AUTHOR=Viecceli Camila , Mattos Ana Carolina Viana , Costa Maria Carolina Bittencourt , Melo Rafael Borba de , Rodrigues Ticiana da Costa , Czepielewski Mauro Antonio 

TITLE=Evaluation of ketoconazole as a treatment for Cushing’s disease in a retrospective cohort

JOURNAL=Frontiers in Endocrinology

VOLUME=Volume 13 - 2022

YEAR=2022

URL=https://www.frontiersin.org/journals/endocrinology/articles/10.3389/fendo.2022.1017331

DOI=10.3389/fendo.2022.1017331

ISSN=1664-2392

ABSTRACT=The first-line treatment for Cushing's disease is transsphenoidal surgery, after which the rates of remission are 60 to 80%, with long-term recurrence of 20 to 30%. Drug therapies are indicated for patients without initial remission or with surgical contraindications or recurrence, and ketoconazole is one of the main available therapies. The objective of this study was to evaluate the safety profile of and treatment response to ketoconazole in Cushing's disease patients followed up at the endocrinology outpatient clinic of a Brazilian university hospital.
Of the 172 Cushing's disease patients who were followed up between 2004 and 2020, 38 received ketoconazole. However, complete data was only available for 33 of these patients. Of these, 26 (78%) underwent transsphenoidal surgery prior to using ketoconazole, 5 of whom (15%) had also undergone radiotherapy; 7 used ketoconazole as a primary treatment. Ketoconazole use ranged from 14 days to 14.5 years.  A total of 22 patients had a complete response (66%), 3 patients had a partial response (9%), and 8 patients had no response to treatment (24%), including those who underwent radiotherapy while using ketoconazole. Patients whose hypercortisolism was controlled or partially controlled with ketoconazole had lower baseline 24-hour urinary free cortisol levels than the uncontrolled group (times above the upper limit of normal: 0.62 [SD, 0.41] vs. 5.3 [SD, 8.21]; p < 0.005, respectively), in addition to more frequent previous transsphenoidal surgery (p < 0.04). The prevalence of uncontrolled patients remained stable over time (approximately 30%) despite ketoconazole dose adjustments or association with other drugs, which had no significant effect. One patient received adjuvant cabergoline from the beginning of the follow-up, and it was prescribed to 9 others due to clinical non-response to ketoconazole alone. Ten patients (30%) reported mild adverse effects, such as nausea, vomiting, dizziness and loss of appetite. Only 4 patients had serious adverse effects that warranted discontinuation.
Ketoconazole effectively controlled hypercortisolism in 66% of Cushing's disease patients, being a relatively safe drug for those without remission after transsphenoidal surgery or whose symptoms must be controlled until a new definitive therapy is carried out.