The Treatment of Cushing's Disease

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.

Figure 1.

Comorbidities and clinical complications associated with excessive mortality in CD.

Figure 2.

Schematic treatment algorithm for current management of CD. The dashed line means that the treatment option is presently considered an optional choice.

Figure 3.

Main factors that can unfavorably affect the outcome of pituitary surgery in CD.

Figure 4.

Main factors that can unfavorably affect the outcome of SRT in CD.

Figure 5.

Mechanisms of action and targets for drugs currently used in the treatment of CD.

Figure 6.

Summary of the site of action of adrenal-directed drugs.

Figure 7.

Results of a multicenter retrospective study on ketoconazole (FReSKO study) performed in French centers on 197 patients with CD. The graph shows the daily urinary cortisol (fold upper limit normal [ULN] level) before (circles) and after (triangles) treatment period. Patients were divided on the basis of final dose of ketoconazole (represented by the numbers above urinary cortisol levels in μg/d) and ordered on the basis of the initial urinary cortisol levels. [Modified from F. Castinetti et al: Ketoconazole in Cushing's disease: is it worth a try? J Clin Endocrinol Metab. 2014;99(5):1623–1630 (508), with permission. © The Endocrine Society.].

Figure 8.

Results of single center prospective open lable study on cabergoline performed in Naples Center on 20 patients with CD. A, Changes in urinary cortisol levels (in μg/d) during the entire period of the study in the individual patients. B, Response of urinary cortisol levels (in μg/d) to short-term (upper graph) and long-term (lower graph) treatment in the individual patients. Squares represent the baseline urinary cortisol levels, whereas triangles represent urinary cortisol levels at the end of follow-up. [Modified from R. Pivonello et al: The medical treatment of Cushing's disease: effectiveness of chronic treatment with the dopamine agonist cabergoline in patients unsuccessfully treated by surgery. J Clin Endocrinol Metab. 2009:94(1):223–230, 2009 (656), with permission. © The Endocrine Society.]

Figure 9.

Results of a multicenter, prospective, randomized, double-blind, phase III study on pasireotide performed in several international centers on 103 patients with CD and with available urinary cortisol levels included in the study. The graph shows the absolute change of urinary cortisol levels (in nmol/d) before and after 6 months of treatment in individual patients belonging to the group randomized to 600 μg (red) or 900 μg (blue) twice of day. Patients were ordered on the basis of initial urinary cortisol levels. [Modified from A. Colao et al: A 12-month phase 3 study of pasireotide in Cushing's disease. N Engl J Med. 2012;366(10):914–924 (698), with permission. © Massachusetts Medical Society.]

Figure 10.

Comparison of the results of the studies investigating the effectiveness of cabergoline in two main studies (A and B) and the effectiveness of pasireotide in the large phase III study, at 12-month follow-up (C and D). A, Pivonello et al (656): prospective nonrandomized study, 20 patients; full response, urinary cortisol levels in the normal range. B, Godbout et al (658): retrospective nonrandomized study, 30 patients; full response, urinary cortisol levels in the normal range; partial response, urinary cortisol level decrease < 125% of upper limit of normal. C, Colao et al (698): prospective, randomized, double-blind phase III study, 162 patients, pasireotide 600 μg; full response: urinary cortisol levels in the normal range; partial response: urinary cortisol level decrease ≥ 50%. D, Colao et al (698): prospective, randomized, double-blind phase III study, 162 patients, pasireotide 900 μg; full response, urinary cortisol levels in the normal range; partial response, urinary cortisol level decrease ≥ 50%. *, This group includes nonresponsive patients at 12-month follow-up and patients who discontinued for: 1) unsatisfactory therapeutic effect; 2) consent withdrawal; and 3) study protocol deviation.