In 1932, Dr Harvey Cushing published his findings on a series of patients with what he called the “killing disease,” revealing that the median survival for most of his patients was less than 5 years from diagnosis.1 With advances in surgical techniques and medical management of comorbidities, the standardized mortality ratio for patients with Cushing’s disease still is elevated two- to fivefold. The surgical remission rates for corticotroph adenomas are approximately 75 % for microadenomas and <50 % for macroadenomas, although this is dependent on the surgical center.2 Further, recurrence rates are substantial. Endocrinologists have been left with few options for the treatment of patients who have failed surgery or have recurred. Ketoconazole inhibits multiple steps in cortisol synthesis, but has been subject to a black box warning from the US Food and Drug Administration (FDA) regarding potential for liver damage. Offlabel use of the dopamine agonist, cabergoline, has been shown to lower cortisol levels, but only in a subset of patients and, even then, some responders will escape from control and manifest elevated cortisol.3 At the extreme, adrenalectomy is an option but requires that there is good control of the pituitary adenoma, usually by prior treatment with radiotherapy, or there is risk of unchecked growth of the residual tumor cells, resulting in Nelson’s disease.
Three years ago, our armoury against Cushing’s disease was expanded with the regulatory approval of two pharmaceutical agents. Mifepristone (Korlym, Corcept Therapeutics) (previously known as RU486) is a glucocorticoid receptor antagonist that blocks the effects of cortisol at the tissue level. It was approved by the European Medicines Agency (EMA) in 2011 as an orphan drug for the treatment of endogenous hypercortisolemia. Shortly after, the FDA approved mifepristone for the treatment of hyperglycemia associated with hypercortisolemia. The second addition was pasireotide (Signifor, Novartis Pharmaceuticals), which is a somatostatin receptor agonist (SRA) approved by the EMA and FDA in 2012. Pasireotide has a strong affinity for somatostatin receptor 5, which enables it to inhibit adrenocorticotropic hormone (ACTH) secretion from corticotroph adenoma cells, unlike its predecessors octreotide and lanreotide. For Cushing’s disease patients who are out of options, both therapies have potential. However, the choice of the right therapy must take into account patient-specific characteristics and the positive features and adverse effects of both drugs.
Mifepristone is capable of rapid improvement in the clinical signs and symptoms of hypercortisolemia. The SEISMIC trial included subjects with Cushing’s syndrome of many etiologies: adrenocortical carcinoma, ectopic ACTH, bilateral adrenal hyperplasia, and corticotroph adenomas.4 After 24 weeks of therapy, those subjects with a previous diagnosis of diabetes had improved glucose levels, including lowered fasting glucose, glycated hemoglobin, and glucose excursions during glucose tolerance testing. Thus, the FDA approval was for the treatment of hypercortisolemia accompanied by hyperglycemia. Weight decreased and there were improvements in the scores of questionnaires designed to test for depression, cognition, and quality of life.
As mifepristone blocks cortisol feedback at the level of the corticotroph adenoma, the ACTH and cortisol levels rise two- to threefold,5 so determining clinical efficacy for dose titration can be challenging, and the clinician has to rely on surrogate markers, such as improvement in Cushing’s syndrome-related symptoms and signs as well as indirect laboratory markers, such as lowered glycated hemoglobin. Mifepristone can be so effective in blocking the glucocorticoid receptor that patients can present with symptoms reminiscent of adrenal insufficiency, including nausea and vomiting, fatigue, arthralgias, and dizziness, in spite of elevated cortisol.4 It is important that these symptoms are recognized and treated by holding the drug and administering moderate dose of dexamethasone (2–4 mg every 6–12 hours), rather than “weaker” glucocorticoids, in order to overcome the high affinity of mifepristone for the receptor. As mifepristone does not bind and inhibit the mineralocorticoid receptor, the increase in cortisol with therapy can lead to hypokalemia, hypertension, and peripheral edema. These consequences often can be managed with the addition of potassium supplements and spironolactone. Mifepristone also antagonizes the progesterone receptor so that premenopausal women can develop endometrial thickening and dysregulated vaginal bleeding. With the block in feedback on a residual corticotroph adenoma, there is a theoretical concern for unchecked growth, as is seen in Nelson’s syndrome. However, imaging data from the SEISMIC extension revealed that of 36 tumors, only four showed an increase in size and three of these enlarging tumors were invasive macroadenomas at baseline.5
Given the above discussion, the choice of mifepristone for a patient with Cushing’s disease must take into patient-specific characteristics. Positive considerations include the need for a fast clinical response, such as for a sick patient who needs to undergo a surgical procedure and patients with hyperglycemia or diabetes secondary to their Cushing’s syndrome. On the other hand, clinicians also must consider the menstrual or reproductive status of their female patients, the ability of the patient to adhere to important medications, such as potassium supplements, as well as the volume and aggressiveness of the residual tumor.