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Lewis S. Blevins, Jr., MD, California Center for Pituitary Disorders at UCSF, San Francisco, California
Transsphenoidal surgery is the initial treatment of choice for most patients with proved or highly suspected Cushing’s disease. Published reports demonstrate that, in experienced centers, remission following surgery can be expected in 80-90% of patients with microadenomas and 50-65% of patients with macroadenomas. Recurrent hypercortisolism can be expected in about 10% of patients with microadenomas and one-third of patients with macroadenomas who enter remission after surgery. When faced with patients who have persistent or recurrent hypercortisolism due to a clearly documented ACTH-producing pituitary tumor one must carefully consider all of the different treatment alternatives in the context of the affected patient. Ideal therapeutic strategies include those that are directed at resolution of the hypercortisolism and also control of the offending tumor. In many cases, however, these objectives of treatment must be dealt with independently. Patients should be advised of the available treatments, the expected outcomes, risks, inconveniences, and costs so that they can make informed decisions on how best to proceed.
What about repeat surgery?
Repeat transsphenoidal surgery should be considered for all patients with residual or recurrent Cushing’s disease that is identifiable on MRI of the pituitary gland. Those with macroadenomas and accessible tumor visible on MRI may benefit from a marked reduction in tumor and a consequent fall in ACTH and cortisol levels. We do not, however, favor repeat surgery for patients who have evidence of invasion of the cavernous sinuses, sellar floor, or extension of the tumor into inaccessible suprasellar regions. In general, approximately one-half to three-quarters of patients with microadenomas can be expected to enter remission following repeat surgery when the procedures are performed by experienced neurosurgeons. Repeat surgery rarely results in remission in patients with macroadenomas but can be useful to control tumor mass effects and reduce ACTH and cortisol levels when other modalities have failed.
Does radiotherapy work?
Remission can be expected in 50-80% of adult subjects treated with conventional fractional megavoltage radiation therapy. Unfortunately, the response to treatment is delayed and only 50% of patients are in remission 18 months after treatment. As many as two-thirds of patients may develop deficiencies of one or more anterior pituitary hormones following radiotherapy. Stereotactic radiosurgery, most commonly in the form of “gamma knife” radiosurgery, results in normalization of cortisol levels in 50 to 75% of patients. The mean time to normalization of cortisol levels is approximately 12 months suggesting that stereotactic radiosurgery may be somewhat more efficacious than conventional radiotherapy in patients with Cushing’s disease who have failed surgery. We favor stereotactic radiosurgery whenever possible and especially in younger patients. Suitable patients are those with lesions on MRI, those with microadenomas identified on MRI preoperatively and histologic evidence of tumors at the time of surgery regardless of whether tumors are seen on postoperative imaging studies, and those who have cavernous sinus or bony invasion. Patients with suprasellar lesions in the proximity of the optic pathways are generally referred for conventional radiotherapy.
Are there any available medical treatments?
In the event that repeat surgery will be delayed by more than 4-8 weeks, and especially while awaiting beneficial effects of radiotherapy, steroid biosynthesis inhibitors may be used to gain control of hypercortisolism and thus improve the overall health status of the treated patients. Ketoconazole, an anti-fungal agent, is first line therapy in my practice. I start treatment with 200 mg twice daily. The dose is escalated as needed in 2-4 week intervals to a maximum dose of 400 mg four times daily in attempt to achieve normal urinary cortisol excretion rates. Success can be achieved in nearly three-quarters of patients. Aminoglutethimide and metyrapone are also effective drugs but are difficult if not impossible to obtain these days. Mitotane is effective in patients with Cushing’s disease but many will discontinue treatment due to the side-effects of the drug. Measurement of urinary cortisol excretion rates at regular intervals is necessary in order to identify those refractory to treatment, those who suffer from breakthrough hypercortisolism, and also to detect hypocortisolism in those who may have responded to radiotherapy. Medical therapy should be discontinued for 6 weeks to permit reassessment of cortisol levels in patients who have been treated with radiotherapy and whose urinary cortisol excretion rates are in or below the lower quarter of the normal range.
Are there any medical treatments currently in clinical trials?
As previously reported in this newsletter (Spring, 2008) a medication called SOM230 (pasireotide) is currently in clinical trials for Cushing’s disease.
Also, a medication called Mifepristone is currently being evaluated in clinical trials as an agent to block the effects of cortisol and improve the symptoms and signs of Cushing's syndrome. The drug is orally administered and works at the level of the cell to inhibit the binding of cortisol to its receptor, the glucocorticoid receptor. There are several reports in the medical literature of mifepristone improving the signs and symptoms of Cushing's (Johanssen S. Allolio B 2007 Eur J Endocrionl 157:561-569). Unlike ketoconazole and other adrenostatic medications, mifepristone does not result in lower cortisol levels but reduces the effects of cortisol on tissues of the body.
Corcept Therapeutics has initiated the SEISMIC study, an open-label study of the efficacy and safety of CORLUX™ (mifepristone) in the treatment of endogenous Cushing's syndrome. Subjects with most forms of endogenous Cushing's syndrome, including those with Cushing's disease whose pituitary surgery has not been curative, are eligible to participate. Study participants will receive 6 months of the glucocorticoid antagonist mifepristone. All participants receive active drug while in the SEISMIC study. At the conclusion of the study, participants will be given the opportunity to continue mifepristone if they have had clinical benefit.
Study centers are located throughout the United States. In cases where the closest study center requires travel, travel expenses will be paid for by Corcept Therapeutics. If you are interested in further information, please contact Corcept at 1-877-367-6550 or visit www.cushingsstudy.com.
What about adrenalectomy?
Bilateral adrenalectomy is usually reserved as a last resort to manage refractory or progressive hypercortisolism in patients with Cushing’s disease. A decision to recommend adrenalectomy is not to be taken lightly as the operative mortality for open bilateral adrenalectomy approaches 5% and as many as 20% of patients suffer from problems with their incisions, bleeding disorders, perioperative infections, etc. More recent laparscopic bilateral adrenalectomy procedures report 0 to .2% mortality with a lower rate of complication, however some procedures require conversion to the open approach. (Young WF et al Clin Endocrinol (Oxf) 2008 68:13-9, Duh QY Surg Endosc 2008: 22:202-7). Further, in my experience, the typical patient requires hospitalization for adrenal crises once every year or two. Nelson’s syndrome, which is an increase in pituitary tumor size after adrenalectomy, develops in approximately one-fifth of patients and may require additional tumor-directed therapy. The risk of development of Nelson’s syndrome following adrenalectomy can be reduced by one-half by administration of conventional or stereotactic radiotherapy.
Suggested Reading
Cushing’s Syndrome 2002 Ed. Blevins L. pp 344. Kluwer Academic Publshers, Norwell, MA
Invitti C, Giraldi FP, de Martin M, Cavagnini F. Diagnosis and management of Cushing’s syndrome: results of an Italian multicentre study. Study Group of the Italian Society of Endocrinology on the Pathophysiology of the Hypothalamic-Pituitary-Adrenal Axis. J Clin Endocrinol Metab. 1999 84:440-448.
Bochicchio D, Losa M, Buchfelder M, et al. Factors influencing the immediate and late outcome of Cushing’s Disease treated by transsphenoidal surgery: A retrospective study by the European Cushing’s Disease Survey Group. J Clin Endocrinol Metab. 1995 80:3114-3120.
Blevins L, Christy J, Khajavi M, Tindall G. Outcomes of therapy for Cushing’s disease due to adrenocorticotropin-secreting pituitary macroadenomas. J Clin Endocrinol Metab. 1998 83:63-67.
Estrada J, Boronat M, Mielgo M, et al. The long-term outcome of pituitary irradiation after unsuccessful transsphenoidal surgery in Cushing’s disease. N Engl J Med, 1997 336:172-7.
O’Riordain D, Farley D, Young W, et al. Long-term outcome of bilateral adrenalectomy in patients with Cushing’s syndrome. Surgery 1994 116:1088-94.
Hammer GD, Tyrrell JB, Lamborn KR, Applebury CB, Hannegan ET, Bell S, et al: Transsphenoidalmicrosurgery for Cushing's disease: initial outcome and long-term results. J Clin Endocrinol Metab 89:6348-6357, 2004
Editor’s Note: Dr. Lewis Blevins is a neuroendocrinologist who currently serves as the medical director of the California Center for Pituitary Disorders at UCSF in San Francisco, California. He edited a book on Cushing’s Syndrome and has also published several papers on the topic. He spends his free time painting California and Irish landscapes in oil on linen, playing music on the Irish (Uilleann) bagpipes, and writing.
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