Institut Mutualiste Montsouris,...
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Prise en charge du cancer du pancréas
Christophe Louvet Institut Mutualiste Montsouris, Paris
Journée SFPO, Paris, 9 octobre 2014
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Conflits d’intérêt
Participation à un board d’experts :
Celgène
Roche
Sanofi
Nucana
Amgen
Clovis Pharma
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Généralités
• Plus de 210 000 nouveaux cas par an dans le monde (2000).
• 2.1% de tous les cancers
• 10% des cancers digestifs
• + 1.7% / an (homme) ; + 2.1% / an (femme)
• 6ème cause de décès par cancer
• La mortalité par cancer du pancréas est à peu près égale à l’incidence
• Survie à 5 ans : 4%
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Stratégie globale
Maladie résécable
Stades I-II
~ 20%
Chirurgie
Chimio adjuvante
Maladie non résécable
Localement
avancée
Stade III (IV-A)
30-40%
Metastatique
Stade IV (IV-B)
40-50%
Chimio
Nouvelles drogues
Soins de confort Chimio
Radiochimio ?
Chirurgie seconde ?
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Traitement des formes
métastatiques
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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
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L’étude Burris (1997)
Gemcitabine n=63
5-Fluorouracile n=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
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Gem ± Pemetrexed (Oettle, Ann Oncol 2006) 6.3 6.2 NS
Gem ± CPT-11 (Rocha-Lima, JCO 2006) 6.6 6.3 NS
Gem ± Exatecan (Abou-Alfa, JCO 2006) 6.2 6.7 NS
Gem ± Cisplatin (Heinemann, JCO 2006) 6.0 7.5 NS
Gem ± Oxaliplatine (Louvet, JCO 2005) 7.1 9.0 NS
Gem ± Oxaliplatine (Poplin, JCO 2009) 4.9 5.9 NS
Gem ± 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 NS
Gem ± 5FU/LV (Riess, JCO 2005) 6.2 5.9 NS
Etudes de phases III dans les cancers du pancréas
(chimiothérapie conventionelle)
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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
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Résumé de la méta-analyse dans les cancers
du 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 < 0.0001
Gem vs Gem + sel de platine / fluoropyrimidine (PS 2) 574 1.08 NS
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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 en 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
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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)
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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)
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Gemcitabine perfusion de 30mn ou
de 10 mg/m²/mn?
R
Gemcitabine
1500 mg/m²
10mg/m²/min
Gemcitabine
2200mg/m²
30 min N=80
Rép 16.6%
PFS 3.4 mois
OS 8 mois
Survie à 1 an: 23%
Rép 2.7%
PFS 1.9 mois
OS 5 mois
Survie à 1 an : 0%
Tempero, JCO 2004
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Prodige 4 - ACCORD 11 trial design
Stratification :
center
performance status: 0 versus 1
location of the tumor: head versus other location of the primary
Metastatic
pancreatic
cancer
R
A
N
D
O
M
I
Z
E
Folfirinox
Gemcitabine
6 months of chemotherapy recommended
CT scans: obtained
every 2 months
for both arms:
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Folfirinox
N=171
Gemcitabine
N=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+SD 70.2% 50.9% 0.0003
Progression 15.2% 34.5%
Not assessed 14.6% 14.6%
Median duration
of response 5.9 mo. 4 mo. ns
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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 36
Months
Gemcitabine Folfirinox
Stratified Log-rank test, p<0.0001
HR=0.57 : 95%CI [0.45-0.73]
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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
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AE, % per patient
Folfirinox
N=167
Gemcitabine
N=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 arm
One toxic death occurred in each arm
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AE, % per patient
Folfirinox N=167 Gemcitabine N=169
p
All 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 0.0022 18.6
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nab®-Paclitaxel is the First Tumor-Targeted Nanomedicine
to Leverage the Natural Transport Properties of Albumin
130 nm in size1,2
1. Desai et al. SABCS. 2004 [Abstract 1071].
2. Kratz et al. J Control Release. 2008;132(3):171-183.
3. Peters,Jr. Serum albumin. Adv Protein Chem. 1985;37:161-245.
4. Desai. Drug Delivery Report. 2008;Winter 2007/2008(16):35-41.
5. Paal et al. Eur J Biochem. 2001;268:2187-2191.
nab® is a registered trademark of Celgene Corporation.
Albumin
Paclitaxel
nab-Paclitaxel
complex
nab-Paclitaxel
individual molecule
4-14 nm in size3,4
• A single molecule of albumin can bind up to 6 or 7 molecules of paclitaxel5
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nab®-Paclitaxel + Gemcitabine In Patients With
Metastatic Pancreatic Cancer Study Design
IV, intravenous; MTD, maximum tolerated
dose.
Phase I1
gemcitabine 1000 mg/m2 followed by
nab-paclitaxel 100, 125, or 150 mg/m2 IV
on days 1, 8, and 15 every 28 days
using standard 3+3 phase I dose-escalation design
Open label phase I/II study in chemotherapy-naive patients with
metastatic adenocarcinoma of the pancreas1
Phase II1
accrual continued at the MTD to ≥ 42 patients to
evaluate efficacy and safety of the combination
1.Von Hoff D, et al. J Clin Oncol. 2011. Published online October 3, 2011.
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Randomized Phase III Study of Weekly
nab-Paclitaxel plus Gemcitabine vs
Gemcitabine Alone in Patients with
Metastatic Adenocarcinoma of the
Pancreas (MPACT)
Daniel D. Von Hoff,1 Thomas Ervin,2 Francis P. Arena,3 E. Gabriela Chiorean,4 Jeffrey Infante,5
Malcolm Moore,6 Thomas Seay,7 Sergey A. Tjulandin,8 WenWee Ma,9 Mansoor N. Saleh,10 Marion
Harris,11 Michele Reni,12 Ramesh K. Ramanathan,1 Josep Tabernero,13 Manuel Hidalgo,14 Eric Van
Cutsem,15 David Goldstein,16 Xinyu Wei,17 Jose Iglesias,18 Markus F. Renschler 17
1 TGen, Scottsdale Healthcare, AZ, USA; 2 Cancer Specialists, Fort Myers, FL, USA; 3 Arena Onc Assoc, Lake Success, NY, USA; 4 Indiana
Univ, IN, USA; 5 Sarah Cannon Res Inst, Nashville, TN, USA; 6 Princess Margaret Hosp Toronto, Canada; 7 Atlanta Cancer Care, GA, USA; 8
Blokhin Cancer Res Ctr, Moscow, Russia; 9 Roswell Park Cancer Inst, Buffalo, NY, USA; 10 Cancer Specialists, Atlanta, GA, USA; 11 Southern
Health, East Bentleigh, VIC, Australia; 12 San Raffaele Sci Inst, Milan, Italy; 13 Vall d'Hebron Univ Hosp, Barcelona, Spain; 14 Centro Integral
Oncológico Clara Campal, Madrid, Spain; 15 Leuven Univ, Belgium; 16 Prince of Wales Hosp, Sydney, NSW, Australia; 17 Celgene, Summit,
NJ, USA; 18 Bionomics, Thebarton, Australia
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Study Design
1:1, stratified by KPS, region, liver metastasis
Planned N = 842
• Stage IV
• No prior treatment for
metastatic disease
• KPS ≥70
• Measurable disease
• Total bilirubin ≤ULN
nab-Paclitaxel 125 mg/m2 IV qw 3/4 weeks
+
Gemcitabine 1000 mg/m2 IV qw 3/4 weeks
Gemcitabine 1000 mg/m2 IV qw for 7/8 weeks
then qw 3/4 weeks
Von Hoff et al., ASCO GI 2013 LBA148
Primary Endpoint:
– OS
Secondary Endpoints:
– PFS and ORR by
Independent Review
(RECIST)
Safety and Tolerability
– by NCI CTCAE v3.0
• With 608 events, 90% power to detect OS
HR = 0.769 (2–sided α = 0.049)
• 1 interim analysis for futility
• Treat until progression
• CT scans every 8 weeks
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Overall Survival
Months
Pro
po
rtio
n o
f S
urv
ival
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
1.0
0.0
0 3 6 9 12 15 18 21 24 27 30 33 36 39
Pts at Risk
nab-P + Gem:
Gem:
431
430
357
340
269
220
169
124
108
69
67
40
40
26
27
15
16
7
9
3
4
1
1
0
1
0
0
0
nab-P + Gem
Gem
OS, months
Events/N (%) Median (95% CI) 75th Percentile
333/431 (77) 8.5 (7.89–9.53) 14.8
359/430 (83) 6.7 (6.01–7.23) 11.4
HR = 0.72
95% CI (0.617–0.835)
P = 0.000015
Von Hoff et al., ASCO GI 2013 LBA148
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OS - Prespecified Subgroups
Group
0.125 0.25 0.5 1.0 2.0
HR
All Patients
nab-P + Gem
Events / N
Gem
Events / N HR
333 / 431 359 / 430 0.72
188 / 254 209 / 242 0.65
145 / 177 150 / 188 0.81
138 / 186 141 / 173 0.72
195 / 245 218 / 257 0.72
142 / 179 146 / 161 0.61
187 / 248 212 / 268 0.75
142 / 191 155 / 180 0.59
188 / 237 201 / 246 0.80
290 / 365 309 / 360 0.69
43 / 66 50 / 70 0.86
21 / 33 16 / 21 0.41
159 / 202 163 / 206 0.75
104 / 136 121 / 140 0.79
49 / 60 59 / 63 0.50
47 / 60 43 / 56 1.07
96 / 122 95 / 120 0.83
151 / 197 171 / 195 0.61
50 / 61 53 / 59 0.67
62 / 64 59 / 62 0.84
14 / 38 17 / 38 0.72
207 / 268 230 / 271 0.68
Age <65 Years
Age ≥65 Years
Female
Male
KPS 70-80
KPS 90-100
Australia
Western Europe North America
Eastern Europe
Primary Tumor Location: Head
Primary Tumor Location: Other
No Liver Metastases
Liver Metastases
Normal CA19-9
CA19-9 ULN to <59 x ULN
CA19-9 ≥59 x ULN
>3 Metastatic Sites
1 Metastatic Site
3 Metastatic Sites
2 Metastatic Sites
Von Hoff et al., LBA148 Favors Gem Favors nab-P + Gem
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EVOLUTION
1997
2005
2007
2011
2013
Soins de confort
Gemcitabine
Gemcitabine; option « doublet » si IP 0-1
Gemcitabine; option « doublet » si IP 0-1;
option Gemcitabine + Erlotinib
FOLFIRINOX si IP 0-1; Gemcitabine si IP 2
FOLFIRINOX ou Gemcitabine + Abraxane si IP 0-1 ? ;
Gemcitabine si IP 2
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Maladie localement avancée
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Role of radiation therapy in locally advanced pancreatic cancer highly debated
• High rate of distant metastasis
chemotherapy
• Local control remains an important issue
chemoradiation (CRT)
Background
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Chauffert B et al. Ann Oncol 2008
Gem
CRT
Frontline CRT versus chemotherapy in LAPC
Loehrer P et al. J Clin Oncol 2011
Contradictory results
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Huguet F et al, J Clin Oncol 2007
CRT after 3 months of induction chemotherapy
Promising strategy
Induction CT followed by CRT in LAPC
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LAP07 study
XRT
Cape
XRT
Cape
1 month = Gemcitabine (1000 mg/m2)/wkX3
Until
progression
Erlotinib : 100 mg/d with gem
150 mg/d as single agent Cape XRT
Secondary surgery allowed at any time
Capecitabine plus radiation
R1
R2
R2 E
VA
LU
AT
ION
: n
on
pro
gre
ss
ive
EV
AL
UA
TIO
N :
no
n p
rog
res
siv
e
EV
AL
UA
TIO
N
EV
AL
UA
TIO
N
EV
AL
UA
TIO
N
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Overall Survival
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Traitement adjuvant
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ESPAC-1 :
Démonstration du bénéfice d’une chimiothérapie adjuvante (5FU / AF)
Neoptolemos et al, NEJM 2004; 350:1200-10
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Copyright restrictions may apply.
CONKO 01: gemcitabine vs observation
Oettle, H. et al. JAMA 2007;297:267-277; Neuhaus et al, ASCO GI 2009, A 4504
0
0.25
0.50
0.75
1
Su
rviv
al
0 12 24 36 48 60 72 84 96 108
months
Gemcitabine Median : 22.8 months (IC 95% : 18,5-27,2)
Observation Median : 20.2 months (IC 95% : 17,7-22,8)
Log Rank p=0.005
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ESPAC-3 : 5FU / AF vs Gemcitabine
Median S(t)= 23.0 m (95%CI:21.1, 25.0)
Median S(t)= 23.6 m (95%CI:21.4, 26.4)
c2LR=0.74, p=0.39, HRGEM VS 5FU/FA=0.94 (95%CI: 0.81, 1.08)
Neoptolemos et al. , ASCO2009
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Synthèse
La chimiothérapie adjuvante double le % de survie à 5 ans
Chirurgie Chirurgie + CT
médiane survie survie à 5 ans médiane survie survie à 5 ans
ESPAC-1 (5FU/AF) 14 mois 8.4% 19.7 mois 21.1%
CONKO 01 (gem) 20.2 mois 11.5% 22.1 mois 22.5%
ESPAC-3 (5FU/AF) 23.0 mois 20% *
ESPAC-3 (gem) 23.6 mois 22% *
* : estimation
La gemcitabine n’est pas supérieure au 5FU/AF (efficacité) : HR 0.94, p = 0.39
tendance pour les N+ , tendance pour les résections R1
La gemcitabine est supérieure au 5FU/AF pour les paramètres suivants : tolérance, incidence des SAE, compliance / dose-intensité
Confirmation des facteurs pronostiques (quel que soit l’étude ou le traitement)
Grade, Stade, N0 vs N+, R0 vs R1
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Biomarker Prognostic Predictive Current clinical impact
CA 19.9 Yes No No
CTC / cDNA Yes No No
miRNAs Yes No ? (Anti-sens)
Proteomic / LAMC Yes No No
Genomic profiles Yes No No
hENT1 No Yes (Gem) Likely (Gem)
dCK No Yes (Gem) Likely (Gem)
CDA No Yes (Gem toxicity) Likely (Gem)
SPARC Yes ? ? (Abraxane)
Histone modifications Yes ? ? (5FU)
Hedgehog Yes ? ? (HH inhibitors)
CXCR4 Yes ? ? (CXCR4 inhibitors)
HGF / c-Met Yes ? ? (c-Met inhibitors)
SMAD4 ? ? ?
HER2 ? ? ? (HER2 inhibitors)
EGFR ? (No) No No
VEGFR ? (No) No No
IGFR ? (No) No No
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Gemcitabine: mechanisms of action
Intracellular uptake
hENT1
hCNT 3
Activation
dCK
– Nucleoside Phosphate Kinase
Inactivation
– CDA
– DCTD
– 5’-NT
Action
– Inhibition DNA synthesis
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Survie selon l’expression de hENT1: Etude RTOG 9074
Farell JJ, et al. Gastroenterology 2009
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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
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Expérience Franco-Belge
Marechal R, Bachet JB, Mackey J et al, in press
0.0
00.2
50.5
00.7
51.0
0
Surv
ival(
%)
92 89 78 69 59 50 34 29 27 22 18hENT1 high
142 133 105 74 49 33 20 13 10 6 3hENT1 low/moderate
N at risk
0 6 12 18 24 30 36 42 48 54 60
Months
hENT1 low/moderate
hENT1 high
Overall Survival
0.0
00.2
50.5
00.7
51.0
0
Surv
ival(
%)
165 156 134 105 83 67 48 38 34 26 20dCK moderate/high
71 68 50 39 26 17 7 5 3 3 2dCK low
N at risk
0 6 12 18 24 30 36 42 48 54 60
Months
dCK low
dCK moderate/high
Overall Survival
Population « gemcitabine »
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Expérience Franco-Belge
Marechal R, Bachet JB, Mackey J et al, in press
0.0
00.2
50.5
00.7
51.0
0
Surv
ival(
%)
72 68 57 43 37 30 23 17 10 10 10hENT1 high
107 101 75 61 46 38 33 29 27 24 22hENT1 low/moderate
N at risk
0 6 12 18 24 30 36 42 48 54 60
Months
hENT1 low/moderate
hENT1 high
Overall Survival
0.0
00.2
50.5
00.7
51.0
0
Surv
ival(
%)
137 131 105 83 63 53 44 37 29 27 25dCK moderate/high
43 40 29 23 21 16 13 9 8 7 7dCK low
N at risk
0 6 12 18 24 30 36 42 48 54 60
Months
dCK low
dCK moderate/high
Overall Survival
Population « non gemcitabine »
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hENT1 as a predictive marker for patients with resected pancreatic ductal adenocarcinoma with
or without adjuvant gemcitabine or 5FU from patients randomized in the ESPAC1/3 trials
JP Neoptolemos, TF Cox, W Greenhalf, L Garner, F Campbell, D
Palmer, J Mackey, C Dervenis, A Scarpa, C Bassi, MW Buchler for the European Study Group for Pancreatic Cancer
EPC, Prague 21st June 2012
NIHR Liverpool Pancreas
Biomedical Research Unit
Freedom of the
City of
Liverpool
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Liverpool
PBRU
Freedom of the
City of Liverpool
hENT1 IHC TMA core scoring
3+; Hscore=210 2+; Hscore=150
Neg; Hscore=0 1+; Hscore=90
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Liverpool
PBRU
Freedom of the
City of Liverpool
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Liverpool
PBRU
Freedom of the
City of Liverpool
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Impact de hENT1sur les études adjuvantes
US « LAP07-like » : Déséquilibre entre les patients hENT1 low/moderate et les
patients hENT1 high pour atteindre la RTCT après 6 mois de traitement….
ESPAC4 : Gem + Cap probablement > Gem chez les patients hENT1 low/moderate
FOLFIRINOX : Folfirinox probablement > Gem chez les patients hENT1 low/moderate
Nécessité (au moins) d’une stratification…
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Gemcitabine “optimisée”
CO-1.01 :
prodrogue de la gemcitabine
liposoluble
pénétration intracellulaire indépendante des transporteurs
Etude de phase III (2012, multicentrique, 367 patients):
gemcitabine vs CO-1.01
négative, y compris chez les hENT1 –
Ac anti-lapin SP120
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hENT1
« Positive » trials
RTOG
(adjuvant, retrospective)
French-Belgium series
(adjuvant, retrospective)
ESPAC 1&3
(adjuvant, retrospective)
Negative trials
Clovis C01-101
(metastatic, prospective)
ECOG
(metastatic, retrospective)
CONKO-01
(adjuvant, retrospective)
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= ?
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Hedgehog Pathway
In 1980, hedgehog was first
described in flies to look like little
hedgehog with continuous spiky
outer skin due to its mutations.
Crucial for normal organ
development, differentiation
and morphogenesis in Drosophila
Conserved from flies to humans
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Story of cyclopamine
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Veratrum californicum
Inhibits Hh pathway
Story of cyclopamine
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Hedgehog Pathway
Three hh genes in mammals
– Sonic hh-broadest
expression pattern
– Desert hh-restricted
to the developing bone and
cartilage, gut and pancreas
– Indidan hh-gonads and
testes, peripheral nerves
and pancreas
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Hidalgo M and Maitra A. N Engl J Med 2009
Hedgehog (hh) pathway
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Hedgehog (hg) pathway
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Cancers du pancréas
- Maladie métastatique
- Maladie localement avancée
- Maladie opérable
Standard : Folfirinox (IP 0-1), Gemcitabine (IP2)
Options : Gemcitabine + Abraxane
GEMOX, gem FDR
Questions posées : nouvelles drogues, traitement sans gemcitabine
traitements individualisés selon profil génomique
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Cancers du pancréas
- Maladie métastatique
- Maladie localement avancée
- Maladie opérable
Standard : chimiothérapie
Options : chimiothérapie suivie de radiochimiothérapie
Questions posées : place de la radiochimiothérapie optimisée
place des résections secondes
traitements individualisés selon profil génomique
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Cancers du pancréas
- Maladie métastatique
- Maladie localement avancée
- Maladie opérable
Standard : chirurgie puis gemcitabine x 6 mois en adjuvant
Options : chirurgie puis chimio suivie de radiochimio
Questions posées : qualité de la résection R0
Amélioration de la chimiothérapie (Folfirinox ?)
place de la radiochimiothérapie adjuvante
place du traitement néo-adjuvant
traitements individualisés selon profil génomique
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