tumor shrinkage during primary medical therapy in acromegaly. J Clin Endocrinol Metab 2005; 90: 4405 4410. 12 Maiza JC, Vezzosi D, Matta M, et al: Long-term (up to 18 years) effects on GH/IGF-1 hypersecretion and tumour size of primary somatostatin analogue (SSTa) therapy in patients with GH-secreting pituitary adenoma responsive to SSTa. Clin Endocrinol (Oxf) 2007; 67: 282 289. 13 Vance ML, Laws ER Jr: Role of medical therapy in the management of acromegaly. Neurosurgery 2005; 56: 877 885. 14 Turner HE, Thornton-Jones VA, Wass JA: Systematic dose-extension of octreotide LAR: 523

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