Beyond pituitary surgery: Radiosurgery vs. Adrenalectomy vs Medical Treatment when Cushing

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Beyond pituitary surgery Radiosurgery vs.
Adrenalectomy vs Medical Treatment when Cushings
disease persists or recurs

• Theodore C. Friedman, M.D., Ph.D.
• Ian McCutcheon, M.D.
• Magic Foundation
• Symposium on Cushings Syndrome
• February 22, 2009
• Las Vegas, NV

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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)

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Medical treatment for Cushings 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 Cushings patients
• SOM230-somatostatin analog

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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

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Ketoconazole

• Cushings 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

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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

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SOM230 (Pasireotide)

• Somatostatin analogue-investigational drug-may
  shrink tumor and decrease ACTH secretion
• Boscaro et al. JCEM 2009, 94115-122 (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.

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Repeat Surgery/RT

• Dr. M

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Adrenalectomy

• Cures Cushings 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.

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Adrenalectomy-Nelsons syndrome

• Absence of glucocorticoid feedback can in theory
  cause pituitary tumors to grow unchecked
• Leads to pituitary tumor growth, high ACTH levels
  (lt 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 Nelsons syndrome

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Adrenalectomy vs RT

• I usually recommend adrenalectomy as most of my
  patients want an immediate cure and cant 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, Im less worried about RT.
• Some patients get both RT and adrenalectomy

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Cushings Syndrome

• Its 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

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