Beyond pituitary surgery: Radiosurgery vs. Adrenalectomy vs Medical Treatment when Cushing s disease persists or recurs

1. Beyond pituitary surgery: Radiosurgery vs. Adrenalectomy vs Medical Treatment when Cushing�s disease persists or recurs Theodore C. Friedman, M.D., Ph.D. Ian McCutcheon, M.D. Magic Foundation Symposium on Cushing�s Syndrome February 22, 2009 Las Vegas, NV

2. What to do if the patient is not cured by initial surgery Confirm diagnosis Medical management (Dr. F) Re-operate (Dr. M) Radiation therapy-conventional or high-dose (Dr. M) Bilateral adrenalectomy (Dr. F)

3. Medical treatment for Cushing�s syndrome *Ketoconazole-The best Metyrapone- available on a compassion use basis from company Aminoglutethimide- not sure if available RU486-easy to get adrenal insufficiency and hard to monitor or correct adrenal insufficiency Mitotane-permanent adrenal insufficiency, hard to swallow Trilostane- can be given IV Carbergoline-sporadic Avandia- diabetes medicine-works in a percentage of Cushing�s patients *SOM230-somatostatin analog

4. Ketoconazole Works by blocking several steps in cortisol biosynthesis. May also inhibit pituitary cell growth Has a pretty short half-life-usually given 3X/day Side effect-elevation of liver tests, which is reversible on stopping drug. Liver test abnormalities are more pronounced at higher doses. Check liver tests at baseline and every 3 months

5. Ketoconazole Cushing�s syndrome is a disease of high night time cortisol, some patients have low daytime cortisol. Several options Give 200 mg 1 hr before bedtime to decrease night time cortisol Give 200 mg 3X/day-often lunch, dinner and bedtime Give 800-1200 mg throughout day plus 20 mg of hydrocortisone in the morning Can go up on the dose for severe hypercortisolism

6. Ketoconazole Works in almost all patients Educate patients about adrenal insufficiency Can be used to determine how much of patients symptoms are due to high cortisol. Can be used to get patients healthier prior to surgery. May decrease the drop from high cortisol to normal cortisol I use it often before adrenalectomy (may decrease hyperplasia seen on pathology) Monitor symptoms, UFC (not 17OHS) and serum cortisol Can be used for years with monitoring of liver tests (LFTs) and pituitary tumor Should be gold-standard to compare new drugs

7. SOM230 (Pasireotide) Somatostatin analogue-investigational drug-may shrink tumor and decrease ACTH secretion Boscaro et al. JCEM 2009, 94:115-122 (Dr. Ludlam 2nd author) 15 day open label study-39 patients, 29 completed study and were included in analysis 22/29 (76%) had a reduction in UFC 5/29 had normalization of UFC Decrease in cortsiol and ACTH levels. 92% had side effects Nausea, diarrhea and high blood sugar (36%)!. Does not seem as good as ketoconazole to me.

8. Repeat Surgery/RT Dr. M

9. Adrenalectomy Cures Cushing�s 99% of the time -adrenal rest tissue is very rare Can be done laproscopically Much less mortality than before Can be done one adrenal (larger one) at a time (with radiation after first adrenal) Need lifelong hydrocortisone, fludrocortisone and probably DHEA Higher risk of adrenal insufficiency than if hypopituitarism Bracelet and solucortef, emergency letter, nausea meds. Most of my patients have done well with adrenalectomy Still I recommend pituitary surgery over adrenalectomy as most pituitary patients are off most medicines in one year.

10. Adrenalectomy-Nelson�s syndrome Absence of glucocorticoid feedback can in theory cause pituitary tumors to grow unchecked Leads to pituitary tumor growth, high ACTH levels (< 1500 pg/mL is probably normal) and hyperpigmentation. Happens more frequently in aggressive, rapidly growing tumors, most of my patients have slow growing tumors Need to monitor pituitary tumor by MRI yearly-if tumor grows, need surgery Pituitary radiation probably decreases likelihood of Nelson�s syndrome

11. Adrenalectomy vs RT I usually recommend adrenalectomy as most of my patients want an immediate cure and can�t wait the time for RT to kick in Exception, someone well controlled on ketoconazole Aggressively growing pituitary tumors may also lead me to RT How hypopit they are affects the decision, if already hypopit, I�m less worried about RT. Some patients get both RT and adrenalectomy

12. Cushing�s Syndrome It�s not so rare Lets get better �A topic not addressed is that many patients who are obese, depressed, hypertensive, or diabetic have �researched� the Internet and are convinced they have CS.�-Another Prominent Endocrinologist. I like patients to research the Internet and become informed. Lets educate everyone