Clinical and Endocrine Responses to Pituitary Radiotherapy in Pediatric Cushing’s Disease: An Effective Second-Line Treatment

Treatment of Cushing’s disease (CD) is one of the most challenging tasks in endocrinology. The first-line treatment, transsphenoidal pituitary surgery, is associated with a high failure rate and a high prevalence of recurrence. Re-operation is associated with an even higher rate of a failure and recurrence. There are three main second-line treatments for CD – pituitary radiation therapy (RT), bilateral adrenalectomy and chronic cortisol-lowering medical treatment. All these treatments have their limitations. While bilateral adrenalectomy provides permanent cure of the hypercortisolism in all patients, the unavoidable chronic adrenal insufficiency and the risk of development of Nelson syndrome are of concern. Chronic cortisol-lowering medical treatment is not efficient in all patients and side effects are often a limiting factor. RT is efficient for approximately two-thirds of all patients with CD. However, the high prevalence of pituitary insufficiency is of concern as well as potential optic nerve damage, development of cerebrovascular disease and secondary brain tumours. Thus, when it comes to decide appropriate treatment for patients with CD, who have either failed to achieve remission with pituitary surgery, or patients with recurrence, the pros and cons of all second-line treatment options must be considered.

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Treatment Options in Cushing's Disease

Clinical Medicine Insights Oncology ◽

10.4137/cmo.s6198 ◽

2012 ◽

Vol 6 ◽

pp. CMO.S6198 ◽

Cited By ~ 11

Author(s):

Ahmed Rizk ◽

Juergen Honegger ◽

Monika Milian ◽

Tsambika Psaras

Keyword(s):

Pituitary Adenoma ◽

Medical Therapy ◽

Treatment Option ◽

Cushing’S Disease ◽

Treatment Options ◽

Bilateral Adrenalectomy ◽

Metabolic Effects ◽

Cushing's Disease ◽

Line Treatment ◽

Second Line

Endogenous Cushing's syndrome is a grave disease that requires a multidisciplinary and individualized treatment approach for each patient. Approximately 80% of all patients harbour a corticotroph pituitary adenoma (Cushing's disease) with excessive secretion of adrenocorticotropin-hormone (ACTH) and, consecutively, cortisol. The goals of treatment include normalization of hormone excess, long-term disease control and the reversal of comorbidities caused by the underlying pathology. The treatment of choice is neurosurgical tumour removal of the pituitary adenoma. Second-line treatments include medical therapy, bilateral adrenalectomy and radiation therapy. Drug treatment modalities target at the hypothalamic/pituitary level, the adrenal gland and at the glucocorticoid receptor level and are commonly used in patients in whom surgery has failed. Bilateral adrenalectomy is the second-line treatment for persistent hypercortisolism that offers immediate control of hypercortisolism. However, this treatment option requires a careful individualized evaluation, since it has the disadvantage of permanent hypoadrenalism which requires lifelong glucocorticoid and mineralocorticoid replacement therapy and bears the risk of developing Nelson's syndrome. Although there are some very promising medical therapy options it clearly remains a second-line treatment option. However, there are numerous circumstances where medical management of CD is indicated. Medical therapy is frequently used in cases with severe hypercortisolism before surgery in order to control the metabolic effects and help reduce the anestesiological risk. Additionally, it can help to bridge the time gap until radiotherapy takes effect. The aim of this review is to analyze and present current treatment options in Cushing's disease.

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Long-term anterior pituitary function in patients with paediatric Cushing’s disease treated with pituitary radiotherapy

Acta Endocrinologica ◽

10.1530/eje-06-0588 ◽

2007 ◽

Vol 156 (4) ◽

pp. 477-482 ◽

Cited By ~ 20

Author(s):

L F Chan ◽

H L Storr ◽

P N Plowman ◽

L A Perry ◽

G M Besser ◽

...

Keyword(s):

Cushing’S Disease ◽

Anterior Pituitary ◽

Serum Cortisol ◽

Pituitary Function ◽

Cushing's Disease ◽

Serum Prolactin ◽

Second Line ◽

Anterior Pituitary Function

Background/objective: Pituitary radiotherapy (RT) is an effective second-line treatment for paediatric Cushing’s disease (CD). Although the short-term effects of pituitary RT are well documented, there are less data on possible long-term sequelae. We report the long-term anterior pituitary function in a cohort of paediatric CD patients treated with pituitary RT. Patients and methods: Between 1983 and 2006, 12 paediatric CD patients (10 males and 2 females) of mean age 11.4 years at diagnosis (range 6.4–17.4) underwent second-line pituitary RT (45 Gy in 25 fractions), following unsuccessful transsphenoidal surgery. Out of 12, 11 patients were cured by RT (cure interval 0.13–2.86 years) defined by mean serum cortisol of <150 nmol/l on 5-point day curve and midnight sleeping cortisol of <50 nmol/l. Long-term data are available for six male patients, who received RT at the age of 7.0–17.6 years. The mean follow-up from the completion of RT was 10.5 years (6.6–16.5). Results: At a mean of 1.0 year (0.11–2.54) following RT, GH deficiency (peak GH <1–17.9 mU/l) was present in five out of six patients. On retesting at a mean of 9.3 years (7.6–11.3) after RT, three out of four patients were GH sufficient (peak GH 19.2–50.4 mU/l). Other anterior pituitary functions including serum prolactin in five out of six patients were normal on follow-up. All the six patients had testicular volumes of 20–25 ml at the age of 14.5–28.5 years. Conclusion: This series of patients illustrates the absence of serious long-term pituitary deficiency after RT and emphasises the importance of continued surveillance.

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PDB21 Chart Audit and Budget Impact Analysis of Pasireotide Versus Second-Line Therapies in the Treatment of Cushing's Disease in Germany

Value in Health ◽

10.1016/j.jval.2012.08.1664 ◽

2012 ◽

Vol 15 (7) ◽

pp. A497

Author(s):

X. Badia ◽

A. Forsythe ◽

V. Stemmer ◽

G. Cummins

Keyword(s):

Cushing’S Disease ◽

Impact Analysis ◽

Budget Impact ◽

Budget Impact Analysis ◽

Cushing's Disease ◽

Second Line ◽

Chart Audit

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The Treatment of Cushing's Disease

Endocrine Reviews ◽

10.1210/er.2013-1048 ◽

2015 ◽

Vol 36 (4) ◽

pp. 385-486 ◽

Cited By ~ 170

Author(s):

Rosario Pivonello ◽

Monica De Leo ◽

Alessia Cozzolino ◽

Annamaria Colao

Keyword(s):

Medical Therapy ◽

Cushing’S Syndrome ◽

Cushing’S Disease ◽

Pituitary Tumor ◽

Cushing's Syndrome ◽

Cushing's Disease ◽

Primary Therapy ◽

Line Treatment ◽

Adrenal Surgery ◽

Disease Remission

Abstract Cushing's disease (CD), or pituitary-dependent Cushing's syndrome, is a severe endocrine disease caused by a corticotroph pituitary tumor and associated with increased morbidity and mortality. The first-line treatment for CD is pituitary surgery, which is followed by disease remission in around 78% and relapse in around 13% of patients during the 10-year period after surgery, so that nearly one third of patients experience in the long-term a failure of surgery and require an additional second-line treatment. Patients with persistent or recurrent CD require additional treatments, including pituitary radiotherapy, adrenal surgery, and/or medical therapy. Pituitary radiotherapy is effective in controlling cortisol excess in a large percentage of patients, but it is associated with a considerable risk of hypopituitarism. Adrenal surgery is followed by a rapid and definitive control of cortisol excess in nearly all patients, but it induces adrenal insufficiency. Medical therapy has recently acquired a more important role compared to the past, due to the recent employment of novel compounds able to control cortisol secretion or action. Currently, medical therapy is used as a presurgical treatment, particularly for severe disease; or as postsurgical treatment, in cases of failure or incomplete surgical tumor resection; or as bridging therapy before, during, and after radiotherapy while waiting for disease control; or, in selected cases, as primary therapy, mainly when surgery is not an option. The adrenal-directed drug ketoconazole is the most commonly used drug, mainly because of its rapid action, whereas the glucocorticoid receptor antagonist, mifepristone, is highly effective in controlling clinical comorbidities, mainly glucose intolerance, thus being a useful treatment for CD when it is associated with diabetes mellitus. Pituitary-directed drugs have the advantage of acting at the site responsible for CD, the pituitary tumor. Among this group of drugs, the dopamine agonist cabergoline and the somatostatin analog pasireotide result in disease remission in a consistent subgroup of patients with CD. Recently, pasireotide has been approved for the treatment of CD when surgery has failed or when surgery is not an option, and mifepristone has been approved for the treatment of Cushing's syndrome when associated with impairment of glucose metabolism in case of the lack of a surgical indication. Recent experience suggests that the combination of different drugs may be able to control cortisol excess in a great majority of patients with CD.

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