Algoritme de tractament dels GEPNETs

Transcripción

1 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 /03/2015

2 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)

3 O Toole. Postgraduate couse ENETS 2015

4 Yao JC, Hassan M, Phan A, et al. J Clin Oncol. 2008;26: Epidemiology

5 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)

6 Prognosis depending on disease stage Yao JC, Hassan M, Phan A, et al. J Clin Oncol. 2008;26:

7 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

8 Medical treatment in GEP-NETs: When? Adjuvant? -> No data (NEC g.3?) Advanced disease: Locoregional unresectable or metastatic GEP-NETs

9 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

10 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

11 SSA: Antihormonal action Oberg K et al. Ann Oncol 2004 Modlin IM et al. Aliment Pharmacol Ther 2010

12 PROMID: Evaluation of the Antiproliferative Effect of Octreotide LAR 30 mg Phase III randomized, double-blind, placebo-controlled study Patients with midgut NETs Treatment naïve Histologically confirmed Locally inoperable or metastatic Well differentiated Measurable (CT/MRI) Functioning or nonfunctioning RANDOMIZATION (1:1) Octreotide LAR 30 mg im every 28 days Placebo im every 28 days Treatment until CT/MRI documented tumour progression or death Month 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:

13 PROMID study WD M1 Midguts Ki67<2%

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15 -Octreoscan: positive - Pancreas/intestinal/CU P

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17 Molecular pathways and targets in NETs

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23 Raymond et al N Engl J Med 2011

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25 Respuestas Tumorales Objetivas según RECIST Mejor respuesta tumoral confirmada, n (%) Respuesta completa Respuesta parcial Enfermedad estable/sin respuesta Progresión objetiva No evaluable Sunitinib (n=86) 2 (2.3) 6 (7.0) 54 (62.8) 12 (14.0) 12 (14.0) Placebo (n=85) (60.0) 23 (27.1) 11 (12.9) Tasa de respuesta objetiva (95% IC) 9.3% (3.2%, 15.4%) 0 Valor a dos lados de la p para la diferencia en los tratamientos Mediana (rango) duración de la respuesta, 8.1 ( ) meses Enfermedad estable >6 meses, n (%) 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

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28 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

29 Evidence based treatment Octeotride in Midgut NET (PROMID) Lanreotide in intestinal/pancreat ic/cup NET (Ki 67 < 10%) (CLARINET) - 1 drug class approved for intestinal NET - 4 approved teratment for pnet Chemotherapy: - Alkaylating agents in pnets - CDDP+VP16 in NEC g.3 Everolimus in progressive pnet (RADIANT-3) Sunitinib in progressive pnet

30 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

31 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 177Lu- DOTATATE (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

32 What is the correct sequence? PRRT SSA Chemo therapy Everoli mus TAE/TA CE Suniti nib

33 TAE/TACE? OLT??

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35 NET multidisciplinary team

36 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

37 We need new predictive biomarkers

38 Future prespective Phase III randomized SEQTOR Trial

39 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 (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.

40 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

41 Gràcies per la vostra atenció!