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Update on Cushing’s disease
Beverly MK Biller, MD Professor 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, HRA Pharma, Ipsen, 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
The Endocrine Society Clinical Guidelines First-line treatment for Cushing’s Syndrome
Operation by an experienced surgeon is recommended as the initial treatment
So, other therapies should be used mainly for
persistent or recurrent Cushing’s disease
Nieman JCEM 2015
Cushing’s disease (CD) Case 36 year old pregnant woman with:
• Facial rounding • Hypertension • Fungal infections
Cushing’s syndrome later diagnosed with high UFC levels; ACTH not low
Pituitary MRI: ? small right lesion
IPSS: Centralized
Clear clinical and biochemical features of CS; testing pointed to pituitary
PATIENT PHOTO
Cushing’s disease (CD)
• 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
Before surgery
~8 years after
surgery
Moved away
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
We were wrong – it is higher!
y ,
WWWWWWWWWe
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 were as 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)
Case
• 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
• 2012 new diabetes (DM), weight gain, ↑ blood pressure
• Asked local endo if CD back; told no: metformin helped DM, lost weight, serum cortisol “normal”
Case
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
• These patients had typical recurrences − mild clinical & biochemical abnormalities − one had unchanged MRI, abnormal UFCs − one had normal UFCs, abnormal MRI
• Recurrence may be many years after surgery − 31 series with N>40: relapse between 6m-12y − This patient 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 (m) for midnight cortisol
- 45 m for 1mg overnight DST - 51 m for UFC
• Thus, all post-surgery 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
Lindholm 0.31 (0.14-0.69)
•
0.126 7.93 1
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
Cushing’s syndrome and etiology established biochemically
Treat co-morbidities
ACTH-dependent Cushing’s syndrome ACTH-independent Cushing’s syndrome
Presumed EAS Imaging: No tumor
Presumed CD Based on IPSS or >6
mm mass
Presumed EAS Imaging: Tumour
Remission Tumor resection Resection not possible
Monitor for recurrence
Failed surgery, no surgery, or recurrence
Adrenal imaging
Unilateral or bilateral adrenalectomy
Treat metastatic disease if applicable Remission
Repeat localization studies if applicable
Control hypercortisolism If Cushing’s disease, consider:
Repeat transsphenoidal surgery Pituitary-directed medical treatment Radiotherapy and steroidogenesis inhibitors
For all etiologies, consider: Steroidogenesis inhibitors GC receptor antagonist Bilateral adrenalectomy Nieman JCEM 2015
dent Cushing’s synd e ACTH-independent Cushing’s s
Presued o
m
umor r
Failed surgery, no surgery,or recurrence
aging
rena
R
ol hypercortisolismer:urgery
Endocrine Society Clinical Guidelines – Treatment of Cushing’s synrome
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
GGGGGG n GRRRRRRs onADRENALECTOMY Ad l l d
MEDICATIONS
Pituitary gland RPITUITARY 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
19
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) 20
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 knife proton beam
No direct comparisons available • RS may be faster • For CD, similar cortisol control
21
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
CRH
ACTH
Cortisol
Adrenal glands
Pituitary gland Cabergoline* Pasireotide
Ketoconazole* Metyrapone* Mitotane* Etomidate* LCI699*
Potential targets for medical treatment 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
UFC
(μg/
24h)
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
Col
ao N
EJM
201
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 subcutaneous 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 mgPasireotide 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 similar to bid subcut use
CRH
ACTH
Cortisol
Adrenal glands
Pituitary gland Cabergoline* Pasireotide
Ketoconazole* Metyrapone* Mitotane* Etomidate* LCI699* 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)
What are the treatment options for recurrent Cushing‘s disease? 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 intolerance
most 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) (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)
X Cortisol
11 OHlase
11deoxycortisol
(Jeffcoate BMJ 1977, Thorén Acta Endocrinol (Copenhagen)1985, Verhelst Clin Endo 1991, Daniel JCEM 2015) (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
ReductionIncrease
Normal: 600nmol/L=21.7 mcg/dl
Slide kindly provided by John Newell-Price, presented at OR-02-3 by Eleni Daniel
(not FDA approved for CD)
− 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
on metyrapone Daniel JCEM 2015
33
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
CYP
11B2
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) 34
Mea
n U
FC
SE
(fol
d U
LN)
0
1
2
3
4
5
6
7
1 14 28 42 56 70 84 Day
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)
35
Longer-term extension Change in UFC after 22 weeks of LCI699*
UFC
(nm
ol/2
4h)
7000
9000
11000
2000
1800
1600
1400
1200
1000
800
600
400
200
0 Patients
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 range 11–138 nmol/24h
(* not FDA approved) (Fleseriu & Pivonello Pituitary 2016)
CRH
ACTH
Cortisol
Adrenal glands
Pituitary gland Cabergoline* Pasireotide
Ketoconazole* Metyrapone* Mitotane* Etomidate* LCI699*
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
What are the treatment options for recurrent Cushing‘s disease?
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
HbA
1c (%
)
p<0.001 vs baseline
N=25 N=22 N=20
mea
n S
D
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 S
E)
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
hang
e fro
m b
asel
ine 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)
CRH
ACTH
Cortisol
Adrenal glands
Pituitary gland Cabergoline* Pasireotide
Ketoconazole* Metyrapone* Mitotane* Etomidate* LCI699*
Many choices - how to decide which treatment to use?
GR
Mifepristone
GRs on target tissues
(* investigational for Cushing’s) Tissues
CRH
ACTH
Cortisol
Adrenal glands
Pituitary gland
Cabergoline*Pasireotide
Ketoconazole* Metyrapone* Mitotane* Etomidate*LCI699*
RGRGR
Mifepristone
GRs on target tissues
(* investigational for Cushing’s) Tissuees
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
Especially with mifepristone and ketoconazole* (*not FDA approved for Cushing’s)
• 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 outcomes
- 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
Case Outcome
Before second surgery 2013
After second surgery June 2014
Most recent visit 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
Conclusions – Cushing’s
• 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 • Emerging therapies include:
– More sophisticated transsphenoidal techniques – Stereotactic radiosurgery refinements – New medications and new versions of older medications – There are other medications in earlier development
Thank you
Questions?