Treatment of Pituitary-Dependent Cushing’s Disease with the Multireceptor Ligand Somatostatin Analog Pasireotide (SOM230): A Multicenter, Phase II Trial

Boscaro, Marco; Ludlam, W.H.; Atkinson, Brew; Glusman, J. E.; Petersenn, Stephan; Reincke, Martín; Snyder, Peter J.; Tabarin, Antoine; Biller, Beverly M. K.; Findling, James W.; Melmed, Shlomo; Darby, C. H.; Hu, Ke; Wang, Y.; Freda, Pamela U.; Grossman, Ashley; Frohman, Lawrence A.; Bertherat, Jérôme

doi:10.1210/jc.2008-1008

Cited by 270 publications

(182 citation statements)

References 25 publications

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“…For some tumours (although not microadenomas), pre-TBA urinary cortisol serves as a useful marker of corticotrophinoma tumour size and functionality, and may be a useful predictor of the subsequent Nelson's syndrome development (3,33,40). However, the evidence is not conclusive, and a correlation between urinary cortisol levels and the risk of subsequent development of Nelson's syndrome has not been demonstrated in some studies (13,30,32).…”

Section: High Urinary Cortisolmentioning

confidence: 99%

Nelson's syndrome

Barber

Adams²,

Ansorge³

et al. 2010

European Journal of Endocrinology

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Nelson's syndrome is a potentially life-threatening condition that does not infrequently develop following total bilateral adrenalectomy (TBA) for the treatment of Cushing's disease. In this review article, we discuss some controversial aspects of Nelson's syndrome including diagnosis, predictive factors, aetiology, pathology and management based on data from the existing literature and the experience of our own tertiary centre. Definitive diagnostic criteria for Nelson's syndrome are lacking. We argue in favour of a new set of criteria. We propose that Nelson's syndrome should be diagnosed in any patient with prior TBA for the treatment of Cushing's disease and with at least one of the following criteria: i) an expanding pituitary mass lesion compared with pre-TBA images; ii) an elevated 0800 h plasma level of ACTH (O500 ng/l) in addition to progressive elevations of ACTH (a rise of O30%) on at least three consecutive occasions. Regarding predictive factors for the development of Nelson's syndrome post TBA, current evidence favours the presence of residual pituitary tumour on magnetic resonance imaging (MRI) post transsphenoidal surgery (TSS); an aggressive subtype of corticotrophinoma (based on MRI growth rapidity and histology of TSS samples); lack of prophylactic neoadjuvant pituitary radiotherapy at the time of TBA and a rapid rise of ACTH levels in year 1 post TBA. Finally, more studies are needed to assess the efficacy of therapeutic strategies in Nelson's syndrome, including the alkylating agent, temozolomide, which holds promise as a novel and effective therapeutic agent in the treatment of associated aggressive corticotroph tumours. It is timely to review these controversies and to suggest guidelines for future audit.

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Section: High Urinary Cortisolmentioning

confidence: 99%

Nelson's syndrome

Barber

Adams²,

Ansorge³

et al. 2010

European Journal of Endocrinology

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“…Three clinical studies have shown that pasireotide in dosages between 750 and 2400 mg/day can reduce UFC levels in patients with CD (see the 'Medical therapy for different causes of CS-Pituitary-dependent CS' section below). Induction of hyperglycemia, which may require glucose-lowering therapy, is an important side effect of pasireotide (Boscaro et al 2009, Feelders et al 2010a,b, Colao et al 2012. In healthy volunteers, pasireotide-induced hyperglycemia was shown to be due to inhibition of incretin secretion with a concomitant decreased insulin secretion (Henry et al 2011).…”

Section: Drugs With Proven Clinical Efficacymentioning

confidence: 99%

“…Glucose levels were most effectively lowered with glucagon-like peptide 1 agonists or dipeptidyl peptidase 4 (an enzyme that inactivates the incretins) inhibitors (Henry et al 2011). Other than hyperglycemia, pasireotide might cause gastrointestinal side effects (Boscaro et al 2009, Colao et al 2012.…”

Section: Drugs With Proven Clinical Efficacymentioning

confidence: 99%

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New developments in the medical treatment of Cushing's syndrome

Pas¹,

Herder²,

Hofland³

et al. 2012

Endocrine-Related Cancer

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Cushing's syndrome (CS) is a severe endocrine disorder characterized by chronic cortisol excess due to an ACTH-secreting pituitary adenoma, ectopic ACTH production, or a cortisol-producing adrenal neoplasia. Regardless of the underlying cause, untreated CS is associated with considerable morbidity and mortality. Surgery is the primary therapy for all causes of CS, but surgical failure and ineligibility of the patient to undergo surgery necessitate alternative treatment modalities. The role of medical therapy in CS has been limited because of lack of efficacy or intolerability. In recent years, however, new targets for medical therapy have been identified, both at the level of the pituitary gland (e.g. somatostatin, dopamine, and epidermal growth factor receptors) and the adrenal gland (ectopically expressed receptors in ACTH-independent macronodular adrenal hyperplasia). In this review, results of preclinical and clinical studies with drugs that exert their action through these molecular targets, as well as already established medical treatment options, will be discussed.

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“…In a phase 2 study, pasireotide reduced mean 24-hour urinary free cortisol (UFC), serum cortisol, and plasma ACTH in patients with CD (7). Subsequently, a phase 3 study (CSOM230B2305) in CD patients demonstrated that 12 months of pasireotide not only decreased 24-hour UFC, serum and salivary cortisol, and plasma ACTH levels but also improved clinical signs and symptoms (8).…”

Section: Introductionmentioning

confidence: 99%

Effective Medical Therapy for Cushing Disease Can Increase the Susceptibility to Relative Hypocortisolism

Yuen

Mercado

Moloney

et al. 2018

AACE Clinical Case Reports

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Objective: Pasireotide is approved for treatment of adults with Cushing disease (CD) with persistent hypercortisolism for whom surgery has failed or is not an option. Effective medical therapy for CD may increase the susceptibility of relative hypocortisolism during acute stress because of a patient's inability to compensate by increasing endogenous adrenocorticotropic hormone (ACTH) and cortisol secretion. We describe a patient with CD on pasireotide therapy for 7 years in whom biochemical eucortisolemia was achieved but subsequently experienced several distinct episodes of relative hypocortisolism during periods of acute illness.Methods: A 67-year-old man with biochemical confirmation of CD exhibited clinical and biochemical features of persistent hypercortisolism after transsphenoidal surgery despite pituitary magnetic resonance imaging showing no residual or recurrent tumor. He was enrolled into a phase 3 study (NCT00434148) and was initated on twice-daily subcutaneous pasireotide.Results: Long-term pasireotide therapy normalized 24-hour urinary free cortisol, serum cortisol, and ACTH levels. The patient subsequently developed type 2 diabetes mellitus and was managed effectively with oral hypoglycemic agents and insulin therapy. During a routine clinic assessment 79 months after study enrollment, he reported symptoms suggestive of relative hypocortisolism during three distinct substantially acute stressful health events in the preceding 18 months.Conclusion: Successful achievement of eucortisolemia with long-term medical therapy may increase susceptibility to relative hypocortisolism and precipitate symptoms of adrenal insufficiency during periods of acute stress in patients with CD. We recommend that such patients should be counseled on glucocorticoid stress dosing to prevent such events that could lead to adrenal crisis. (AACE Clinical Case Rep. 2018;4:e1-e6) Abbreviations: ACTH = adrenocorticotropic hormone; CD = Cushing disease; FPG = fasting plasma glucose; GH = growth hormone; HbA 1c = hemoglobin A 1c ; T2DM = type 2 diabetes mellitus; TSS = transsphenoidal surgery; UFC = urinary free cortisol

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Treatment of Pituitary-Dependent Cushing’s Disease with the Multireceptor Ligand Somatostatin Analog Pasireotide (SOM230): A Multicenter, Phase II Trial

Abstract: Pasireotide produced a decrease in UFC levels in 76% of patients with Cushing's disease during the treatment period of 15 d, with direct effects on ACTH release. These results suggest that pasireotide holds promise as an effective medical treatment for this disorder.

Cited by 270 publications

References 25 publications

Nelson's syndrome

Nelson's syndrome

New developments in the medical treatment of Cushing's syndrome

Effective Medical Therapy for Cushing Disease Can Increase the Susceptibility to Relative Hypocortisolism

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