Combination therapy for Cushing’s disease: effectiveness of two schedules of treatment. Should we start with cabergoline or ketoconazole?

Abstract

Cushing's disease (CD) is associated with increased morbidity and mortality. Until now, no medical treatment has been shown to be totally satisfactory when administrated alone. This study aimed to assess the effectiveness of cabergoline with added ketoconazole and of the same combination in reverse, using urinary free cortisol (UFC) and late night salivary cortisol (LNSC) levels as biochemical markers of the treatments' efficacy in CD patients. A prospective analysis conducted on 14 patients (f/m = 12/2; median age 52, range 33-70 years) divided into two groups: 6 patients initially treated with cabergoline for 4-6 months (rising from 0.5-1 mg/week up to 3.0 mg/week), after which ketoconazole was added (group A); and 8 patients first took ketoconazole alone for 4-6 months (rising from 200 mg/day to 600 mg/day), then cabergoline was added (group B). Patients were compared with 14 age-matched patients in prolonged remission after effective neurosurgery for CD. The combination therapy led to UFC normalization in 79 % of patients with no differences between the groups; only one patient failed to respond at all. Neither drug succeeded in controlling the disease when taken alone. LNSC dropped when compared to baseline levels, but not to a significant degree (p = 0.06), and it remained significantly higher than in controls (p = 0.0006). Associating cabergoline with ketoconazole may represent an effective second-line treatment, achieving a satisfactory reduction in UFC levels and clinical improvement. Although the combined treatment lowered patients' LNSC levels, they remained higher than normal, indicating a persistent subclinical hypercortisolism; the implications of this condition need to be considered. No differences emerged between the two treatment schedules.

Treatment of Cushing's disease: a mechanistic update

“…In contrast to previously reported cases during long-term cabergoline monotherapy, patients on combined pasireotide-cabergoline treatment did not exhibit escapism (Feelders & Hofland 2013). It would seem that UFC normalization in combination therapies remains at approximately 80% regardless of which drug is administered first: cabergoline with ketoconazole or, ketoconazole with cabergoline (Barbot et al 2014).…”

Efficacy and safety of once-monthly pasireotide in Cushing's disease: a 12 month clinical trial

“…Few studies have investigated the value of late-night salivary cortisol in monitoring response to medical treatment in patients with Cushing's disease, with varying outcomes. [18][19][20][21] As such, the potential role of late-night salivary cortisol during monitoring of medical treatment remains to be determined. In this study, normal late-night salivary cortisol levels were seen in 22-23% of patients at months 7 and 12.…”

A venous thromboembolism risk assessment model for patients with Cushing’s syndrome

“…Hormonal parameters were assessed as reported elsewhere [29][30][31]. Briefly, midnight serum cortisol (range \7.5 lg/ dL) and UFC levels (range 90-694 nmol/24 h) were initially measured by RIA using commercial kits and, for UFC, by liquid chromatography-tandem mass spectrometry from December 2011 onwards (normal range 16-170 nmol/24 h) [30]; salivary cortisol was measured by RIA assay [31]; and plasma ACTH levels (normal range 10-50 ng/L) were measured by IRMA.…”