CLUBE DA HIPÓFISE Ano VII Reunião III/2013 · (hipopituitarismo) 2 – Radioterapia (50–60%)...

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