Post on 03-Apr-2015
FOLFIRINOX : un nouveau standard dans les
adénocarcinomes pancréatiques ?
FOLFIRINOX : un nouveau standard dans les
adénocarcinomes pancréatiques ?
Christophe LouvetInstitut Mutualiste Montsouris, Paris
SFCP, Ajaccio, 10/05/2012
ADK pancréatique métastatique:Chimiothérapie ou soins de confort ?
ADK pancréatique métastatique:Chimiothérapie ou soins de confort ?
Auteur Regime n patients
Med. Surv. (mo)
Qol
Mallinson 1980
5-FU+Mtx+Vcr + cyclo + MMC BSC
21
19
10.5
2.2*
Frey 1981
5-FU + CCNU BSC
65 87
3.0 3.9
Andersen 1981
5-FU + BCNU BSC
20 20
3.2 3.4
Palmer 1994
FAM BSC
23 20
8.2 3.8*
Glimelius 1996
5-FU + LV + Etoposide BSC
29
24
6.0
2.5*
benefice dans le groupe CT
* p < 0.05
L’étude Burris (1997)L’étude Burris (1997)
Gemcitabinen=63
5-Fluorouracilen=63
Bénéfice clinique
5.65 mois ** 4.41 mois Survie médiane
** p = 0.0025
Burris H A, et al.: JCO 15: 2403, 1997
23.8% * 4.8%
* p = 0.0022
Gem ± Pemetrexed (Oettle, Ann Oncol 2006) 6.3 6.2 NSGem ± CPT-11 (Rocha-Lima, JCO 2006) 6.6 6.3 NSGem ± Exatecan (Abou-Alfa, JCO 2006) 6.2 6.7 NS
Gem ± Cisplatin (Heinemann, JCO 2006) 6.0 7.5 NSGem ± Oxaliplatine (Louvet, JCO 2005) 7.1 9.0 NSGem ± Oxaliplatine (Poplin, JCO 2009) 4.9 5.9 NSGem ± Cisplatin (Colucci, ASCO 2009) 8.3 7.2 NS
Gem Gem + X p
Gem ± 5FU bolus (Berlin, JCO 2002) 5.4 6.7 NS
Gem ± Capecitabine (Cunningham, JCO 2009) 6.2 7.1 NS
Gem ± Capecitabine (Herrmann, JCO 2007) 7.3 8.4 NSGem ± 5FU/LV (Riess, JCO 2005) 6.2 5.9 NS
Etudes de phases III dans les cancers du pancréas(chimiothérapie conventionelle)
Copyright © American Society of Clinical OncologySultana, A. et al. J Clin Oncol; 25:2607-2615 2007
Méta-analyse de survie: Gemcitabine versus Gemcitabine + autre drogue
Copyright © American Society of Clinical OncologySultana, A. et al. J Clin Oncol; 25:2607-2615 2007
Analyse par sous-groupe :Gemcitabine vs Gemcitabine + autre drogue
Résumé de la méta-analyse dans les cancersdu pancréas avancés
N pts HR p
Gem vs Gem + drogue X 4465 0.91 0.004
Gem vs Gem + sel de platine 1248 0.85 0.01
Gem vs Gem + fluoropyrimidine 1813 0.90 0.03
Gem vs Gem + autre drogue 1404 0.99 NS
Gem vs Gem + sel de platine / fluoropyrimidine (PS 0-1) 1108 0.76 < 0.0001Gem vs Gem + sel de platine / fluoropyrimidine (PS 2) 574 1.08 NS
Gem Gem + X p
Gem ± Erlotinib (Moore, JCO 2007) 5.9 6.4 .03
Gem ± Bevacizumab (Kindler, ASCO 2007) 6.1 5.8 NS
Gem ± Cetuximab (Philip, ASCO 2007) 5.9 6.4 NS
Gem ± GV1001 (Buanes, ASCO 2009) 7.3 5.9 NS
Gem – Erlotinib ± Beva (Van Cutsem, JCO 2009) 6.0 7.1 NS
Gem ± Axitinib (Kindler, ESMO 2009) 7.4 8.2 NS
Gem ± Aflibercept : arrêt pour futilité, « press release » 2009
Etudes de phases III dans les cancers du pancréas(thérapies ciblées)
Gem ± Marimasmat (Bramhall, BJC 2002) 5.5 5.5 NS
Gem ± Tifarbinib (Van Cutsem, JCO 2004) 6.0 6.4 NS
Anti-EGFRAnti-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)
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)
AntiangiogéniquesAntiangiogéniques
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)
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)
Gemcitabine perfusion de 30mn ou de 10 mg/m²/mn?
Gemcitabine perfusion de 30mn ou de 10 mg/m²/mn?
R
Gemcitabine1500 mg/m²10mg/m²/min
Gemcitabine2200mg/m²
30 minN=80
Rép 16.6%PFS 3.4 moisOS 8 moisSurvie à 1 an: 23%
Rép 2.7%PFS 1.9 moisOS 5 moisSurvie à 1 an : 0%
Tempero, JCO 2004
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
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;364:1817-25.
Prodige 4 - ACCORD 11 trial design
Stratification :
center performance status: 0 versus 1 location of the tumor: head versus other location of the primary
Metastaticpancreaticcancer
RANDOMIZE
Folfirinox
Gemcitabine
6 months of chemotherapy recommended
CT scans: obtained
every 2 months
for both arms:
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 18-75 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
Flow Chart
Folfirinox Gemcitabine Total
Total randomized 171 171 342
Did not fulfill all eligibility criteria
8* 7* 15 (4%)
Untreated patients 4 2 6 (2%)
ITT population 171 171 342 (100%)
Safety population 167 169 336 (98%)
*Folfirinox arm : 2 patients > 76 years; one patient PS=2; 5 patients with high bilirubin, high creatinine or low platelets
*Gemcitabine arm: 7 patients with high bilirubin, high creatinine or low platelets
Patients characteristics
CharacteristicFolfirinox
N=171
GemcitabineN=171
p
Median age (yrs)
[range]
61
[25-76]
61
[34-75]NS
Sex Male
Female
106 (62%)
65 (38%)
105 (61.4%)
66 (38.6%) NS
Baseline PS 0
1
2
64 (37.4%)
106 (62.0%)
1 (0.6%)
66 (38.6%)
105 (61.4%)
0 (0.0%)NS
Location of primary Head
Other
62 (36.3%)
109 (63.7%)
60 (35.1%)
111 (64.9%) NS
Disease characteristics
CharacteristicFolfirinox
N=171
GemcitabineN=171
p
Synchronous metastases
Metachronous metastases
156 (91.2%)
15 (8.8%)
161 (94.2%)
10 (5.8%)
NS
NS
Median nr. of involved sites
CA19-9 59 ULN
2 (1-6)
68 (41.5%)
2 (1-6)
77 (46.7%)
NS
NS
Measurable site
Liver
Pancreas
Nodes
Lungs
Peritoneal
149 (88.2%)
89 (52.7%)
48 (28.4%)
33 (19.5%)
33 (19.5%)
150 (87.7%)
91 (53.2%)
39 (22.8%)
49 (28.7%)
32 (18.7%)
NS
NS
NS
0.049
NS
Objective Response Rate
FolfirinoxN=171
GemcitabineN=171
p
Complete response 0.6% 0%
Partial response 31% 9.4% 0.0001
CR/PR 95% CI [24.7-39.1] [5.9-15.4]
Stable disease 38.6% 41.5%
Disease control
CR+PR+SD70.2% 50.9% 0.0003
Progression 15.2% 34.5%
Not assessed 14.6% 14.6%
Median durationof response
5.9 mo. 4 mo. ns
Progression-Free Survival
0.00
0.25
0.50
0.75
1.00
Pro
babili
ty
171 121 85 42 17 7 4 1 1 0 0 0 0Folfirinox171 88 26 8 5 2 0 0 0 0 0 0 0Gemcitabine
Number at risk
0 3 6 9 12 15 18 21 24 27 30 33 36Months
Gemcitabine Folfirinox
p<0.0001
HR=0.47 : 95%CI [0.37-0.59]
Median PFS Folfirinox: 6.4 mo. Median PFS Gemcitabine: 3.3 mo
Overall Survival
0.00
0.25
0.50
0.75
1.00
Pro
babili
ty
171146116 81 62 34 20 13 9 5 3 2 2Folfirinox171134 89 48 28 14 7 6 3 3 2 2 2Gemcitabine
Number at risk
0 3 6 9 12 15 18 21 24 27 30 33 36Months
Gemcitabine Folfirinox
Stratified Log-rank test, p<0.0001
HR=0.57 : 95%CI [0.45-0.73]
Overall Survival
Folfirinox
N=171
Gemcitabine
N=171 p HR
Median survival[CI 95%]
11.1 mo.[ 9 - 13.1]
6.8 mo.[ 5.5 - 7.6]
<0.0001 0.57
1-yr. survival 48.4% 20.6%
18-mo. survival 18.6% 6%
Median follow up: 26.6 months [95% CI: 20.5 – 44.9]
Safety: hematological AEs
AE, % per patient
FolfirinoxN=167
GemcitabineN=169
p
All Grade 3/4 All Grade 3/4 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 54.8 2.4 0.008
5.4
42.5 % of the pts received G-CSF in the F arm vs 5.3% in the G armOne toxic death occurred in each armAE, adverse event
Safety: main non-hematological AEs
AE, % per patientFolfirinox N=167 Gemcitabine N=169
pAll Grade 3/4 All Grade 3/4
Infection without neutropenia
6 1.2 7.1 1.8 NS
Peripheral neuropathy 70.5 9 0.6 0 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 1.2 0.0001
Alopecia (grade 2) 32.5 (11.4) 3.0 (0.6) 0.0001
ALT 64.8 7.3 83.8 0.002218.618.6
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 18-75 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
Gemcitabine: mécanisme d’actionGemcitabine: 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
Uptake intracellulaire hENT1 hCNT 3
Activation dCK
– Nucleoside Phosphate Kinase
Inactivation– CDA
– DCTD
– 5’-NT
Action– Inhibition de la synthèse de l’ADN
471 patients assessed for eligibility
434 assessable
37 excluded adjuvant treatment unknown (n= 10)
not analyzable (n=10 ) inclusion in retrospective study (n=17)
Adjuvant treatment(n=292)
Non gemcitabine-containing (n=49)Radiotherapy alone (n=3) RT + 5FU (n=46)
No adjuvant treatment (n=142)
gemcitabine-based (n=243)Gemcitabine monotherapy (n=208)Gemox (n=35 )
Non Gemcitabine population Gemcitabine population
Expérience Franco-Belge
Marechal R, Bachet JB, Mackey J et al, in press
Expérience Franco-Belge
Marechal R, Bachet JB, Mackey J et al, in press
0.0
00.2
50.5
00.7
51.0
0S
urv
ival(
%)
92 89 78 69 59 50 34 29 27 22 18hENT1 high142 133 105 74 49 33 20 13 10 6 3hENT1 low/moderate
N at risk
0 6 12 18 24 30 36 42 48 54 60Months
hENT1 low/moderate
hENT1 high
Overall Survival
0.0
00.2
50.5
00.7
51.0
0S
urv
ival(
%)
165 156 134 105 83 67 48 38 34 26 20dCK moderate/high71 68 50 39 26 17 7 5 3 3 2dCK low
N at risk
0 6 12 18 24 30 36 42 48 54 60Months
dCK low
dCK moderate/high
Overall Survival
Population « gemcitabine »
Expérience Franco-Belge
Marechal R, Bachet JB, Mackey J et al, in press
0.0
00.2
50.5
00.7
51.0
0S
urv
ival(
%)
72 68 57 43 37 30 23 17 10 10 10hENT1 high107 101 75 61 46 38 33 29 27 24 22hENT1 low/moderate
N at risk
0 6 12 18 24 30 36 42 48 54 60Months
hENT1 low/moderate
hENT1 high
Overall Survival
0.0
00.2
50.5
00.7
51.0
0S
urv
ival(
%)
137 131 105 83 63 53 44 37 29 27 25dCK moderate/high43 40 29 23 21 16 13 9 8 7 7dCK low
N at risk
0 6 12 18 24 30 36 42 48 54 60Months
dCK low
dCK moderate/high
Overall Survival
Population « non gemcitabine »
Expérience Franco-Belge
Marechal R, Bachet JB, Mackey J et al, in press
Time (months)
726660544842363024181260
Cum
ulat
ive
Sur
viva
l
1,00
,75
,50
,25
0,00
N at risk
hENT1 low and any dCK
36 30 18 10 6 5 3 1 0 0 0 0 0
hENT1 moderate and any dCK
106 103 87 64 43 28 18 12 10 7 3 2 1
hENT1 high and dCK low 22 22 17 14 10 7 3 3 3 3 2 1 1
hENT1 high and dCK high 69 66 60 54 47 43 30 25 23 19 16 13 9
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 ????