tumores neuroendÓcrinos … · – neoplasia endocrina múltiple (nem), tipo 1 y tipo 2/carcinoma...
TRANSCRIPT
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
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.
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.
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
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.
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
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
Growth and proliferation
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
Raymond E, Dahan L, Raoul J-L, et al. N Engl J Med. 2011;364:501-513.
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)
Raymond E, Dahan L, Raoul J-L, et al. N Engl J Med. 2011;364:501-513.
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)
Raymond E, Dahan L, Raoul J-L, et al. N Engl J Med. 2011;364:501-513.
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*
Raymond E, Dahan L, Raoul J-L, et al. N Engl J Med. 2011;364:501-513.
Study A6181111
* Local review
68 68
Subgroup PFS Analysis
Raymond E, Dahan L, Raoul J-L, et al. N Engl J Med. 2011;364:501-513.
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*
Raymond E, Dahan L, Raoul J-L, et al. N Engl J Med. 2011;364:501-513.
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
Raymond E, Dahan L, Raoul J-L, et al. N Engl J Med. 2011;364:501-513.
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
Raymond E, Dahan L, Raoul J-L, et al. N Engl J Med. 2011;364:501-513.
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
Raymond E, Dahan L, Raoul J-L, et al. N Engl J Med. 2011;364:501-513.
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
Growth and proliferation
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
Yao JC, Shah MH, Ito T, et al. N Engl J Med. 2011;364:514-523.
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)
Yao JC, Shah MH, Ito T, et al. N Engl J Med. 2011;364:514-523.
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)
Yao JC, Shah MH, Ito T, et al. N Engl J Med. 2011;364:514-523.
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
Yao JC, Shah MH, Ito T, et al. N Engl J Med. 2011;364:514-523.
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
Yao JC, Shah MH, Ito T, et al. N Engl J Med. 2011;364:514-523.
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)
Yao JC, Shah MH, Ito T, et al. N Engl J Med. 2011;364:514-523.
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
Yao JC, Shah MH, Ito T, et al. N Engl J Med. 2011;364:514-523.
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
Yao JC, Shah MH, Ito T, et al. N Engl J Med. 2011;364:514-523.
RADIANT-3
Overall Survival Analysis
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
Overall Survival Analysis
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
Yao JC, Shah MH, Ito T, et al. N Engl J Med. 2011;364:514-523.
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
Yao JC, Shah MH, Ito T, et al. N Engl J Med. 2011;364:514-523.
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
Yao JC, Shah MH, Ito T, et al. N Engl J Med. 2011;364:514-523.
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