Thursday, March 31, 2011

Pasireotide Alone or with Cabergoline and Ketoconazole in Cushing's Disease

To the Editor:

 

Cushing's disease, which is caused by an adrenocorticotropin-secreting pituitary adenoma, is associated with increased morbidity and mortality.1 Currently, there is no effective medical therapy for Cushing's disease. However, recent studies identified the somatostatin-receptor subtype 5 and dopamine-receptor subtype 2 as potential therapeutic targets in Cushing's disease.2

Pasireotide is a new somatostatin analogue that binds with high affinity to somatostatin-receptor subtypes 1, 2, and 3, and it especially has high-affinity binding to somatostatin-receptor subtype 5.3 In a recent 15-day pilot study, pasireotide normalized the excretion of urinary free cortisol in 17% of patients with Cushing's disease.4 Cabergoline, a dopamine-receptor subtype 2 agonist, can also normalize levels of urinary free cortisol in Cushing's disease, but this effect is often not maintained during prolonged treatment.5 Because the majority of adrenocorticotropin-secreting adenomas simultaneously express somatostatin-receptor subtype 5 and dopamine-receptor subtype 2,2 we hypothesized that pasireotide and dopamine-receptor subtype 2 agonists may have synergistic effects in the treatment of Cushing's disease. Finally, ketoconazole suppresses cortisol production at the adrenal level through inhibition of steroidogenic enzymes.1 In a prospective, open-label, multicenter trial, we used a stepwise approach for the medical treatment of Cushing's disease, with pasireotide as the initial form of treatment and the sequential addition of cabergoline and low-dose ketoconazole.

Seventeen patients with Cushing's disease (mean age, 45.7 years; 13 women) were included in an 80-day trial with normalization of levels of urinary free cortisol as the main outcome measure. All patients began treatment with 100 μg of pasireotide subcutaneously three times daily; this dose was increased to 250 μg subcutaneously three times daily at day 15 if the level of urinary free cortisol had not normalized. At day 28, cabergoline was added to pasireotide at a dose of 0.5 mg every other day (this dose was increased to 1.0 mg every other day after 5 days and 1.5 mg every other day after 10 days) if the level of urinary free cortisol remained elevated. If the level of urinary free cortisol had not normalized at day 60, ketoconazole was added at a dose of 200 mg thrice daily.

Pasireotide monotherapy induced sustained normalization of the level of urinary free cortisol in 5 of 17 patients (29%) (Figure 1A  
(Figure 1A Levels of Urinary Free Cortisol after Treatment for Cushing's Disease.).

 

The addition of cabergoline normalized urinary free cortisol values in an additional 4 of 17 patients (24%). At day 60, a total of 8 of 17 patients (47%) still had elevated urinary free cortisol levels with pasireotide–cabergoline combination therapy, although a trend toward normalization of levels of urinary free cortisol was observed in all but one patient, with a mean (±SE) decrease of 48±6% in the level of urinary free cortisol. The addition of low-dose ketoconazole induced biochemical remission in six of these eight patients at day 80, increasing the number of patients with a complete response to 88%.

Figure 1B shows the effects of 28 days of pasireotide monotherapy in relation to the severity of hypercortisolism at baseline. In patients with mild hypercortisolism and those with severe hypercortisolism, significant reductions in the level of urinary free cortisol of up to 67% of the baseline value were observed.

Along with the normalization of the level of urinary free cortisol, the clinical features of Cushing's disease improved, including a decrease in body weight (−2.4±0.9 kg), waist circumference (−4.2±1.3 cm), systolic blood pressure (−12±4 mm Hg), and diastolic blood pressure (−8±3 mm Hg). Adverse events included disturbance of glucose homeostasis (glycated hemoglobin level, 5.8±0.2% to 6.7±0.3%; P<0.01) and a decrease in levels of serum type I insulin-like growth factor to below the lower limit of the normal range in 9 of 17 patients.

Thus, stepwise medical therapy for Cushing's disease with the use of three drugs that differentially target somatostatin-receptor subtype 5 and dopamine-receptor subtype 2 receptors in the adrenocorticotropin-secreting adenoma and steroidogenic enzymes in the adrenal cortex resulted in biochemical control in nearly 90% of patients.

Richard A. Feelders, M.D., Ph.D.
Christiaan de Bruin, M.D., Ph.D.
Erasmus Medical Center, Rotterdam, the Netherlands

Alberto M. Pereira, M.D., Ph.D.
Johannes A. Romijn, M.D., Ph.D.
Leiden University Medical Center, Leiden, the Netherlands

Romana T. Netea-Maier, M.D., Ph.D.
Ad R. Hermus, M.D., Ph.D.
Radboud University Nijmegen Medical Center, Nijmegen, the Netherlands

Pierre M. Zelissen, M.D., Ph.D.
University Medical Center Utrecht, Utrecht, the Netherlands

Ramona van Heerebeek
Frank H. de Jong, Ph.D.
Aart-Jan van der Lely, M.D., Ph.D.
Wouter W. de Herder, M.D., Ph.D.
Leo J. Hofland, Ph.D.
Steven W. Lamberts, M.D., Ph.D.
Erasmus Medical Center, Rotterdam, the Netherlands

Disclosure forms provided by the authors are available with the full text of this article at NEJM.org.

5 References

From http://www.nejm.org/doi/full/10.1056/NEJMc1000094