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C.J. STRASBURGER and F. KOHEN

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J A Romijn and C J Strasburger

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P. WALGER, H. LEHNERT, J. BEYER, C. STRASBURGER, D. HELLHAMMER and H. VETTER

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I Schreiber, M Buchfelder, M Droste, K Forssmann, K Mann, B Saller and C J Strasburger

Objective: The GH receptor antagonist pegvisomant is a highly effective new treatment option in acromegaly. The German Pegvisomant Observational Study (GPOS) was started to monitor long-term safety and efficacy of pegvisomant as prescribed in clinical practice.

Design: GPOS is an observational, multi-center, surveillance study, which comprises non-interventional data collection.

Methods: Of the 229 patients included in the study, 90.4% had previous pituitary surgery, 43.2% were treated by radiation therapy, and 94.3% had previous medical therapy for acromegaly that had been discontinued mainly due to persistent IGF-I elevation or side effects. The intention-to-treat population included 177 patients with at least one post-baseline efficacy measurement.

Results: IGF-I levels decreased from 1.75±0.91-fold the upper limit of normal at baseline to 1.05± 0.62 at the 6-month visit, 0.96±0.60 at the 12-month visit, and to 0.89±0.41-fold after 24 months (P<0.0001). Mean duration of pegvisomant therapy was 51.8±35.8 weeks (median=51.9 weeks). IGF-I was normalized in 64.4% at 6 months with a median dose of 15.0 mg/day, in 70.9% at 12 months, and in 76.3% at 24 months. Fasting glucose levels improved from 114.4±45.9 to 101.5± 42.8 mg/dl after 6 months (P<0.01) and to 100.6±33.2 mg/ml after 12 months (P<0.01). General physical condition measured by specific signs and symptoms score improved significantly. Adverse events occurring in >1% were injection site reactions in 7.4%, elevated liver enzymes (>3 times of normal) in 5.2% (3.1% spontaneously normalized during continued treatment), reported increase of pituitary tumor volume in 5.2% (which was verified in 3.1%), and headache in 1.7%.

Conclusions: Pegvisomant is generally well tolerated with a safety profile similar to that reported in clinical trials and can effectively reduce IGF-I in patients with acromegaly refractory to conventional therapy.

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H Biering, B Saller, J Bauditz, M Pirlich, B Rudolph, A Johne, M Buchfelder, K Mann, M Droste, I Schreiber, H Lochs and C J Strasburger

Objective: The new GH receptor antagonist pegvisomant is the most effective medical therapy to normalize IGF-I levels in patients with acromegaly. Based on currently available data pegvisomant is well tolerated; however, treatment-induced elevation of transaminases has been reported and led to the necessity for drug discontinuation in some patients in the pivotal studies. The aim of this study was to evaluate and characterize the prevalence of elevated transaminases and to describe in detail the findings in a single case who required drug discontinuation because of elevation of transaminases which emerged during treatment and who underwent liver biopsy.

Design and methods: Retrospective safety analyses were carried out on 142 patients with acromegaly receiving pegvisomant treatment in Germany between March 2003 and the end of 2004. Of these patients, 123 were documented in a post-marketing surveillance study, one case of elevated transaminases was reported spontaneously and the other patients were treated in a clinical study.

Results: Mean treatment duration with pegvisomant in the ongoing observational study at the end of 2004 was 28.3 ± 19.9 (S.D.) weeks. Twelve out of the 142 patients had elevated transaminases above three times the upper limit of normal, likely caused by biliary obstruction in five of the patients. All patients but one affected by elevated transaminases had been previously treated with somatostatin analogues. In six out of 142 (4%) of patients, pegvisomant was permanently withdrawn because of elevated transaminases. The same number of patients showed a transient increase of transaminases with either spontaneous remission without dose modification (n = 4) or no re-increase of transaminases after temporary discontinuation and re-exposure (n = 2). The liver biopsy of one patient who was permanently withdrawn showed a chronic mild hepatitis with a mixed portal inflammation including eosinophilic granulocytes.

Conclusions: Liver function tests should be regularly followed on pegvisomant treatment. Biliary complications, which may arise from restitution of normal gall bladder motility after cessation of somatostatin analogue treatment, need to be differentiated from pegvisomant-induced abnormalities. The histological pattern of the liver biopsy performed in one of the patients showed a mild chronic active hepatitis. The lack of dose dependency and rather low frequency of elevated transaminases in those cases where a biliary disorder was excluded render this reaction an idiosyncratic drug toxicity.

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S Petersenn, M Buchfelder, M Reincke, C M Strasburger, H Franz, R Lohmann, H-J Quabbe, U Plöckinger and the Participants of the German Acromegaly Register

Background

Data on surgical and medical treatment outcomes in acromegaly mostly originate from specialized centers. We retrospectively analyzed the data on surgery, primary somatostatin analog (SSA) therapy, surgery preceded by SSA, and SSA preceded by surgery in 1485 patients from the German Acromegaly Register.

Methods

Two trained nurses visited all centers (N=42) for data acquisition.

Results

Primary surgery: out of 889 patients, 554 yielded analyzable data (microadenomas 22.9%, macroadenomas 77.1%). GH and IGF1 normalized in 54.3 and 67.2%. Partial or total pituitary insufficiency occurred in 28.6% initially and 41.2% post-surgery. Primary SSA (≥3 months): out of 329 patients, 145 yielded analyzable data (microadenomas 26.7%, macroadenomas 73.3%). GH and IGF1 normalized in 36.3 and 30.5%, increasing to 40.8 and 41.5% with longer SSA (≥360 days) in 54 patients. Pituitary function did not change. SSA (≥3 months) prior to surgery: out of 234 patients, 93 yielded analyzable data. Post-surgery GH and IGF1 was normalized in 62.9 and 68.4%. GH improvement was slightly, but significantly better after SSA pretreatment. Surgery followed by SSA: out of 122 patients, 34 yielded analyzable data. GH and IGF1 normalized during SSA in 24.1 and 45.5%. Relative GH decrease was significantly larger compared with primary SSA.

Conclusions

Pituitary surgery was more effective to lower GH and IGF1 concentrations than primary SSA. Primary SSA may be an option in selected patients. SSA prior to surgery only marginally improved surgical outcome. Debulking surgery may result in better final outcome in patients with a high GH concentration and a large tumor.

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S M Webb, X Badia, M J Barahona, A Colao, C J Strasburger, A Tabarin, M O van Aken, R Pivonello, G Stalla, S W J Lamberts and J E Glusman

Chronic exposure to hypercortisolism has significant impact on patient's health and health-related quality of life (HRQoL), as demonstrated with generic questionnaires. We have developed a disease-generated questionnaire to evaluate HRQoL in patients with Cushing's syndrome (CS; CushingQoL).

Objective

Validate the CushingQoL questionnaire in patients with CS in clinical practice conditions.

Design

Observational, international, cross-sectional study.

Methods

A total of 125 patients were recruited by 14 investigators from Spain, France, Germany, The Netherlands, and Italy over a 2-month period. Clinical and hormonal data were collected and correlated with results of the generic short form 36 (SF-36) questionnaire, a question on self-perceived general health status and the CushingQoL score.

Results

A total of 107 patients were pituitary-dependent and 18 adrenal-dependent CS; 104 (83%) were females, mean age 45 years (range 20–73 years); 39 (31%) were currently hypercortisolemic; and 47 (38%) adrenal insufficient. In clinical practice, CushingQoL was feasible (117; 94% of patients fully responded to the questionnaire in a mean time of 4 min), reliable (Crohnbach's α=0.87), and valid (factorial analysis demonstrated unidimensionality and Rasch analysis lead to a final version with 12 items). A significant (P<0.001) correlation was observed between CushingQoL score and patients self-perceived general health status and dimensions of SF-36 (Pearson's correlation coefficient ≥0.597). Patients with current hypercortisolism scored worse (lower) than those without (44±22 vs 56±21, P=0.004). Linear regression analysis identified female gender and hypercortisolism as significant predictors for worse QoL.

Conclusion

CushingQoL is useful to evaluate HRQoL in patients with CS and correlates with clinical parameters.

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M Buchfelder, D Weigel, M Droste, K Mann, B Saller, K Brübach, G K Stalla, M Bidlingmaier, C J Strasburger and on behalf of the investigators of the German Pegvisomant Observational Study

In treatment-resistant patients with acromegaly, pharmacotherapy with pegvisomant (Somavert) is a highly effective option. However, safety concerns have been raised related to a potential increase in tumor size during long-term pegvisomant treatment. Therefore, neuroradiological monitoring of tumor extension and volume was performed in the German Pegvisomant Observational Study, which covers 87% of patients treated with pegvisomant in Germany. As of 15 July 2007, a total of 307 patients (156 males and 151 females) had been included in the study and were on pegvisomant therapy for an average of 86.7 weeks. Median and mean doses of pegvisomant were 15 and 16.6 mg/day respectively. Out of these 307 patients, 18 were reported to have tumor-size increases as adverse events. From these 18 patients, all available serial magnetic resonance images were collected. Identical or similar sequences were chosen and the region of interest was magnified and compared across time after the best possible fit had been achieved by size and gray-scale correction. All available images were carefully re-evaluated according to this method. In 10 out of the 18 patients, there was no evidence of tumor-size increase, when the pre-treatment scans were compared with the most recent follow-up investigations. In two out of the remaining eight patients, there was a rebound effect observed after withdrawal of somatostatin analog treatment, but no further progression. In another three out of the eight patients, tumor-size increase had already been documented before pegvisomant treatment was commenced, during preceding somatostatin analog treatment and continued therapy. In the last three patients, tumor progression after the start of pegvisomant treatment was confirmed. All three patients had undergone pituitary surgery as primary treatment, but had not been pre-treated with radiotherapy. In all three cases, the tumor increase was not considered clinically significant and the investigators decided to continue pegvisomant treatment. In conclusion, in this large group of pegvisomant-treated patients, tumor progression was rare. It was reported in between 2 and 3% of patients treated, and did not exceed the expected rate in patients with acromegaly not treated with pegvisomant. In over one-half of patients, reports of tumor increase could not be confirmed by re-evaluation. This was mostly due to non-identical gantry projections. Misjudgements mainly occurred when only images from two individual investigations, rather than the entire series of scans, were compared. Thus, we recommend a careful serial evaluation of all available images to avoid misinterpretations and erroneous alerts. As from this presently largest database of acromegalic patients treated with pegvisomant, tumor-growth rate appears not to be different from patients on other treatment modalities. Although these data are reassuring with regard to the concern of somatotroph adenoma growth under peripheral GH receptor blockade, further study is required.

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M Buchfelder, S Schlaffer, M Droste, K Mann, B Saller, K Brübach, G K Stalla, C J Strasburger and on behalf of the investigators of the German Pegvisomant Observational Study

Pivotal studies have demonstrated that pharmacotherapy with pegvisomant (Somavert) is a highly effective treatment for acromegaly. Since clinical experience with the drug was very limited, the Pegvisomant Observational Study was launched in Germany immediately with the drug becoming commercially available to patients early in 2004. Its purpose was to record safety and efficacy data on as many patients as possible.

As of 12th August 2008 a total of 371 patients (185 males, 186 females) had been included in the study. They were on pegvisomant therapy for an average of 118 weeks. Median and mean doses of pegvisomant were 15 and 16.4 mg/day respectively. Treatment efficacy was monitored by IGF1 levels and the patients symptoms were evaluated by completion of a questionnaire (patient-assessed acromegaly symptom questionnaire). Safety data included liver function tests, fasting glucose, HbA1c measurements, and tumor size monitoring by repeated magnetic resonance imaging.

Normalization of IGF1 ranged from 55.7% of the 273 patients assessed after 6 months to 71.3% of 202 patients assessed after 24 months of treatment. It was 70.7% after 36 months (133 patients), 64.8% at 48 months (71 patients), and 58.4% after 60 months (24 patients). In 39 patients (10.9%) treatment was discontinued due to serious adverse events or adverse events with 25 (6.7%) of these patients having a potential causal relationship with the pegvisomant treatment. Liver function tests became abnormal in 20 patients and another three patients were recorded to have hepatobiliary disorders. Tumor size increase was reported in 20 patients, but only confirmed in nine patients by careful revision of all available images. Local injection site reactions were observed in 12 patients.

In conclusion, in this large group of pegvisomant-treated patients, long-term data for up to 5 years of treatment are now available. In 71.3% of patients with previously not sufficiently treatable acromegaly, IGF1 levels were normalized by pegvisomant therapy. Elevated transaminases usually normalized after discontinuation but in half of the affected patients also despite continuation of treatment without dose alteration. Tumor progression was a rare event. It did not exceed the expected rate in patients with acromegaly not treated with pegvisomant. As from this presently largest database of acromegalic patients treated with pegvisomant, long-term results are encouraging. The German data are now merged into the global ACROSTUDY and will constitute a major portion of the international ACROSTUDY project as a continuing global web-based observational study.

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D B Allen, P Backeljauw, M Bidlingmaier, B M K Biller, M Boguszewski, P Burman, G Butler, K Chihara, J Christiansen, S Cianfarani, P Clayton, D Clemmons, P Cohen, F Darendeliler, C Deal, D Dunger, E M Erfurth, J S Fuqua, A Grimberg, M Haymond, C Higham, K Ho, A R Hoffman, A Hokken-Koelega, G Johannsson, A Juul, J Kopchick, P Lee, M Pollak, S Radovick, L Robison, R Rosenfeld, R J Ross, L Savendahl, P Saenger, H Toft Sorensen, K Stochholm, C Strasburger, A Swerdlow and M Thorner

Recombinant human GH (rhGH) has been in use for 30 years, and over that time its safety and efficacy in children and adults has been subject to considerable scrutiny. In 2001, a statement from the GH Research Society (GRS) concluded that ‘for approved indications, GH is safe’; however, the statement highlighted a number of areas for on-going surveillance of long-term safety, including cancer risk, impact on glucose homeostasis, and use of high dose pharmacological rhGH treatment. Over the intervening years, there have been a number of publications addressing the safety of rhGH with regard to mortality, cancer and cardiovascular risk, and the need for long-term surveillance of the increasing number of adults who were treated with rhGH in childhood. Against this backdrop of interest in safety, the European Society of Paediatric Endocrinology (ESPE), the GRS, and the Pediatric Endocrine Society (PES) convened a meeting to reappraise the safety of rhGH. The ouput of the meeting is a concise position statement.