Use of Mifepristone Beneficial for Some with Cushing's Disease

Long-term mifepristone treatment increased adrenocorticotropic hormone levels in approximately two-thirds of patients with Cushing’s disease in a long-term, open-label study in the Journal of Clinical Endocrinology and Metabolism.

“However, ACTH increases did not predict ACTH secreting tumor progression,” said first author Maria Fleseriu, MD, Associate Professor of Medicine/Endocrinology and Neurological Surgery, and Director of the OHSU Northwest Pituitary Center, Oregon Health and Science University, Portland, Oregon. She added that ACTH or cortisol levels do not need to be monitored in patients receiving mifepristone for Cushing’s disease.

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Building on the SEISMIC Study

“The investigators previously showed that mifepristone induces both clinical and metabolic improvement in the majority of patients in the [6-month] SEISMIC study,” Dr. Fleseriu explained. “As expected by the mechanism of action of this drug, cortisol, and ACTH increased in patients with CD, but it was unclear what will happen long term,” she said.

In the present study, the researchers followed 27 patients from the open-label SEISMIC study for a median of 11.3 months (range 0.05-42 months) in a long-term extension trial. The patients received 300-1200 mg mifepristone once daily.

The majority of patients (72%) experienced a two-fold or greater increase in ACTH level. The ACTH levels increased in the first few weeks of treatment and remained stable over the duration of the extension trial. ACTH increase was directly correlated with the mifepristone dose, and levels returned to near baseline levels after treatment discontinuation. Radiation did not have any effect on ACTH level.

Lack of Tumor Progression Found in Majority of Patients

The study included 7 patients with macroadenomas, 9 with microadenomas and 20 with nonvisible tumors on magnetic resonance imaging at baseline. “Throughout the study duration, pituitary tumors became smaller in 2 patients (one patient had previous radiation), and grew in 3 patients with macroadenomas and 1 with initial nonvisible tumor. However, one of the macroadenomas was very aggressive even before starting mifepristone,” Dr. Fleseriu said.    

“Interestingly, ACTH increases in the 4 cases with tumor progression were similar to those in the patients whose tumors did not grow,” Dr. Fleseriu said. “The patients with macroadenomas need to be carefully watched and have repeat imaging. Lack of tumor progression in the majority of patients is encouraging for now; however, longer-term studies in a larger number of patients are needed,” she added.  

This study, though the largest prospective study to date, including patients who have been treated for a median of 12 months, and none of the patients have been treated for more than 36 months.  

Clinical Implications

“The implications of this study are that patients who have Cushing’s disease and receive mifepristone must undergo surveillance for evidence of tumor progression, including repeat measures of ACTH levels as well as periodic magnetic resonance imaging of their pituitary tumors,” commented Lewis S. Blevins, Jr, MD, Clinical Professor of Neurological Surgery and Medicine, Medical Director, California Center for Pituitary Disorders, University of California, San Francisco. “Patients with macroadenomas would seem to be more likely to experience tumor progression during therapy with mifepristone,” Dr. Blevins said.

“The study includes a reasonably large sample size, the largest to date, and provides useful information,” Dr. Blevins commented. “Unfortunately, however, the duration of study was short. Long-term post-marketing studies will likely better illustrate the likelihood of tumor progression in treated patients,” he noted. “It is not clear, in the few patients who did experience tumor growth, whether this is related to the drug or explained by the natural progression of aggressive pituitary tumors,” he added.

“Mifepristone is a viable treatment alternative in patients with residual and recurrent hypercortisolism due to Cushing's disease,” Dr. Blevins continued. “In my opinion, the benefits outweigh the risks yet patient’s must be monitored carefully for side effects of treatment, including electrolyte disturbances and Nelson’s syndrome, and women should be monitored for endometrial hyperplasia and dysfunctional uterine bleeding,” he said. 

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