Traitement

de la Maladie de Cushing

Xavier Bertagna,

Laurence Guignat, Camille Baudry,

Guillaume Assié, Rossella Libé,

Lionel Groussin, Jérôme Bertherat

Centre de Référence des Maladies Rares de la Surrénale

Service des Maladies Endocriniennes et Métaboliques

Hôpital Cochin

Fédération Maghrébine d’Endocrinologie

Alger, Novembre 2012

Chirurgie hypophysaire (data base Française)

Rencontre Nationale d'Endocrinologie Cochin Mercredi 28 Mars 2012

338 CHIRURGIES

Histologie positive

274 (81.1%)

Histologie négative

58 (17.2%)

Histologie indéfinie

6 (1.78%)

Bilan post opératoire immédiat (<6 mois après chirurgie) 299 patients

Echec

44 (14.7%)

Rémission

225 (75.3%)

Indéfini

30 (10.0%)

Critères de Rémission: - hypocortisolisme (Cortisolémie 8h< 50ng/ml ou réponse insuffisante au synacthène) - eucortisolisme (2/3 critères normaux parmi cortisolurie, cortisolémie à minuit, cortisolémie après freinage minute 1 mg dexaméthasone)

Rémission (%) (C.Carrasco)

Rémission (%) (S.Bennis)

IRM + 85,20% 88,20%

IRM - 57,90% 65,80%

Reprise 60% 71,40%

Chirurgie Hypophysaire

Sous Labiale

(n=110)

Endoscopique

(n=106)

S. Gaillard Unpublished (Hôpital Foch, Suresnes)

CUSHING’S DISEASE

- outcome of primary pituitary surgery -

TSS

IMMEDIATE

(3-6 months)

10 YEARS

100

54 28 18

62 20

Immediate

failures

Recurrences

ACTH

CORTISOL

Traitements de l’hypercortisolisme Maladie de Cushing

Surgery (TSS)

Action Pbs

Immédiat ++ (IRM ?)

Succès

Echecs, Récid.

Different ways to control hypercortisolism…

Corticotroph Tumor Progression (CTP)

- « occurrence » of an adenoma -

MRI – at ADX MRI + at follow-up

Corticotroph Tumor Progression (CTP)

- « increase » of an adenoma -

MRI + at ADX Increase at follow-up

Lack of Corticotroph Tumor Progression

After

8 years

After

9 years

Months after adrenalectomy

Corticotroph Tumor Progression

after Bilateral Adrenalectomy

- MRI approach -

Patients without

Corticotroph Tumor

Progression

Assié G. et al. J Clin Endocrinol Metab 2007

During « pregnancy »

No evidence

- of « accelerated » Corticotroph Tumor Progression

- of « accelerated » ACTH rise

Jornayvaz FR. , Assié G. et al. J Clin Endocrinol Metab 2011

X-Ray

Nelson’s syndrome …

Adrenalectomy

time

MRI

TSS

…today:

Corticotroph Tumor Progression

ACTH

CORTISOL

Traitements de l’hypercortisolisme Maladie de Cushing

Surgery (TSS)

Bilateral adx

Action Pbs

Immédiat

Immédiat

++ (IRM ?)

Cause. CTP ?

Succès

+++

Echecs, Récid.

ACTH

CORTISOL

Traitements de l’hypercortisolisme Maladie de Cushing

Chirurgie

Chirurgie

Anticorticotropes

Anti-glucocorticoides

Anticortisoliques Riposte

ACTH

ACTH

CORTISOL

ACTH

CORTISOL

DOC

Androgènes

RU 486

Maladie de Cushing : trois jours sous RU 486

UFC X 10

Antiglucocorticoide : Mifépristone

Cas cliniques : Nieman et al.(JCEM 1985), Chrousos et

al.(Kidney Int 1988), Cassier et al.(Eur J

Endocrinol 2008), Castinetti (EJE 2009). Johanssen

S, Allolio B. Eur J Endocrinol. 2007. Review.

Efficacité : Favorable (diabète, peau, obésité, système

nerveux central)

Problèmes : Hypokaliémie. HTA

Monitorage ?

Insuffisance surrénale ? Supplémentation ?

Merits and pitfalls of mifepristone in Cushing's syndrome.

Castinetti F, Fassnacht M, Johanssen S, Terzolo M, Bouchard P, Chanson P, Do Cao C, Morange I, Picó A, Ouzounian S, Young

J, Hahner S, Brue T, Allolio B, Conte-Devolx B.

Eur J Endocrinol. 2009 Jun;160(6):1003-10.

The use of the glucocorticoid receptor antagonist mifepristone in Cushing's syndrome.

Castinetti F, Brue T, Conte-Devolx B.

Curr Opin Endocrinol Diabetes Obes. 2012 Apr 25. [Epub ahead of print]

Mifepristone, a glucocorticoid receptor antagonist, produces clinical and metabolic benefits in

patients with Cushing’s syndrome

Fleseriu M et al. J Clin Endocrinol Metab 2012

24-Week, open-label multicenter study

A single daily oral dose (600 – 1200 mg)

42 patients with Cushing’s disease (18 Radiotherapy), with T2DM/IGT or HTN

Long term Mifepristone in Cushing’s disease….?

Clinical improvement

Glucose, Blood pressure, weight change, …quality of life

Adverse events

Fatigue, nausea, headache, hypokalemia

Adrenal insufficiency in two patients

Endometrial hyperplasia

Hormone changes

UFC increased 7.7 fold and plateaued

(Baseline six weeks after discontinuation)

Anticortisoliques

Deux classes

Inhibiteurs de

la stéroidogénèse

Métopirone

Ketoconazole (Nizoral)

Etomidate

Action : immédiate

Effets secondaires : +/-

Echappement

Table 4 Efficacy of ketoconazole in previously published reports of the literature.

Only studies including more than five patients are reported.

a Some of the studies included patients previously treated by conventional radiotherapy.

Author Patients

number

Mean follow-up

(months)

Controlled patients (%) Side effects

(%)

Sonino (30) 28a 7 93 29

Loli (23) 6 8 100 0

Cerdas (35) 6 1 100 40

Mortimer (28) 8 0.5 100 25

McCance (36) 6 0.5 83 50

Engelhardt (37) 7 0.5 14 0

Our study 38 22.6 51.5 29

All studies 99 5.7 74 25

Castinetti et al. Eur J Endocrinol 2008

0

200

400

600

800

1000

1200

1400

janv-08 mars-08 sept-08 mars-08 juil-10 juin-11 sept-11 janv-12 fev-12

0

1

2

3

4

5

6

7

8

ACTH

FLU

TSSMETOPIRONE

Testo

DOC 51ULN

Maladie de Cushing

Echappement sous Metopirone

Testo

(ng/ml)

Anticortisoliques

Deux classes

Inhibiteurs de

la stéroidogénèse

Métopirone

Ketoconazole (Nizoral)

Etomidate

Action : immédiate

Effets secondaires : +/-

Echappement

Adrénolytiques

O, p’ DDD (Mitotane, Lysodren)

Action : retardée

Effets secondaires : +

Après Tt

Avant Tt

Atrophie surrénalienne sous O,p’ DDD

Median time to remission: 6,7 months [5,2-8,2]

Remission rates under Lysodren : 72 %

Months

Persistent

hypercortisolism

• 76 treated with MITOTANE out of 219

patients with CD diagnosed between

1993 and 2009, at Cochin Hospital.

• C. Baudry et al. Unpublished

0

50

100

150

200

250

300

0

5

10

15

20

25

30

3 6 9 12 0

Months

Daily Mitotane (g)

Plasma Mitotane (µg/ml)

Salivary

Cortisol

(ng/ml)

Plasma Mitotane

Salivary cortisol under O,p’ DDD treatment

(ACTH-dependent Cushing’s syndrome)

Dex 1 mg in the morning

ACTH

CORTISOL

Traitements de l’hypercortisolisme Maladie de Cushing

Surgery (TSS)

Bilateral adx

Adr.lytiques (Lyso)

Anti-gluco (RU486)

Inh. (Eto/Méto/KTZ)

Action Pbs

Immédiat

Immédiat

Immédiat

Retardée

Immédiat

++ (IRM ?)

++

Cause

EIs, Monitorage

Eis +, atrophie

Succès

+++

+

+

(Eis), Echapp

Echecs, Récid.

PP

AMPc

AMPc

nur 77c-Fos

POMC

F

F

FPKC

CREB

P P

LIF

JAK

ATP

AC

GR

SST

HSP

STATDAG

AVP

PLC

IP3

InP

c-Jun

PKA

AP-1c-Fos

nur 77 Neuro D1 Tpit Ptx1

PP

F

DACRH

La cellule corticotrope

Time course of response to

cabergoline

Pivonello et al J Clin Endocrinol Metab 94: 223, 2009

Rossella Libé, M.D.

INSERM Unité 1016, Paris, France

Lionel Groussin, M.D., Ph.D.

Université Paris Descartes, Paris, France

Jérôme Bertherat, M.D., Ph.D.

Hôpital Cochin, Paris, France

0

250

500

750

1000

1250

1500

1750

2000

2250

2500

2750

Uri

na

ry f

ree

co

rtis

ol (

nm

ol/

d)

600

g

x2/d

600

g

x2/d

450

g

x2/d

600 g x2/d

Seven years treatment under SOM 230

Mai 2011 Fév 2004

Libé R. et al. New Engl J Med 2012

0

50

100

150

200

250

300

350

400

450

-30 0 15 30 45 60

pre-surgery

early post-surgery

SOM 230

Time (min)

AC

TH

(

pg

/ml)

Desmopressin-induced ACTH response

Profils d’affinité aux récepteurs de la

somatostatine SOM 230

Cinétique de l’effet de pasiréotide sur 12 mois

dans la Maladie de Cushing

33

Identification précoce des non-répondeurs : >90% patients non contrôlés à M1 et M2 demeurent non contrôlés à M6

Tendance similaire pour:

• cortisol sérique

• cortisol salivaire

• ACTH plasmatique

Colao et al. N Engl J Med 2012;366:914-24 (Mars)

600 µg bid

(n=82)

900 µg bid

(n=80)

Overall

(n=162)

6 months

*Response [95% CI], n (%) 12 (14.6)

[7.0, 22.3]

21 (26.3) [16.6,

35.9]

33 (20.4) [14.2,

26.6]

12 months

Fully controlled, n (%) 11 (13.4) 20 (25.0) 31 (19.1)

Partially controlled, n (%) 13 (15.9) 2 (2.5) 15 (9.3)

Uncontrolled, n (%) 58 (70.7) 58 (72.5) 116 (71.6)

SOM 230 : Response status at 12 months

*NOTE: Responder was a patient with UFC ≤ULN who did not require

uptitration

Fully controlled: UFC ≤ULN; partially controlled: UFC >ULN, but had ≥50%

reduction from baseline; uncontrolled: UFC >ULN and <50% reduction from

baseline; CI, confidence intervals

Colao AM, … Biller B AES Boston 2011

SOM 230 : Safety profile

• Safety of pasireotide was generally similar to other somatostatin

analogues, except for hyperglycemia

– Most frequently reported AEs were gastrointestinal

– 12% of patients had ≥1 SAE suspected to be drug related

– No deaths during treatment

• As expected with an effective treatment for Cushing’s disease,

some patients (8%) experienced hypocortisolism

– Responded to dose reduction and/or temporary

corticosteroid substitution

• 72.8% of patients had at least one hyperglycemia-

related AE (no diabetic ketoacidosis or hyperosmolar coma)

Colao AM, … Biller B N Engl J Med 2012

ACTH

CORTISOL

Traitements de l’hypercortisolisme Maladie de Cushing

Surgery (TSS)

Bilateral adx

Adr.lytiques (Lyso)

Anti-gluco (RU486)

Inh. (Eto/Méto/KTZ)

Action Pbs

Immédiat

Immédiat

Immédiat

Retardée

Immédiat

++ (IRM ?)

+

Cause

EIs, Monitorage

EIs, atrophie

Succès

+++

+

+

EIs, Echapp

Echecs, Récid.

Direct (SMS/DA) Rapide +/- EIs (SOM)

ACTH

CORTISOL

Traitements de l’hypercortisolisme Maladie de Cushing

Surgery (TSS)

Bilateral adx

Adr.lytiques (Lyso)

Anti-gluco (RU486)

Inh. (Eto/Méto/KTZ)

Action Pbs

Immédiat

Immédiat

Immédiat

Retardée

Immédiat

++ (IRM ?)

++

Cause

EIs, Monitorage

EIs, atrophie

Succès

+++

+

+

EIs, Echapp

Echecs, Récid.

Direct (SMS/DA) Rapide +/- EIs (SOM)

Radiotherapy Retardée + Eis, Pit

Difficultés

Maladie rare

Physiopathologie mystérieuse

Etudes controlées (PPAR-γ, Retinoids, …)

Evaluer l’efficacité

Sur la sécrétion cortisolique ?

Sur les manifestations cliniques ?

Réversibilité des complications

Terrain, durée

la « part du cortisol »

Pistes

Physiopathologie

Nouveaux médicaments/approches

- Anti-ACTH (corticostatines, analogues ACTH) ?

- Anti-tumoraux (Temozolomide) ?

- LCI 699

- Associations

Volume

expansion

11-Deoxycortisol

Androgens

DOC

(Fasciculata/reticularis)

Pregnenolone

11-Deoxycortisol

(Cortisol)

Progesterone

17-OH progesterone

Cholesterol

Renin

(Glomerulosa)

DOC

(Aldosterone)

Pregnenolone

Progesterone

Cholesterol

(18-OH corticosterone)

(Corticosterone)

CYP11B1

LCI699 CY

P11B

2

ACTH

LCI699

- +

LCI699:

Anticipated effects in Cushing’s disease

X

X

LCI699

in 12 patients with Cushing’s Disease

UFC

Mean ± SE

(fold ULN)

0

1

2

3

4

5

6

7

1 14 28 42 56 70 84

LCI699 dose escalation Washout

Day

X Bertagna, R Pivonello, M Fleseriu, AH Hamrahian,M Boscaro, BMK Biller, Y Zhang, P Robinson, A Taylor, C

Watson, M Maldonado ECE/ICE Florence 2012

Pasireotide alone

or with cabergoline and ketoconazole in Cushing's disease.

Feelders RA, de Bruin C, Pereira AM, Romijn JA, Netea-Maier RT, Hermus

AR, Zelissen PM, van Heerebeek R, de Jong FH, van der Lely AJ, de Herder

WW, Hofland LJ, Lamberts SW.

N Engl J Med. 2010 May 13;362(19):1846-8.

1

10

100

1000

10000

Log d

ail

y U

FC

excr

etio

n [

µg/2

4h

]

100000

Mitotane, metyrapone, and ketoconazole combination therapy as an alternative to rescue adrenalectomy for severe ACTH-dependent

Cushing's syndrome.

Kamenický P, Droumaguet C, Salenave S, Blanchard A, Jublanc C, Gautier JF, Brailly-Tabard S, Leboulleux S, Schlumberger M,

Baudin E, Chanson P, Young J.

J Clin Endocrinol Metab. 2011 Sep;96(9):2796-804

Mitotane 3 g

Metyrapone 2 g

Ketoconazole 0.8 g

ADX

MET

TSS

SOM

CAB

LCI

KTZ

RX

RU

LYS

The Cushingame :

looking for a consensus treatment !

ACTH

CORTISOL

Traitements de l’hypercortisolisme Maladie de Cushing

Surgery (TSS)

Bilateral adx

Adr.lytiques (Lyso)

Anti-gluco (RU486)

Inh. (Eto/Méto/KTZ)

Action Pbs

Immédiat

Immédiat

Immédiat

Retardée

Immédiat

++ (IRM ?)

++

Cause

EIs, Monitorage

EIs, atrophie

Succès

+++

+

+

EIs, Echapp

Echecs, Récid.

Direct (SMS/DA) Rapide +/- EIs (SOM)

Radiotherapy Retardée + Eis, Pit

One hundred

years…

still a challenging

disease, Jean

Pierre !!

The pituitary body and its disorders. 1912

Harvey Cushing Jean Pierre Luton