Theodore C. Friedman, M.D., Ph.D. (the Wiz) Professor of Medicine-UCLA Chairman, Department of Internal Medicine Charles R. Drew University Dr. Friedman’s Endocrinology Clinic What to do when Cushing’s symptoms return? MAGIC Adult Convention Chicago, IL July 22, 2016

What to do if the patient is not cured by initial surgery or cured and then symptoms returns? How do you tell if you are cured? Recurrence vs never cured Confirm diagnosis Re-operate Medical management Bilateral adrenalectomy (BLA) Radiation therapy-conventional or high-dose

Are you cured? Hard to tell In sustained pre-op hypercortisolism, normal corticotrope cells are suppressed. Cure used to be morning cortisol < 4 ug/dL When tumor is removed, ACTH and cortisol are low post-op In episodic Cushing’s, this often doesn’t occur. Surgeon usually discharges patients on hydrocortisone. I recommend geting a 8 am cortisol, ACTH and electrolytes on day 5 after holding hydrocortisone replacement for 24 hr.

Cushing’s disease: postop considerations Patient who feels bad postop (achy, nauseous) is more likely cured than one who feels well Watch for frank adrenal crisis Cure of cortisol excess may unmask other diseases suppressed by steroids

Are you cured? The lower the day 5 cortisol the more likely the cure. Morning cortisol is often in the ug/dL range and patient is still cured. Cortisol above 20 ug/dL or ACTH above 30 are bad signs.

Symptoms of cure Cortisol levels drop from high to normal, leads to relative glucocorticoid insufficiency Joint pains, abdominal pain, weakness, nausea, vomiting, headache and “hit by a speeding truck” are signs of relative low cortisol and good signs. Low sodium is common post-op and also gives headache and nausea (measure sodium on day 5) Psychological and psychiatric symptoms (depression, anxiety) may get worse after surgery due to low brain CRH levels and patients (and spouses) should be warned.

Why would you be uncured? Part of the tumor left behind- a few cells or one arm of the octopus Multiple tumors and only one removed. Incidentaloma removed, ACTH secreting tumor left behind Invasion outside of sella Misdiagnosed. If uncured, taper of hydrocortisone, re-document hypercortisolism and consider repeat surgery. Hyperplasia –entire gland involved

Pathology Classic Cushing’s patients have clear tumors that stain for ACTH. Crooke’s hyaline change occurs with sustained pre-op hypercortisolism. Episodic patients may or may not be hypercortisolemic at the time of surgery, so staining for ACTH may be negative (tumor not active) Tumors are often tiny and either discarded by suction or missed by pathologist. I have never seen Crooke’s hyaline changes in any of my patients Most of my patients have unclear or negative pathology in spite of being cured. Several patients showed adrenal hyperplasia and enlarged adrenals when they went for adrenalectomy, yet had normal pituitary pathology.

The nondiagnostic operation Specimen typically small, frozen section is unreliable Tumor may disappear into the suction Pathologist may be unfamiliar with pituitary disease Lesion may be truly occult Look for Crooke’s hyaline changes in normal gland (occasionally in tumor too)

Pathology-Hyperplasia Classic corticotrope hyperplasia was described in Russia and involves the corticotrope cells in the whole pituitary being enlarged and suggests an abundance of CRH. What we see is a small pocket of ACTH-staining cells that are larger than normal corticotrope cells, but not a clear tumor. My guess is this is an early tumor. Often see multiple tumors connected by a barbell or an octopus with 8 arms. In some cases, there is a tumor of ACTH-staining cells on one side and hyperplasia adjacent to it. Patients with hyperplasia due worse, but can still be cured with more aggressive pituitary surgery.

Corticotroph hyperplasia ? Intermediate stage preceding adenoma formation Can cause clinically significant cortisol excess Surgical resection may require removal of part of normal gland as margins may be indistinct Recurrence rate unknown Difficult to cure with surgery alone

Recurrence of Cushing’s disease (Dr. McCutcheon’s data) 10-30% are not cured by surgery –90% with microadenoma go into remission 10-15% of those “cured” will relapse over 10 years of followup Reoperation induces remission in: –73% overall –90% if discrete adenoma found –41% if no adenoma found

Other pituitary hormones Surgery can damage pituitary cells. High cortisol also suppresses pituitary function-cure from Cushing’s can improve pituitary function Order of susceptibility of pituitary cells GH LH, FSH leading to low estradiol (irregular periods) and testosterone TSH ACTH AVP At 2 months, I check IGF1, freet4, free T3, TSH, testosterone If low IGF1, especially compared to pre-op, I do GH stimulation testing- glucagon stimulation test Hypothyroidism or growth hormone deficiency can look like uncured Cushing’s and should be looked for.

Uncured-what do next Re-document hypercortisolism Reconfirm pituitary source Repeat pituitary MRI- “post operative changes” may mean recurrent tumor If visible pituitary tumor, repeat surgery. If no visible tumor, consider ketoconazole or other medications to decrease cortisol synthesis (hear Dr. Heaney’s talk tomorrow). Consider repeat surgery, scrapping the cells at the edge of the tumor Consider adrenalectomy or radiation therapy

Recurrence If symptoms/high cortisol recur: –Repeat testing including MRI of sella If true recurrence, consider: –Repeat surgery (50-60% success)-I recommend if pituitary tumor is seen. –Medical treatments: Drugs (ketoconazole, Korlym. metyrapone, cabergoline, SOM230 etc.) Adrenalectomy Radiosurgery

Hemihypophysectomy: yes/no? If no tumor found, do hemiremoval (40%), ?guided by petrosal lateralization Rigorous analysis of specimen –Only 20% will show tumor Retest patient –If cortisol still high, consider: False localization to sella Reoperation and total hypophysectomy Radiosurgery or limited-field irradiation (conformal, IMRT)

Medical treatment for Cushing’s syndrome *Ketoconazole-In my opinion, the best Korlym (RU486)-can get adrenal insufficiency and hard to monitor or correct adrenal insufficiency Metyrapone- available on a compassion use basis from company Aminoglutethimide- not sure if available Mitotane-permanent adrenal insufficiency, hard to swallow Trilostane- can be given IV *Cabergoline-sporadic *Paseriotide-somatostatin analog

Ketoconazole Off-label use, not FDA approved for Cushing’s syndrome. Works by blocking several steps in cortisol biosynthesis. May also inhibit pituitary cell growth Has a pretty short half-life-6-8 hrs-I often give it at night as Cushing’s disease is marked by high cortisol at night. Side effect-elevation of liver tests, which is reversible on stopping drug. Liver test abnormalities are more pronounced at higher doses-> 1200 mg. Check liver tests at baseline and every 2-3 months

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 and 3 hr before bedtime to decrease night time cortisol –Give 200 mg 3X/day-often lunch, dinner and bedtime –Give mg throughout day plus 20 mg of hydrocortisone in the morning –Can go up on the dose for severe hypercortisolism –I usually give patients some 5 mg pills of hydrocortisone to be taken in the AM, if symptoms of adrenal insufficiency (nausea, vomiting, diarrhea, abdominal pain, achy).

Ketoconazole Works in almost all patients Educate patients about adrenal insufficiency Interacts with drugs, especially statins. Rarely, long QT interval on EKG 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 post-op 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

Cabergoline The D2-receptor agonist, cabergoline, at doses of 0·5–7 mg/week, leads to long-term biochemical remission in about 30% of patients. Side effects include nausea, headache, and dizziness; cardiac valve fibrosis seen was not noted in doses given to patients with Cushing’s disease. This treatment represents an off –label use of the drug.

Korlym (Mifepristone) Mifepristone is a glucocorticoid and progesterone receptor antagonist that can ameliorate the signs and symptoms of Cushing’s syndrome. Because it increases ACTH and cortisol concentrations in patients with Cushing’s disease, clinical cortisol-dependent variables (hyperglycemia and hypertension) need to be used to adjust the dose. The absence of a measurable marker makes it hard to monitor. Adverse events include symptoms of cortisol insufficiency (fatigue, nausea, vomiting, arthralgias, and headache), increased mineralocorticoid effects (hypertension, hypokalaemia, and oedema), and antiprogesterone effects (endometrial thickening) Mifepristone is approved in the USA for the treatment of hyperglycemia related to Cushing’s syndrome in non-surgical candidates. My second choice.

SOM230 (Pasireotide) Pasireotide is a somatostatin receptor ligand. FDA approved A trial of 162 patients showed that subcutaneous pasireotide at a dose of 600 μg or 900 μg twice a day normalized UFC production in 15% of patients receiving the 600 μg dose and 26% of patients receiving the 900 μg dose. Hyperglycemia occurred in 73% of patients. Does not seem as good as ketoconazole to me.

Adrenalectomy Cures Cushing’s 95% of the time –but we have 7 of 50 patients with adrenal remnant tissue Can be done laproscopically-even through belly button-no scar! Much less mortality than before Can be done one adrenal (larger one) at a time 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.

Adrenalectomy Rate of remission: % Done laparoscopically Must remove both adrenals completely Risk of subsequent adrenal crisis: – < 1 yr after surgery: 36% – > 1 yr after surgery: 44% Thus, vigilance is required

Problem: adrenal remnant We have 7/50 patients with BLA who developed adrenal remnant tissue. One was cured by ethanol ablation One was cured by removal of remnant tissue (I think) One had RT to her pituitary, and is making just the right amount of cortisol and doesn’t need hydrocortisone or fludrocortisone replacement.

Problem: adrenal remnant CT with contrast of adrenal remnant tissue measuring 11.2 mm by 4.5 mm. CT posterior approach ethanol ablation of residual adrenal tissue.

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

Who might get adrenalectomy 39 yr old woman with Cushing’s x 1 yr TSS removed corticotroph hyperplasia High cortisol persisted, but MRI was normal Chose BLA as relief more immediate

Who might get radiosurgery 33 yo woman Cushing’s x 13 yr TSS in 2004 and again in 2007 Cortisol never normalized Scarring will make removal difficult

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

How to decide? Radiosurgery Takes a year to work Dependent on highly technical factors for efficacy Works best with defined target Chance of losing hormone function depends on target size / dose Adrenalectomy Effect on tumor more immediate Effect on cortisol more immediate, hence risk of Addisonian crisis and need for immediate cortisol replacement Risk of Nelson’s Either method can fail!

Risks of RT Tumor effects –edema –Hemorrhage Injury to nearby structures –optic nerves or chiasm –temporal lobe(s) of brain Injury to distant structures –scalp hair loss

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Thanks Magic Foundation for inviting me and doing great work! Great job Dianne