TUMORES NEUROENDÓCRINOS GASTROENTEROPANCREÁTICOS...

Mariano Dioca

SERIVIO DE ONCOLOGIA MEDICA INSTITUTO DE ONCOLOGIA ÁNGEL H.ROFFO, UBA

15 de marzo de 2012

TUMORES NEUROENDÓCRINOS GASTROENTEROPANCREÁTICOS

TNE-GEP

INTRODUCCIÓN

1- Son tumores originados en células enterocromafines.

2-tienen una amplia distribución en todo el organismo.

3-Las CE son las células endocrinas más comunes y se identifican con mayor

frecuencia en la submucosa del intestino y de bronquios.

4-Sin importar su origen primario, todos los tumores carcinoides comparten

características histológicas, inmunohistoquimicas y ultraestructurales, pueden

producir o contener una variedad de aminas, péptidos, y prostaglandinas.

5-El carcinoide, es el tumor endócrino más común del tracto gastrointestinal .

DATOS HISTÓRICOS

1. Primeras descripciones de un tumor carcinoide fueron realizadas

por Lubarsh en 1888.

2. El carcinoide de íleon fué descripto por primera vez por Ranson

en 1890.

3. Oberndorfer utilizó el termino ―karzinoide‖ para describir

aquellos tumores que tenían un comportamiento más indolente

que el adenocarcinoma.

4. El término ―síndrome carcinoide‖ es utilizado para describir las

complejas manifestaciones producidas por la liberación sistémica

de uno o más de sus componentes.

4 4

NETs Are Often Diagnosed Late

Vinik AI, Silva MP, Woltering EA, et al. Pancreas. 2009;38:876-889.

1 2 3 4 5 6 7 8 9

Time (yr)

Primary tumour growth

Metastases

Flushing

Diarrhea

Death

Vague abdominal symptoms

Estimated time to diagnosis: 5 to 7 yr

*

*

*Symptoms of carcinoid syndrome

5 5

Localized Metastatic

50%

27%

23%

Distant metastases

Regional spread

Data from an analysis of 28,515 cases of NET identified in the SEER registries

Yao JC, Hassan M, Phan A, et al. J Clin Oncol. 2008;26:3063-3072.

*These data are of the cases in which stage was reported.

20% of cases did not provide disease stage information

Metastatic Disease Is Common at Presentation

Tumores neuroendocrinos (TNEs): Un grupo diverso

de neoplasias malignas, un desafío clínico

Tumores que se originan en las células enterocromafines localizadas en el tejido neuroendocrino en todo el organismo

Los TNEs se presentan con síntomas funcionales y no funcionales e incluyen un grupo heterogéneo de neoplasias 1,2

– Neoplasia endocrina múltiple (NEM), tipo 1 y tipo 2/carcinoma medular de tiroides

– Tumores neuroendocrinos gastroenteropancreáticos (TNE-GEP)

– Tumores de células de los islotes

– Feocromocitoma/paraganglioma

– Carcinoide pulmonar poco diferenciado/ de células pequeñas/atípico

– Carcinoma de pulmón de células pequeñas

– Carcinoma de células de Merkel

Referencias: 1. Dorland’s Medical Dictionary Web site. Available at: http://www.dorlands.com. Accessed November 10, 2008. 2. Modlin IM, Kidd M, Latich I,2. Zikusoka MN, Shapiro MD. Current status of gastrointestinal

carcinoids. Gastroenterology. 2005;128:1717-1751.

CARACTERÍSTICAS DE TUMORES CARCINOIDES

CLASIFICACIÓN

.Williams y Sandler clasificaron a los tumores carcinoides basándose en su

probable sitio embriológico de origen.

.Los tumores en cada grupo tienen distintas características histológicas así

como también distinto metabolismo y productos secretorios.

8 8

Segun sitio embriologico de origen

Generally characterized by their ability to produce peptides that may lead to associated syndromes (functional vs nonfunctional)1,2

Historically classified based on embryonic origin3

Foregut tumours

Midgut tumours

Hindgut tumours

Today, primary tumour location is recommended for NET classification4

1. Modlin IM, Öberg K, Chung DC, et al. Lancet Oncol. 2008;9:61-72. 2. Modlin IM, Kidd M, Latich I, et al. Gastroenterology. 2005;128:1717-1751.

3. NCCN. In: Practice Guidelines in Oncology. V.1. 2008. February, 2008. 4. Klimstra DS, Modlin IM, Adsay NV, et al. Am J Surg Pathol. 2010;34:300-313.

Foregut • Thymus

• Esophagus

• Lung

• Stomach

• Pancreas

• Duodenum

Midgut • Appendix

• Ileum

• Cecum

• Ascending colon

Hindgut • Distal large bowel

• Rectum

La clasificación de la OMS agrupa los

TNEs por factores diagnósticos

Referencias: 1. Strosberg JR, Nasir A, Hodul P, Kvols L. GI Cancer Res. 2008; 2:113-125. 2. Klöppel G, Perren A, Heitz PU. Ann Ny Acad Sci. 2004; 1014:13-27.

Clasificación de la OMS

Tumor neuroendocrino

bien diferenciado1,2

Carcinoma neuroendocrino

bien diferenciado1,2

Carcinoma neuroendocrino

poco diferenciado,2

Comportamiento biológico

Baja malignidad Baja malignidad Alta malignidad

Metástasis – + +

Índice Ki-67 (%) <2 >2 >10

Infiltración, angioinvasión

– + +

Tamaño del tumor ≤2 cm

>2 cma

>2 cm

>3 cma Cualquier tamaño

aTNE de páncreas

Pronóstico de pacientes con TNEs

Bueno Malo

?

WHO 1980 WHO 2000 WHO 2010

I. Carcinoid

Well-differentiated endocrine tumour

(WDET)

Well-differentiated endocrine

carcinoma (WDEC)

Poorly differentiated endocrine

carinoma/small-cell carcinoma (PDEC)

Neuroendocrine tumours

Grade 1

Grade 2

Neuroendocrine carcinoma

Grade 3

II. Mucocarcinoid

III. Mixed forms carcinoid-

adenocarcinoma

Mixed exocrine-endocrine carcinoma

(MEEC)

Mixed adenoneuroendocrine

carcinoma (MANEC)

IV. Pseudotumour lesions Tumour-like lesions (TLL) Hyperplastic and preneoplastic

lesions

Bosman FT, et al. WHO Classification of Tumours of the Digestive System. Lyon, France: IARC Press; 2010.

Clasificación WHO año 2010

11

Premisa: “Todas Las Neoplasias

Neuroendócrinas son potencialmente

malignas…”

WHO Classification 2010: Neuroendocrine Neoplasms of the GEP System

EPIDEMIOLOGIA

1. La incidencia global de los tumores carcinoides (TC) es de 1 a 2 casos

por cada 100.000 habitantes en los Estados Unidos.

Similar a varios paises de Europa.

2. En Argentina? ………..no hay datos disponibles.

3. Esta incidencia varia de acuerdo al género, edad, y raza.

4. La distribución de TC en series de autopsias difiere de lo reportado en

los estudios clínicos.

5. Una serie de autopsias de la clínica Mayo y de Malmo, Suecia, reportaron

que la incidencia de TC es de 0.65 a 1.2 %, lo cual representa el 28% de

todas las neoplasias del intestino delgado.

6. Se diagnostican en la 5ta. o 6ta. década de la vida .

7. Tienen una incidencia mas alta en afro-americanos

EPIDEMIOLOGIA

1. Al momento del diagnóstico, 40-60 % de los Ptes. están asintomáticos.

LA INCIDENCIA SE ENCUENTRA EN

AUMENTO??

EPIDEMIOLOGIA

EPIDEMIOLOGIA

1. La incidencia aumentó de 1,09/100.000 (año 73) a 5,25/100.000 (año 2004).

2. El sitio primario mas fte. varió según raza y sexo.

Mujeres: mayor tendencia a 1rios en pulmón, estómago, apéndice y ciego.

Hombre: timo,duodeno, páncreas, yeyuno-íleon, y recto.

-Pulmón fué el NET prio. más fte en blancos (30%), yeyuno-íleon también (17%)

17 17

Incidence of NETs Is Increasing*

SEER = Surveillance, Epidemiology, and End Results (for malignant NETs)

*Approximate 5-fold increase between 1975 and 2004

Approximate 7-fold increase also evident in Norwegian registry

Incid

en

ce P

er

100,0

00

1.40

Year

NET Site

1.20

1.00

0.80

0.60

0.40

0.20

0

Lung

Colon

Small intestine

Rectum

Pancreas

Yao JC, Hassan M, Phan A, et al. J Clin Oncol. 2008;26:3063-3072.

La incidencia de TNE aumenta con más

rapidez que otras neoplasias malignas

Adaptada con permiso. Yao JC, Hassan M, Phan A , et al. J Clin Oncol. 2008;26:3063–3072.

19 19 La Rosa S, Klersy C, Uccella S, et al. Hum Pathol. 2009;40:30-40.

Correlacion del TNM Staging

con Sobrevida

Patients With Well-Differentiated Pancreatic NET

Stage I

P<0.001

Pro

po

rti

on

Alive

Stage II

Stage III

Stage IV

I (n = 44)

II (n = 44)

III (n = 34)

IV (n = 33)

Time (mo)

0.00

0.25

0.50

0.75

1.00

0 48 96 144 192 240

Sobrevida

1.La mediana de sobrevida fué de 75 meses.

2-G1 (124 meses). G2 (64 meses). G3 y G4 (10 meses).

3-Edad al dx. raza y sexo, también fueron fact.pronósticos.

Siendo las mujeres en todas las categorías quienes tuvieron

mayores sobrevidas.

4-Sitio primario: también fué un potente predictor de

sobrevida.

EPIDEMIOLOGIA (sobrevida)

El uso de análogos de la somatostatina

impacta en la sobrevida??

Sobrevida según año de

diagnostico (JCO-Yao, jun/08)

Metodos Diagnósticos

HISTOLOGIA II

(IHQ) Marcan cromogranina, sinaptofisina, y enolasa neuroespecifica. Los elementos ultraestructurales identificados por microscopia electrónica (ME) son los gránulos neurosecretorios densos, pero en la practica la ME se utiliza poco debido a la rapidez y al bajo costo de la IHQ.

La determinación de ki-67 permite dividir estos pacientes en dos grupos:

.ki-67 < al 10%, lo cual determinará enfermedad de lenta progresión.

.> al 10% que implicará un curso más agresivo, con mayor potencial de invasión y metástasis, este último grupo será pasible de tratamiento quimioterápico.

Diagnóstico y evaluación de los TNEs

La constelación de síntomas puede

dificultar el diagnóstico diferencial1,2

Menopausia

SII

Enfermedad intestinal funcional

Ansiedad

Neurosis

Alergia a los alimentos

Edema

Asma

Alcoholismo

Tirotoxicosis

Úlcera péptica

TNE

Síntomas

• Sudoración

• Enrojecimiento

• Diarrea

• Dolor abdominal

intermitente

• Broncoconstricción

• Sangrado GI

• Cardiopatía

Referencias: 1. Vinik A Moattari AR. Dig Dis Sci. 1989;34(3)Supp1:14S-27S. 2. Toth-Fejel S, Pommier RF. Am J Surg. 2004;187:575-579.

Los síntomas inespecíficos son comunes a múltiples diagnósticos

Los TNEs son en su mayoría asintomáticos hasta que

son metastásicos1

• Algunos TNE producen síntomas locales inespecíficos que se deben a los efectos de la masa tumoral y son similares a otros tumores sólidos malignos en una localización anatómica dada1 — Síntomas abdominales imprecisos

— Obstrucción intestinal

— Ictericia debida a obstrucción del conducto biliar

Los síntomas sistémicos son consecuencia de las hormonas peptídicas liberadas por el tumor2

— Síndrome carcinoide

— Diarrea acuosa, hipocalemia, aclorhidria

— Síndrome glucagonoma

— Síndrome de Zollinger-Ellison

— Síndrome hipoglucémico

Referencias: 1. Modlin IM, Moss SF, Chung DC, Jensen RT, Snyderwine E. J Natl Cancer Inst. 2008;100(18):1282-1289. 2. Mougey AM, Adler DG. Neuroendocrine tumors: review and clinical update. Hosp Phys. 2007;51:12-20.

DIAGNÓSTICO

1-MARCADORES

A. 5-HIAA (normal de 2-8 MG/24hs.) . 50% tienen niveles

urinarios elevados aún sin evidencia de síndrome carcinoide.

Un nivel anormal tiene sensibilidad del 70% y una especificidad

del 88 a 100%; los niveles se correlacionan con la carga

tumoral. Pero…..

Vegetales y frutas incluyendo la banana, el kiwi, el aguacate, los platanos,

el tomate, la guaifenesina, el acetaminofen, los salicilatos, y la l-dopa

pueden afectar los niveles urinarios del 5-HIAA.

B-Cromogranina A (CGA), es una proteína de 49-kD

contenida en los gránulos neurosecretorios de células de

tne.

.Es un marcador útil para medir respuesta a

tratamiento, y podría tener un valor pronostico.

Cromogranina A (CgA): Una valiosa

herramienta diagnóstica y pronóstica

Un nivel sérico elevado de CgA y/o tinción inmunohistoquímica (IHC) del tumor para CgA es diagnóstico de TNEs

Ofrece una sensibilidad del 85% y una especificidad del 96% para TNEs1

La CgA se usa para monitorear la respuesta al tratamiento

Referencias: 1. Campana D, Nori F, Piscitelli L, Norselli-Labate AM, et al. J Clin Oncol. 2007; 25(15):1967-1973. 2. Peracchi M, Conte D, Gebbia C, et al. Eur J Endocrinol. 2003;148:39-43.

3. Eriksson B, Öberg K, Stridsberg M. Digestion. 2000;62(suppl 1):33-38.

Cromogranina A (CgA)

Clara correlación entre carga tumoral y concentraciones séricas de

CgA2

Las mediciones de CgA se han vuelto el parámetro más importante para el

diagnóstico y el monitoreo de TNE3

Referencias: 1. Oberg K, Stridsberg M. Adv Med Biol. 2000;482:329-337. 2. Taupenot L, Harper KL, O’Connor DT. N Engl J Med. 2003;348:1134-1149. 3. Ardill JE, Erikkson B. Endocr Relat Cancer. 2003;10:459-462.

La CgA sérica como indicación de presencia

tumoral1

DIAGNÓSTICO POR IMÁGENES

3-DIAGNÓSTICO POR MEDICINA NUCLEAR

a.Mas del 80% de los TC expresan receptores de membrana para

somatostatina. El análogo de la somatostatina (octreotide), se utiliza

tanto en la detección como en el tratamiento de carcinoides,

cuando se lo utiliza marcado con Indio 111 se une a los receptores

de somatostatina 2 y 5.

b.El Centellograma con analogos de la somatostatina marcado con

indio o Tc99 tiene una sensibilidad del 80 al 90%, Es uno de los

estudios mas importantes para localizar TC primarios y sus Mtts.

C.Predice la respuesta a la terapia con análogos de la somatostatina,

la intensidad de la marcación indica el nivel de concentración de

receptores.

Indio In-111 Pentetreotida (Octreoscan™)

Imagen del Octreoscan

• Detecta y localiza TNEs y metastásis1

• Estadificación de los TNEs1

• Seguimiento de los pacientes para evaluar recurrencia1

• Selección de pacientes con enfermedad metastásica para tratamiento con radionúclidos del receptor de péptidos2

Referencias: 1. Mougey AM, Adler DG. Neuroendocrine tumors: review and clinical update. Hosp Phy. 2007;43(11):12-20. 2. Kenning EP, Kwekkeboom DJ, Bakker WH, et al. Somatostatin receptor scintigraphy with

[IIIIn-DTPA-D-Phe1]- an [123]-Ty3]-octreotide: the Rotterdam experience with more than 1000 patients. Eur J Nucl Med. 1993;20(8):716-731.

-PET SCAN

1-FDG-PET: Recomendable solo en tumores pobremente

diferenciados y con elevada tasa de proliferacion. No sera

util en tumores bien diferenciados con bajo metabolismo.

2-PET-5-HTP ? Esperiencia de la Universidad de Uppsala.

PET/CT con 68Ga-DOTATATE presenta ventajas sobre los exámenes

convencionales al mostrar en una sola imagen de fusión la sobreexpresión local

de receptores de somatostatina. Las imágenes son claramente de mejor

resolución, menor costo y de disponibilidad permanente en comparación con la

cintigrafía SPECT con 111In-Octreotide. Por lo tanto, el estudio con imágenes

PET/CT con 68Ga-DOTATATE debería ser la técnica de elección para el

diagnóstico, etadificación, re-estadificación y control de tratamiento de tumores

neuroendocrinos. Adicionalmente esta técnica permite seleccionar ptes para

tratamiento sistémico con péptidos radioactivos.

41

Tumores Neuroendócrinos Avanzados

La evolución de la terapia

Factors Influencing the Therapeutic

Decision

• Type of NET

• TNM stage and grade

• Extent of liver involvement

• Functioning vs nonfunctioning tumour

• Patient’s performance status

• Availability of different therapeutic modalities

Most patients receive a combination of treatment modalities

Current Systemic Treatment Options for

Patients With Advanced NETs

Somatostatin analogues

Interferon-alfa

Chemotherapy

Peptide receptor–targeted therapy

Molecular-targeted therapies

44

48 48

Expression of sstr in NET Subtypes

Prevalence on NET type1:

Carcinoid 76% 80% 43% 68% 77%

Gastrinoma 79% 93% 36% 61% 93%

Insulinoma 76% 81% 38% 58% 57%

Nonfunctioning islet cell tumour 58% 88% 42% 48% 50%

Inhibitory effect2,3:

Hormone secretion + + +

Proliferation + + + +

Induction of apoptosis + +

1. Hofland LJ. J Endocrinol Invest. 2003;26 (8 suppl):8-13. 2. Ferrante E, Pellegrini C, Bondioni S, et al. Endocr Relat Cancer. 2006;13:955-962.

3. Susini C, Buscail L. Ann Oncol. 2006;17:1733-1742.

sstr2 is the most prevalent

49 49

Therapy Targeting Somatostatin

Pathway

Caspase 8 p53 Bax

Growth and proliferation

secretion ligands

IGF-1R

IGF-1

Angiogenesis

Survival

signaling

SHP1

Ca2·

K+ sstr1-5

sst analogue

NFcb

Protein synthesis

transcription growth and proliferation

apoptosis

Broader Binding Profile of Pasireotide May

Provide Greater Therapeutic Benefit

51 51

Octreotide LAR for Symptom Relief

Octreotide LAR is a somatostatin analogue currently indicated for

symptom relief in patients with functionally active neuroendocrine

tumours (NETs)1

Octreotide reduces severe diarrhea and flushing episodes

Octreotide LAR targets somatostatin receptors (sstr), specifically

subtype 2, to inhibit hypersecretion of hormones and bioactive

amines and peptides2

Approximately 80% of NETs express sstr23

sstr2 is considered of particular therapeutic relevance because of its

abundance in GI and pNETs3

sstr1–3 function to reduce tumour secretions and inhibit tumour growth

by promoting apoptosis and cell cycle arrest4

1. Sandostatin® [prescribing information]. East Hanover, NJ; Novartis Pharmaceuticals Corporation; 2010. 2. Öberg K, Kvols L, Caplin M, et al.

Ann Oncol. 2004;15:966-973. 3. Hofland LJ, Lanberts SWJ. Endocr Rev. 2003;24:28-47. 4. Florio T. Front Biosci. 2008;13:822-840.

52 52

42% REDUCTION in

Diarrhea Frequency1,2

4.3

2.5

0

1

2

3

4

5

Baseline Week 24

Med

ian

Nu

mb

er

of

Sto

ols

/Day

1. Rubin J, Ajani J, Schirmer W, et al. J Clin Oncol.1999;17:600-606. 2. Anthony L, Freda PU. Curr Med Res Opin. 2009;25:2989-2999.

4.5

0.7

0

1

2

3

4

5

Baseline Week 24

Med

ian

Nu

mb

er

of

Flu

sh

ing

s/D

ay

84% REDUCTION in

Flushing Frequency1,2

N = 47 N = 33

Octreotide LAR Provides Effective

Symptom Relief

Octreotide: Direct Antiproliferative

Effect

sst2

sst5

↑ Apoptosis ↓ Cell growth

PI3K

PDK1

Akt

GSK3β

p53

↑Zac1

mTOR

p70S6K

sst2

JNK

G protein

SHP1

NF-KB

G protein

G protein

SHP1

SHP2

Src

PTPŋ

MAPK

p27

cGMP ↓

PKG ↓

• sst2 and sst5 binding

downregulates MAPK

• sst2 binding effects the

P13K/Akt/mTOR pathway

and SHP1 signalling

• Antiproliferative effect also mediated via protein tyrosine phosphatase (PTPase) modulation

1. Theodoropoulou M, Zhang J, Laupheimer S, et al. Cancer Res. 2006;66:1576-1582. 2. Florio T. Front Biosci. 2008;13:822-840. 3. Grozinsky-Glasberg S,

Franchi G, Teng M, et al. Neuroendocrinol. 2008;87:168-181. 4. Susini C, Buscail L. Ann Oncol. 2006;17:1733-1742.

54

Direct and Indirect Antiproliferative

Effects of Octreotide LAR

Susini C, Buscail L. Ann Oncol. 2006;17:1733-1742.

Indirect antiproliferative effect

Antiproliferative effect of

octreotide

Binding of the

somatostatin receptor on

tumour cells

Direct antiproliferative effect

Inhibition

of growth

factor

effects

Inhibition

of cell cycle

Pro-

apoptotic

effect

Systemic effect

Inhibition of

growth factor

and trophic

hormones

Immune

system

modulation

Inhibition of

angiogenesis

Combination Strategies for Advanced

NETs

SSA Angiogenesis

inhibitors Cytotoxics

GFR Inhibitors

(IGF/EGF)

PRRT

(sequential)

Loco-regional

Tx Interferon-alfa

mTOR inhibitors

Somatostatin analogues are the least toxic drugs –

a suitable partner for combination with other agents

59 59

Pancreatic Neuroendocrine Tumours

(pNETs)

Annual incidence of 3 per million (SEER)1

1% of pancreatic malignancies by incidence; 10% by

prevalence2

Median OS in patients with distant disease is

approximately 2 yr from time of diagnosis and has not

changed for 20 yr1,2

Limited treatment options are available for pNETs; there

is an unmet need for novel therapies in this patient

population

1. Yao JC, Hassan M, Phan A, et al. J Clin Oncol. 2008;26:3063-3072. 2. Yao JC, Eisner MP, Leary C, et al. Ann Surg Oncol. 2007;14:3492-3500.

60 60

Involvement of VEGF in the Angiogenesis of

NET

NETs are highly

vascularized and express

VEGF and VEGF-R1

VEGF expression

correlates with

decreased PFS duration2

Angiogenesis inhibitors

that target VEGF have

been shown to have

clinical activity in NET3

1.Yao JC, Phan AT, Hoff PM, et al. J Clin Oncol. 2008;26:1316-1323. 2. Phan AT, Wang L, Xie K, et al. J Clin Oncol. 2006;24(18s suppl). Abstr 4091.

3. Eriksson B. Curr Opin Oncol. 2010;22:381-386.

IGF-1

HER2

EGF

Metabolism

TSC1/2

PTEN

Aberrantly activated PI3K/AKT/mTOR pathway

tumour Cell


IGF-1R

mTOR ERK

RAF

MEK

EGFR

PDGFR

PDGF

Angiogenesis

Endothelial Cell

VEGF

VEGFR

Survival

Angiogenic factors

Angiogenesis

Compound VEGFR PDGFR FGFR KIT

FLT-3

RET RAF-K

SUNITINIB

SORAFENIB

VATALANIB

Angiogenesis Proliferation

PAZOPANIB

Small Molecule TKIs Evaluated in NETs

62 62

Phase III Trials of Targeted Therapies in

Pancreatic Neuroendocrine Tumours (pNETs)

Two randomized, placebo-controlled, phase III trials have demonstrated clinical benefit in patients with advanced pNET

Study A6181111: Sunitinib (multitargeted tyrosine kinase inhibitor [VEGFR, PDGFR]) vs placebo1

RADIANT-3: Everolimus (mTOR inhibitor) vs placebo2

1. Raymond E, Dahan L, Raoul J-L, et al. N Engl J Med. 2011;364:501-513. 2. Yao JC, Shah MH, Ito T, et al. N Engl J Med. 2011;364:514-523.

63 63

Sunitinib vs Placebo in Advanced pNET Phase III randomized, placebo-controlled, double-blind trial

Trial stopped after early unplanned analysis showed efficacy and safety benefit

Primary Endpoint: PFS

Secondary Endpoints: OS, ORR, TTR, duration of response, safety, and patient-reported outcomes

Patients with

advanced pNET,

N = 171/340

patients enrolled

Sunitinib 37.5 mg/day orally

Continuous daily dosing*

n = 86

Placebo*

n = 85

*With best supportive care

Somatostatin analogues were permitted

Raymond E, Dahan L, Raoul J-L, et al. N Engl J Med. 2011;364:501-513.

Study A6181111

1:1

R

A

N

D

O

M

I

Z

E

64 64

Key Eligibility Criteria

Advanced well-differentiated pNET

Radiologic disease progression within 12 mo

Measurable disease per RECIST criteria

WHO PS <2, adequate blood counts and serum chemistry

Exclusion criteria

Previous tyrosine kinase or VEGF inhibitor treatment

Cardiac events or pulmonary embolism within 12 mo

Cardiac dysrhythmias, prolonged QTc, or LVEF ≤50%

Brain metastases

Study A6181111


65 65

Baseline Characteristics

Sunitinib (N = 86)

Placebo (N = 85)

Median age, yr (range) 56 (25–84) 57 (26–78)

Male, n (%) 42 (49) 40 (47)

Female, n (%) 44 (51) 45 (53)

ECOG Performance Status, n (%)

0 53 (62) 41 (48)

1 33 (38) 43 (51)

2 0 1 (1)

Number of disease sites, n (%)

1 30 (35) 23 (27)

2 31 (36) 26 (31)

≥3 24 (28) 35 (41)

Presence of distant metastases, n (%)

Any, including hepatic 82 (95) 80 (94)

Extrahepatic 21 (24) 34 (40)


Study

A6181111

66 66

Prior Therapies

Sunitinib

(n = 86)

Placebo

(n = 85)

Somatostatin analogues, n (%) 30 (35) 32 (38)

Systemic chemotherapy, n (%) 57 (66) 61 (72)

Streptozocin 24 (28) 28 (33)

Anthracyclines 27 (31) 35 (41)

Fluoropyrimidines 20 (23) 25 (29)


Study A6181111

67 67

0.8

0.6

0.4

0.2

0

1.0

Pro

po

rti

on

of

Pati

en

ts

5 10 15 20 25 0

Sunitinib

39 19 4 0 0 86 Sunitinib

28 7 2 1 0 85 Placebo

Number at risk

Time (mo)

Placebo

Kaplan-Meier median PFS

Sunitinib: 11.4 mo

Placebo: 5.5 mo

HR = 0.42 (95% CI, 0.26–0.66) P<0.001

Progression-free Survival*


Study A6181111

* Local review

68 68

Subgroup PFS Analysis


Cox proportional-hazards analysis

Subgroup No. All Patients 171 Age <65 yr 126 ≥65 yr 45 Race White 101 Nonwhite 70 Sex Male 82 Female 89 ECOG Performance Status 0 94 1 or 2 77 No. of disease sites ≤2 112 ≥3 59 Type of disease Extrahepatic distant 55 Regional 114 Use of somatostatin analogue No 103 Yes 68 No. of previous systemic regimens 0 or 1 121 ≥2 50 Functioning tumour No 86 Yes 46 Ki67 ≤5% 43 >5% 29 Interval between diagnosis and randomization <3 yr 89 ≥3 yr 82

0.42 (0.26-0.66) 0.47 (0.28-0.79) 0.22 (0.07-0.70) 0.49 (0.26-0.92) 0.35 (0.18-0.70) 0.37 (0.20-0.70) 0.48 (0.24-0.94) 0.40 (0.22-0.74) 0.45 (0.22-0.94) 0.44 (0.24-0.77) 0.43 (0.20-0.94) 0.54 (0.24-1.17) 0.41 (0.23-0.74) 0.41 (0.22-0.75) 0.43 (0.21-0.89) 0.33 (0.19-0.59) 0.61 (0.27-1.37) 0.26 (0.13-0.54) 0.75 (0.30-1.84) 0.38 (0.16-0.92) 0.63 (0.24-1.71) 0.43 (0.24-0.79) 0.29 (0.13-0.66)

1.0 2.0 0.0

Sunitinib Better Placebo Better

Hazard Ratio (95% CI)

Study A6181111

69 69

RECIST 1.1*

Objective Tumour Responses1

Sunitinib

(n=86)

Placebo

(n=85)

Best tumour response, n (%) Complete response Partial response Stable/no response Objective progression Not evaluable

2 (2) 6 (7)

54 (63) 12 (14) 12 (14)

0 0

51 (60) 23 (27) 11 (13)

Objective response rate (95% CI) 9.3% (3.2–15.4) 0

P=0.007

Median time to response, mo (range) 3.1 (0.8–11.1) -

Duration of response, mo (range) 0.9 to >15.0 -

Response Rates

1. Raymond E, Dahan L, Raoul J-L, et al. N Engl J Med. 2011;364:501-513. 2. Eisenhauer EA, Therasse P, Bogaerts J, et al. Eur J Cancer 2009;45:228-247.

* Confirmation not required when PFS is primary endpoint.2

Study A6181111

70 70

Maximum % Change From Baseline*


Confirmed partial or complete response

Placebo Sunitinib

-100

-80

-40

-20

20

40

Ch

an

ge F

rom

Base

lin

e (

%)

-60

0

60

*In sum of longest diameters of target lesions

Study A6181111

71 71

Overall Survival Analysis

1. Raymond E, Dahan L, Raoul J-L, et al. N Engl J Med. 2011;364:501-513.

0

6-mo survival:

Sunitinib: 92.6% (95% CI, 86.3–98.9) Placebo:

85.2% (95% CI, 77.1–93.3)

20

40

60

80

100

Pro

bab

ilit

y o

f O

vera

ll S

urviv

al (%

)

Time (mo) Since Randomization

0 5 10 15 20 25

No. at Risk

Sunitinib 86 60 38 16 3 0

Placebo 85 61 33 12 3 0

HR = 0.41 (95% CI, 0.19–0.89)

P=0.02 (2-sided unstratified log-rank test)

Placebo

Sunitinib

Study A6181111

72 72

Adverse Events

Sunitinib toxicities were similar to those seen in other tumour types

Grade 3/4 AEs (≥ 5%) in the sunitinib arm included neutropenia (12%), hypertension (10%), leukopenia (6%), PPE* (6%), asthenia (5%), diarrhea (5%), fatigue (5%), and abdominal pain (5%)

Most frequently reported all-grade AEs with sunitinib were diarrhea (59%), nausea (45%), asthenia (34%), vomiting (34%), and fatigue (33%)

Grade 5 AEs

Sunitinib: 1 drug related—cardiac failure

Placebo: 1 drug related—dehydration

* Palmar-plantar erythro-dysesthesia


Study A6181111

73 73

Quality of Life

EORTC QLQ-C30 data analyzed for the first 10 cycles

Sunitinib: 73/86 patients

Placebo: 71/85 patients

No significant difference between arms in global health-related

quality of life

Patients in the sunitinib group had clinically and statistically

significant worsening of diarrhea compared with patients in the

placebo group


Study A6181111

74 74

Conclusion

Sunitinib provided a clinically meaningful 5.9 month

improvement in median PFS compared with placebo

in patients with advanced pNETs

Toxicities were consistent with those observed in

other trials of sunitinib


Study A6181111

75 75

Rationale for mTOR Inhibition in NETs

mTOR is a central regulator of growth, proliferation, cellular metabolism, and angiogenesis1-3

mTOR pathway activation is observed with genetic cancer syndromes associated with pNET4

TSC2, NF1, VHL

Everolimus has demonstrated antitumour activity in pNETs in 2 phase II studies5,6

1. O’Reilly T, McSheehy PM. Transl Oncol. 2010;3:65-79. 2. Meric-Bernstam F, Gonzalez-Angulo AM. J Clin Oncol. 2009;27:2278-2287.

3. Faivre S, Kroemer G, Raymond E. Nat Rev Drug Disc. 2006;5:671-688. 4. Jiao Y, Shi C, Edil BH, et al. Science. 2011 Jan 20 [Epub ahead of print]. 5. Yao

JC, Phan AT, Chang DZ, et al. J Clin Oncol. 2008;26:4311-4318. 6. Yao JC, Lombard-Bohas C, Baudin E, et al. J Clin Oncol. 2010;28:69-76.

VHL

TSC1/

2

PTEN

NF1

ligand and receptor expression IGF-1

IGF-1R

IGF-1 VEGF

VEGFR

Metabolism

mTOR inhibition blocks downstream tumourigenic effects of aberrantly activated PI3K/AKT/mTOR pathway

sstr


Angiogenesis

IGF-1R

Negative feedback

Activated AKT may stimulate pathways that bypass mTOR

mTOR

Survival

X

X X X X

mTOR inhibitor

Altered Expression of mTOR Pathway

Proteins in pNETs

71

58

85

0

10

20

30

40

50

60

70

80

90

Perc

en

tag

e o

f P

rim

ary

pN

ET

s

(N =

137)

Low TSC2 Low PTEN Low TSC2,

PTEN or both

Missiaglia E, Dalai I, Barbi S, et al. J Clin Oncol. 2010;28:245-255.

• Most primary pNETs express low levels of TSC2 and/or PTEN, which are key

inhibitors of the mTOR pathway

TSC2 = tuberous sclerosis 2; PTEN = phosphatase and tensin homologue

TSC2

PTEN

Low High

76

77 77

mTOR Pathway in Sporadic pNETs

0 5 10 15 20

High-level TSC2

Low-level TSC2

Overa

ll S

urviv

al

Time (yr)

1.0

0.5

0 5 10 15 20

High-level TSC2 Low-level TSC2

Pro

gre

ssio

n-f

ree

Su

rviv

al

Time (yr)

1.0

0.5

Time (yr)

0

High-level PTEN

Low-level PTEN

Pro

gre

ssio

n-f

ree

Su

rviv

al

1.0

0.5

5 10 15 20

Missiaglia E, Dalai I, Barbi S, et al. J Clin Oncol. 2010;28:245-255.

TSC2 Expression

PTEN Expression

78 78

RADIANT-3 Study Design

Everolimus 10 mg/d +

best supportive care*

n = 207

Placebo +

best supportive care*

n = 203

Multiphasic CT or MRI performed every 12 wk

Treatment

until disease

progression

Patients with

advanced pNET,

N = 410

Stratified by:

• WHO PS

• Prior chemotherapy

Crossover

1:1

*Concurrent somatostatin analogues allowed

R

A

N

D

O

M

I

Z

E

Primary endpoint:

• PFS (RECIST)

Secondary endpoints:

• Response, OS, biomarkers, safety, and PK

Randomization August 2007—May 2009

Phase III Double-blind, Placebo-controlled Trial

Yao JC, Shah MH, Ito T, et al. N Engl J Med. 2011;364:514-523.

79 79

Key Eligibility Criteria Advanced low- or intermediate-grade pNET

Radiologic disease progression within 12 mo

Measurable disease per RECIST criteria

Multiphasic CT scan or MRI

Prior antitumour therapy allowed

WHO PS <2, adequate blood counts and serum

chemistry


RADIANT-3

80 80

Baseline Patient Characteristics

Everolimus 10 mg (n = 207)

Placebo (n = 203)

Median age, yr (range) 58 (23–87) 57 (20–82)

Male (%) 110 (53) 117 (58)

Female (%) 97 (47) 86 (42)

WHO Performance Status (%)

0 139 (67) 133 (66)

1 62 (30) 64 (32)

2 6 (3) 6 (3)

Number of disease sites (%)

1 51 (25) 62 (31)

2 85 (41) 64 (32)

≥3 70 (34) 77 (38)

Histologic grade (%)

Well-differentiated 170 (82) 171 (84)

Moderately differentiated 35 (17) 30 (15)

Unknown 2 (1) 2 (1)


RADIANT-3

81 81

Prior Therapies

Everolimus

n = 207

Placebo

n = 203

Somatostatin analogues (%) 101 (49) 102 (50)

Systemic antitumour

therapy (%) 119 (58) 118 (58)

Chemotherapy 104 (50) 102 (50)

Targeted therapy 10 (5) 14 (7)

Immunotherapy 7 (3) 9 (4)

Hormonal therapy 2 (1) 2 (1)

Other 20 (10) 26 (13)


RADIANT-3

82 82

Patient Disposition

Everolimus (n = 207*)

n (%)

Placebo (n = 203*)

n (%)

Treatment ongoing† 66 (32) 26 (13)

Patient discontinuation 141 (68) 177 (87)

Disease progression 92 (44) 163 (80)

AEs 36 (17) 7 (3)

Death 4 (2) 4 (2)

Withdrawal of consent 4 (2) 3 (2)

Protocol deviations 4 (2) 0

Lost to follow up 1 (1) 0

Duration of exposure (mo)

Median 8.79 3.74

Range 0.25–27.47 0.01–37.39

Crossover to everolimus ---- 148 (73)

*Safety population †Data cut-off: February 28, 2010


RADIANT-3

83 83

Progression Free Survival

• P-value obtained from stratified 1-sided log-rank test

• HR obtained from stratified unadjusted Cox model

No. of patients still at risk

Everolimus

Placebo

207

203

189

177

153

98

126

59

114

52

80

24

49

16

36

7

28

4

21

3

10

2

6

1

2

1

0

1

Kaplan-Meier median PFS

Everolimus: 11.0 mo

Placebo: 4.6 mo

HR = 0.35; 95% CI (0.27–0.45)

P<0.001

0

1

0

0

Time (mo)

100

80

% E

ven

t-fr

ee

Censoring times

Everolimus (n/N = 109/207)

Placebo (n/N = 165/203)

60

40

20

0

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30


RADIANT-3

84 84

Everolimus Provided a Durable PFS

Benefit

Everolimus 10 mg

n = 207

Placebo

n = 203

PFS; Kaplan Meier estimates (95% CI)

3 mo 84.0 (78.0–88.4) 58.5 (51.2–65.0)

6 mo 69.5 (62.4–75.5) 31.9 (25.4–38.5)

12 mo 45.6 (37.7–53.1) 15.4 (10.5–21.2)

18 mo 34.2 (25.9–42.7) 8.9 (4.0–16.3)

Median PFS, mo (95% CI) 11.0 (8.41–13.86) 4.6 (3.06–5.39)


RADIANT-3

85

Subgroup PFS Analysis

*Independent adjudicated central review

E = everolimus 10 mg PO daily; P = placebo

0

Subgroups (N) Investigator review (410) Central review* (410) Prior chemotherapy Yes (89) No (221) WHO Performance Status 0 (279) 1 or 2 (131) Age Group <65 yr (299) ≥65 yr (111) Gender Male (227) Female (183) Race Caucasian (322) Asian (74) Region America (185) Europe (156) Asia (69) Prior long-acting SSA Yes (203) No (207) Tumour grade Well-diff. (341) Moderately diff.(65)

HR

Median PFS (mo)

E P 0.35 11.0 4.6 0.34 11.4 5.4

0.34 11.0 3.0 0.41 11.1 5.5

0.39 13.8 5.4 0.30 8.3 3.0

0.39 11.0 4.5 0.36 11.1 4.9

0.41 11.0 4.6 0.33 11.0 3.3

0.41 10.8 4.6 0.29 19.5 3.8

0.36 11.0 4.6 0.47 10.8 4.6 0.29 19.5 2.9

0.40 11.2 3.7 0.36 10.8 4.9

0.41 10.9 4.6 0.21 16.6 3.0

Hazard Ratio

Favors Everolimus Favors Placebo

1 0.4 0.8


RADIANT-3

86 86

Response Rates

RECIST 1.0

Objective Tumour Responses

Everolimus 10 mg

n = 207

n (%)

Placebo

n = 203

n (%)

Complete response (CR) 0 0

Confirmed Partial response (PR) 10 (5) 4 (2)

Stable disease (SD) 151 (73) 103 (51)

Progressive disease (PD) 29 (14) 85 (42)

Unknown 17 (8) 11 (5)

2-sided P-value for treatment difference* P<0.001

Disease control rate (CR + PR +SD) 161 (78) 107 (53)

*Wilcoxon 2-sample test


RADIANT-3


Everolimus 10mg

N = 207

Placebo

N = 203

No. of events – n (%) 51 (24.6%) 50 (24.6%)

HR = 1.05; 95% CI [0.71-1.55]; P = 0.594

No. censored – n (%) 156 (75.4%) 153 (75.4%)

Kaplan-Meier estimates [95% CI] at:

3 months 97.1 [93.6-98.7] 98.5 [95.5-99.5]

6 months 93.1 [88.7-95.9] 91.6 [86.8-94.7]

12 months 82.3 [76.0-87.0] 82.6 [76.5-87.3]

18 months 73.1 [65.1-79.6] 73.9 [66.1-80.2]

24 months 57.3 [43.0-69.2] 62.8 [51.1-72.4]

148 (73%) placebo patients crossed over to receive everolimus

Median F/U 17 months; medians not reached at this analysis.

Hazard ratio is obtained from the unadjusted stratified Cox model.

P-value is obtained from the stratified one-sided log rank test.

RADIANT-3

1. Yao JC, Shah MH, Ito T, et al. N Engl J Med. 2011;364:514-523; 2. Yao JC, Shah M, Ito T, et al. Presented at: 35th ESMO Congress; October 8-12, 2010; Milan,

Italy. Abstr LBA9.

88

88


148 placebo patients crossed over at time of progression to receive everolimus

1. Yao JC, Shah MH, Ito T, et al. N Engl J Med. 2011;364:514-523; 2. Yao JC, Shah M, Ito T, et al. 35th ESMO Congress 2010; Milan, Italy. Abstract #LBA9.

100

80

60

40

20

0

Perc

en

tage o

f even

t-fr

ee

No. of patients still at risk

Censoring Times1

Everolimus (n/N = 51/207)

Placebo (n/N = 50/203)

Everolimus

Placebo

207

203

Kaplan Meier median

Everolimus: NA months

Placebo : NA months

Hazard Ratio: 1.05

95% CI [0.71,1.55]

Log-rank p-value = 0.59

0 2 4 6 8 10 12 14 16 18 20 22 24 26

Time (months)

203

199

195

195

188

183

181

174

162

160

122

129

97

109

74

87

53

63

38

42

26

23

9

16

5

7

28 30

0

3

0

1

32

0

0

RADIANT-3

89 89

Adverse Events

Everolimus toxicities were similar to those seen in other

tumour types

Most frequently reported all-grade treatment-related AEs with

everolimus were stomatitis (64%), rash (49%), diarrhea (34%),

fatigue (31%), and infections (23%)

Grade 3/4 AEs (≥ 5%) in the everolimus arm included stomatitis

(7%), anemia (6%), and hyperglycemia (5%)

One patient with insulinoma (on glucocorticoid therapy) died

from acute respiratory distress syndrome; considered

treatment-related

RADIANT-3


90 90

Summary

RADIANT-3 enrolled 410 patients with advanced pNET, the

largest-ever placebo-controlled phase III clinical trial in this

patient population

Everolimus provided a statistically and clinically significant 65%

reduction in risk for progression vs placebo in patients with

pNET (HR = 0.35, P<0.001)

Median PFS: everolimus 11.0 mo, placebo 4.6 mo; a 6.4-mo improvement or

2.4-fold increase in median PFS

18-mo PFS rate of 34% vs 9% placebo demonstrates a durable benefit

Consistent benefit in all subgroups

Everolimus has an acceptable safety profile


RADIANT-3

91

Overall Conclusions - New targeted agents have

emerged in the treatment of patients with pNETS

Sunitinib, as compared with placebo, provided a clinical benefit

in PFS for patients with advanced pNETs

Everolimus, as compared with placebo, provided both a

statistically and clinically significant benefit in PFS for patients

with advanced pNETs

Toxicities were consistent with those observed in other trials

of sunitinib

Everolimus was associated with a low rate of severe adverse

events

EL ALGORRITMO DE TRATAMIENTO DEBE MODIFICARSE


Por último….

La incidencia de los tumores neuroendócrinos se

encuentra en aumento.

Contamos con nuevas drogas útiles que han aumentado

no solo la sobrevida global de los ptes sino tambien su

calidad de vida.

Tambien contamos con nuevos métodos diagnósticos.

Nuevos radiotrazadores.

Solo falta un detalle más…..

ONCOLÓGOS

EXPERTOS EN MEDICINA NUCLEAR

RADIOTERAPEUTAS

CIRUJANOS

ENDOCRINÓLOGOS

UN TRABAJO EN CONJUNTO

GRACIAS POR SU ATENCION!!

TUMORES NEUROENDÓCRINOS GASTROENTEROPANCREÁTICOS...

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