A previous issue of this newsletter covered the first line treatment options for Cushing’s disease and Cushing’s syndrome as outlined in the recently published Endocrine Society guidelines. This summary will discuss the options for treatment in cases of recurrent or persistent Cushing’s disease or in patients where surgery is not an option.

Cushing’s Disease

Reported cure rates for initial surgery performed by experienced surgeons is 73-76% for microadenomas and 43% for macroadenomas. Thus, some patients experience an unsuccessful first surgery. Of patients who achieve remission after a first surgery, one series reported recurrence in 23% of patients with microadenomas and 33% of patients with macroadenomas. Because recurrence can occur long after successful surgery, patients should be monitored with cortisol levels every year.

Options for treatment following unsuccessful surgery or a recurrence include repeat pituitary surgery, radiation therapy, medical treatment and bilateral adrenalectomy. Treatment decisions should take into account the patient’s preference, treatment goals, size and location of residual tumor, other medications, treatment side effects, gender and age, cost of medications, etc.

Repeat Pituitary Surgery

Repeat pituitary surgery is suggested in patients with evidence of incomplete tumor removal or a pituitary tumor visible on imaging. In one series, early repeat pituitary surgery following an unsuccessful surgery resulted in remission in 12/17 patients (71%) in patients with tumors found during the initial surgery. In cases of recurrence, one series reported that 22/31 (71%) patients experiencing a recurrence, achieved remission with another pituitary surgery. Repeat pituitary surgeries result in a lower remission rate than initial surgery and carry an increased risk for loss of normal pituitary function for other pituitary hormones (hypopituitarism).

Radiation Therapy

Radiation of the pituitary gland or tumor is another treatment option. Radiation may be used as a first line treatment in patients who are not candidates for surgery or have large invasive tumors that cannot be completely removed. Radiation therapy is most usually used for persistent Cushing’s or in cases of a recurrence. All types of radiation require time (months or years) to normalize cortisol levels. While waiting for the radiation to become effective, it is necessary to control the patient on medical therapy. It is recommended that medications be used to control the hypercortisolism prior to undertaking radiation therapy, to ensure that control can be achieved while awaiting the results of radiation.

Several radiation treatments are available. Conventional radiation therapy delivered over a period of 6 weeks results in remission in up to 83% of adult patients from 6-60 months after treatment, usually within 2 years. Children usually experienced remission in 9-18 months.

Stereotactic radiation therapy, also referred to as radiosurgery, requires only one treatment. Radiosurgery delivery systems include Gamma knife, linear accelerator and proton beam. Radiosurgery is administered by placing the patient in a frame to correctly position the patient and computer assisted planning and MRI is used to identify the treatment area. The radiation is delivered through many ports and precisely focused. At least several millimeters are needed between the targeted area and optic structures to avoid subsequent vision problems. Compared to conventional radiotherapy, radiosurgery may result in more rapid biochemical control and less damage to surrounding structures; however this has not been unequivocally demonstrated. Radiosurgery can be used in patients with a clear tumor area or in patients without identified tumor on imaging, in which cases, the entire sella is targeted. Presently, there are no direct comparisons of remission rates between these approaches. Radiosurgery has been shown to yield remission results similar to conventional radiotherapy.

Following radiotherapy or radiosurgery, it is recommended that patients stop their cortisol-reducing medication every 6-12 months so either a 24hr urine or serum cortisol can be obtained off medication to determine when the radiation is taking effect. This should be done sooner in patients experiencing symptoms of adrenal insufficiency.

Following any type of radiation, some patients do not achieve a normal diurnal rhythm. 24 hr urine cortisol may be normal, but late night salivary cortisol may continue to be elevated and cannot be used to determine control of cortisol. Also, recurrences are observed, so patients achieving remission with any type of radiation need to be followed annually.

Ectopic Tumors

Once located, ectopic tumors (non-pituitary ACTH secreting tumors) causing Cushing’s syndrome can be surgically removed with one reported remission rate of 76%. However, some ectopic tumors are very small and cannot be found on imaging. These patients require additional treatment options to normalize cortisol levels. Some ectopic tumors can be metastatic, which complicates surgical treatment.

Medical Treatment for Persistent Cushing’s Disease and Ectopic Tumors

Medical therapy for Cushing’s syndrome of any cause has improved over the last several years. Medical therapy is appropriate for any patient who has persistent hypercortisolism after transsphenoidal surgery, any patient who is not a surgical candidate, and cases of ectopic Cushing’s where the tumor cannot be located or is metastatic.

Medical treatments available include:

1. Medications that work at the level of the adrenal gland to decrease cortisol production
2. Medications that target the pituitary corticotropes to decrease ACTH production
3. Medication that blocks the action of cortisol at the glucocorticoid receptor

Because adrenal insufficiency can occur in any patient receiving medical therapy, patients need to be educated about adrenal insufficiency and closely monitored. Medication side effects can overlap with adrenal insufficiency symptoms. Medical therapy can be used to reduce cortisol to normal levels or to reduce cortisol to undetectable or very low levels. The latter strategy, referred to as “block and replace,” requires that patients receive cortisol replacement. Medication that blocks the action of cortisol at its receptor does not reduce cortisol levels, so titration of the dose is based on cortisol-dependent parameters, such as blood glucose in a diabetic.

Medications That Inhibit Cortisol Production

This category of medications includes ketoconazole, metyrapone, mitotane and etomidate.

Ketoconazole: Ketoconazole has been used to treat Cushing’s syndrome for many years, however, it is used off-label for this purpose and is not FDA (or EMA) approved for this use. The FDA has issued a “black box” warning due to abnormal liver enzyme levels and rare severe liver dysfunction. Mild elevations of liver enzymes occur in approximately 10-15% of patients, usually when starting the medication or after a dose increase. In these cases, levels usually return to normal 2-4 weeks after stopping ketoconazole. If enzyme levels are increased less than 3-fold, most clinicians will continue treatment, and monitor frequently. Cases of severe liver injury are estimated to occur in one in 15,000 patients and the medication should be stopped.

Ketoconazole has a rapid onset of action and decreases cortisol to normal levels in approximately 75% of patients with Cushing’s disease and 44% of those with ectopic tumors. Refer to complete guideline for further discussion.

Metyrapone: Metyrapone also acts at the adrenal gland to inhibit cortisol production. Studies indicate that metyrapone controls cortisol levels in 50-75% of patients. Side effects most usually occur when the medication is initially started or when the dose is increased. The most common side effect, gastrointestional irritation, is usually corrected by taking the medication with food. Women may find increased facial hair undesirable and acne may be observed. Patients also need to be monitored for low potassium levels, swelling and hypertension. Metyrapone causes an increase in some compounds that can cross-react in some laboratory methods of cortisol measurements, usually immunoassays. As a result, specific assays should be used.

Mitotane: In the United States, mitotane is usually reserved for treatment of adrenal cancer. Mitotane can normalize cortisol levels, but has a slow onset of action, so that this may not occur for six months. While mitotane has been shown to be effective in 72-82% of patients with Cushing’s disease, side effects often lead to discontinuation

Etomidate: Etomidate can be used in an emergency situation to rapidly decrease cortisol levels. Etomidate is administered intravenously and patients require extremely close monitoring in an ICU. Etomidate is used primarily in seriously ill patients who cannot take oral medications and who have acute unmanageable symptoms such as respiratory failure or severe psychosis.

Pituitary-Directed Medications

Pituitary corticotrope tumors have several types of cellular receptors that are involved in ACTH production. Blocking these receptors can decrease ACTH production, thus controlling cortisol levels. These medications are generally not effective in adrenal causes of Cushing’s syndrome and their effects on ectopic ACTH-producing tumors has not yet been determined. These medications include Pasireotide and Cabergoline.

Pasireotide: Pasireotide is FDA approved for treatment of Cushing’s disease patients who are not surgical candidates or have had an unsuccessful transsphenoidal surgery or recurrence of a pituitary tumor. In a phase 3 clinical trial, pasireotide normalized urine cortisol in 20% of 162 patients. Blood pressure, triglycerides, cholesterol, weight and health-related quality of life also improved. Normalization of cortisol occurs within the first 1-2 months. Tumor volume was decreased by 44% in 75 patients with visible tumors on MRI. The side effect of most concern with pasireotide is an elevation of blood sugar. High blood sugar occurred in 73% of patients.

Cabergoline: Cabergoline targets a different receptor than pasireotide in the pituitary tumor. Cabergoline is not FDA approved for the treatment of Cushing’s disease, but is commonly used to treat prolactin secreting pituitary tumors. In small studies, 30-40% of patients with Cushing’s disease were controlled long term on cabergoline. However, up to 29% of patients re-develop increased cortisol levels over time. Blood pressure and blood sugar improved and tumor volume decreased or stayed the same in the small number of patients with a visible tumor on MRI. Side effects include nausea, dizziness and asthenia. There has been one reported heart problem with cabergoline use in Cushing’s syndrome patients.

Cortisol Receptor Blockade – Mifepristone

Mifepristone is FDA approved for the treatment of Cushing’s syndrome in patients with diabetes or high blood sugar who are not surgical candidates or have had a failed transsphenoidal surgery. Mifepristone acts by blocking the cortisol receptor (a protein in cells), which in turn blocks the cellular effects of cortisol. Cortisol remains elevated and in some cases increases, thus cortisol cannot be used to determine appropriate medication doses. Rather, symptoms are monitored. In one study, mifepristone led to improvements in blood sugar in 60% of patients and blood pressure improved in 40%. ACTH increased more than 2 fold in 31/43 patients with Cushing’s disease. Three pituitary macroadenomas increased in volume and one decreased in size. Side effects included fatigue, nausea, vomiting, aches, and headaches. Hypertension, swelling and low potassium were also observed as was vaginal bleeding.

Combination Therapy

Some medications can be combined if cortisol normalization is not achieved with the use of a single medication. Ketoconazole and metyrapone are often combined in cases of severe hypercortisolism. Cabergoline also has been combined with ketoconazole and pasireotide. Additional trials of combination therapy are needed.

Targeted Medical Therapy for Ectopic Cushing’s

Several case studies have shown that octreotide can achieve short to mid-term control of hypercortisolism caused by ectopic ACTH-producing tumors, but without affecting tumor volume. Cabergoline also has been used with some success or in combination with octreotide. In cases of ectopic ACTH secreting metastatic thyroid cancer, a class of medication termed tyrosine kinase inhibitors successfully controlled hypercortisolism in a few patients.

Bilateral Adrenalectomy

Surgical removal of both adrenal glands can be suggested in cases of unidentified or metastatic ectopic tumors or in situations of life threatening illness. Patients with ectopic Cushing’s should continue to be imaged for ectopic tumors. Pituitary imaging is also suggested as some of these patients may have a pituitary tumor.

Bilateral adrenalectomy in patients with Cushing’s disease may result in increased ACTH and tumor progression. Nelson’s syndrome, characterized by increased ACTH levels, darkening of the skin, and growth of the pituitary tumor, may develops in patients with Cushing’s disease following bilateral adrenalectomy. The rate of progression to Nelson’s syndrome is controversial, but may be about 20%. The risk is greatest in those patients with a visible tumor on MRI. Tumor progression that does not include all of the components of Nelson’s syndrome is observed in an additional 50% of patients. It is unclear whether radiation prior to adrenalectomy decreases the occurrence of Nelson’s. Patients should be monitored for ACTH levels, hyperpigmentation and tumor enlargement for life.

Conclusion

While surgery is in general the optimal treatment of Cushing’s syndrome, a variety of other modalities are available for patients in whom surgery is not possible or is unsuccessful, or in patients who recur. In patients with Cushing’s disease, choices include forms of radiation treatment, repeat surgery, medical treatment or bilateral adrenalectomy. In patients with ectopic ACTH secretion, choices include medical treatment or bilateral adrenalectomy. In all cases, the choice of second line therapy is individualized to the patient’s unique circumstances.

By Dr. Lynnette Nieman, Summer, 2016

Editor’s Note: Dr. Lynnette Nieman, NIH, NICHD, Bethesda, MD chaired the task force which also included Beverly M.K. Biller of Massachusetts General Hospital in Boston, MA; James W. Findling of the Medical College of Wisconsin in Milwaukee, WI; M. Hassan Murad of the Mayo Clinic in Rochester, MN; John Newell-Price of the University of Sheffield in Sheffield, U.K.; Martin O. Savage of the William Harvey Research Institute at Barts and the London School of Medicine and Dentistry in London, U.K.; and Antoine Tabarin of CHU de Bordeaux and INSERM at the University of Bordeaux, Bordeaux France. The guideline was published in the August issue of the Journal of Clinical Endocrinology and Metabolism. The CSRF believes that this guideline will assist in the transfer of knowledge from experts in Cushing’s to other endocrinologists with less experience, resulting in better patient care. You might want to let your physicians know about this important guideline.