clube da hipÓfise ano vii reunião iii/2013 · (hipopituitarismo) 2 – radioterapia (50–60%)...
TRANSCRIPT
Ecos do Pituitary e Endo 2013
Luíz Antônio de Araújjo
CLUBE DA HIPÓFISE
Ano VII – Reunião III/2013 24/07/2013
13 th PITUITARY CONGRESS
JUNE 12 – 14, 2013. San Francisco, CA
THE ENDOCRINE SOCIETY’S
95TH ANNUALK MEETING & EXPO
JUNE 15 – 18, 2013 – San Francisco, CA
Symposium Schedule
Cushing Diagnosis – New Options
Hershel Raff - USA
How to Differentiate Central from ACTH- Dependent
Cushing’s Syndrome
John Neweell-Price - UK
Peri-operative of Patients with Cushing’s Disease
Ashley Grossmann – UK
Cushing’s Disease: Evaluation and Management
Richard Feelders - Neetherlad
S. Cushing - Diagnóstico
Especificidade / Intervalo de Confiança
Cortisol pós Dexa 1mg(5)/2mg(1,8)90 (87 a 93)
Cortisol / urina de 24 horas 96 (93 a 98)
Cortisol salivar às 24 horas, RIA 84 (79 a 89)
Cortisol salivar às 24 horas, MS/MS 92 (88 a 95)
2 Testes: normal 84 - 90
Condições Associadas, drogas, coleta, ensaio…RIA
-> IRMA -> HPLC -> LC/MS/MS (espectrometria de massa)
Cushing – Diagnóstico de Localização
Testes com altas doses de dexametasona (8 mg)
ACTH basal
ACTH / Cortisol pós-DDAVP/CRH (50% / 30%)
Imagem : TC/RM*
Cateterismo Seletivo de Seios Petrosos Inferiores –
SPI (BIPPS)
ACTH pós DDAVP / CRH na SPI
Octreoscan
D. Cushing - Tratamento
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
When Surgery Fails ? 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)
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
Pasireotide
Adrenal-directed agents
Indication
Metyrapone
Ketoconazole
Mitotane
LC1699 In development
Glucocorticoid receptor antagonists
Indication
Mifepristone Hyperglycemia in patients with
Cushing’s syndrome and DM/IGT*
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
Periférica
2 – Metyrapone (250 a 6000mg / dia)
Pre - operative therapy of 62 patients with active disease
50% had normalized UFC; for 4 (1 – 31) months.
Side Effects:
Acne + hirsutism
Hypokalemia
Edema
Hypertension AVAILABILITY ?
Skin rash
Lethargy + dizziness
Nausea
Medicamentos de ação
Periférica
3 – Etomidate (0,04 a 0,05mg / kg / h IV)
Cortisol target levels (depending on clinical circumstances)
4 – LC 1699
Mecanismo de ação: Inibidor da B hidroxilase
(esteroidogênese)
Dose: 4 -> 100 mg / dia
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
Pasireotide
Adrenal-directed agents
Indication
Metyrapone
Ketoconazole
Mitotane
LC1699 In development
Glucocorticoid receptor antagonists
Indication
Mifepristone Hyperglycemia in patients with
Cushing’s syndrome and DM/IGT*
Medicamentos de ação
Periférica
3 – Mifepristone (300 a 1200mg /d)
Side Effects:
Acne + hirsutism
Fatigue
Edema
Hypokalemia
Headache
Lethargy + dizziness
Nausea + vomiting
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
Pasireotide
Adrenal-directed agents
Indication
Metyrapone
Ketoconazole
Mitotane
LC1699 In development
Glucocorticoid receptor antagonists
Indication
Mifepristone Hyperglycemia in patients with
Cushing’s syndrome and DM/IGT*
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 (1,2,3,5)
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
Tratamentos Combinados e
Futuro
1 – Cabergoline + Ketoconazole
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 (
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
LC1699 In development
Glucocorticoid receptor antagonists
Indication
Mifepristone Hyperglycemia in patients with
Cushing’s syndrome and DM/IGT*
Follow-Up After Surgery
Hidrocortisona: NÃO É ADMINISTRADA
Dosagens cortisol sérico: pré-op, 6h, 12h e 24h pós-op
Iniciada reposição glicocorticóide após insuficiência adrenal
Prednisona 5 mg vo às 8h
Dexametasona 0,5 mg vo às 8h
Cortisol sérico e urinário 10-12 dias após CTE
Coleta cortisol sérico 48h após dose de dexametasona
Após período de dependência ao glicocorticóide,
submetidos ao teste com 1mg de dexametasona “overnight”
anual
Symposium Schedule
Acromegaly Treatment
Vivien Bonert – USA (Cedars-Sinai MC)
Acromegaly: Diagnosis and Management
Peter Trainer - UK
Mannagement of Prolactinomas During Pregnancy
Syed Imran – Canada
Temozolamide and Aggressive Pituitary Tumours:
Longer –term Follow-up
Ann Mc Cormack - Australia
Controle Bioquímico: Cura/Controle
Giustina et al.,JCEM 95:3141-3148,2010
Controle bioquímico: Cura/Controle
Acromegalia curada/controlada:
GH randomico <1μg/litro
GH após TTOG 75g < 0.4 μg/litro
IGF-1 normal para idade e sexo
Taxas Cura: cirurgia
12-06 – Curada
1. Sheppard, M. Clinical Endocrinology 2003; 58: 387-99.
2. Nomikos P, et al. Eur J Endocrinol. 2005;152:379-87.
Preditores de Cura Cirúrgica
Valor basal do GH pré-operatório:
Avaliação de 61pacientes
Pre-op Cure rate
GH <40mU/L 70%
GH >40mU/l 22%
A Nasruddin, B Borland, PD Lees & DD Sandeman1 Endocrine Abstracts,2009
Taxas Cura: tto medicamentoso
3. Melmed S, et al. J Clin Endocrinol Metab. 2009;94:1509-17.
4. Colao A, et al. J Endocrinol Invest. 2006;29:1017- 20.
5. Neggers S, et al. J Clin Endocrinol Metab. 2007;92:4598-601.
Radioterapia
RT Convencional (fracionada)
RT Estereotáxica (dose única = radiocirurgia)
33
Eventos Adversos
dano cerebral (atrofia cerebral, gliose
hipotalâmica, alterações de lobo temporal,
radionecrose e acidente vascular cerebral)
perda visual
hipopituitarismo
hipogonadismo – 50%
insuficiência adrenal – 37%
hipotireoidismo central – 37%
tumores cerebrais secundários - 2% após 20
anos
34
Radioterapia
RT Convencional X RT Estereotáxica
Metanálise de 12 estudos IGF1 normalizou em
33%. (radiocirurgia estereotáxica ~ RT convencional).
Radiocirurgia em média após 1,6 anos
RT convencional em média de 7,1 anos
35
Barkan AL. Radiotherapy in acromegaly: the argument against. Clin Endocrinol (Oxf). 2003;58(2):132-5.
Recomendações
A Radioterapia está indicada nos casos em que as
outras modalidades terapêuticas falharam e,
especialmente, para tumores de comportamento mais
agressivo.
36
37
Preditores de Cura da
Acromegalia
PREDITORES DE CURA TTO CIRÚRGICO TTO CLÍNICO
IDADE SIM NÃO
TAMANHO DO TUMOR SIM CONTROVERSO
INVASIVIDADE DO TUMOR SIM ---
NÍVEL DE GH SIM SIM
EXPERTISE CIRÚRGICA SIM ---
HISTOLOGIA
IMUNOHISTOQUIMICA
SIM SIM
MARCADOR GENÉTICO SIM SIM
TESTE DOSE --- DESUSO
Evolução do tratamento
Individualizar/Analisar os preditores
Particularidades de cada centro
12-06 - Curada 4 C + OCT + CB + RT.
26 anos de evolução.
Curada
Management of Prolactinomas
During Pregnancy - Microadenomas
RNM: Não
Tratamento Farmacológico: Não
Mannagement of Prolactinomas
During Pregnancy - Macroadenomas
Mannagement of Prolactinomas
During Pregnancy _ Macroadenomas
Mannagement of Prolactinomas
During Pregnancy
RNM: Sim
Mannagement of Prolactinomas
During Pregnancy
Tratamento Farmacológico: Sim
Mannagement of Prolactinomas
During Pregnancy
Mannagement of Prolactinomas
During Pregnancy
Aborto Expontâneo: - / Gemelaridade: - Malformação Congênita: 3,9%
Temozolamide and Aggressive Pituitary
Tumours: Longer – term Follow-up –
Ann McCormack – Australia
34 pacientes (25 homens e 9 mulheres), idade
média de 52,7 anos, (24 adenomas, 10
carcinomas). média de 2,5 cirurgias e 1,5 Rt, com
Ki 67 >3% (20/24)
Média de 8,9 ciclos. Resposta hormonal em 61% e
radiológica em 67,7% / 3 meses -> 36 meses, com
redução da mortalidade
1 paciente responsivo: evolução da doença
11 pacientes responsivos: recurrência
Óbito em 27% responsivos x 67% não responsivos
Eventos adversos ???
Therapeutic Algorithm - ENDO
Obrigado pela Atenção
www.endoville.com.br
Agradecimentos: Dra. Julia Appel Dr. Andrei Koerbel Aos nossos pacientes