by ecancer reporter Clare Sansom

Cushing’s disease is characterised by abnormal increases in secretion of the hormone corticotrophin, also known as adrenocorticotropic hormone or ACTH, from the anterior pituitary gland.

By far the most common although not the only cause of this disease is an adenoma of the pituitary gland.

Its symptoms include rapid weight gain and the onset of diseases associated with obesity including arterial hypertension, hypercholestaemia, glucose intolerance (including diabetes mellitus) and cardiovascular disease.

It is not to be confused with Cushing’s syndrome, which is the name given to similar symptoms when they arise from the high doses of steroids that are often prescribed to treat serious diseases including cancer.

The disease is well treated with surgery, but about 30% of patients still relapse; secondary treatments can include further surgery, radiotherapy or drugs. There have, however, been few studies of the effectiveness of drug treatment for Cushing’s disease.

Drugs that activate a class of receptor known as somatostatin receptor subtype 5 inhibit the secretion of corticotrophin and can therefore be considered potential therapies for Cushing’s disease. An international group of researchers led by Beverly Biller of Massachusetts General Hospital, Boston, MA, USA has now conducted a Phase III clinical trial of one such drug, pasireotide, for this condition. They recruited 162 patients who met the main diagnostic criterion for Cushing’s disease of mean urinary cortisol levels at least 1.5 times the upper limit of the normal range; all had persistent or recurrent disease or were newly diagnosed but not considered suitable for surgery.

Eighty patients were randomized to receive subcutaneous doses of 900 mg of pasireotide twice daily, and a further 82 to receive similar twice daily treatment of 600 mg of the drug. After three months, all patients with urinary cortisol levels above their own baseline levels or above twice the top of the normal range were un-blinded and assigned a further twice daily dose of 300 mg over their initial study dose.

After six months, all patients entered an open-label trial period of a further six months during which any patient could receive an increase in dose at any time up to a maximum of 1200 mg twice daily. The primary end point was a normal urinary cortisol level after six months’ treatment with no dose increase. Secondary end points included cortisol levels assessed every three months, regardless of dose increases; symptom control; and overall quality of life.

A total of seventy-eight patients (48%) completed the full twelve months of the study. The majority of patients experienced decreases in urinary cortisol levels during the first six months, with 12 patients in the lower dose group (95% confidence interval, 7-22) and 21 in the higher dose group (95% confidence interval, 17-36) meeting the primary end point criterion; statistical significance was reached only for the higher dose group. Cortisol levels remained normal after twelve months in twenty patients. In general, patients with lower urinary cortisol levels at baseline showed a better response to the drug.

Rapid clinical improvements were seen in all responding patients as their cortisol levels dropped. These included decreases in both systolic and diastolic blood pressure, and in blood cholesterol levels; increases in health-related quality of life, measured using the CushingQoL questionnaire; and weight loss. Adenoma volumes, measured at baseline, six and twelve months using magnetic resonance imaging, also decreased.

There were relatively few serious adverse events, and those that occurred were similar to those seen with other somatostatin analogues. However, 13% of patients developed hyperglycemia and 7% diabetes mellitus. Glucose-lowering medication was initiated or increased in 74 (46%) of the 162 patients during the trial period. Some patients also had symptoms consistent with abnormally low glucocorticoid levels, but these were all resolved by a temporary decrease in pasireotide dose.

The researchers concluded that, despite some increase in risk of glucose intolerance, pasireotide should be considered as a potential treatment for patients suffering from corticotrophin-secreting pituitary adenomas, that is, from Cushing’s disease.

Reference

Colao, A., Petersenn, S., Newell-Price, J., Findling, J.W., Gu, F., Maldonado, M., Schoenherr, U., Mills, D., Salgado, L.R. and Biller, B.M. for the Pasireotide B2305 Study Group (2012). A 12-Month Phase 3 Study of Pasireotide in Cushing’s Disease. N Engl J Med 366, 914-24.