1. Update in the treatment of Cushing’s disease
Pr Antoine TABARIN

4. Consequences of Cushing’s disease
Osteoporotic fractures
Increased morbidity
Neuropsychiatric disturbances
Diabetes/
hyperlipidemia
Cushing’s disease
Impaired health-related quality of life
Cardiovascular disease
3- to 5-fold higher mortality
Cerebrovascular events
Infection

5. Patients with persistent Cushing’s disease have higher rates of morbidity and mortality
Study
Lindholm (n=56)
Hammer (n=236)
Dekkers (n=59)
Clayton (n=54)
Overall (I2=82.2%, P=0.001)
SMR (95% CI)
0.31 (0.14, 0.69)
1.18 (0.56, 2.48)
1.80 (0.75, 4.32)
3.30 (1.37, 7.93)
1.20 (0.45, 3.18)
0.126 1
7.93
Remission
Lindholm (n=17)
Hammer (n=53)
Dekkers (n=15)
Clayton (n=6)
Overall (I2=67.2%, P=0.027)
5.06 (2.27, 11.26)
2.80 (1.33, 5.87)
4.38 (1.82, 10.52)
16.00 (6.66, 38.44)
5.50 (2.69, 11.26)
0.026 1
38.4
Persistent disease
Clayton RN et al. J Clin Endocrinol Metab 2011
Note: Weights are from random effects analysis

7. Hypercholes-terolemia Hypertriglyc-eridemia
Metabolic disease may persist after biochemical cure of hypercortisolism
100 80 40
Patients (%) 60
Obesity
Hypertension
DM/IGT
Hypercholes-terolemia
Hypertriglyc-eridemia 20
Active Cushing’s disease
Short-term remission
Long-term remission 70 60 40
Patients (%) 50 20 30 10
At diagnosis
After cure
Controls
Diabetes
Dyslipid-emia
Hyper-tension
Central obesity
Pivonello R et al. Endocrinol Metab Clin North Am Barahona MJ et al. Front Horm Res 2010

8. Mortality and Sequelae in patients cured of Cushing’s disease
May be related to the duration of exposure to cortisol
Fallo, F., et al. Am J Hypertens 1996; Lambert, J.K et al. J Clin Endocrinol Metab 2013; Resmini, E., et al. J Clin Endocrinol Metab 2012
Imply a prompt treatment of hypercortisolism
Mortality
May be related to the persistence of hypertension and diabetes
Extabe J et al. Clin Endocrinol 1994 ; Boland M. Clin Endocrinol 2011; Clayton RN et al. Lancet Diabetes Endocrinol 2016
Imply an active treatment of persistent comorbidities

10. Transsphenoidal surgery in Cushing’s disease
In experienced hands, transsphenoidal surgery often leads to rapid and sustained remission of hypercortisolism with low morbidity
Surgery is the only option that may offer a definitive cure with minor side effects
It is of upmost importance to choose an experienced surgeon to guarantee the best efficiency and minimize side effects
It is of upmost importance to discuss between the patient, surgeon and endocrinologist what will be done in case of negative surgical exploration. Total hypophysectomy should not be performed
If surgery fails all the other therapeutic options remain available

11. Do patients with non-visible adenomas have lower surgical success rates?
Study
Success rate in patients with visible microadenomas (%)
Success rate in patients with non-visible adenomas (%)
Bochiccio et al. 1995 87 74
Barrou et al. 1997 93 58
Rees et al. 2002
100 69
Salenave et al. 2004 88 78
Testa et al. 2007 75 73
Jehle et al. 2008 82 79
Sun et al. 2012 86
Yamada et al. 2012 98 50
Swearingen et al. unpublished 95 89
Visible adenomas: 75–100%
Non-visible adenomas: 50–89%
First-line surgery is an appropriate treatment for patients with non-visible corticotroph adenomas

12. SMR cured by pituitary surgery only : 0.94 [0.53 - 1.54] NS
Clayton RN et al. Lancet Diabetes Endocrinol 2016
SMR cured by pituitary surgery only : [ ] NS
SMR NOT cured by pituitary surgery only : [ ] (p˂000.5)

14. Diagnosing early recurrence
Recurrence is usually a slow process
Clinical manifestations in adults may be delayed
Alterations of classical biological parameters may be delayed

15. LNSC and recurrence
The intra-individual variability of LNSC is higher during recurrence than during remission (P < 00001)
Early- Recurrence
CCI = 0,24
Remission
CCI = 0,69
Danet –Lamassou et al. Clin Endocrinol 2015 15

16. Second-line treatments in Cushing’s disease
The impossible algorithm..the Cushing game…
Bertagna X et al. JCEM 2013

17. Second line treatments for Cushing’s disease
Medical
history
Patient wishes
Concomitant medications
Individualize treatment
Comorbidities
Efficacy
profile
Cost
Safety
profile
Some changes in this slide
Availability
Multidisciplinary team
Share decision-making with the patient 17

18. Medical options in Cushing’s Disease
Tumor-directed Therapy
Pasireotide
Cabergoline
Adrenal-Directed Therapy
Steroidogenesis Inhibitors
Mitotane
GR Directed Therapy
Mifepristone
ACTH
Cortisol GR

19. Pasireotide Efficacy Results
600 µg x 2/j (n=82)
900 µg x 2/j (n=80)
Overall (n=162)
6 months
*Reponse, n (%)
12 (14.6)
21 (26.3)
33 (20.4)
[95% CI]
[7.0, 22.3]
[16.6, 35.9]
[14.2, 26.6]
Colao AM et al. NEJM 2012 19

20. Mean fasting plasma glucose (mg/dL)
Safety
73% of patients had an hyperglycemia-related AE
Mean fasting plasma glucose (mg/dL)
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
Normoglycemic patients at baseline :
glucose intolerance: 43%
diabetes : 34%
Gh suppression ? 20

21. Cabergoline Short-term (≤ 12 mois)
Introduction
Patients and Methods
Results
Discussion
62 patients
53 patients
Monotherapy
9 (patients)
Association
21 complete responders
(40 %)
4 partial responders
(7 %)
28 non responders
(53 %)
Controlled
Controlled
Not *
Ferriere A et al. EJE 2016

22. Responders - Long-term (> 12 months)
Cabergoline
Responders - Long-term (> 12 months)
Introduction
Patients and Methods
Results
Discussion
12 long term responders (23 %)
18 short-term responders
4 Escape to treatment
2 « intolerance »
Duration of ttt : ± 8.4 Mo (19 – 105)
Cabergoline dosage : 1.7 ± 0.2 mg / week

23. Steroido- genesis inhibitors
Metyrapone, Ketoconazole, Etomidate, LCI699
Efficient and rapid effect (hours to days)
Do not restore circadian rhythm of cortisol
Two Strategies : titration vs block and replace
Metyrapone

24. Metyrapone 81% treated with dose titration Short-term treatment
115 patients with Cushing’s disease
81% treated with dose titration
Short-term treatment
Around 50% controlled
Long-term treatment (38 > 6 Mo)
Around 70% controlled
No escape phenomenon
Dosage in CD : 1350 mg/d (500 – 3500) divided in 3-4 doses
Daniel E et al., JCEM 2015

25. Metyrapone Plasma cortisol Plasma 11 deoxycortisol metyrapone
Schöneshöfer M et al. JEI 1980
Monaghan PJ et al. Ann Clin Chem, 2011
metyrapone
Plasma cortisol
Plasma 11
deoxycortisol

26. Ketoconazole Efficacy Side Effects : Numerous drug interactions
At the last follow-up, 49.3% of patients had normal UFC levels with a median dose of 600 mg
Normalization of UFC is associated with improvement of hypertension, hypokalemia, and diabetes
Side Effects :
20.5% stopped the treatment due to intolerance.
Major liver intolerance in 2.5% of patients. No fatal hepatitis was observed.
Unknown side effects : male hypogonadism ?
Numerous drug interactions
Castinetti F et al. JCEM 2014

28. How to define “control” of hypercortisolism ?
MacKenzie et al. Pituitary 2014

29. Cardiovascular risk and mild hypercortisolism
Median Follow-Up : 4.2 y
Debono et al. JCEM 2014 29

30. Normalize UFC ……
Is it an acceptable target…?

31. Is BLA efficient to cure Cushing’s syndrome ?
Author N
Hypertension
Diabetes
BMI
Phenotype
Muscle
Weakness
Menstrual Regularity
Emotional
Disorders
Tomita et al 16 93 75
N/A 78
Zeiger et al 29 79 86 77 89
Vella et al 80
100
Hawn et al 6 83 50 33
Li et al.
2005 12
Chow et al. 2008 64 35 81 84
Alberda et al. 2012 17 87 72 90 65 62
Oswald et al. 2014 34 19 57 NA 76 47 71
Mean
64%
66%
70%
80%
68%
71%
75%
Bien sur regression in not 100% as in other ttts et delai
IMMEDIATE CURE OF HYPERCORT BUT HAVE TO WAIT FOR REGRESSION OF SYMPTOMS

32. Drawbacks of BLA : adrenal insufficiency
Hydrocortisone over-replacement is correlated with the persistence of comorbidities (hypertension Oswald et al. EJE 2014)
Imperfections of currently available therapies
Bias of frequent occult glucocorticoid self- medication and over-replacement
Only three patients (2%) experienced a relapse of CS with clinical signs of hypercortisolism

33. Nelson’s syndrome versus Corticotroph tumor progression
Assié G et al. JCEM 2007

34. Corticotroph tumor progression
Stable adenoma
Assié G et al. JCEM 2007

35. Corticotroph tumor progression
Author N
Follow-up, Mo
Definition of NS
NS (%)
Acosta et al. 1999 20
N/A
Radiological evidence (CT) 5
Hawn et al. 2002 10 29
Radiological evidence (MRI)
Thompson et al 33 42 9
Assié et al. 2007 52 55 40
Oswald et al. 2014
132 24

36. Can we predict corticotroph tumor progression ?
Sex
Pregnancy
Pathology of the adenoma (Ki67, p53 etc..)
Age
Short duration of Cushing’s disease
MRI before surgery
ACTH following BLA
(NS = 1369 and 1710 ng/L, without NS = 369 and 266 ng/L). No ??
Age travail de Kloppenborg 48 patients not confirmed by Assié
Yes
Kemink et al. JCEM 1994; Pereira RA Clin Endocrinol 1998 ; Assié G et al. JCEM 2007

37. How soon and how long would you monitor pituitary MRI for CTP ?
Occurs in up to 50% of patients
May occur within 1 year
Within 3 y in 50% of patients
Tendancy to plateau after 7 y
Assié G et al. JCEM 2007

38. Can we prevent corticotroph tumor progression ?
Preventive pituitary radiotherapy ?
Pros
Cons
Jenkins et al. JCEM 1995
Nagesser et al World J Surg 2000
Gil-Cardenas et al. Surgery 2007
Mc Cance et al. Clin Endocrinol 1995
Sonino et al JCEM 1996
Pereira et al Clin Endocrinol 1998
en fait peu de sens sauf pour les grosses tumeurs au départ
La plupart des études sont faites avec les critères classiques de nelson
Pivonello R et al. Endocr Rev 2015

40. SEVERE CUSHING’ SYNDROME IS LIFE-THREATNING IN THE SHORT TERM
SEVERE CUSHING’ SYNDROME IS AN ENDOCRINE EMERGENCY

42. Steroidogenesis Inhibition using ketoconazole + metyrapone
Corcuff JB et al. EJE. 2015
Baseline : 40 x ULN
W1 : 3.2 x ULN (N in 50%)
M1 : 0.5 x ULN (N in 73%)

43. Thank you for your attention

44. Repeat pituitary surgery in Cushing’s disease
Reduced success rate # 58 %
Possible recurrence # 16%
Increased risk of hypopituitarism # 38%
Related to the extend of surgery
< to RXT
Debatable predictors of success
previous incomplete resection,
presence of a pituitary lesion on imaging
intraoperative tumor detection
Recurrence after after 25 mo of follow-up
Pivonello R et al. Endocr Rev 2015

45. Pituitary radiotherapy in Cushing’s disease
Conventional fractionated stereotaxic RXT
Median remission after surgery 70%
Delay : 1 – 4 y
Gammaknife radiosurgery
Median remission : 40 – 60 %
Delay : 2 – 4 y / shorter than conv.
Recurrence : 9%
Other benefits : tumor control
Side effects : hypopituitarism
Pivonello R et al. Endocr Rev 2015
Castinetti F et al. Nat rev endocr 2010

46. Preferred in women over metyrapone
Treatment
Efficiency
Adverse Effects
Comments
Ketoconazole
Hours > 50%
Severe in < 5%
20% intolerance
Drug interaction
Preferred in women over metyrapone
Caution with drug interactions
Metyrapone
GI Side effects Hirsutism
Hypokalemia
UFC monitoring
Preferred in men over ketoconazole
Mitotane
Slow (6 mo) – 75%
Numerous
30% intolerance
Prolonged chemical adrenalectomy
Teratogen
Pasireotide
Weeks – 25%
Frequent hyperglycemia
Expensive
Cabergoline
Weeks ? 30%
Mild
Secondary escape
Delay of action unknown
Mifepristone
Rapid – % ?
Difficulty to monitor

47. Drawbacks of BLA : adrenal crisis
Author
Study N
Causes of AI
Median follow-up
Addison’s crisis
Death
Ritzel et al.
Retro
203
BLA
42 Mo
9.3/100 patient-y ND
Osswald et al. 50
132 Mo
4.1/100 patient-y 2%
Primary and secondary adrenal insufficiency
Hahner et al.
444
primary AI = 254 secondary AI=190
6092 patient-y
6.3/100 patient-y
Prospective
434
primary AI =221 secondary AI =202
24 Mo
8.3/100 patient-y
0.9%
Congenital adrenal hyperplasia
Reisch et al.
122
CAH
35 y
5.8/100 patient-y
Education
Adapted from Reincke et al. EJE 2015

48. Can we predict corticotroph tumor progression ?
Plasma ACTH during the year following BLA
CTP
No CTP
Age travail de Kloppenborg 48 patients not confirmed by Assié
Assié G et al. JCEM 2007

49. Management of corticotroph tumor progression
Observation and repeated imaging
Limited size/progression and no anatomical damage
Pituitary surgery
mandatory if chiasm compression
Success rate : 10-70% (small tumors no extrasellar invasion)
Radiation therapy
significant tumor progression, despite surgery/surgery NA
50 – 90% control with CRT or GK
Drugs
Pasireotide ?
Cabergoline…anecdotal
temozolomide
Small samples and heretogeneous series
Pb target clear and discrete for GK
Drugs have been the less studied
Toutes ont morbidité pasireotide surtout qq données in vitro

50. Dogs Humans Mitotane at “high” doses Destruction of Adrenal Cortex
Adrenolytic
Drugs
Mitotane at “high” doses
Destruction of Adrenal Cortex
Results in adrenal Insufficiency
Delayed Effect
Dogs
Humans
Before
After
Nelson A, Woodard G. 1949, Arch. Path

51. Mitotane 76 patients treated with MITOTANE at Cochin Hospital (Paris)
Months
Persistent hypercortisolism
Global remission rate: 72%
Time to remission: 6.7 mo [ ]
Median dose : 2.7 ± 1.2 g / d
Mitotane level over 8,5 mg/l: 100 % remission
Baudry C et al. , EJE 2012

52. Mitotane : Tolerance
Mild intolerance
Intolerance leading to Mitotane discontinuation
Gastro-intestinal signs
36 (47%)
5 (7%)
Increased transaminases :
13 (17%)
1 (1%)
>ULN 11
>3x ULN 2
Increased GGT :
>3xULN 24
>5xULN 12
Neurologic signs
23 (30%)
6 (9%)
Lipid disorders:
54 (71%)
LDL cholesterol > 3.35 mmol/l
15 (20%)
LDL cholesterol > 5.16 mmol/l
19 (25%)
Triglycerides > 2.28 mmol/l
25 (34%)
Mild neutropenia
Skin rash
3 (4%)
Gynecomastia (men)
3 (18%)
Other
2 (3%)
Up to 30%
discontinuation
rate
Baudry C et al. EJE 2012
Accumulation within adipose tissue and teratogenicity