Recurrent Cushing’s Disease -...
Transcript of Recurrent Cushing’s Disease -...
Recurrent Cushing’s Disease (CD):
How big is the problem and what are our options?
Beverly MK Biller, MDProfessor of Medicine
Harvard Medical School
Neuroendocrine Clinical Center
Massachusetts General Hospital
Boston, MA
PI of research grants from Cortendo & Novartis to MGH
Occasional consulting for Cortendo, Novartis
Slides will indicate investigational medications (includes those available for other indications but not approved for Cushing’s)
Disclosure of potential relevant conflicts
of interest and non-approved medications
Cushing’s disease (CD) Case 1
- 36 year old pregnant woman with
• facial rounding
• hypertension
• fungal infections
- Cushing’s syndrome later
diagnosed with high urine free
cortisols (UFCs)
- ACTH not suppressed
- Head MRI ? small right lesion
- Inferior petrosal sinus
sampling centralized
Clear clinical and biochemical features of CS; testing points to pituitary
Patient
photo
Cushing’s disease (CD) Case
Before
surgery
~8 years after
surgery;
Moved to AZ
• 36 year old with CD pituitary surgery by expert surgeon
very low cortisol levels post-op
• In remission good clinical improvement, euthyroid, eugonadal,
normal growth hormone axis
• HPA axis recovered in ~1 year off glucocorticoids
Patient
photo
Patient
photo
Case 2
- 27 yo F with CD diagnosed after pregnancy
- MRI showed 1cm macroadenoma
- Pituitary surgery 2011 levels normal (not low)
- Good clinical improvement over the next year
Patient
photos
Cushing’s disease (CD) Cases
What are their chances of recurrence?
We used to say 5-10% of CD cases recur, but
Swearingen Ann Int Med 1999
Patient
photos
0
Valassi 2010 (n=620)
Alwani 2010 (n=79)
Jagannathan 2009 (n=261)
Fomekong 2009 (n=40)
Atkinson 2008 (n=42)
Jehle 2008 (n=193)
Prevedello 2008 (n=167)
Xing 2008 (n=266)
Carrasco 2008 (n=68)
Romanholi 2008 (n=57)
Patil 2008 (n=215)
Rollin 2007 (n=108)
Pouratian 2007 (n=111)
Acebes 2007 (n=44)
Shah 2006 (n=65)
Hoffmann 2006 (n=100)
Esposito 2006 (n=40)
Atkinson 2005 (n=63)
Hammer 2004 (n=289)
Rollin 2004 (n=41)
Pereira 2003 (n=78)
Chen 2003 (n=174)
Flitsch 2003 (n=147)
Shimon 2002 (n=82)
Rees 2002 (n=54)
Barbetta 2001 (n=68)
Chee 2001 (n=61)
Imaki 2001 (n=49)
10 20 30 40 50 60 70 80 90 100
Patients (%)
Remission
Recurrence
Recurrence rates wereas high as 27%!
Studies in the last 5 years have shown even higher rates
Most are from expert centers
Recurrent Cushing’s after transsphenoidal surgery(28 studies with varied definitions of biochemical control, follow up, number of subjects)
(70-90% with expert surgeon)
• 2012 new diabetes (DM), weight
gain, ↑ blood pressure
• Told no, because - metformin controlled the DM
- she was able to lose wt
- serum cortisol was “normal”
Case 1
1990s
~2013
• Came to Boston for evaluation
• 8/8 UFCs were normal; looked well
• but 66% of late night salivary
cortisols (LNSCs) were high
Patient
photos
Case
Head MRI(first in many years)
Mass on right side of
pituitary gland
~1.5 x 1.3 x 0.7 cm
? right cavernous sinus
invasion
Normal gland pushed left
Case 2
• Fall 2013 recurrent symptoms
‒ emotional lability/moodiness
‒ weight gain
‒ but did not look Cushingoid
• Serum cortisols done locally were “normal”
• LNSCs & UFCs 1-2 fold upper limit of normal
• Head MRIs unchanged over 2 years
Patient
photo
• These patients had typical
recurrences− mild clinical features
− mild biochemical abnormalities
− one had unchanged MRI, abnormal UFCs
− one had normal UFCs, abnormal MRI
• Case 2 had a high probability of recurrence– tumor >1cm
– no adrenal insufficiency post-op but
• Patients without positive predictors may
also recur (Case 1)
(Tritos Nature Rev Endocrinol 2011)
CasesPatient
photos
• Recurrence may be many years after surgery− 31 series with N>40: relapse between 6m-12y
− Case 1 recurred at 21 years! Longest we’ve seen: 27y
• Sequence of hormone changes in recurrent CD− ↑midnight cortisol (serum or saliva) usually precedes ↑UFC
− mean time to elevation: 38 months for midnight cortisol
45 months for 1mg overnight DST
51 months for UFC
• All post-op patients must be followed– Can’t rely on UFC alone for diagnosis
– Use LNSC, ONDST
– LNSC appears to be most sensitive test
Cases
(Khalil EJE 2011, Tritos Nature Rev Endocrinol 2011, Carroll ENDO 2014 , Danet-Lamasou Clin Endo 2014)
Patient
photos
Late night salivary cortisol
• High sensitivity and specificity (93-100%)
• Especially helpful in early Cushing’s, recurrences
• Normal levels exclude dx in most cases
• Easily performed at home
• Before dental care; avoid hand creams
• Pt chews on cotton, places into tube, mails
• Several samples recommended
• Normal ranges differ widely by lab
• May be high in day/night switch, late pregnancy,
other circumstances
How many of you use this test? – please raise your hand if you do
It was an effort to make this available at our hospital
Insurance coverage is variable and different for different labs
Late‐night salivary cortisol to screen for
early‐stage recurrence of CD after pituitary surgery
Danet-Lamasou Clin Endo 2014
Remission
Sequences
30
0
15
25
20
10
5
LNSC
(n
M)
Sequences: successive measurements of
LNSC for each individual patient
normalrange
Late‐night salivary cortisol to screen for
early‐stage recurrence of CD after pituitary surgery
Danet-Lamasou Clin Endo 2014
Remission
Sequences
30
0
15
25
20
10
5
LNSC
(n
M)
Recurrence
Sequences
30
0
15
25
20
10
5
LNSC
(n
M)
Sequences: successive measurements of
LNSC for each individual patient
normalrange
Lindholm 0.31 (0.14-0.69)
•
0.126 7.931
Hammer
Dekkers
Clayton
Overall(I-squared = 82.2%; p = 0.001)
1.18 (0.56-2.48)
1.80 (0.75-4.32)
3.30 (1.37-7.93)
1.20 (0.45-3.18)
Mortality among CD patients in remission
Clayton R N et al. JCEM 2011;96:632-642.
Hammer
5.06 (2.27-11.26)•
•
•
•
0.026 38.4
Clayton R N et al. JCEM 2011;96:632-642.
1
Lindholm
Dekkers
Clayton
Overall (I-squared = 67.2%, p = 0.027)
2.80 (1.33-5.87)
4.38 (1.82-10.52)
16.0 (6.66-38.44)
5.50 (2.69-11.26)
Mortality among CD patients with recurrence
CRH
ACTH
Cortisol
Adrenal glands
Pituitary gland
Cabergoline*
Pasireotide
Ketoconazole*
Metyrapone*
Mitotane*
Etomidate*
What are the treatment options for recurrent Cushing‘s disease?
GR
Mifepristone
GRs on
target tissues
Tissues(* not FDA approved for Cushing’s)
RADIATION
ADRENALECTOMY
MEDICATIONS
PITUITARY SURGERY
Repeat transsphenoidal surgery
• Pros
− Well tolerated
− Immediate effect (if successful)
− Chance for tumor removal and remission
• Cons
− Glucocorticoids needed until axis recovers
− Higher risk of pituitary hormone deficiencies
− Risk of recurrent Cushing’s
− Lower chance of success than 1st surgery (<75%)
Remission rates after repeat transsphenoidal
surgery for persistent or recurrent CD
0 20 40 60 80 100
Nakane 1987 (N=8)
Friedman 1989 (N=31)
Ram 1994 (N=17)
Knappe 1996 (N=24)
Shimon 2002 (N=13)
Locatelli 2005 (N=12)
Benveniste 2005 (N=30)
Hofmann 2006 (N=16)
Hofmann 2008 (N=35)
Aghi 2008 (N=13)
Patil 2008 (N=36)
Wagenmakers 2009 (N=8)
Remission Rate (%)
Varied definitions of biochemical control, follow up, Ns
(McLaughlin Can J Neurol Sci 2011)
1st surgery
remission
rates 70-90%
2nd surgery
remission
rates lower,
but it works for
some patients
Bilateral Adrenalectomy
• Pros
− Immediate remission from cortisol excess
− Permanent (usually)
− Well tolerated (especially if laparoscopic)
• Cons
− Risks of abdominal surgery
− Lifelong gluco- & mineralocorticoid
replacement and risk of adrenal crisis
− Long term risks› Nelson’s syndrome ~ Corticotroph Tumor Progression
› Recurrent Cushing’s (rare)
22
Radiation
CONVENTIONAL
Six weeks of daily tx• Conventional
Fractionated
• Radiosurgery (RS)
− Single high dose to target
− Lower dose to other tissue
− 3 types
› Linear accelerator (LINAC)
› Gamma knife
› Proton beam
LINAC
gamma knifeproton beam
No direct comparisons available
• RS may be faster
• For CD, similar cortisol control
23
Radiation
0 10 20 30 40 50 60 70 80 90 100
Littley 1990
Murayama 1992
Levy 1991
Tsang 1996
Estrada 1997
Witt 1998
Laws 1999
Sheehan 2000
Kobayashi 2002
Devin 2004
Colin 2005
Jagannathan 2007
Minniti 2007
Petit 2008
Wilson 2014
Patients (%)
Tumor control
(83-100%)
Biochemical
control (28-86%)
(Starke Curr Opin Endocrinol Diab Obes 2010, Tritos Nature Rev Endocrinol 2011, Wilson J Clin Neurosci 2014)
15 studies with at least 20 pts
Varied RT methods, definitions of tumor & biochemical control, follow up, Ns
24
Radiation
CONVENTIONAL
Six weeks of daily tx
• Pros
− Well tolerated
− Single treatment (if radiosurgery)
− Provides tumor control in most patients
− Biochemical control in some patients
• Cons
− Delayed effectiveness (6 months to many years)
− Medical treatment needed in the interim
− Long term risks:› Pituitary hormone deficiencies/need for replacement
› Risk to surrounding neurovascular structures
› Risk of secondary neoplasia
› Recurrence (rare)
(Starke Curr Opin Endocrinol Diab Obes 2010, Tritos Nature Rev Endocrinol 2011, Wilson J Clin Neurosci 2014)
Case 2
• 29 yo F with history of Cushing’s surgery 2011
• Fall 2013 recurrent Cushing’s, options were discussed
Patient asked,
“Isn’t there a medication
I can take instead of
having surgery again?”
Patient
photo
CRH
ACTH
Cortisol
Adrenal glands
Pituitary gland
Cabergoline*
Pasireotide
Ketoconazole*
Metyrapone*
Mitotane*
Etomidate*
LCI699*
Potential targets for medical Tx of Cushing‘s disease
GR
Mifepristone
GRs on
target tissues
Tissues(* not FDA approved for Cushing’s)
Rationale: affinity for receptors on corticotroph adenomas
• cabergoline for dopamine (D2) receptor
• pasireotide for somatostatin (sst5) receptor
↓ ACTH secretion
Cabergoline in Cushing’s disease
• 20 Cushing’s disease pts, mean UFC > 2-fold above nl
• 2-year study: 1-7mg/wk cabergoline (median 3.5mg/wk)
• 2 dropouts for “asthenia, hypotension”; adrenal insufficiency?
• Cardiac echos: tricuspid regurg progressed in 1, no change in others
• Similar findings in two other studies; suggests this is an option for CD
Non-
responders
Early response,
Later “escape”
Long-term
responders
normal range
months
(Pivonello JCEM 2009, Godbout EJE 2010, Vilar Pituitary 2010)(not FDA approved for Cushing’s disease)
“Responder” means normal UFC
2500
Pasireotide - baseline & month 6 UFCs
Individual patients sorted by baseline UFC
Color denotes starting dose
UF
C (
μg
/24
h)
0
180
360
540
720
1400 600 µg s.c. bid
900 µg s.c. bid
normal
Baseline UFC
Month 6 UFC
Month 6 UFC ULN*
<52.5 μg/24h
Normal UFC, n (%) 12 (14.6) 21 (26.3) 33 (20.4)
Colao NEJM 2012
N=103
Colao NEJM 2012
600 µg sc bid 900 µg sc bid All patients
Clinical changes on pasireotide up to 12m
Cola
oN
EJM
2
01
2
FDA approved for CD pts not controlled with/able to have surgery
Subcutaneous pasireotide side effects
• Adrenal insufficiency symptoms in 13 (8%)
– Responded to dose reduction and/or temporary corticosteroids
• Most frequent side effects were gastrointestinal
• Similar to other SMS analogues, except for hyperglycemia
• 73% of patients had at least one hyperglycemia event
– No diabetic ketoacidosis or hyperosmolar coma
– Attainment of UFC control did not prevent hyperglycemia
Colao NEJM 2012
Mechanism based on study in healthy volunteers:
Pasireotide reduces incretin & insulin secretion,
without affecting insulin sensitivity
Changes in glycemia on pasireotide
Mean fasting
plasma glucose
(mg/dL)
600 µg bid (n=82) 900 µg bid (n=80)
Mean HbA1c
(%)
600 µg bid (n=82) 900 µg bid (n=80)
90
100
110
120
130
140
150
Baseline Day 15 Month 3 Month 6 Month 12
5
6
7
8
Baseline Month 2 Month 6 Month 12
Of the 67 patients who were normoglycemic at baseline, 14 (21%) remained normal,
29 (43%) became pre-diabetic and 23 (34%) became diabetic during treatment
Henry JCEM 2013
Colao NEJM 2012
Pasireotide LAR* (once monthly)
Lacroix ENDO 2016*(not FDA approved for Cushing’s)
0 20 40 60
≥1.5 to <2.0 x ULN
≥2.0 to ≤5.0 x ULN
Pasireotide LAR 10 mg
Pasireotide LAR 30 mg
Screening mUFC
Percentage of responders
(mUFC ≤ULN at month 7)
n=18/49
n=18/51
n=13/25
n=13/25
36.7%
35.3%
52.0%
52.0%
•150 patients randomized to 10mg/month or 30mg/month
• Proportion of “Responders” (normal UFC) at month 7 by
pasireotide LAR dose according to baseline UFC group
Side effects were
similar to bid
subcutaneous
CRH
ACTH
Cortisol
Adrenal glands
Pituitary gland
Cabergoline*
Pasireotide
Ketoconazole*
Metyrapone*
Mitotane*
Etomidate*
LCI699*
Potential targets for medical Tx of Cushing‘s disease
Tissues
GR
Mifepristone
GRs on
target tissues
(* not FDA approved for Cushing’s)
Several used for over 50 years
Reduce cortisol by inhibiting adrenal steroidogenesis
ACTH ↑ in pituitary Cushing’s
(? of escape)
Ketoconazole
• Approved for treatment of fungal infections
• Inhibits several enzyme steps in cortisol production
• 4 past studies w/ >15 CD pts: cortisol control 49-99%
What‘s new?
• Large multicenter, retrospective French study− 200 patients on monotherapy at 14 centers over 17y
− Mean final dose 780mg/d (range 200-1200mg)
− Control (2 consecutive normal UFCs) in 49%
− Clinical improvements in DM, HTN, hypokalemia
− ~20% discontinued for intolerancemost common: gastrointestinal, adrenal insuff, pruritis
− Liver enzyme elevations in 18% (>5XULN, 2.5%)
• Conclusion: effective with acceptable side effects
(Castinetti EJE 2008 & JCEM 2014, Sonino Clin Endo 1991, Valassi Clin Endo 2012, clinicaltrials.gov)(not FDA approved for Cushing’s)
Metyrapone
• Inhibits last enzyme step in cortisol synthesis
• Cortisol control reportedly ~75% − 3 studies from 1970s to early 1990s (15-53 patients)
What‘s new?
• Large multicenter, retrospective UK study (ENDO 2014 oral)
− 160 patients on metyr monotherapy at 13 centers over 16y
− Control based on cortisol day curve or UFC or am cortisol
− 74% controlled overall in Cushing‘s syndrome(about 2/3rds who took metyrapone over 5m had CD)
XCortisol
11bOHlase
11deoxycortisol
(Jeffcoate BMJ 1977, Thorén Acta Endocrinol (Copenhagen)1985,
Verhelst Clin Endo 1991, Daniel ENDO 2014) (not FDA approved for Cushing’s)
(Jeffcoate BMJ 1977, Thorén Acta Endocrinol (Copenhagen)1985,
Verhelst Clin Endo 1991, Daniel ENDO 2014)
Change in 9am cortisol during treatment for each individual patient
0
300
600
900
1200
1500
1800
151 patients
9a
m c
ort
iso
l (n
mo
l/l)
ReductionIncrease
Normal: 600nmol/L=21.7 mcg/dl
Slide kindly provided by John Newell-Price
(not FDA approved for Cushing’s)
− Dose in CD patients with eucortisolemia was ~1.4 g/d
− 25% had side effects (most common: GI, hypoadrenalism)
Conclusion: effective with satisfactory safety profile
(Daniel JCEM 2015)
37
Potent inhibitor of 11β-hydroxylase (CYP11B1) and aldosterone synthase (CYP11B2)
Blocks last steps in cortisol and aldosterone production
Hormones distal to the block fall
and proximal hormones rise
- Oral, longer half-life than metyrapone (allows twice-daily dosing)
- Higher potency (in vitro IC50 for CYP11B1 of 2.5 nM vs. 7.5 nM)
IC50, half maximal inhibitory concentration
Pregnenolone
11-deoxycortisol
Cortisol
Cholesterol
ACTH
Aldosterone
CY
P11B
2
Corticosterone
18-OH corticosterone
LCI699
CYP11B1
Abnormal
feedback loop in
Cushing’s disease
Progesterone
Dehydroepiandrosterone
Androstenedione
Testosterone
11-deoxycorticosterone
Estradiol
Estrone
X
X
11-deoxycortisol
ACTH
Testosterone
11-deoxycorticosterone
Investigational medication LCI699 (osilodrostat)*
Mechanism of action
(* not FDA approved)
38
Me
an U
FC
±S
E (
fold
ULN
)
0
1
2
3
4
5
6
7
1 14 28 42 56 70 84Day
LCI699 dose escalation Washout
Open-label, proof-of-concept study with LCI699*
was positive in 12 adults with Cushing’s disease
• Oral medication, given twice daily
• Dose escalated every 2 weeks until UFC normalized
• Maintained until day 70, followed by 2-week washout
Bertagna JCEM 2014
At day 70:
• 11/12 had normal UFC
• Most common side
effects: fatigue, nausea
(* not FDA approved)
39
Longer-term extension
Change in UFC after 22 weeks of LCI699*U
FC
(n
mo
l/2
4h
)
7000
9000
11000
2000
1800
1600
1400
1200
1000
800
600
400
200
0Patients
Baseline
Week 22
Follow-up cohort
Expansion cohort
Overall response (n=19):
• Controlled, n=15 (78.9%)
• Uncontrolled, n=2 and
discontinued, n=2 (21.1%)
normal
range11–138 nmol/24h
(* not FDA approved) (Fleseriu & Pivonello Pituitary 2016, clinicaltrials.gov)
CRH
ACTH
Cortisol
Adrenal glands
Pituitary gland
Cabergoline*
Pasireotide
Ketoconazole*
Metyrapone*
Mitotane*
Etomidate*
LCI699*
Potential targets for medical Tx of Cushing‘s disease
GR
Mifepristone
GRs on
target tissues
(* not FDA approved for Cushing’s) Tissues
Blocks action of cortisol at glucocorticoid receptor (GR)
Doesn’t lower cortisol; ACTH and cortisol ↑ in pituitary Cushing’s
Oral glucocorticoid (GR) antagonist - greater affinity than
cortisol or dexamethasone for the receptor
Also has antiprogestin activity
Phase 3 clinical trial in 50 patients reported in 2012
FDA approval for Cushing’s syndrome with hyperglycemia
Mifepristone in Cushing’s Syndrome
Blocks receptor (does not ↓cortisol) so response was assessed clinically
− Patients had diabetes/impaired glucose tolerance or HTN
− Primary endpoints related to improvements in these disorders
(25% reduction in AUCgluc on OGTT, 5mmHb reduction in DBP)
(Fleseriu JCEM 2012)
Decrease in HbA1c in diabetes cohort
4
5
6
7
8
9
10
Baseline Week 16 Week 24/ET
Hb
A1c (
%)
p<0.001
vs baseline
N=25 N=22N=20
me
an ±
SD
p<0.001
vs baseline
Glucoses on
OGTT and
insulin levels
also decreased
significantly
Diabetes drugs
were reduced in
7/15 patients
(Fleseriu JCEM 2012)
(mea
n ±
SE
)Decrease in weight
-9%
-8%
-7%
-6%
-5%
-4%
-3%
-2%
-1%
0%
1%
2%
D7 D14 D28 W6 W8 W10 W12 W16 W20 W24
% C
hange f
rom
baselin
e
Baseline 99.5 ± 4.4 kg
n=46
↓ 5.7 ± 1.5%
p<0.001
vs Baseline
/ET
(Fleseriu JCEM 2012, Katznelson Clin Endo 2013)
“Global Clinical Assessment”
of many features, including
appearance in photographs,
rated by 3 independent
reviewers improved in
88% of patients (p<0.001)
• Adrenal insufficency (AI)− Classified as AI or typical symptoms & treatment with glucocorticoid (dex) in 7
− High measured cortisols despite AI may be misleading
• Most common: nausea, fatigue, headache
• Hypokalemia− Common, associated with alkalosis, edema; treated with K & spironolactone
− Likely due to mineralocorticoid receptor activation from rising cortisol
• Endometrial Effects (progesterone receptor blockade)− Increased endometrial thickness in half of women
− 5 cases of vaginal bleeding
− 3 women had D&C for unresolved endometrial thickening after discontinuation
• Thyroid – elevated TSH
• Lipids – decreased HDL
Drug-drug interactions require careful attention
Mifepristone side effects
(Fleseriu JCEM ‘12, Endocrine Practice ’13)
Phase III
Long-acting pasireotide
Levo-ketoconazole
Osilodrostat (LCI699)
Phase II
Roscovitine
Gefitinib
CORT125134
Preclinical/other
Retinoic acid
Silibinin
ALD1613
Possible future options:
What drugs* are in development?
(* not FDA approved for Cushing’s)
* Especially with mifepristone and ketoconazole
Severity/urgency, treatment goals (cortisol/tumor)
Other medications
(beware drug–drug
interactions)*
Medical history and patient
factors
Method of delivery
(oral versus injection)
Side-effect profile
Cost and availability
How do we decide which medication to use?
Consider many factors
Tailor choice to each patient’s individual situation
Case 1 Outcome
Before second surgery
2013
After second surgery
June 2014 Dec 2015
• She decided to undergo second transsphenoidal surgery by an
expert pituitary surgeon; “I’d be happy with another 20-year
remission by spending just 1 day in the hospital” in remission
• Diabetes and hypertension resolved (medications stopped)
• Pituitary hormone replacements adjusted, feeling well
Patient
photos
• 29 yo F Cushing’s disease recurrence
• Treatments discussed; considering the options
• Phone call to fellow… patient was excited to report….
• Pregnant! What are the treatment options now?
• Choices are limited
• Metyrapone* started
(* not FDA approved for this use) (Lindsay JCEM 2005)
Case 2 Outcome
- targeted UFCs in normal pregnant range, 1.5-2 fold above ULN
- due to concern about precursors proximal to 11ßOHlase blockade,
careful monitoring of potassium & blood pressure (weekly OB visits)
She delivered a healthy boy!
Patient
photo
Conclusions
• All patients in remission from CD should
have lifelong monitoring for recurrence
• Late night salivary cortisol levels are more
sensitive than other tests
• Treatment is important to lower mortality risk
• Management should be individualized
Thank you
Questions?