Magic Conference: Cushing’s Disease, Are We Closer to Medical Therapies?

MEETING NOTES : Dr. Heaney

Meeting Created: July 20, 2012 3:18 PM

Lombard

Cushing’s Disease, Are We Closer to Medical Therapies?

A significant proportion of patients with Cushing's Disease are not cured by primary surgical
treatment, the disease is prone to relapse and significantly damages quality of life. Adjuvant
radiotherapy is an increasingly unattractive option for clinicians who wish to spare their
patients hypopituitarism and other potential complications. Some pharmacological options are
currently available but tend to have dose-limiting side effects. New agents recently approved or
under investigation will be discussed and strategies to select the optimal drug or drug
combination for individual patients reviewed. 

Dr Anthony Heaney

Cushings

• Iatrogenic 1% taking oral steroids
• Creams, inhaled, parental, rectal, articular

Endogenous, 2-3/million a year

• Pituitary-dependent (75%), ACTH secretion

Ectopic ACTH, CRH secretion 

At risk populations for Cushing's?

• Adrenal incedentaloma. 9.2% have Cushing's

Why treat?

• Increased mortality, survival 4.6 years untreated
• Quality of life
• Improve blood pressured and bone density

Clival chordoma?  (look this up later) Clivus bone behind pituitary. http://en.wikipedia.org/wiki/Clivus_(anatomy)

Surgery is first-line therapy

• Experienced surgeon
• 65-90% remission
• Large tumors is less than 65%
• Success rate for repeat surgery is lower
• Reoperation has greater risk for pituitary damage
• Microadenoma 5-10% risk of remission at 5 years
• 30% don't get remission

Radiation

• Control, in 50-60 %
• Relapse possible
• Nelson's
• Can take a long time to control symptoms

Medical therapy

• Ketoconazole: antifungal, lowers testosterone and cortisol.  Several side effects, no impact on pit tumor, adjust dose over time
• Metyrapone: side effects.  Can be used in pregnancy, clinical trials coming soon, no impact on pituitary tumor, dose adjusted over time
• Mitotane
• Pasireotide, control within 1-2 months or not at all, decrease in BP and UFC.  Hyperglycemia.  Some patients discontinued due to that
• Korlym, trying to find correct dose, not an accurate assessment of adrenal insufficiency.  May need sprolactone for hypokalemia?  Blocks all cortisol, need to monitor.  Korlym reps say it's only blocking number 2 receptor.  Could become hyper adrenal/adrenal crisis.  It's a challenge.  Blocks progesterone receptor-termination of pregnancy, pregnancy tests, unopposed estrogen can cause hypertrophy of uterus and unexplained vaginal bleeding
• Combination therapy. Start with pasireotide, then add Cabergoline, then Keto.  Possible AI but can measure cortisol with these drugs
• LCI 699 originally for high BP. Normalized UFC in 11 of 12 Cushies.  US study

Advantages

• No/less surgery
• Gradual reduction of cortisol. Is that better?
• Life-long therapy

Somatostatin action in Cushing's

Normalizing UFC

Orphan disease has major pharmacy attention-we are getting closer?