Therapy-resistant Cushing's disease – how to define, how to treat?

Cushing's disease (CD) is a rare disorder with severe morbidity and excess mortality, mostly due to the clinical consequences of hypercortisolism. First-line treatment is transsphenoidal surgery, which results in remission in more than 65% of patients. Notable, recurrence rate up to 26% have been reported during long-term follow-up. Both for residual and recurrent disease, repeated surgery, radiation, medical treatment, and bilateral adrenalectomy are potential options, depending on the presence of a defined pituitary mass, the severity of cortisol excess, and patient's preference. Whereas only surgery and radiation offer the potential of cure, they largely depend on the experience of the center involved. Furthermore, especially the latter is characterized by slow development of efficacy over years and relevant side effects. For that reason, therapy-resistant CD may be defined by the lack of biochemical normalization and/or tumor control after surgery. Once ongoing disease after (repeated) surgery is established, radiation may be considered, especially in patients with defined residual and/or growing tumor mass. Medical treatment needs to be offered until radiation becomes effective, or as an alternative. Bilateral adrenalectomy is usually reserved for patients with severe morbidity due to excessive biochemical output. Options for medical treatment include pituitary-targeted therapy by pasireotide and/or dopamine agonists, adrenal-targeted therapy including ketoconazole and metyrapone, and the glucocorticoid-receptor antagonist mifepristone. Notable, only pasireotide and to a lesser extent mifepristone are licensed for the use in CD, depending on the health care system involved. Medical therapy by single or multiple agents offers the chance of biochemical control in a relevant percentage of patients, but specific side-effects needs to be discussed with the patient. In the rare event of aggressive tumor growth, continuous treatment with temozolomide may offer the chance of disease stabilization. In summary, the potential for disease control in CD has recently been improved by advances in surgical and radiation techniques, and the development of new medical approaches.