Institut Mutualiste Montsouris, Paris

Présentation au sujet: "Institut Mutualiste Montsouris, Paris"— Transcription de la présentation:

1 Institut Mutualiste Montsouris, Paris
FOLFIRINOX : un nouveau standard dans les adénocarcinomes pancréatiques ? Christophe Louvet Institut Mutualiste Montsouris, Paris SFCP, Ajaccio, 10/05/2012

2 ADK pancréatique métastatique: Chimiothérapie ou soins de confort ?

3 L’étude Burris (1997) 23.8% * 4.8% Gemcitabine 5-Fluorouracile n=63
Bénéfice clinique Survie médiane 5.65 mois ** 4.41 mois * p = ** p = Burris H A, et al.: JCO 15: 2403, 1997

4 Etudes de phases III dans les cancers du pancréas
(chimiothérapie conventionelle) Gem Gem + X p Gem ± Pemetrexed (Oettle, Ann Oncol 2006) NS Gem ± CPT-11 (Rocha-Lima, JCO 2006) NS Gem ± Exatecan (Abou-Alfa, JCO 2006) NS Gem ± 5FU bolus (Berlin, JCO 2002) NS Gem ± Capecitabine (Cunningham, JCO 2009) NS Gem ± Capecitabine (Herrmann, JCO 2007) NS Gem ± 5FU/LV (Riess, JCO 2005) NS Gem ± Cisplatin (Heinemann, JCO 2006) NS Gem ± Oxaliplatine (Louvet, JCO 2005) NS Gem ± Oxaliplatine (Poplin, JCO 2009) NS Gem ± Cisplatin (Colucci, ASCO 2009) NS

5 Méta-analyse de survie: Gemcitabine versus Gemcitabine + autre drogue
Sultana, A. et al. J Clin Oncol; 25:

6 Analyse par sous-groupe : Gemcitabine vs Gemcitabine + autre drogue
Sultana, A. et al. J Clin Oncol; 25:

7 Résumé de la méta-analyse dans les cancers
du pancréas avancés N pts HR p Gem vs Gem + drogue X Gem vs Gem + sel de platine Gem vs Gem + fluoropyrimidine Gem vs Gem + autre drogue NS Gem vs Gem + sel de platine / fluoropyrimidine (PS 0-1) < Gem vs Gem + sel de platine / fluoropyrimidine (PS 2) NS

8 Etudes de phases III dans les cancers du pancréas
(thérapies ciblées) Gem Gem + X p Gem ± Marimasmat (Bramhall, BJC 2002) NS Gem ± Tifarbinib (Van Cutsem, JCO 2004) NS Gem ± Erlotinib (Moore, JCO 2007) Gem ± Bevacizumab (Kindler, ASCO 2007) NS Gem ± Cetuximab (Philip, ASCO 2007) NS Gem ± GV1001 (Buanes, ASCO 2009) NS Gem – Erlotinib ± Beva (Van Cutsem, JCO 2009) NS Gem ± Axitinib (Kindler, ESMO 2009) NS Gem ± Aflibercept : arrêt pour futilité, « press release » 2009

9 Anti-EGFR Preuve du concept avec l’erlotinib (Moore, JCO 2007)
Pas de confirmation avec le cetuximab (Philip, ASCO 2008) Pas de synergie avec le bevacizumab (Van Cutsem, JCO 2009) Pas de marqueur moléculaire prédictif (K-ras?) Rash prédictif de survie ? (Moore, 2007; Van Cutsem, 2009)

10 Antiangiogéniques Résultats négatifs en phase III avec mAb, TKI
et VEGF-trap CALBG (G + Beva) (Kindler, JCO 2008) AVITA (G + B + Erlo) (Van Cutsem, JCO 2009) AGILE (G + Axitinib) (Kindler, ESMO/ECCO 2009) VANILLA (G + Aflibercept) (Press release-stop pour futilité) Pas de marqueur prédictif (polymorphisme VEGFR-1 ?) Pas de “surrogate marker” (PA diastolique?) (Spano, Lancet 2008)

11 Gemcitabine perfusion de 30mn ou de 10 mg/m²/mn?
Rép 16.6% PFS 3.4 mois OS 8 mois Survie à 1 an: 23% Gemcitabine 1500 mg/m² 10mg/m²/min R Rép 2.7% PFS 1.9 mois OS 5 mois Survie à 1 an : 0% Gemcitabine 2200mg/m² 30 min N=80 Tempero, JCO 2004

12 RANDOMIZED PHASE III TRIAL COMPARING FOLFIRINOX (5FU/leucovorin, irinotecan and oxaliplatin) VS GEMCITABINE AS FIRST-LINE TREATMENT FOR METASTATIC PANCREATIC ADENOCARCINOMA Prodige 4 - ACCORD 11/0402 trial: final results T. Conroy, F. Desseigne, M. Ychou, M. Ducreux, O. Bouché, R. Guimbaud, Y. Bécouarn, C. Montoto-Grillot, S. Gourgou-Bourgade, A. Adenis, FNCLCC-FFCD Prodige group Centre Alexis Vautrin, Nancy; Centre Léon Bérard, Lyon; Centre Val d'Aurelle, Montpellier; Institut Gustave Roussy, Villejuif; Centre Hospitalier R. Debré, Reims; Institut Claudius Regaud, Toulouse; Institut Bergonié, Bordeaux; Fédération Nationale des Centres de Lutte Contre le Cancer - BECT, Paris; Centre Oscar Lambret, Lille; FRANCE

13 FOLFIRINOX versus Gemcitabine for Metastatic Pancreatic Cancer
Thierry Conroy, M.D., Françoise Desseigne, M.D., Marc Ychou, M.D., Ph.D., Olivier Bouché, M.D., Ph.D., Rosine Guimbaud, M.D., Ph.D., Yves Bécouarn, M.D., Antoine Adenis, M.D., Ph.D., Jean-Luc Raoul, M.D., Ph.D., Sophie Gourgou-Bourgade, M.Sc., Christelle de la Fouchardière, M.D., Jaafar Bennouna, M.D., Ph.D., Jean-Baptiste Bachet, M.D., Faiza Khemissa-Akouz, M.D., Denis Péré-Vergé, M.D., Catherine Delbaldo, M.D., Eric Assenat, M.D., Ph.D., Bruno Chauffert, M.D., Ph.D., Pierre Michel, M.D., Ph.D., Christine Montoto-Grillot, M.Chem., and Michel Ducreux, M.D., Ph.D., for the Groupe Tumeurs Digestives of Unicancer and the PRODIGE Intergroup* N Engl J Med 2011;364:

14 Prodige 4 - ACCORD 11 trial design
6 months of chemotherapy recommended CT scans: obtained every 2 months for both arms: R A N D O M I Z E Folfirinox Metastatic pancreatic cancer Gemcitabine Stratification : center performance status: 0 versus 1 location of the tumor: head versus other location of the primary

15 Inclusion Criteria Histologically/cytologically confirmed pancreatic adenocarcinoma ECOG performance status of 0 or 1 Measurable metastases No prior cytotoxic chemotherapy No prior abdominal radiotherapy Age years Adequate hematopoietic, hepatic and renal function Bilirubin < 1.5 UNL No unstable angina or myocardial infarction within 12 months before entry Written informed consent

16 Flow Chart Folfirinox Gemcitabine Total Total randomized 171 342
Did not fulfill all eligibility criteria 8* 7* 15 (4%) Untreated patients 4 2 6 (2%) ITT population 342 (100%) Safety population 167 169 336 (98%) *Folfirinox arm : 2 patients > 76 years; one patient PS=2; patients with high bilirubin, high creatinine or low platelets *Gemcitabine arm: 7 patients with high bilirubin, high creatinine or low platelets

17 Patients characteristics
Folfirinox N=171 Gemcitabine p Median age (yrs) [range] 61 [25-76] [34-75] NS Sex Male Female 106 (62%) 65 (38%) 105 (61.4%) 66 (38.6%) Baseline PS 1 2 64 (37.4%) 106 (62.0%) 1 (0.6%) 0 (0.0%) Location of primary Head Other 62 (36.3%) 109 (63.7%) 60 (35.1%) 111 (64.9%)

18 Disease characteristics
Folfirinox N=171 Gemcitabine p Synchronous metastases Metachronous metastases 156 (91.2%) 15 (8.8%) 161 (94.2%) 10 (5.8%) NS Median nr. of involved sites CA19-9  59 ULN 2 (1-6) 68 (41.5%) 77 (46.7%) Measurable site Liver Pancreas Nodes Lungs Peritoneal 149 (88.2%) 89 (52.7%) 48 (28.4%) 33 (19.5%) 150 (87.7%) 91 (53.2%) 39 (22.8%) 49 (28.7%) 32 (18.7%) 0.049

19 Objective Response Rate
Folfirinox N=171 Gemcitabine p Complete response 0.6% 0% Partial response 31% 9.4% 0.0001 CR/PR 95% CI [ ] [ ] Stable disease 38.6% 41.5% Disease control CR+PR+SD 70.2% 50.9% 0.0003 Progression 15.2% 34.5% Not assessed 14.6% Median duration of response 5.9 mo. 4 mo. ns

20 Progression-Free Survival
Median PFS Folfirinox: 6.4 mo. Median PFS Gemcitabine: 3.3 mo

21 Overall Survival

22 Overall Survival Median survival 11.1 mo. 6.8 mo. <0.0001 0.57
Median follow up: 26.6 months [95% CI: 20.5 – 44.9] Folfirinox N=171 Gemcitabine p HR Median survival [CI 95%] 11.1 mo. [ ] 6.8 mo. [ ] <0.0001 0.57 1-yr. survival 48.4% 20.6% 18-mo. survival 18.6% 6%

23 Safety: hematological AEs
AE, % per patient Folfirinox N=167 Gemcitabine N=169 p All Grade 3/4 Neutropenia 79.9 45.7 54.8 18.7 0.0001 Febrile Neutropenia 7.2 2.4 0.6 0.009 Anemia 90.4 7.8 94.6 5.4 NS Thrombocytopenia 75.2 9.1 0.008 5.4 42.5 % of the pts received G-CSF in the F arm vs 5.3% in the G arm One toxic death occurred in each arm AE, adverse event

24 Safety: main non-hematological AEs
AE, % per patient Folfirinox N=167 Gemcitabine N=169 p All Grade 3/4 Infection without neutropenia 6 1.2 7.1 1.8 NS Peripheral neuropathy 70.5 9 0.6 0.0001 Vomiting 61.4 14.5 43.2 4.7 0.002 Fatigue 87.3 23.2 78.7 14.2 0.036 Diarrhea 73.3 12.7 30.8 Alopecia (grade 2) 32.5 (11.4) 3.0 (0.6) ALT 64.8 7.3 83.8 0.0022 18.6

25 Inclusion Criteria Histologically/cytologically confirmed pancreatic adenocarcinoma ECOG performance status of 0 or 1 Measurable metastases No prior cytotoxic chemotherapy No prior abdominal radiotherapy Age years Adequate hematopoietic, hepatic and renal function Bilirubin < 1.5 UNL No unstable angina or myocardial infarction within 12 months before entry Written informed consent

26 Gemcitabine: mécanisme d’action
Uptake intracellulaire hENT1 hCNT 3 Activation dCK Nucleoside Phosphate Kinase Inactivation CDA DCTD 5’-NT Action Inhibition de la synthèse de l’ADN

27 Expérience Franco-Belge
471 patients assessed for eligibility 37 excluded adjuvant treatment unknown (n= 10) not analyzable (n=10 ) inclusion in retrospective study (n=17) 434 assessable No adjuvant treatment (n=142) Adjuvant treatment (n=292) Non gemcitabine-containing (n=49) Radiotherapy alone (n=3) RT + 5FU (n=46) gemcitabine-based (n=243) Gemcitabine monotherapy (n=208) Gemox (n=35 ) Non Gemcitabine population Gemcitabine population Marechal R, Bachet JB, Mackey J et al, in press 27

28 Expérience Franco-Belge
Population « gemcitabine » Marechal R, Bachet JB, Mackey J et al, in press 28

29 Expérience Franco-Belge
Population « non gemcitabine » Marechal R, Bachet JB, Mackey J et al, in press 29

30 Expérience Franco-Belge
N at risk hENT1 low and any dCK  36 30 18 10 6 5 3 1 hENT1 moderate and any dCK  106 103 87 64 43 28 12 7 2 hENT1 high and dCK low  22 17 14 hENT1 high and dCK high  69 66 60 54 47 25 23 19 16 13 9 Marechal R, Bachet JB, Mackey J et al, in press 30

31 CONCLUSIONS FOLFIRINOX = nouveau standard, oui mais ….
Chez les patients réellement PS 0 et 1 Chez les patients avec une bilirubine normale En première ligne métastatique (localement avancé ?) Qu’en est-il chez les patients PS 0/1, bili normale et hENT1 high ????