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Advances in panceratic cancer Advances in panceratic cancer
management management
Christophe LouvetHôpital Saint-Antoine
Paris, France.
Beyrouth, 14/11/08
Landscape of Pancreatic Cancer
• More than 210 000 new cases per year around the world (2000)
• 2.1% of all cancers• 10% of GI cancers• + 1.7% / yr (men) ; + 2.1% / yr (women)
• 6th cause of cancer-related death• Pancreatic cancer mortality almost equal to incidence• 5-yr overall survival : 4%
Landscape of Pancreatic Cancer
• p53 mutation (70%)• K-ras mutation (90%)• p16 mutation (80%)
• EGF-r overexpression (> 60%)• VEGF overexpression• Loss of somatostatin antiproliferative effect (loss of
SSTR2 receptor)
Pancreatic mass : sometimes different from pancreatic tumor
Pancreatic tumor : sometimes different from pancreatic adenocarcinoma
Definitive need for a pathological diagnosis
Pancreatic cancer: current treatment options
• Symptomatic treatment: – pain– jaundice
• Resectable (stage I-II, 10 – 20%) : surgery followed by chemotherapy (chemoradiation ?)
• Locally-advanced disease (stage III-IVA, 40%): chemoradiation ? chemotherapy ?
• Metastatic disease (stage IVB, 40 – 50%):chemotherapy (gemcitabine)
Aims of the initial work-up
1- diagnosis
- if accessible met, biopsy of met
- if no met US endoscopyCT-scan guided biopsylaparoscopy / laparotomyresection
Aims of the initial work-up
2- guide for treatment strategy
Resectable disease
Surgery
Resection of disease
Adjuvant treatment ?
No resection
Go to LA
MDA criteria
“ Potentially resectable disease:
1) no extrapancreatic disease,
2) a patent SMV-PV confluence (assuming the technical ability to resect and reconstruct this venous confluence), and
3) a definable tissue plane between the tumor and regional arterial structures including the celiac axis, common hepatic artery and SMA. “
MDA criteria
N median survival p (months)
GITSG, Arch Surg 1985
- Surgery 21 11 - RT (20 Gy x 2) + 5 FU D1-D3 < 0,02 then 5 FU weekly / 2 yrs 22 20
EORTC, Ann Surg 1999
- Surgery 54 12,6 0,09 NS
- RT (20 Gy x 2) + 5 FU PC 60 17,1
Adjuvant CTRT phase III studies
ESPAC 1
99008800770066005500440033002200110000
0 12 84
110000
24 36 48 60 72
p<0.001
CONKO-001:
DFS99008800770066005500440033002200110000
0 12 84
110000
24 36 48 60 72
OS
p = 0.06
Surgery vs surgery followed by gemcitabine
Ongoing Adjuvant Trials in Resected Pancreatic Cancer
Trial Target N Treatment Arms Primary Endpoint
ESPAC-3 (Phase III)
990 5-FU-LV vs
Gemcitabine
2-y OS
EORTC 40013-22012 (Phase II-III)
538 Gemcitabine vs Gemcitabine → Gem + RT
Phase III: DFS/OS
Aims of the initial work-up
2- guide for treatment strategy
Locally-advanced disease« No met, no resection »
« never resectable » « border-line resectable »
Chemotherapy ?Chemoradiation ?
Chemotherapy ?Chemoradiation ?
Secondary surgery ?
Treatment of metastatic pancreatic cancerChemotherapy or BSC ?
Study Regimen npatients
Med. Surv.(mo)
Qol
Mallinson1980
5-FU+Mtx+Vcr+ cyclo + MMCBSC
21
19
10.5
2.2*Frey1981
5-FU + CCNUBSC
6587
3.03.9
Andersen1981
5-FU + BCNUBSC
2020
3.23.4
Palmer1994
FAMBSC
2320
8.23.8*
Glimelius1996
5-FU + LV +EtoposideBSC
29
24
6.0
2.5*
benefitin chemogroup
* p < 0.05
Treatment of metastatic pancreatic cancerThe Burris Study
R
Gemcitabine
5-Fluorouracil
1000 mg/m2 30 min infusion
Weekly for 7 w , 1 w rest, then 3w /4w
600 mg/m2 30 min infusion
weekly
Primary Objective :
Clinical Benefit
n=129
Treatment of metastatic pancreatic cancer
The Burris Study
• Clinical Benefit– PS improvement (>20% in Karnofsky index)– and / or Pain decrease (> 20%)– and / or Antalgics consumption decrease (> 50%)– and / or Weight increase (> 7%)
– For at least 1 month
Treatment of metastatic pancreatic cancerThe Burris Study
Clinical Benefit
Gemcitabine 23.8% p = 0.0022
5-Fluorouracil 4.8%
Treatment
Treatment of metastatic pancreatic cancerThe Burris Study
Gemcitabinen=63
5-Fluorouraciln=63
Median Survival 5.65 months * 4.41 months
6-months survival 46% 31%
9-months survival 24% 6%
12-months survival 18% 2%
* p = 0.0025
Burris H A, et al.: JCO 15: 2403, 1997
Gemcitabine: activation and mechanism of action
• Gemcitabine: a deoxycytidine analogue
• Requires intracellular uptake followed by sequential phosphorylation to active metabolite form
Gem Gem Gem-MP Gem-DP Gem-TP
• Blocks DNA synthesis/replication at several steps
incorporation into DNA*
deoxycytidine kinase
inhibition of RR
NT
Treatment of metastatic pancreatic cancer
• Gemcitabine 30’ infusion or 10 mg/m²/mn fixed dose rate ?
R
Gemcitabine1500 mg/m²10mg/m²/min
Gemcitabine2200mg/m²
30 minN=80
RR 16.6%PFS 3.4 monthsOS 8 months1-yr survival : 23%
RR 2.7%PFS 1.9 monthsOS 5 months1-yr survival : 0%
Tempero, JCO 2004
Randomized phases III in Pancreatic Cancer
Gem ± Marimasmat (Bramhall, 2002) 5.5 5.5
Gem ± Pemetrexed (Richards, 2004) 6.3 6.2Gem ± CPT-11 (Rocha-Lima, 2004) 6.6 6.3Gem ± Exatecan (O’Reilly, 2004) 6.2 6.7
Study OS gem (m) OS gem + drug X (m)
Gem vs Gem-Cap study (Cunningham)
Median survival 12-month (months, 95%CI) survival
GEM 6.0 (5.4, 7.1) 19%GEM-CAP 7.4 (6.5, 8.5) 26%
Hazard Ratio:0.80 (95% CI: 0.65, 0.98)Log rank p=0.026; χ2
LR=4.93
Randomized phases III in Pancreatic Cancer
Gem ± Marimasmat (Bramhall, 2002) 5.5 5.5
Gem ± Pemetrexed (Richards, 2004) 6.3 6.2Gem ± CPT-11 (Rocha-Lima, 2004) 6.6 6.3Gem ± Exatecan (O’Reilly, 2004) 6.2 6.7
Study OS gem (m) OS gem + drug X (m)
Gem ± 5FU bolus (Berlin, 2002) 5.4 6.7
Gem ± Capecitabine (Cunningham, 2005) 6.0 7.4
Gem ± Capecitabine (Herrmann, 2005) 7.3 8.4Gem ± 5FU/LV (Riess, 2005) 6.2 5.9
GEM-GEMOX Study : Overall survival
Gem Gemox
median 7.1 m 9.0 m
6-mth 60.4% 68.0%8-mth 45.3% 56.5%9-mth 40.0% 48.1%1-yr 27.8% 34.7%
Overall Survival
0 26 52 78 104 130 1560.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0GemGemox
weeks
% s
urv
ival
p
0.13
Louvet C, et al. J Clin Oncol, 2005
GEM FDR GEMOX
Gem : median = 4.9 monthsGemox : median = 5.9 monthsGem FDR : median = 6.0 months
Gem vs Gemox : NSGem vs Gem FDR : NS
Randomized phases III in Pancreatic Cancer
Gem ± Marimasmat (Bramhall, 2002) 5.5 5.5
Gem ± Pemetrexed (Richards, 2004) 6.3 6.2Gem ± CPT-11 (Rocha-Lima, 2004) 6.6 6.3Gem ± Exatecan (O’Reilly, 2004) 6.2 6.7
Gem ± Cisplatin (Heinemann, 2003) 6.0 7.5Gem ± Oxaliplatin (Louvet, 2004) 7.1 9.0Gem vs Gem FDR vs Gemox (Poplin, 2006) 4.9 6.0 5.9
Study OS gem (m) OS gem + drug X (m)
Gem ± 5FU bolus (Berlin, 2002) 5.4 6.7
Gem ± Capecitabine (Cunningham, 2005) 6.0 7.4
Gem ± Capecitabine (Herrmann, 2005) 7.3 8.4Gem ± 5FU/LV (Riess, 2005) 6.2 5.9
Nucleus
AntireceptorAntibodies± Toxins
TyrosineKinase
Inhibitors
FarnesylTransferase
Inhibitors
Hormone Agonists/Antagonists
ApoptosisAgonists
Antisense
Angiogenesis Inhibitors(Angiostatin, Endostatin
& Anti-VEGF)
MetalloproteinaseInhibitors
Matrix Degradation(Collagenases,Gelatinases &Stromelysins)
Immune SystemActivation (Vaccines,
Monoclonal antibodies)
Tumor CellGrowthFactorReceptors
IntracellularSignalingMolecules
Overview: Targeted Therapies
AntimetabolitesMicrotubule inhibitors
K-ras and farnesyltransferase inhibitors
No positive results in clinical trials
to date
GEMCITABINE ± ERLOTINIB Phase III Study
Overall Survival by Treatment Arm
0%
20%
40%
60%
80%
100%
0 12 24 36Months After Registration
GemcitabineGemcitabine and Cetuximab
N369366
Events338331
Medianin Months
66
P = 0.14
5.96.4
S0205: Primary EndpointS0205: Primary EndpointSurvival of All PatientsSurvival of All Patients
HR = 1.09 (95% CI: 0.93, 1.27)
CALGB 80303: Overall Survival by Treatment Arm
Bevacizumab 5.8 mo
Placebo 6.1 mo
HR = 1.03
P = 0.78
0 5 10 15 20 25
Months from Study Entry
0.0
0.2
0.4
0.6
0.8
1.0
Pro
po
rtio
n S
urv
ivin
g
BevacizumabPlacebo
Randomized phases III in Pancreatic Cancer
Gem ± Marimasmat (Bramhall, 2002) 5.5 5.5
Gem ± Pemetrexed (Richards, 2004) 6.3 6.2Gem ± CPT-11 (Rocha-Lima, 2004) 6.6 6.3Gem ± Exatecan (O’Reilly, 2004) 6.2 6.7
Gem ± Cisplatin (Heinemann, 2003) 6.0 7.5Gem ± Oxaliplatin (Louvet, 2004) 7.1 9.0Gem vs Gem FDR vs Gemox (Poplin, 2006) 4.9 6.0 5.9
Study OS gem (m) OS gem + drug X (m)
Gem ± 5FU bolus (Berlin, 2002) 5.4 6.7
Gem ± Capecitabine (Cunningham, 2005) 6.0 7.4
Gem ± Capecitabine (Herrmann, 2005) 7.3 8.4Gem ± 5FU/LV (Riess, 2005) 6.2 5.9
Gem ± Tifarbinib (Van Cutsem, 2004) 6.0 6.4Gem ± Erlotinib (Moore, 2005) 5.9 6.4Gem ± Bevacizumab (Kindler, 2007) 6.1 5.8Gem ± Cetiximab (Philip, 2007) 5.9 6.4
How to move on ?
1- Better knowledege on :
pancreatic cancer cellsrelationships between tumoral, endothelial and stromal cellspancreatic cancer patients
hopefully resulting in new drugs and new strategies
EGFR1IGFRIMC-A12CP-751CP-871 EGFR1
Ub
Ub
Ub
Ub
Ub
UbUb
Ub
UbUb
Cell cycle prog.Cellular adhesionProliferationAnti- apoptosis
Pro
teas
om
e
20S
19S
Bortezomib
NF?B
TNF-?IL6Bcl2
VEGFCyclin D1D2MYC
survival proliferation angiogenesis metastasis
antisense oligonucleotide
Grb2
MEK
ERK
PDK
p70S6K
STAT
STAT5
STAT5
STAT
STAT
SrcRasRasSOS
FTFTIFTISorafenib
c-Junc-mycc-Fos
FT
CetuximabPanitumumabEMD-72000Matuzumab
Raf
PI3K
AKt
mTOR
GefitinibErlotinibLapatinibCI-1033EKB-569AEE788 EXEL 7647BIBW2992
PIP2 PIP3
NF-B
PTEN
RapamycineTsemsirolimus/CCI-779Everolimus/RAD001AP23573
STAT3
elF
-4E
4E-B
P
4E-B
Pel
F-4
E
proliferationsurvival
pRb
p53
Abl
STAT STAT
MAP
K
Jak
p53
Gene transcription
R
G protein
PKC
GSK3β
CI-1040
Enzastaurin
How to move on ?
1- Better knowledege on :
pancreatic cancer cellsrelationships between tumoral, endothelial and stromal cellspancreatic cancer patients
hopefully resulting in new drugs and new strategies
2- Optimize the available tools :
Definitively separate strategies and studies in metastatic and in locally-advanced pancreatic cancer patients
0.0
00.2
50.5
00.7
51.0
0
Surv
ival p
rob
ab
ilitie
s
0 3 6 9 12 15 18 21 24 27 30 33 36 39Time in Months
Gemcitabine CHRT
Overall Survival according to treatment arm
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 %
First-intention CRT : FFCD-SFRO trialChauffert. ASCO 2006, # 4008
selection CT
CRT may increase survival
in patients with LA disease stable
after 3 months chemotherapy
compared to CT continuation
10.8 months vs 7,4 months (p = 0.005)
15 months vs 11,7 months (p = 0.0009)
Arm A1 :
Arm A2 :
Arm B1 :
Arm B2 : CRT
CRTE
VA
LU
AT
ION
: n
on
pro
gre
ssiv
e
EV
AL
UA
TIO
N :
no
n p
rog
ress
ive
3 perfusions of gemcitabine (1000 mg/m2)
Untilprogression
Erlotinib 100 mg/d when combined to Gem150 mg/d as single agent
capecitabine
irradiation
EV
AL
UA
TIO
N
EV
AL
UA
TIO
N
EV
AL
UA
TIO
N
Secondary surgery allowed in each arm at any time
R1 R2
Locally Advanced cancer of Pancreas study LAP 07
Conventional No Nodal RT
How to move on ?
1- Better knowledege on :
pancreatic cancer cellsrelationships between tumoral, endothelial and stromal cellspancreatic cancer patients
hopefully resulting in new drugs and new strategies
2- Optimize the available tools :
Definitively separate strategies and studies in metastatic and in locally-advanced pancreatic cancer patients
Prophylactic anticoagulation ?
How to move on ?
1- Better knowledege on :
pancreatic cancer cellsrelationships between tumoral, endothelial and stromal cellspancreatic cancer patients
hopefully resulting in new drugs and new strategies
2- Optimize the available tools :
Definitively separate strategies and studies in metastatic and in locally-advanced pancreatic cancer patients
Prophylactic anticoagulation ?
Methods and endpoints
ENDPOINTS AND METHODS
Response rate : NO (particularly in LAPC)
Clinical Benefit : NO (not commonly used)
PFS : NO (no impact of 2nd line)
OS : YES
ENDPOINTS AND METHODS
Response rate : NO (particularly in LAPC)
Clinical Benefit : NO (not commonly used)
PFS : NO (no impact of 2nd line)
OS : YES
Phase II studies ???
ENDPOINTS AND METHODS
Response rate : NO (particularly in LAPC)
Clinical Benefit : NO (not commonly used)
PFS : NO (no impact of 2nd line)
OS : YES
Phase II studies ???
Meta-analysis ???
Randomized phases III in Pancreatic Cancer
Study PFS/TTP(m) OS (m) N pts
Gem ± 5FU bolus (Berlin, 2002) 3.4 6.7 362
Gem ± Cisplatin (Heinemann, 2003) 5.3 7.5 190Gem ± Oxaliplatin (Louvet, 2004) 5.8 9.0 313
Gem ± Capecitabine (Herrmann, 2005) 4.8 8.4 319Gem ± 5FU/LV (Riess, 2005) 4.9 5.9 466
Gem ± Erlotinib (Moore, 2005) 3.7 6.4 530
Gem ± Capecitabine (Cunningham, 2005) NA 7.4 533
Gem ± 5FU/Capecitabine
Gem ± Platinum-analogs
Gem ± erlotinib
Need more than 500 pts to demonstrate survival advantage
Regimen nOR
(%)
PFS
(mo)
Survival
(mo)
GemOx vs Gem
GemPlat vs Gem
313
190
28* vs 16
12 vs 10
5.7* vs 3.7
5.3* vs 3.1
9.0 vs 7.1
7.5 vs 6.0
Gem + Capecitabine vs Gem
53314*
7 -
7.4*
6.0
Gem + Erlotinib vs Gem
5308
8.6
3.75*
3.55
6.4*
5.9
Gemcitabine-based Combinationsevidence from randomised trials
*significant
Regimen nOR
(%)
PFS
(mo)
Survival
(mo)
Gem + Platinum-Analog vs Gem
50322*
14
5.5*
3.45
8.3*
6.7*
Gem + Capecitabine vs Gem
53314
7 -
7.4*
6.0
Gem + Erlotinib vs Gem
5308
8.6
3.75*
3.55
6.4*
5.9
Gemcitabine-based Combinationsevidence from randomised trials
*significant
Regimen nSurvival
(mo)HR p
Gem + Platinum-Analog vs Gem
5038.3*
6.7* 0.77 0.031*
Gem + Capecitabine vs Gem
5337.4*
6.0 0.80 0.026
Gem + Erlotinib vs Gem
5306.4*
5.9 0.81 0.034
Gemcitabine-based Combinationsevidence from randomised trials
*significant
How to move on ?
1- Better knowledege on :
pancreatic cancer cellsrelationships between tumoral, endothelial and stromal cellspancreatic cancer patients
hopefully resulting in new drugs and new strategies
2- Optimize the available tools :
Definitively separate strategies and studies in metastatic and in locally-advanced pancreatic cancer patients
Prophylactic anticoagulation ?
Methods and endpoints
Gemcitabine-free regimens ?
Phase II trial of irinotecan/docetaxel for advanced pancreatic cancer with randomization between
irinotecan/docetaxel and irinotecan/docetaxel plus C225, a monoclonal antibody to the epidermal growth factor
receptor (EGF-r) : an Eastern Cooperative Oncology Group
Study (E8200)
B. A. Burtness, M. Powell, J. Berlin, D. Liles, A. Chapman, E. Mitchell, A. B. Benson, Eastern Cooperative Oncology Group
Fox Chase Cancer Center, Philadelphia; Dana-Farber Cancer Institute, Boston; Vanderbilt University, Nashville; East Carolina University School of Medicine , Greenville; Thomas
Jefferson University, Philadelphia; Northwestern University, Chicago
#4519
Treatment Arm ALIVEDEAD MEDIANTOTAL
A 43 37 6 6.5B 43 40 3 5.3
Sur
viva
l Pro
babi
lity
Overall Survival by Treatment Arm - E8200
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
Overall Survival Time in Months
0 5 10 15 20 25 30 35
RANDOMIZED PHASE II TRIAL COMPARING FOLFIRINOX (5FU/LEUCOVORIN, IRINOTECAN
AND OXALIPLATIN) VS GEMCITABINEAS FIRST-LINE TREATMENT FOR METASTATIC PANCREATIC
ADENOCARCINOMA
FIRST RESULTS OF THE ACCORD 11/0402 TRIAL M. Ychou1, F. Desseigne2, R. Guimbaud3, M. Ducreux4, O. Bouché5,
Y. Bécouarn6, A. Adenis7, C. Montoto-Grillot8, E. Luporsi9, T. Conroy9
1. Centre Val d'Aurelle, Montpellier 2. Centre Léon Bérard, Lyon
3. Institut Claudius Regaud, Toulouse 4. Institut Gustave Roussy, Villejuif
5. Centre Hospitalier R. Debré, Reims 6. Institut Bergonié, Bordeaux
7. Centre Oscar Lambret, Lille 8. FNCLCC, Paris
9. Centre Alexis Vautrin, Nancy, FRANCE
#4516
Results – Efficacy
FOLFIRINOX (A)n = 44
Gemcitabine (B)n = 44
Complete Response (CR) 0 0
Partial Response (PR)[ 95 % IC ]
14 (31.8 %)[18.6-47.6 %]
5 (11.4 %) [3.8-24.6 %]
Stable Disease (SD)
Progressive Disease (PD)
Non Evaluable (NE)**
* Panel confirmed 15 PR in arm A and 2 in arm B** 2 non treated and 4 ineligible
12 (27.3 %)
15 (34.1 %)
3 (6.8 %)
9 (20.4 %)
27 (61.4 %)
3 (6.8 %)
Investigators Response Rate* (ITT Population)
How to move on ?
1- Better knowledege on :
pancreatic cancer cellsrelationship between tumoral, endothelial and stroma cellspancreatic cancer patients
hopefully resulting in new drugs and new strategies
2- Optimize the available tools :
Definitively separate strategies and studies in metastatic and in locally-advanced pancreatic cancer patients
Prophylactic anticoagulation ?
Methods and endpoints
Gemcitabine-free regimens ?
Genomics and proteomics for individualized strategies ?
ASCO 07, June 3rd.
K-ras mutation and EGF-r expression(Moore and coll, # 4521)
Samples from 117 pts (out of the 569 included in the PA3 study)
Only « trends » on survival, since sample size limits the conclusions.
K-ras mutant (79% of pts) better than K-ras WT unexpected
Among K-ras mutant : gem > or = to gem + T expected
Fish neg (53% of pts) better than Fish pos expected
Among Fish pos, gem + T = gem unexpected
#4521
Among K-ras WT: gem + T > or = to gem expected
Among Fish neg, gem + T > gem unexpected
Pancreatic cancer: new management• Symptomatic treatment:
– pain– jaundice
• Resectable (R0 resection) : surgery followed by chemotherapy (± biotherapy) (± chemoradiation) neoadjuvant treatment ?
• Resectable (R1 resection) :surgery followed by chemotherapy (± biotherapy) followed by chemoradiationneoadjuvant treatment ?
• Locally-advanced disease : chemotherapy (± biotherapy) followed by chemoradiationsecondary resection ?
• Metastatic disease :chemotherapy (doublets ?) (± biotherapy ?)investigational new drugs ; gemcitabine-free regimens ? ; tailored choice of treatment according to molecular issues ?
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