Download What To Do When Cushing`s Returns

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?
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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?
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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?
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The lower the day 5 cortisol the more likely the cure.
Morning cortisol is often in the 10-15 ug/dL range and
patient is still cured.
Cortisol above 20 ug/dL or ACTH above 30 are bad
signs.
Symptoms of cure
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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?
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Part of the tumor left behind- a few cells or one arm of
the octopus
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Multiple tumors and only one removed.
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Incidentaloma removed, ACTH secreting tumor left
behind
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Invasion outside of sella
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Misdiagnosed.
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If uncured, taper of hydrocortisone, re-document
hypercortisolism and consider repeat surgery.
• Hyperplasia
– entire gland involved
Pathology
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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
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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
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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
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GH
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LH, FSH leading to low estradiol (irregular periods)
and testosterone
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TSH
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ACTH
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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
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Reconfirm pituitary source
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Repeat pituitary MRI- “post operative changes” may
mean recurrent tumor
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If visible pituitary tumor, repeat surgery.
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If no visible tumor, consider ketoconazole or other
medications to decrease cortisol synthesis (hear Dr.
Heaney’s talk tomorrow).
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Consider repeat surgery, scrapping the cells at the edge
of the tumor
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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 800-1200 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
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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: 90-100%
• 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
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
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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
Adrenalectomy
• Takes a year to work
• Effect on tumor more
immediate
• Dependent on highly
technical factors for
• Effect on cortisol more
efficacy
immediate, hence risk
of Addisonian crisis and
• Works best with defined
need for immediate
target
cortisol replacement
• Chance of losing
• Risk of Nelson’s
hormone function
depends on target size /
dose
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
Visit goodhormonehealth.com
• For more information or to schedule an
appointment.
• Talk will posted in a few days
• [email protected]
Thanks
• Magic Foundation for inviting me
and doing great work!
• Great job Dianne