1. No category

Algoritme de tractament dels
GEPNETs
Dr Àlex Teulé
Servei d’ Oncologia mèdica i Càncer Hereditari
Institut Català d’Oncologia. L’Hospitalet del
Llobregat (Barcelona)
3a SESSIÓ DE LA SCMN DEL CURS 2014-2015
19/03/2015
Gastroenteropancreatic Neuroendocrine
Tumors (GEPNETs): BACKGROUND
• Tumors derive from diffuse neuroendocrine
system of the gastrointestinal tract and pancreas
• NETs are characterized by their ability to produce
and secrete a large number of peptide hormones
• GEPNETs comprise a heterogeneous family of
neoplasms with a wide and complex spectrum of
clinical behaviour.
– Depending on the hormone secretion: Functioning or
non-functioning (with or without clinical syndrome)
O’Toole. Postgraduate
couse ENETS 2015
Epidemiology
Yao JC, Hassan M, Phan A, et al. J Clin Oncol. 2008;26:3063-3072.©
Factors influencing the therapeutic
decision
• Type of NET tumor
• TNM stage and grade
• Extent of liver involvement
• Extrahepatic disease
• Functioning vs non-functioning tumor
• Performance status and comorbilities
• Availability of different therapeutic options
• Expression of somatostatin receptor by imaging (octreoscan, PET Ga-DOTATOC,
DOTATE, DOTANOC)
Prognosis depending on disease stage
Yao JC, Hassan M, Phan A, et al. J Clin Oncol. 2008;26:3063-3072
2010 WHO classification for Neuroendocrine
Neoplasms of the Digestive System
Prognostic factors and Overall
Survival in pancreatic NETs
Ekebland et al. Clin Can Res 2008
Medical treatment in GEP-NETs:
When?
• Adjuvant? -> No data (NEC g.3?)
• Advanced disease: Locoregional
unresectable or metastatic GEP-NETs
Adjuvant therapy after liver metastases resection
• Very few data
• Not recommended
SLP
SG
Criteria for CT or not:
Multidisciplinary
oncological staff –>
Selection bias
Maire F, et al. Surgery 2009
Treatment options in metastatic GEP-NETs
• Surgery
• Locally ablative techniques
- Radiofrequency ablation, microwave ablation, laser ablation, cryoablation
- Used as stand-alone therapy or as surgical adjuncts
• Medical treatment:
–
–
–
–
–
–
Somatostatin analogues (SSA)
Interferon-alpha
PRRT
Everolimus
Sunitinib
Chemotherapy
• Locoregional-directed liver therapies:
– TAE/TACE/SIRT
• OLT
SSA: Antihormonal action
Oberg K et al. Ann Oncol 2004
Modlin IM et al. Aliment Pharmacol Ther 2010
PROMID: Evaluation of the Antiproliferative Effect
of Octreotide LAR 30 mg
• Phase III randomized, double-blind, placebo-controlled study
Month
•
•
Octreotide LAR
30 mg im
every 28 days
RANDOMIZATION (1:1)
Patients with midgut NETs
• Treatment naïve
• Histologically confirmed
• Locally inoperable
or metastatic
• Well differentiated
• Measurable (CT/MRI)
• Functioning or nonfunctioning
Treatment until
CT/MRI
documented
tumour
progression or
death
Placebo im
every 28 days
3
6
9
12
15
18
Primary endpoint: Time to tumour progression (blinded central review)
Secondary endpoints: objective response rate, survival, quality of life, safety
Rinke A et al. J Clin Oncol 2009;27:4656–4663
PROMID
study
WD M1
Midguts
Ki67<2%
-Octreoscan: positive
Pancreas/intestinal/CU
P
Molecular pathways and targets in NETs
Raymond et al N Engl J Med 2011
Respuestas Tumorales Objetivas según RECIST
Sunitinib
(n=86)
Placebo
(n=85)
Respuesta completa
2 (2.3)
0
Respuesta parcial
6 (7.0)
0
Enfermedad estable/sin respuesta
54 (62.8)
51 (60.0)
Progresión objetiva
12 (14.0)
23 (27.1)
No evaluable
12 (14.0)
11 (12.9)
9.3% (3.2%, 15.4%)
0
Mejor respuesta tumoral confirmada, n (%)
Tasa de respuesta objetiva (95% IC)
Valor a dos lados de la p para la diferencia en
los tratamientos
Mediana (rango) duración de la respuesta,
meses
Enfermedad estable >6 meses, n (%)
0.0066
8.1 (1.0–15.0)
–
30 (34.9)
21 (24.7)
Las respuestas tumorales fueron evaluadas utilizando RECIST 1.1
tasa de respuesta objetiva = pacientes con una respuesta tumoral parcial o completa
NEC G.3: Chemotherapy
Response rate and Overall
Survival with CDPP+VP16
1ª linea: CDDP+VP16
2ª linea: No esquema
establecido
Sorbye H, et al. Cancer 2014
Evidence based treatment
Octeotride in
Midgut NET
(PROMID)
Lanreotide in
intestinal/pancreat
ic/CUP NET (Ki 67
< 10%)
(CLARINET)
Chemotherapy:
- Alkaylating agents in
pNETs
- CDDP+VP16 in NEC
g.3
- 1 drug class approved for intestinal NET
- 4 approved teratment for pNET
Everolimus in
progressive pNET
(RADIANT-3)
Sunitinib in
progressive pNET
Terapias dirigidas al hígado: TACE/TAE/SIRT
No estudios randomizados comparando las diferentes técnicas ni
comparándolas contra cirugía o tratamientos sistémicos. Del Prete M, et al. J Exp Clin Cancer Res. 2014
Peptide Receptor Radionuclide Therapies (PRRT)
•
Not available in all countries (only in tumors with
uptake in somatostatin receptor imaging)
•
Numerous large, non-randomized cohort analyses have
reported encouraging survival rates with this approach
(PFS aprox 30 months) and variable results in tumor
responses (0-30%)
•
Currently this approach remains investigational, and
randomized trials to further evaluate the relative benefit
and potential toxicities of radiopeptide therapy in
advanced NETs are needed.
•
NETTER-1 trial is ongoing: A multicentre, stratified,
open, randomized, comparator-controlled, parallelgroup phase III study comparing treatment with 177LuDOTATATE (plus Octeotride 30 mg LAR/28d) to
Octreotide LAR 60 mg/28d in patients with inoperable,
progressive, somatostatin receptor positive, midgut
carcinoid tumours.
NCCN Guidelines 2014: Neuroendocrine tumors
What is the correct sequence?
PRRT
SSA
Chemo
therapy
Everoli
mus
TAE/TA
CE
Suniti
nib
¿?
TAE/TACE?
OLT?
NET multidisciplinary team
Perspectivas futuras
• Puntes débiles de los tratamientos actuales. Diseño de ensayos
clínicos futuros fase III
• Selección de pacientes (biomarcadores)
• Secuencialidad
• Nuevas dianas
• Nuevas drogas
• Combinaciones
• Reversión o superación de las resistencias
We need new predictive biomarkers
Future prespective
Phase III randomized SEQTOR Trial
Other trials
•
•
•
•
•
•
•
•
•
•
•
•
FLUTE (phase II randomized lung/thymus NETs: LAN v120 mg vs placebo)
RADIANT-4 (phase III nonfx intestine, lung or CUP: everolimus vs placebo)
CLARINET forte (pNET/midgut progressing to LAN 120 mg/4w: 120 mg/2w)
REMINET (dudodeno-pancreatic NET: manteinance with LAN 120mg vs
placebo)
NETTER-1 (phase III: Lu-PRRT+30 mg octeotride LAR vs octeotride LAR 60
mg)
CASTOR (refractory non-pNET: randomized IFNα-2b vs PRRT)
CONTROL NETS (pNET/midgut: ranomized CAPTEM vs PRRT)
OCLURANDOM (pNET phase II rand: Lu vs Sunitinib)
CALGB 80701 (phase II ran pNET: Everolimus vs Everolimus+Beva)
ECOG /ACRIN 2211 (phase II rand pNET: TEM vs CAPTEM)
Clinical trials in NEC g.3
Potential new targets: Dovitinib, EPO906, Fosbretabulin tromethamine, virus,
palbociclib, sunitinib+TH-302, pazopanib, bevacizumab, etc.
Take home messages
•
GEP-NENs are heterogenous and have several different therapies:
– In one hand, multiple treatments are available for WD pNETs but
without comparative phase III trials
– In the other hand, WD GI NETs have less medical options (SSA,
PRRT)
• G.2 (ki67>10%)?
• Negative somatostatin receptor imaging?
•
Currently, the first choice depends on grade, Ki67, tumor burden,
availability of therapy, patient comorbilities and toxicity profile
•
We don’t know the correct sequence in several cases:
– More studies evaluating sequencial treatments
– New predictive biomarkers
– New therapies and combinations
Gràcies per la vostra atenció!