Phase III Trial

Cancer du pancréas : Référentiel et nouveautés
J.L. VAN LAETHEM,MD,PhD
Unité d’oncologie digestive
Erasme University Hospital
ULB-Brussels
[email protected]
PANCREATIC CANCER
Late diagnosis
Palliative treatment
90%
LAD
Metastatic
R0 surgery
10%
5 y. survival: 10-20%
disease
3-6 months
8-12 months
18-20 months
MEDIAN SURVIVAL
Options thérapeutiques
dans le cancer du pancréas
Ere du 5FU et des « BSC »
Ere de la Gemcitabine
Ere des cytotoxiques combinés
Ere des agents biologiques
Chemo(bio)radiation
1.Approche systémique <> métastatique
2.Approche Loco-régionale
3.Approche curative
INNOVONS !!!
1997 : the Burris study  Gemcitabine as a new
standard : median survival =6 months
1997-2006 : no major benefit of combining
cytotoxics,no new active chemotherapy
2005-2007 : anti EGFR therapy erlotinib added to
GEM : small benefit in survival (+ 0.5 month !) ; better
in patients with grade 2 rash
2007: biologics disappointing ! No survival benefit
 median survival = 6.4 months
Traitement systémique
Quel standard?
Quels cytotoxiques?
Apport des biologiques?
Gemcitabine: the standard of care
since 1997
Gemcitabine
5-FU
P value
Patients (n)
Clinical benefit response
63
63
23.8%
4.8%
0.0022
Tumour response
5.4%
0%
ND
Survival
5.65 mo
4.4 mo
0.0025
Time to progression
2.1 mo
0.9 mo
0.0002
18%
2%
0.0025
1-year survival
5-FU=5-fluorouracil
ND = Not determined
Burris et al. J Clin Oncol 1997
Combinaisons Gem + cytotoxics
phase III trials
Auteur
Traitement
n
GEM-CPT-11
360
6.3 mois
NS
Heineman (2003)
GEM-CIS
195
7.6
NS
O'Reilly (2004)
GEM-DX
349
6.2
NS
Richards (2004)
GEM-PMX
565
6.7
NS
Louvet (2005)
GEMOX
313
9.0
NS
Berlin (2003)
GEM-5FU bolus
322
6.7
NS
Riess (2005)
GEM-5FU/LV
466
5.8
NS
Hermann (2005)
GEM-cape
319
8.4
NS
Cunningham (2005)
GEM-cape
533
7.4
HR 0.8
GEM 30’
279
4.9
NS
GEMOX
276
5.9
NS
GEM FDR
277
6.0
HR 0.83
Rocha-lima (2003)
Poplin (2006)
Survie médiane
p
. Overall
survival analysis: gemcitabine versus gemcitabine-based combination
(Combo) chemotherapy
Copyright © American
Society
Clinical
Oncology 25:2607-2615 2007
Sultana,
A. et al.
J ofClin
Oncol;
Subgroup analysis of the different gemcitabine-based combination (Combo)
chemotherapy regimens
Copyright © American
Clinical Oncol;
Oncology
Sultana,
A. etSociety
al. JofClin
25:2607-2615 2007
Cytotoxiques: tendances
Metaanalyses 1:
– GEM combo better than GEM alone
 platinum-based
 capecitabine
– GEM vs 5FU: ? unconclusive
– chemotherapy better than BSC
Sultana, JCO 2007
Metaanalyses 2:
– GEM combo better than GEM alone
 platinum-based
 capecitabine
 good PS
Heinemann, Proc ASCO 2007,Ann Oncol 2007
FolFirinox vs GEM:
 phase II (n = 44/arm)
RR: 38.7% vs 11.7%  phase III
Ychou, Proc ASCO 2007
CDDP/LV5FV2 vs GEM and cross-over in 2nd line
FFCD trial awaited
De la biologie moléculaire à la thérapie
Quelles sont les données moléculaires qui caractérise
le cancer du pancréas?
Comment exploiter les nouvelles cibles moléculaires
et quel sera le gain thérapeutique?
Comment évaluer et prédire rapidement l’activité anti
tumorale?
Molecular Targets in Pancreatic Cancer
Growth Factor Ligand
(EGF, VEGF)
ECM
Integrin
Homodimer
ras
Y
FAK
Y
Y
raf
MEK
Src
Y
Y
Y
PI3K
EGF Receptor
Pro-MMP
Akt
ERK
Nucleus
Regulation of Gene Transcription
Molecular Events in Pancreatic Cancer
Oncogene Activation / Overexpression
– K-ras
Receptor Tyrosine Kinase Overexpression
– HER2/neu
– Epidermal Growth Factor Receptor
Tumor Suppressor Mutations
– p 53
– p 16
– SMAD4 (DPC4)
Nuclear Transcription Factor Activation
Other Events
– Angiogenesis – VEGF, IL-8
– Invasion – Cadherins, Matrix Metalloproteinases
– Inflammation – NFkB
Molecular Events in Pancreatic Cancer
Target Intervention
Cell Membrane Proteins
– HER2/neu
Herceptin
– EGFR
Antibodies, RTKls
– MMPIs
MMPI inhibitors
– VEGF(R)
Antibodies, RTKis
Signaling intermediates
– Raf-1
Raf-1 Kinase inhibitors (BAY-439006)
– Akt
LY294002
– mTOR
CCI-779, RAD001
Nuclear Transcription Factors
– NF-kB
Natural Products, Velcade, IKK
inhibitors
– Sp-1, Sp-3
Disrupt DNA binding
– PPAR
agonists,LY293111
Expression de l’EGFR dans les tumeurs
solides
Colorectal
Colorectal cancer
Lung
(NSCLC)
Head & neck
(SCCHN)
Head & neck cancer
60–80%
95–100%
Lung cancer (NSCLC)
40–80%
Breast cancer
14–91%
Ovarian cancer
35–70%
Pancreatic cancer
30–89%
Cunningham et al. N Engl J Med 2004;351:337-345. Grandis et al. Cancer 1996;78:1284-1292.
Salomon et al. Crit Rev Oncol Hematol 1995;19:183-232. Walker, Dearing. Breast Cancer Res Treat 1999;53:167176.
Proportion surviving with NED
Disease-free survival, EGFR and TGF
expression in patients with pancreatic
carcinomas
EGFR
TGFα
1.0
1.0
low
0.8
low
0.8
medium
0.6
0.6
0.4
medium
0.4
high
0.2
0.2
p=0.0001
0.0
0
1
high
p=0.0001
0.0
2
3
4
5
6
0
1
2
3
4
5
6
Years after surgery
Friess et al. Cancer Res 1993
Phase III
R
STRATIFICATION
A
GEMCITABINE 1000 mg/m2, IV
N
ERLOTINIB
CENTER
D
PS (0/1 vs. 2)
O
STAGE OF DISEASE
M

100/150 mg, ORAL
n = 569, 25% LA
I
Z
E
GEMCITABINE 1000 mg/m2, IV
PLACEBO
100/150 mg, ORAL
• OVERALL SURVIVAL
• PFS
• QOL
Moore, JCO 2007
NCIC-CTG PA.3 Study:
Overall Survival (100-mg Cohort)
100
HR: 0.81
95% CI: 0.67-0.98
P = .03
Survival, %
80
60
40
Gemcitabine + Erlotinib
Median survival: 6.37 months
1-year survival: 23%
20 Gemcitabine + Placebo
Median survival: 5.95 months
1-year survival: 17%
0
0
6
12
Months
Moore MJ, et al. J Clin Oncol. 2007;25:1960-1966.
18
24
NCIC-CTG PA.3 Study:
Rash vs Survival
Survival correlated with severity of
rash, but not EGFR expression
100
HR: 0.74
P < .037
Survival, %
80
Grade 2
60
40
Grade 0
Grade 1
5
10
Months
20
0
0
15
Moore MJ, et al. J Clin Oncol. 2007;25:1960-1966.
20
Outcome
Rash Severity
Gr 0
Gr 1
Gr ≥ 2
(n = 79)
(n = 102) (n = 101)
Median
survival,
mos
5.3
5.8
10.5
1-year
survival, %
16
9
43
How to predict survival?
Ki-ras mutation and EGF-R expression
Samples from 117 pts (< 569 in the PA 3 study)
Ki-ras mutant (79% pts): better survival than WT
unexpected
Among K-ras mutant: gem  gem + T
expected
Among K-ras WT: gem + T  gem
expected
Fish neg (53% of the pts) better than Fish +
expected
Among Fish pos, gem + T = gem
unexpected
Among Fish neg, gem + T > gem
unexpected
Moore, Proc ASCO 2007; Louvet, Discussion, ASCO 2007
First-Line Gemcitabine ± Cetuximab:
SWOG S0205 Phase III Trial
Stratified by disease status, Zubrod
PS (0/1 vs 2), prior pancreatectomy
Patients with locally
advanced or
metastatic pancreatic
adenocarcinoma
(N = 735)
Gemcitabine 1000 mg/m2/week
for 7 of 8 weeks, then 3 of every 4 weeks
(n = 366)
Gemcitabine 1000 mg/m2/week
for 7 of 8 weeks, then 3 of every 4 weeks +
Cetuximab 400 mg/m2 Week 1,
then 250 mg/m2 weekly
(n = 369)
Primary endpoint: overall survival
Philip PA, et al. ASCO 2007. Abstract LBA4509.
First-Line Gemcitabine ± Cetuximab:
SWOG S0205 Results
No significant difference in overall or progression-free
survival between gemcitabine vs
gemcitabine/cetuximab arms
Time to treatment failure prolonged with
gemcitabine/cetuximab (P = .0014)
No significant difference in response rates between
arms
No major toxicity differences between arms
– Slightly higher incidence of grade 3/4 rash and allergic
reaction in gemcitabine/cetuximab arm
Philip PA, et al. ASCO 2007. Abstract LBA4509.
Cancer du pancréas et antiangiogénèse
Target
Anti Target
Nom
 VEGF
mAb
Bevacizumab (Avastin®)
 VEGF-R1-2-3
TKI
PTK 787 (Schering)
 VEGF-R2-3
TKI
Axitinib (Pfizer)
TKI
AZD2171 (AZ)
Raf- KI
BAY-439006 (Bayer)
PDGFR
 VEGF-Rs
 Raf-kinase
VEGFR
PDGFR
(Sorafenib)
Gemcitabine ± Bevacizumab:
CALGB 80303 Phase III Trial
Stratified by disease status, ECOG
PS (0/1 vs 2), prior radiotherapy
Patients with
advanced pancreatic
adenocarcinoma
(N = 602)
Bevacizumab 10 mg/kg, Days 1 and 15 +
Gemcitabine 1000 mg/m2, Days 1, 8, and 15
of 28-day cycle
(n = 302)
Placebo, Days 1 and 15 +
Gemcitabine 1000 mg/m2, Days 1, 8, and 15
of 28-day cycle
(n = 300)
Primary endpoint: 35% improvement in
survival (from 6 to 8.1 months)
Kindler HL, et al. ASCO 2007. Abstract 4508.
Gemcitabine ± Bevacizumab:
CALGB 80303 Results
No significant difference in overall or progression-free survival between
gemcitabine vs gemcitabine/bevacizumab arms
– Median survival: 6.1 vs 5.8 months, respectively
Patients with locally advanced disease had longer overall survival vs
patients with metastatic disease
– 9.9 vs 5.7 months, respectively (HR: 1.4; P = .009)
Patients with better PS had longer overall survival (PS 0 > PS 1 > PS 2)
– 8.0 vs 4.8 vs 2.8 months, respectively (P = .0001)
No significant difference in response rates between arms
No major toxicity differences between arms, except
– Higher incidence of hypertension and proteinuria in gemcitabine/cetuximab
arm
Kindler HL, et al. ASCO 2007. Abstract LBA4508.
Gemcitabine + Erlotinib ± Bevacizumab:
AVITA (BO17706) Phase III Trial
Gemcitabine + Erlotinib + placebo
Patients with previously
untreated metastatic
pancreatic
adenocarcinoma
(N = 600)
Gemcitabine + Erlotinib +
Bevacizumab 5 mg/kg every 2 weeks
Primary endpoint: improvement in overall survival
(from 6.9 to 9.0 months)
Results pending for 2008
www.roche-trials.com/patient/trials/trial11.html
Thérapies ciblées: non convainquantes
MMI: marimastat:
2 negative trials
monotherapy vs combo
Moore 2003; Bramhall 2002
FTI: Tipifarnib: 1 negative trial
Van Cutsem 2004
Her-neu 2 targeting: Herceptin: disappointing phase II
Safran 2001
Sorafenib:
not active with gem
phase I (n = 17)
Wallace, Proc ASCO 2007
Lapatinib:
Her-1/Her-2 targeting
preliminary data in bilio-pancreatic cancer;
inconclusive
Safran, Proc ASCO 2006
Thérapies ciblées: activité à confirmer
TGF-2 inhibitor AP 12009:
phase I/II n = 17 (P, C, M)
one CR
Oettle, Proc ASCO
Curcumin: NF-Kappa B inhibitor :
phase II : n = 25
prolonged SD
bio-immunological response
Dhillan, Proc ASCO 2007
Sunitinib/axitinib : VEGR 1/2/3 inhibitor
 phase II:
OS 6.9 vs 5.6 (G + Ax vs G) phase III
Spano, Proc ASCO 2007; ECCO 2007
Thérapies ciblées: activité en attente
VEGF-trap: phase III en route: G +/- Aflibercept
Telomerase: GV-1001 vaccine: phase III en route
AEE-788: EGFR/VEGFR inhibition
RAD-001: mTOR inhibitor
Ras/Raf/MEK/ERK cascade: CI 1040 inhibitor (MEK 1-2)
Bcl-2 / Bcl-xL: Apo G2
IGF-R inhibitor…
AURORA kinase…
Phase II et III en seconde ligne dans le cancer du
pancréas
Regimen
PR
SD
Median OS
(%)
(%)
for 2d line
(weeks)
30
23.3
30
25
18
0
16
ND
18
5
27
17.5
30
11
57
27
Oettle (2005)
23
ND
ND
21*
Vs BSC
Phase III
23
CPT-11/FA/5-FU
Ng (2005)
15
0
38
14
33
22
38
25
Oxali/LV/5-FU
Authors & phase
Tsavaris (2005)
Number of
patients
Phase II
Oxali
Androulakis (2005)
Phase II
Paclitaxel
Oettle (2000)
Phase II
Capecitabine/
erlotinib
Oxali/FA/5-FU
Blaszkowsky (2005)
Phase II
10
Phase II
GEMOX
Van Laethem (2005)
Phase II
Aucun standard !
Thérapie systémique: messages
Peu d’avancées
10 ans pour gagner 0.5 mois de survie
Biologiques décevants (Avastin, cetuximab)
Standard = gemcitabine …. + tarceva …. Si on
comprend pour qui et pourquoi
Combinaisons: oui ; PS 0 < gain modeste en survie
(Méta Analyses)
Changer le design des études : stop larges phases III
Investiguer les combinaisons hors gem
Intérêt d’études en 2e ligne
Thérapie loco-régionale
Sélection des patients
Quelles stratégies? CT suivi de CTRT ? CT vs CTRT?
Role délétère de la RT?
Peut on rendre résécable une tumeur non résécable?
Approche néoadjuvante dans le
cancer du pancréas
N’est pas un standard!
Nécéssite un staging précis par EUS + pct, Helical CT + angio CT ou
MR et un preuve cyto et un drainage biliaire adéquat
Différentier les situations suivantes:
Resecable
chirurgie ou
neoadj protocol
borderline res
Non resecable
Tentative de résection chimiothérapie
ou neoadjuvant protocol
chimioRT
?
Confrontation multidisciplinaire basée sur le staging vasculair
Pancreatic cancer staging
Grade1: up to 1/4 circ
Grade 3: 1/2 -3/4 circ
Grade 2: 1/4 - 1/2 circ
Grade 4: > 3/4 circ
Yoshiura, J CAT 2005
Retroperitoneal Margin
SMV
SMA
RP margin
Gemcitabine can be safely combined with
radiation therapy
Gemcitabine active in advanced PC
Gemcitabine is a potent radiation sensitizer of tumour pancreatic cells
in vitro
Gemcitabine has only minor toxicity and can be easily administered in
an outpatient basis

increasing evidence of feasibility and activity of GEM + RT in PC (phases
I-II)
– neoadjuvant setting (Wolffs et al)
– locally advanced disease (Blackstock et al)
– adjuvant setting (Van Laethem et al, EORTC GI/RT group)
Preop gem + cisplatin followed by rapid fr. chemoradiation
for resectable pancreatic adc
Phase I-II study: gem 400 mg/m2 w + 30 Gy EBRT (proc ASCO 2002, Mc
Ginn)
Varadhachary et al (Proc ASCO 2006, abs 4.37)
– n = 77 stage I-II pancreatic head cancer
– gem/cis x 4 cycles q 2 w then gem 400 mg/m2 w + 30 Gy EBRT
restaging 4-6 weeks after the last dose
• 10 PD
• 61 on surgery: 44 pts  R0 resection; pPR (> 50% tumor kill) = 61%
– tox: preop stent occlusion: 44%; GI tox  gr 3; gr ¾ neutro: 29%
– MS  21 months
Pre-clinical evidence of the combination
of Erbitux with radiation
Baselga. Eur J Cancer 2001;37:S16–S22.
Neoadjuvant strategies: novel combinations
Gemcitabine-based chemoradiation
– feasible
– toxicity non negligeable but manageable
– active (pPR-CR)
– no phase III
Gemcitabine
+ platinums
+ capecitabine
+ paclitaxel
bevacizumab

cetuximab
erlotinib
phase I-II
Chemotherapy before chemoradiation strategy can improve
outcome… Non randomized evidence
Belgian Phase I Trial Gem/Cetuximab with RT dose Escalation for
LA/Marginally Resectable Disease
Surgery
Further Rx
Gem + C225 + RT (36, 55, or 50.4 Gy)
Staging
Gem 300 mg/m2 weekly
C225 400 then 250 mg/m2
weekly
EBRT: 36/45/50.4 Gy
Reevaluation
A Demols,JL van Laethem, personal communication
Bevacizumab + capecitabine + RT in LAD
Phase I trial
n = 48
Beva: 2.5, 5, 7.5, 10 mg/kg q2w
Cape: 650-825 mg/m2 bid
RT: 50.4 Gy
Toxicity:
GI gr 2 (43%), gr 3 (4%)
hemato gr 4 (13%), HFS (13%)
3 tumor-associated duodenal ulceration with bleeding (3, 10
and 20 w after RT)
1 tumor-associated duodenal perforation
Efficacy:
9/45 PR (20%) median: 6.2 months
7/45 MR (15%)
27/45 SD (60%)
MS: 15.2 months
Dose: 5 mg/kg BV
Crane, Proc ASCO 2005
IRM Pre et Post traitement
08 / 2005
02/ 2006
Gemox X 2  GEMOX + RT 45 Gy
(Peeters-Van Laethem, ESMO 2006 )
Pre and post-treatment Angio-MR
08 / 2005
02 / 2006
CTRT vs CT in LAD for palliation ?
Randomized Phase III : Chauffert et al, ASCO 2006
Initial CT/RT Gem
vs
Gem alone
CT= Cisp w 1/5, 5FU 300mg/m2 inf w1-6 ; RT= 60 Gy
(2Gy/fr) ; Gem= 1000 mg/m2/w
End point= OS 6  12 months  176 patients
First-intention CRT : FFCD-SFRO trial
Chauffert. ASCO 2006, # 4008
0.00
0.25
0.50
0.75
1.00
Overall Survival according to treatment arm
0
3
6
9
12
15
18
21
24
Time in Months
Gemcitabine
27
30
33
36
39
CHRT
109 patients included, median f.u. : 16 months [1 – 60]
Median survival : CRT = 8 months vs gemcitabine = 14 months
1-year survival : CRT= 24 % vs gemcitabine = 51 %
CTRT vs GEM
CTRT (n=59)
Dose >75% : RT 81%
5FU 52%
cisP 51%
OS 6 m
78%
12 m
24%
med
8.4 m
Toxicity gr 3/4
leuco
17%
thrombo
8.5%
non hémato 37%
GEM (n=60)
Gem 76%
82%
51%
14.3 m
p=0.014
10%
0%
17%
Chauffert et al,ASCO 06
Chemoradiation after chemotherapy induction
Background (2) : selection CT
10.8 months vs 7,4 months (p = 0.005)
CRT may increase survival
in patients with LA disease stable
after 3 months chemotherapy
compared to CT continuation
15 months vs 11,7 months (p = 0.0009)
Study for the
Locally Advanced cancer of the Pancreas
LAP 07
PI: P. Hammel June 2007
The LAP 07 study focuses on LA cancer with 2 questions :
Role of CRT in patient with controled disease?
Role of erlotinib in this form of cancer ?
Study for the Locally Advanced cancer of the Pancreas LAP 07
A : Gem
4 months
R1
B : Gem +
erlotinib (100 mg)
4 months
Non progressive disease
A1: Gem 2 months, then stop
A2 : RCT, then stop
R2
B1 : Gem + erlotinib (100 mg) 2 months
+ erlotinib maintenance (150 mg)
B2 : RCT
+ erlotinib maintenance
Thérapies loco-régionales: messages
Evaluer « finement » la résécabilité
Chirurgie vs traitement d’induction en vue 2d look
Combinaisons innovantes + RT
Pas de RTCT d’emblée
Sélection des patients controllés par CT d’induction
(étude observationnelle-phase III planifiée)
La gemcitabine reste le standard
Approche standard des tumeurs résécables

Pancreaticoduodenectomie (Whipple)

10-20% survie à long terme

Morbidité et mortalité significative ( inversement correlée
à l’experience)

Marges positives fréquentes (retropéritonéales)

20 - 30% patients ne recoivent pas de thérapie postopératoire
Adjuvant Therapy:
Pas de consensus entre US et Europe
GITSG1
–Survival advantage for chemoradiation followed by 5-FU
for 1 year, but
• Early termination, and
• Slow accrual (43 patients in 8 years)
EORTC2
–No survival benefit for chemoradiation, but no
maintenance chemotherapy
1. Kaiser MH, et al. Arch Surg. 1985;120:899-903.
2. Klinkenbijl JH. Ann Surg. 1999;230:776-782.
Adjuvant Chemotherapy:
Outcomes
CONKO-001:
Disease-Free Survival
ESPAC-1: Survival
75%
100%
50%
Survival (%)
Cumulative Disease Free Survival
100%
gemcitabine
25%
75%
50%
Chemotherapy
25%
observation
No chemotherapy
0%
0%
0
12
24
36 48
Months
Oettle H, et al. J Am Med Assoc.
2007;297:267-277.
60
72
84
0
12
24
36
Months
48
60
72
Neoptolemos JP, et al. NEJM. 2004;350:1200-1210.
Adjuvant therapy:ESPAC1 survival results
Arm
Median
survival
chemoRT 15.9 m
No CTRT
17.9 m
ChemoT
20.1 m
No
chemoT
14.7 m
HR
p
2-year
survival
5-year
survival
1.28
.05
29%
10%
41%
20%
40%
21%
30%
8%
0.71
.009
Adjuvant therapy in pancreatic cancer:
Gemcitabine is useful
Randomized multicenter phase III study: CONKO-001
n = 368 after R0/R1 surgical resection
observation
 DFS 6 months; OS
R
Gemcitabine x 6 cycles
Stratification: T, N, grade, R
S + Gem
S alone
n
186
182
R1 surgery
19%
16%
mDFS
14.2 months
7.46 months
19.3 m
11.2 m
0
1
13.1 m
7.0 m
14.0 m
7.9 m
0
1
14.5 m
5.5 m
N
R
P<0.01
Neuhaus, Proc ASCO 2005
RTOG 9704 / US INTERGROUP Phase III Study (Schema)
Resected AdenoCa of the Pancreas
Nodal Status
Neg. vs. Pos.
ARM 1: Pre-CRT 5 – FU
+
CHEMORADIATION (CRT)
+
Tumor Diameter
Post – CRT 5 – FU
< 3cm vs. >3 cm
ARM 2: Pre-CRT GEMCITABINE
Surgical Margins
+
CHEMORADIATION (CRT)
Neg. vs. Pos.
Vs. Unknown
+
Post – CRT GEMCITABINE
RTOG 9704 / US Intergroup Phase III Adjuvant Study
Overall Survival – ‘Pancreatic Head’ Pts Only
100
/ //
/
/
/
75
% ALIVE
Total Dead MST
/
CRT + Gemcitabine 187
CRT+ 5-FU
194
134 1.72
156 1.41
/
/
50
/
/
/
25
p = 0.033
/ //
/ // /// // //
//
/ //
/ ////
Median: 20.6 vs 16.9mos
3-Year: 32% vs 21%
/ ///
// //
0
0
Patients at Risk
RT + GEM
RT + 5FU
1
2
3
4
YEARS FROM RANDOMIZATION
187
194
134
132
77
63
46
31
24
19
Thérapie adjuvante :
recommendations
USA:
– Chirurgie suivie par adjuvant chemoRT (5FU)+/gemcitabine (RTOG 9704)
– preop chemoRT (gemzar ou cape + biologics) en
development
Europe:
– Chirurgie +/- chimiothérapie (5FU + Ac Fol ou Gem)
– adjuvant CTRT (5FU ou gem) :optionnel
– Randomiser les patients :EORTC 40113-22012/FFCD
3304: GEM vs GEM + RT) ?  phase III
Adjuvant treatment in pancreatic cancer
EORTC/FFCD 40013 intergroup trial
Resected
pancreatic
Gemcitabine x4
R
cancer R0
Gemcitabine x2  Gem +
RxT (50.4 Gy)
Phase II-III trial
Endpoints: feasability- survival, DFS (+ 10%)
Patients required: 80/ 490
www.eortc.be
Pancreatic cancer : what we need
To Target new molecular pathways
To assess efficiently and comprehensively innovative
drugs and combinations
To use new models /platforms for translational
research // (pre)clinical evaluation before embarking
large and costly phase III trials
To test enriched pts population based on early
development findings
To transfer relevant active therapy in the periop setting
in order to develop new multimodal strategies
Pancreatic cancer
Predictive factors of prognosis and response
Tumor suppressor genes
p53, DPC4
Microsatellite instability
hMSH2 / hMLH1
Growth factors
EGF, PDGF, TGF, TGF-RII
Hypoxic/vascular factors
microvascular density, VEGF,IL8
Cell proliferation
Ki 67,Cyclin D1
Apoptosis
BAX, Bcl-2
Invasion
Annexins,integrins,chemokines
Genomics > 2002
Proteomics > 2005 (Chen et al, Gastroenterology 2005)
 translational research program attached to clinical trials