Ketoconazole and octreotide as medical treatment for Cushing's disease.

N/A

Octreotide, a somatostatin analog that preferentially binds with sst2, is frequently used in
the treatment of somatotropic pituitary adenomas and neuroendocrine tumors. The
glucocorticoid-mediated sst2 downregulation in corticotroph adenoma cells explains why
octreotide is hardly effective with respect to inhibition of ACTH production in patients
with Cushing’s disease. In contrast, octreotide does inhibit ACTH production in Nelson’s
syndrome, a condition in which patients with Cushing’s disease have undergone bilateral
adrenalectomy and hence, the corticotroph adenoma cells are not exposed to high levels
of cortisol (9). From this, it can be hypothesized that cortisol-lowering therapy with
adrenal blocking agents like ketoconazole may induce upregulation of sst2 in corticotroph
adenomas of patients with Cushing’s disease. Indeed, preliminary data show that
corticotroph adenomas from patients with normalized preoperative UFC excretion (after
medical pre-treatment) have significantly higher sst2 mRNA expression levels compared
to adenomas from patients with elevated preoperative UFC concentrations. This could
potentially have consequences for the efficacy of octreotide in lowering ACTH production
by corticotroph tumor cells.

Baseline, followed by monthly evaluation untill the end of the study period (ie 9 months).

The total study period is estimated at 9 months. Treatment starts with administration of ketoconazole 200 mg four times
daily. Urinary free cortisol (UFC) excretion will be measured after 1, 2 and 3 months. As
soon as UFC excretion has normalized, octreotide treatment will be initialized at a dose
of 20 mg every 4 weeks. Before start of octreotide treatment, an octreotide test will be
performed with serial measurement of ACTH concentrations. If UFC has not normalized
after 2 months of ketoconazole monotherapy, the ketoconazole dosage will be increased
to 3 times 400 mg daily. If after two months of ketoconazole-octreotide combination
therapy UFC levels are still normal, ketoconazole will be stopped. Patients are then
treated with octreotide monotherapy until the end of the study period. If UFC excretion
(mean of 2 collections) increases again (>125% the upper limit of normal (ULN)) under
octreotide/ketoconazole combination therapy or octreotide monotherapy, the octreotide
dosage will be increased to 30 mg every 4 weeks. If UFC excretion does not normalize
under ketoconazole monotherapy, combination therapy with cabergoline (0.5 mg every
other day (qod), which is gradually increased to 1 to 2 mg qod in 15 days) will be started.
After 15 days, the ketoconazole dosage will then be decreased from 1200 mg daily to
800, 600 and 400 mg daily, respectively, in 4 weeks. These patients will not be treated
with octreotide.