Cushing disease affects an estimated 10 to 15 individuals per million population globally, with a higher prevalence observed in females compared with males.1 The disease is associated with significant morbidity and mortality, highlighting the importance of timely and effective treatment.1,2 For most patients, transsphenoidal surgery represents the optimal treatment strategy, with remission rates of approximately 90% in patients with microadenomas (<1 cm in largest diameter) and 65% in patients with macroadenomas (≥1 cm in greatest diameter) when the procedure is performed by an experienced neurosurgeon.2

In cases of persistent or recurrent disease after transsphenoidal surgery, a second surgery may be a feasible option. Remission rates of 55% to 70% have been reported in patients who undergo repeat transsphenoidal surgery and findings suggest that the risk for surgical complications may be elevated compared with the initial surgery.2 Patients who do not respond to transsphenoidal surgery, or for whom the surgery is contraindicated or undesired, may benefit from second- and third-line treatment strategies, including radiation therapy to the sella with interim medical therapy or bilateral adrenalectomy. These approaches are associated with endocrine remission rates of 28% to 84% and >95%, respectively.2,3

To learn more about the management of Cushing disease after transsphenoidal surgery, Endocrinology Advisor interviewed the following experts: Nicholas A. Tritos, MD, DSc, staff neuroendocrinologist at the Neuroendocrine and Pituitary Tumor Clinical Center at Massachusetts General Hospital in Boston, Massachusetts, and associate professor of medicine at Harvard Medical School; Laurence Katznelson, MD, neuroendocrinologist and professor of neurosurgery and medicine (endocrinology) at Stanford University Medical Center in Palo Alto, California; and Maria Fleseriu, MD, FACE, professor of medicine (endocrinology and neurological surgery) and director of the Pituitary Center at Oregon Health & Science University in Portland, Oregon.

Endocrinology Advisor: What are key ways to optimize outcomes after transsphenoidal surgery, and is there a way to predict which patients are likely to have a recurrence? 

Nicholas A. Tritos, MD, DSc: The most important way to optimize surgical outcomes in patients with Cushing disease is to refer them to experienced pituitary neurosurgeons. Many factors have been suggested as being predictive of recurrence; among them, very low morning cortisol levels (<2 µg/dL) after surgery and prolonged requirement for glucocorticoid replacement (>1 year) postoperatively predict a lower recurrence risk. In addition, a variety of stimulation and suppression tests have been suggested as being predictive of recurrence risk. No test is 100% predictive of sustained remission or recurrence, and all of these patients require lifelong follow-up.

Laurence Katznelson, MD: There are a number of techniques used to determine surgical success. Most rely on the fact that following successful surgery for Cushing disease, cortisol levels should fall dramatically, reaching levels consistent with adrenal insufficiency. There are studies showing that the lower the fall in serum cortisol and adrenocorticotropic hormone (ACTH), the greater the chance of long-term remission.4

Different postoperative protocols include withholding peri- and postoperative steroids followed by measurement of serial or morning cortisol vs administration of steroids following surgery, and once doses are tapered, measurement of cortisol via blood or urine testing. In active Cushing disease, there is an exaggerated response of cortisol to stimulation, such as with either desmopressin or corticotropin-releasing hormone. Hence, a persistently abnormal response to such stimuli following surgery may also suggest incomplete surgery.  

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Maria Fleseriu, MD, FACE: Transsphenoidal surgery is the first-line treatment for a large majority of patients with Cushing disease. Some patients, especially in Europe, undergo primary medical treatment for Cushing disease with variable biochemical results, but it does not seem to improve subsequent rates of biochemical normalization after surgery. There have been many advances in surgery since the Harvey Cushing era, with better visualization overall of the pituitary fossa and sphenoid sinus. The endoscope has a panoramic view and achieves better visualization compared with the operating microscope; however, large studies — albeit mostly retrospective — did not show clear differences in biochemical rates of remission with the endoscope vs operative microscope.5

Many groups, including ours [at Oregon Health & Science University], have tried to establish preoperative predictive factors for nonremission, but there is no clear evidence yet. Failure of remission seems to occur when a pituitary adenoma is incompletely removed or missed at surgical exploration and in cases of dural invasion or adenoma outside the pituitary gland. Repeat surgery is one of the second-line options for patients with persistent hypercortisolism; however, remission rates are lower — approximately 50% — and hypercortisolemia can recur in approximately one-quarter of cases. Delayed remission is a small possibility, thus repeat surgery, if chosen, should be postponed until persistent disease is confirmed.

Endocrinology Advisor: What is the recommended course of management for Cushing disease that persists after surgery? 

Dr Tritos: A second pituitary operation can be considered in these patients, especially if there is a visible tumor or a more experienced neurosurgeon is available. Another commonly chosen treatment strategy involves radiation therapy to the sella with interim medical therapy. Bilateral adrenalectomy is another option that will generally lead to cure of hypercortisolism, but carries the risks associated with Addison disease and corticotroph tumor progression/Nelson syndrome. There are several medical therapies in development that may control cortisol excess, but none are curative.

Dr Katznelson: If initial surgery for Cushing disease is unsuccessful and there is demonstration of persistent hypercortisolism, the next step is usually consideration of repeat surgery. Second surgery typically involves a more aggressive approach, including hemi-hypophysectomy. If this procedure is unsuccessful, the next step often involves medical therapy. Although a number of potential medical therapies are available, only 2 are approved by the United States Food and Drug Administration: pasireotide (a somatostatin analog that targets the tumor) and mifepristone (a glucocorticoid receptor antagonist that blocks cortisol systemically).