CLUBE DA HIPÓFISE Ano VII 27/02/2013 Futuro do Tratamento Clínico na Doença de Cushing

Transcrição

1 CLUBE DA HIPÓFISE Ano VII 27/02/2013 Futuro do Tratamento Clínico na Doença de Cushing Luíz Antônio de Araújjo

2 Tratamento da D. Cushing Transsphenoidal surgery is first-line therapy in Cushing s disease Initial success rate 68 98% in patients with a microadenoma 1,2 Remission rates lower (<65%) in patients with a macroadenoma 1 Relapse rate is 2 26% (after months) 2 1 Biller BMK et al. J Clin Endocrinol Metab 2008;93: ; 2 Tritos NA et al. Nat Rev Endocrinol 2011;104:

3 Cirurgia Transesfenoidal PRÉ PO Imediato CRH - CRH - - ACTH ACTH ACTH ACTH + CORTISOL +++ CORTISOL Cortisol - +

4 Conduta Persistência do hipercortisolismo Rescidiva Contra Indicação cirúrgica Recusa da cirurgia

5 Current second-line therapies in Cushing s disease Patients with persistent disease after surgery Repeat surgery Radiation therapy Medical therapy Bilateral adrenalectomy Biller BMK et al. J Clin Endocrinol Metab 2008;93:

6 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)

7 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 LC Medicamentos Antagonistas do Receptor Glicocorticóide. Mifepristone

8 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% 1 Castinetti F et al. Eur J Endocrinol 2008;158:91 99;

9 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)

10 Response at month 12 similar to that at month µg bid (n=82) 900 µg bid (n=80) Overall (n=162) 12 months 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 Fully controlled, n (%) 11 (13.4) 20 (25.0) 31 (19.1) *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 Partially controlled, n (%) 13 (15.9) 2 (2.5) 15 (9.3) Uncontrolled, n (%) 58 (70.7) 58 (72.5) 116 (71.6) Fully controlled: UFC ULN; partially controlled: UFC >ULN but had 50% reduction from baseline; uncontrolled: UFC >ULN and <50% reduction from baseline Colao A et al. N Engl J Med 2012;366:

11 Mean UFC (nmol/24h) Sustained reduction in mean UFC up to 24 months 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 µg bid 900 µg bid Reductions in serum cortisol and plasma ACTH, as well as improvements in signs and symptoms, were sustained ULN (145 nmol/24h) Core study (months) Extension phase (months) Pivonello R et al. ENEA 2012;abst OC05 Significant clinical benefit was determined at the discretion of the investigator

12 Recent advances in medical therapy Cabergoline Adrenal-directed agents Metyrapone Ketoconazole Mitotane LCI699 Mifepristone Pasireotide Indication Off-label Off-label Off-label In development Pituitary-targeted agents Indication Off-label Cushing s disease* Glucocorticoid receptor antagonists Indication Hyperglycemia in patients with Off-label Cushing s syndrome and DM/IGT* *In patients where surgery is unsuitable/has failed DM, diabetes mellitus; IGT, impaired glucose tolerance

13 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

14 Obrigado pela Atenção Agradecimentos: Dra. Julia Appel Equipe Endoville Aos nossos pacientes