There is a paucity of clinical trial data supporting the efficacy of most drugs used to treat Cushing's disease, researchers reported.
Just one drug -- pasireotide -- has been evaluated in a randomized, double-blind trial, but even it was judged by the researchers to have only a 'moderate' level of evidence supporting its effectiveness and safety.
The review of the literature evaluating drug treatments for Cushing's disease, a rare pituitary disorder, is the first to employ a rigorous systematic approach with strict, predefined inclusion criteria and formal analysis of the quality of evidence using an established standard, researcher Monica Gadelha, MD, PhD, of Brazil's Federal University of Rio de Janeiro, and colleagues wrote in the journal Clinical Endocrinology.
"This systematic review indicates that the majority of medical therapies currently used in the treatment of Cushing's disease are supported by a low level of evidence," the researchers wrote. "Further well-designed prospective studies of medications in Cushing's disease would help to inform clinical practice further."
Cushing's disease is the most common form of endogenous Cushing's syndrome, a hormonal disorder resulting from persistent exposure to abnormally high levels of the hormone cortisol. In the case of Cushing's disease, the cortisol is secreted by a pituitary adenoma.
Prolonged exposure to high levels of cortisol raises the risk for diabetes mellitus, cardiovascular disease, osteoporosis and nephrolithiasis. Patients with persistent Cushing's disease have a 3- to 5-fold higher mortality than the general population.
Surgery to remove the pituitary adenoma is the first-line treatment for Cushing's disease in the U.S., and when the procedure is performed by an experienced surgeon, remission rates in patients with smaller tumors range from 65% to 90%. The long-term remission rate is lower, however, because many patients develop recurrent disease.
Several medical therapies are widely used to treat patients who are not candidates for surgery or who experience relapse following surgery.
Novartis Oncology's somatostatin analog drug pasireotide (Signifor) became the only drug approved for this indication in December of last year. And the progesterone-blocking drug mifepristone, best known as the abortion pill once called RU-486, was approved in February of 2012 for the treatment of Cushing's disease-associated hyperglycemia.
Other drugs -- including metyrapone, mitotane, cabergoline, and ketoconazole -- are also used off-label in the treatment of Cushing's, and several have shown better response rates than pasireotide in small studies.
In their systematic review, Gadelha and colleagues identified 15 studies that included at least 10 adults with Cushing's disease and reported treatment responses as the proportion of patients reaching a specified definition of response. Studies examining combinations of medications were excluded from the analysis, as were studies with indefinite diagnoses of Cushing's disease.
For medications other than mifepristone, studies had to report the proportion of patients with normalized urinary free cortisol (UFC), midnight salivary cortisol or midnight serum cortisol.
The studies were scored according to the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) system for rating quality of evidence.
Ten of the 15 included studies reported outcomes specifically for patients with Cushing's disease and the remaining five included patients with other forms of Cushing's syndrome.
The researchers reported that:
- Pasireotide was the only treatment assessed in a randomized trial, and it was judged to have a 'moderate' level of evidence supporting its use. Response rates from three prospective studies of the drug ranged from 17% to 29%.
- The remaining medications were supported by a 'low' or 'very low' level of evidence.
- The highest response rates were reported in a small retrospective studies of metyrapone (75%, one study) and mitotane (72%, one study).
- Response rates were 25% to 50% for cabergoline (four studies) and 45% for ketoconazole (one study).
- Among studies that included patients with other forms of Cushing's syndrome, response rates were 53% to 88% for ketoconazole (three studies), 70% for mitotane (one study), 57% for metyrapone (one study), and 38% to 60% for mifepristone (one study).
But the researchers urged caution in comparing the drugs, citing the variability in the study designs and patient selection endpoints, among other limitations in the research literature.
"The wide variation in the time-frames over which response to treatment was measured makes comparison a challenge," they wrote. "Comparison of response rates reported in the included studies is also complicated by the variation in methodology used to assess response."
They noted that well-designed clinical trials are needed to determine which drugs or drug combinations are most effective in the treatment of Cushing's disease patients.
"Combinations of medical therapies with different modes of action might aid in optimizing the balance of efficacy and safety," they wrote. "Investigational medications, such as bexarotene, LC1699 and retinoic acid, may help to expand the range of future therapeutic options."
Maria Fleseriu, MD, who was not involved in the review, agreed that more drug treatments are needed. But she added that Cushing's patients today have many more drug options than they did just a few years ago.
Fleseriu directs the Pituitary Center at Oregon Health & Science University, where she is an associate professor of medicine and endocrinology.
In a recently published analysis, Fleseriu wrote that pituitary-targeted medical therapies should soon play a more prominent role in treating Cushing's disease, and may become first-line treatments when surgery fails or is contraindicated.
"We now have one drug approved for Cushing's and another approved for diabetes symptoms associated with the disease," she told MedPage Today. "We are moving forward, but we are not where we would like to be. Combination therapy is probably where we are heading, but further studies are needed."
Financial support for this research was provided by Novartis Pharmaceuticals.
Researcher Monica Gadelha reports receiving speaker fees and participating on advisory boards for Novartis. Gadelha and co-author Leonardo Vieira Neto were investigators in Novartis' clinical trials of pasireotide.