A prospective trial with ketoconazole and octreotide combination therapy for treatment of Cushing*s disease.

Cushing's disease is caused by an ACTH-producing pituitary adenoma. The primary
choice of treatment is surgery, but the long-term remission rate is only
50-70%. Therefore, research is performed to develop alternative treatment
modalities. Pituitary irradiation is one of them, but it can take up to a few
years for radiotherapy to become effective. Moreover, there is a considerable
risk of inducing hypopituitarism. Until now, the role of medical therapy for
Cushing's disease is limited. Before surgery, patients are usually pre-treated
with ketoconazole. Ketoconazole is an antimycotic agent that, in relatively
high dosages, inhibits adrenocortical cortisol production. However, these high
dosages are often accompanied by side effects (gastrointestinal,
hepatotoxicity), which limits the long-term use of ketoconazole. Corticotroph
pituitary adenomas predominantly express the somatostatin receptor subtype
(sst) 5 and the dopamine 2 receptor (DA2). Previous studies showed that
cabergoline, a DA2 agonist, and pasireotide, a somatostatin analog with high
affinity for the sst1, 2, 3 and 5, can be effective with respect to normalizing
cortisol levels in patients with Cushing's disease. However, pasireotide can
induce hyperglycemia en appears to be able to render patients groth hormone
deficient. Cabergoline normalizes cortisol levels in approximately 40% of the
patients that have persistent disease after transsphenoidal surgery.
Octreotide, a somatostatin analog with high affinity for the sst2, is hardly
effective in Cushing's disease. This can be explained by the observation that
the sst2 is only expressed to a minor extent by corticotroph adenoma cells. In
vitro studies with AtT20 cells (a murine cell line that serves as a model for
Cushing's disease) showed that the mRNA expression of the sst2 is suppressed by
exposure to high concentrations of glucocorticoids. The hypothesis, therefore,
is that cortisol-lowering therapy with ketoconazole can induce an up-regulation
of the sst2 expression on the adenoma cells. Thereby, the effectivity of
octreotide with respect to controlling the ACTH production by the adenoma would
increase. Preliminary results from in vitro studies indeed showed that adenomas
from patients with normalized preoperative cortiolexcretion had significantly
higher sst2 mRNA expression than adenomas from patients with elevated
preoperative cortisolexcretion.
Therefore, patients will start with the standard therapy ketoconazole in this
study, followed by treatment with octreotide, after which it will be
investigated whether octreotide can induce long-term control of
hypercortisolism after discontinuing ketoconazole. Regarding the side effects
of ketoconazole, this would mean a big improvement in the medical treatment of
Cushing's disease. However, if ketoconazole appears unable to normalize the
cortisol levels, co-administration of octreotide will not prove to be effective
since high levels of cortisol downregulate the sst2 expression of the pituitary
adenoma. In that case, ketoconazole will be combined with cabergoline. A
preliminary study showed that combination therapy with ketoconazole and
cabergoline allows lower dosages of ketoconazole, which decreases the risk of
adverse effects.

The primary endopoint is to determine whether ketoconazole/octreotide
combination therapy, followed by octreotide monotherapy, is an effective
treatment for Cushing's disease.
Secundary endpoints address the effects of this therapy on bone metabolism,
quality of life and coagulation and fibrinolysis.
Moreover, in patients that do not normalize under ketoconazole monotherapy, we
wish to examine the effectiveness of ketoconazole/cabergoline combination
therapy.

Not-randomized, unblinded, prospective intervention study.

Ketoconazole treatment (4 times daily 200 mg, maximum 4 times 300 mg during 1
to maximally 5 months)
Octreotide treatment (1 injection every 4 weeks: 20 - 30 mg during 6 to
maximally 8 months)
Cabergoline treatment (1 tot 2 mg every other day during maximally 6 months)

Routine physical examination and laboratory examination will be performed at
baseline and after 3, 6 and 9 months (end of the study period). At baseline and
after 9 months, patients will complete quality of life questionnaires.
Patients will visit the outpatient clinic monthly. 24-hour urine and salivary
cortisol will be collected at that moment.
In addition, patients will be treated during 9 months, 6 months longer than the
usual period preceding surgery. During these 9 months, patients will be treated
with ketoconazole (3-5 months, oral administration, maximally 1200 mg daily),
octreotide (6-8 months, subcutaneous injection once every 4 weeks) and
cabergoline (6 months, oral administration, 1-2 mg every other day). All three
drugs have relatively mild adverse effects. Ketoconazole can cause impaired
liver function. As indicated in the protocol, the dosage will be lowered in
such cases and, if necessary, the drug will be discontinued.