Futuro do Tratamento Clínico na

Doença de Cushing

Luíz Antônio de Araújjo

CLUBE DA HIPÓFISE – Ano VII 27/02/2013

Tratamento da D. Cushing

Transsphenoidal surgery is first-line

therapy in Cushing’s disease

Initial success rate 68–98% in patients with a microadenoma1,2

Remission rates lower (<65%) in patients with a

macroadenoma1

Relapse rate is 2–26% (after 6–240 months)2

1Biller BMK et al. J Clin Endocrinol Metab 2008;93:2454–2462; 2Tritos NA et al. Nat Rev Endocrinol 2011;104:279–289

Cirurgia Transesfenoidal

PRÉ

ACTH +++

CORTISOL

+++

ACTH -

CRH - CRH -

ACTH -

CORTISOL

-

PO Imediato

ACTH +

Cortisol +

Conduta Persistência do

hipercortisolismo

Rescidiva

Recusa da

cirurgia

Contra

Indicação

cirúrgica

Biller BMK et al. J Clin Endocrinol Metab 2008;93:2454–2462

Current second-line therapies in

Cushing’s disease

Repeat surgery

Patients with persistent disease after surgery

Bilateral adrenalectomy

Radiation therapy

Medical therapy

Tratamento Secundário da

D.Cushing

1 – Cirurgia Transesfenoidal – Reoperação (37 a 73%)

(hipopituitarismo)

2 – Radioterapia (50–60%)

Convencional

Estereotáxica (Radiocirurgia)

(3 a 5 anos / hipopituitarismo)

3 – Adrenalectomia Bilateral (84–91%)

(insuf. glico e mineralocorticóide / S. Nélson)

4 – Terapia Clínica (farmacológica)

Recentes Avanços na

Terapia Clínica

1 – Medicamentos de ação Central (ação sobre o tumor)

Cabergolina

Pasireotide

Outros: PPAR gama agonistas, ácido valpróico,

ciproheptadina, antagonistas da vasopressina.

2 – Medicamentos de ação periférica (bloqueio / Adrenal)

Cetoconazol

Metyrapone

Mitotane

Outros: fluconazol, aminoglutetimida, etomidate

LC1699

3 – Medicamentos Antagonistas do Receptor Glicocorticóide

. Mifepristone

Medicamentos de ação

Periférica

1 – Cetoconazol (400 a 1200mg / dia)

Retrospective study of 38 patients with active disease (17 had

previous surgery)

17 (45%) had normalized UFC; mean follow-up of 23 months

Treatment stopped in first week in five patients (13%) due to

clinical intolerance (GI symptoms) or biological intolerance

(elevated liver enzymes)

AEs included a moderate (<3xULN ) increase in γ-GT (8%),

nausea and diarrhea (5%), aspartate aminotransferase/alanine

aminotransferase 8xULN (3%)

Escape: 15%

1Castinetti F et al. Eur J Endocrinol 2008;158:91–

99;

Medicamentos de ação Central

1 – Cabergolina

Dose: 2 a 3,5 mg / semana

Resultados: Controlados = 35%

Parcialmente Controlados = 40%

Sem Resposta = 25%

Segurança = valvulopatia Mitral / Tricúspede

2 – Análogos de Somatostatina – Pasireotide (SOM 230)

Dose = 900 mcg BID SC; 30 mg 30/30 dias IM (LAR)

Segurança: hiperglicemia / DM, diarréia, náuseas, bradicardia,

insuf. Adrenal

Regulação: EMA (04/12); FDA (12/12)

Response at month 12 similar

to that at month 6

*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

Predetermined criterion for the primary efficacy endpoint was that the lower bound of the 95% CI

had to be greater than 15% for at least one of the dose groups: this was met for the 900 µg group

600 µg bid

(n=82)

900 µg bid

(n=80)

Overall

(n=162)

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)

Colao A et al. N Engl J Med 2012;366:914–924

Fully controlled: UFC ≤ULN; partially controlled: UFC >ULN but had ≥50% reduction from baseline; uncontrolled: UFC >ULN and <50%

reduction from baseline

Sustained reduction in mean UFC

up to 24 months

Pivonello R et al. ENEA 2012;abst OC05

600

400

200

0

1200

1000

800

Mea

n U

FC

(n

mo

l/24

h)

0 3 6 9 12 18 15 21 24

600 µg bid

900 µg bid

ULN (145 nmol/24h)

Core study

(months) Extension phase

(months)

Reductions in serum

cortisol and plasma ACTH,

as well as improvements

in signs and symptoms,

were sustained1

Significant clinical benefit was determined at the discretion of the investigator

58 patients chose to enter a 12-month extension

• These patients had normalization of UFC or were considered to have achieved significant clinical benefit at month 12

• Mean decreases in UFC were maintained up to 24 months

Recent advances in medical therapy

Pituitary-targeted agents

Indication

Cabergoline Off-label

Adrenal-directed agents

Indication

Metyrapone Off-label

Ketoconazole Off-label

Mitotane Off-label

Glucocorticoid receptor antagonists

Indication

Mifepristone Off-label

*In patients where surgery is unsuitable/has failed DM, diabetes mellitus; IGT, impaired glucose tolerance

Pituitary-targeted agents

Indication

Cabergoline Off-label

Pasireotide Cushing’s disease*

Adrenal-directed agents

Indication

Metyrapone Off-label

Ketoconazole Off-label

Mitotane Off-label

LCI699 In development

Glucocorticoid receptor antagonists

Indication

Mifepristone Hyperglycemia in patients with

Cushing’s syndrome and DM/IGT*

Tratamento Futuro

1 – Pasireotide LAR

Dose = 30 mg 30/30 dias IM (LAR)

2 - Pasireotide LAR + Cabergolina

Dose = 30 mg 30/30 dias IM (LAR) + 1 mg / semana

3 – Ácido Retinóico

Mecanismo de ação: Ação no tumor

4 – LC 1699

Mecanismo de ação: Inibidor da B hidroxilase

(esteroidogênese)

Dose: 4 -> 100 mg / dia

Obrigado pela Atenção

www.endoville.com.br

Agradecimentos:

Dra. Julia Appel

Equipe Endoville

Aos nossos pacientes