Aucun titre de diapositive

Report
Advances in panceratic cancer
management
Christophe Louvet
Hôpital 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 endoscopy
CT-scan guided biopsy
laparoscopy / laparotomy
resection
Aims of the initial work-up
2- guide for treatment strategy
Resectable disease
MDA criteria
Surgery
Resection of disease
No resection
Adjuvant treatment ?
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. “
Adjuvant CTRT phase III studies
N
median survival
(months)
p
GITSG, Arch Surg 1985
- Surgery
- RT (20 Gy x 2) + 5 FU D1-D3
then 5 FU weekly / 2 yrs
21
11
< 0,02
22
20
54
12,6
EORTC, Ann Surg 1999
- Surgery
0,09 NS
- RT (20 Gy x 2) + 5 FU PC
60
17,1
ESPAC 1
CONKO-001:
Surgery vs surgery followed by gemcitabine
1
09
00
8
0
7
0
6
0
5
0
4
0
3
0
2
0
1
00
0
DFS
1
09
00
8
7
0
0
6
0
5
4
0
0
3
2
0
0
1
00
p<0.001
12
24
36
48
60
72
84
OS
p = 0.06
0
12
24
36
48
60
72
84
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 4001322012 (Phase IIIII)
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 cancer
Chemotherapy or BSC ?
Study
Regimen
Mallinson
1980
5-FU+Mtx+Vcr
+ cyclo + MMC
BSC
5-FU + CCNU
BSC
5-FU + BCNU
BSC
FAM
BSC
5-FU + LV +
Etoposide
BSC
Frey
1981
Andersen
1981
Palmer
1994
Glimelius
1996
* p < 0.05
n
patients
21
Med. Surv.
(mo)
10.5
19
65
87
20
20
23
20
29
2.2*
3.0
3.9
3.2
3.4
8.2
3.8*
6.0
24
2.5*
Qol
benefit
in chemo
group
Treatment of metastatic pancreatic cancer
The Burris Study
n=129
Gemcitabine
1000 mg/m2 30 min infusion
Weekly for 7 w , 1 w rest, then 3w /4w
R
Primary Objective :
Clinical Benefit
5-Fluorouracil
600 mg/m2 30 min infusion
weekly
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 cancer
The Burris Study
Treatment
Clinical Benefit
Gemcitabine
23.8%
5-Fluorouracil
4.8%
p = 0.0022
Treatment of metastatic pancreatic cancer
The Burris Study
Median Survival
Gemcitabine
n=63
5-Fluorouracil
n=63
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
NT
Gem-MP
*
deoxycytidine kinase
Gem-DP
Gem-TP
inhibition of RR
incorporation into DNA
• Blocks DNA synthesis/replication at several steps
Treatment of metastatic pancreatic cancer
• Gemcitabine 30’ infusion or 10 mg/m²/mn fixed dose rate ?
Gemcitabine
1500 mg/m²
10mg/m²/min
RR 16.6%
PFS 3.4 months
OS 8 months
1-yr survival : 23%
R
N=80
Gemcitabine
2200mg/m²
30 min
RR 2.7%
PFS 1.9 months
OS 5 months
1-yr survival : 0%
Tempero, JCO 2004
Randomized phases III in Pancreatic Cancer
Study
Gem ± Marimasmat (Bramhall, 2002)
Gem ± Exatecan (O’Reilly, 2004)
Gem ± CPT-11 (Rocha-Lima, 2004)
Gem ± Pemetrexed (Richards, 2004)
OS gem (m)
5.5
6.2
6.6
6.3
OS gem + drug X (m)
5.5
6.7
6.3
6.2
Gem vs Gem-Cap study (Cunningham)
Median survival
(months, 95%CI)
GEM
6.0 (5.4, 7.1)
GEM-CAP 7.4 (6.5, 8.5)
Hazard Ratio:
0.80 (95% CI: 0.65, 0.98)
Log rank p=0.026; χ2LR=4.93
12-month
survival
19%
26%
Randomized phases III in Pancreatic Cancer
Study
OS gem (m)
OS gem + drug X (m)
Gem ± Marimasmat (Bramhall, 2002)
Gem ± Exatecan (O’Reilly, 2004)
Gem ± CPT-11 (Rocha-Lima, 2004)
Gem ± Pemetrexed (Richards, 2004)
5.5
6.2
6.6
6.3
5.5
6.7
6.3
6.2
Gem ± 5FU bolus (Berlin, 2002)
Gem ± Capecitabine (Herrmann, 2005)
Gem ± 5FU/LV (Riess, 2005)
Gem ± Capecitabine (Cunningham, 2005)
5.4
7.3
6.2
6.0
6.7
8.4
5.9
7.4
GEM-GEMOX Study : Overall survival
% survival
Overall Survival
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
Gem
Gemox
Gem
0
26
52
78
weeks
104
130
156
Gemox
median 7.1 m
9.0 m
6-mth
8-mth
9-mth
1-yr
68.0%
56.5%
48.1%
34.7%
60.4%
45.3%
40.0%
27.8%
p
0.13
Louvet C, et al. J Clin Oncol, 2005
Gem : median = 4.9 months
Gemox : median = 5.9 months
Gem FDR : median = 6.0 months
Gem vs Gemox : NS
Gem vs Gem FDR : NS
GEM
FDR
GEMOX
Randomized phases III in Pancreatic Cancer
Study
OS gem (m)
OS gem + drug X (m)
Gem ± Marimasmat (Bramhall, 2002)
Gem ± Exatecan (O’Reilly, 2004)
Gem ± CPT-11 (Rocha-Lima, 2004)
Gem ± Pemetrexed (Richards, 2004)
5.5
6.2
6.6
6.3
5.5
6.7
6.3
6.2
Gem ± 5FU bolus (Berlin, 2002)
Gem ± Capecitabine (Herrmann, 2005)
Gem ± 5FU/LV (Riess, 2005)
Gem ± Capecitabine (Cunningham, 2005)
5.4
7.3
6.2
6.0
6.7
8.4
5.9
7.4
Gem ± Cisplatin (Heinemann, 2003)
6.0
Gem ± Oxaliplatin (Louvet, 2004)
7.1
Gem vs Gem FDR vs Gemox (Poplin, 2006) 4.9
7.5
9.0
5.9
6.0
Overview: Targeted Therapies
Antireceptor
Antibodies
± Toxins
Tyrosine
Kinase
Inhibitors
Farnesyl
Transferase
Inhibitors
Apoptosis
Agonists
Immune System
Activation (Vaccines,
Monoclonal antibodies)
Tumor Cell
Antimetabolites
Growth
Microtubule inhibitors
Factor
Receptors
Nucleus
Intracellular
Signaling
Molecules
Hormone Agonists/
Antagonists
Metalloproteinase
Inhibitors
Matrix Degradation
(Collagenases,
Gelatinases &
Stromelysins)
Angiogenesis Inhibitors
(Angiostatin, Endostatin
& Anti-VEGF)
Antisense
K-ras and farnesyltransferase inhibitors
No positive results in clinical trials
to date
GEMCITABINE ± ERLOTINIB
Phase III Study
S0205: Primary Endpoint
Survival
of
All
Patients
Overall Survival by Treatment Arm
100%
N
Gemcitabine
369
Gemcitabine and Cetuximab
366
P = 0.14
80%
Events
338
331
Median
in Months
6
5.9
6.4
6
60%
HR = 1.09 (95% CI: 0.93, 1.27)
40%
20%
0%
0
12
24
Months After Registration
36
0.8
0.6
Bevacizumab
Placebo
0.4
Bevacizumab 5.8 mo
Placebo
6.1 mo
0.2
HR = 1.03
P = 0.78
0.0
Proportion Surviving
1.0
CALGB 80303:
Overall Survival by Treatment Arm
0
5
10
15
20
Months from Study Entry
25
Randomized phases III in Pancreatic Cancer
Study
OS gem (m)
OS gem + drug X (m)
Gem ± Marimasmat (Bramhall, 2002)
Gem ± Exatecan (O’Reilly, 2004)
Gem ± CPT-11 (Rocha-Lima, 2004)
Gem ± Pemetrexed (Richards, 2004)
5.5
6.2
6.6
6.3
5.5
6.7
6.3
6.2
Gem ± 5FU bolus (Berlin, 2002)
Gem ± Capecitabine (Herrmann, 2005)
Gem ± 5FU/LV (Riess, 2005)
Gem ± Capecitabine (Cunningham, 2005)
5.4
7.3
6.2
6.0
6.7
8.4
5.9
7.4
Gem ± Cisplatin (Heinemann, 2003)
6.0
Gem ± Oxaliplatin (Louvet, 2004)
7.1
Gem vs Gem FDR vs Gemox (Poplin, 2006) 4.9
7.5
9.0
5.9
Gem ± Tifarbinib (Van Cutsem, 2004)
Gem ± Erlotinib (Moore, 2005)
Gem ± Bevacizumab (Kindler, 2007)
Gem ± Cetiximab (Philip, 2007)
6.0
5.9
6.1
5.9
6.0
6.4
6.4
5.8
6.4
How to move on ?
1-
Better knowledege on :
pancreatic cancer cells
relationships between tumoral, endothelial and stromal cells
pancreatic cancer patients
hopefully resulting in new drugs and new strategies
EGFR1
Gefitinib
Erlotinib
Lapatinib
CI-1033
EKB-569
AEE788
EXEL 7647
BIBW2992
Abl
Enzastaurin
STAT
Src Grb2
SOS
STAT STAT
FTI
Sorafenib
Ras
PDK
antisense
oligonucleotide
Raf
PI3K
PIP2
PIP3
PTEN
AKt
PKC
MEK
Rapamycine
Tsemsirolimus/CCI-779
Everolimus/RAD001
AP23573
mTOR
CI-1040
GSK3β
M
A
P
K
STAT5
STAT5
pRb
STAT3
ERK
p70S6K
proliferation
Ub
Ub
Ub
Ub
Ub
Ub
Ub
Ub
p53
Ub
TNF -?
IL6
Bcl2
STAT
Gene transcription
NF ?B
Bortezomib
p53
survival
STAT
Cell cycle prog .
Cellular adhesion
Proliferation
Anti -apoptosis
Proteasome
19S
20S
c-Jun
c-myc
c-Fos
Ub
NF-B
4E-BP
G protein
Jak
elF-4E
R
EGFR1
4E-BP
IGFR
Cetuximab
Panitumumab
EMD-72000
Matuzumab
elF-4E
IMC-A12
CP-751
CP-871
survival
proliferation
VEGF
Cyclin D1D2
MYC
angiogenesis
metastasis
How to move on ?
1-
Better knowledege on :
pancreatic cancer cells
relationships between tumoral, endothelial and stromal cells
pancreatic 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
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 %
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)
Arm B2 :
R1
EVALUATION
Arm B1 :
CRT
EVALUATION
Arm A2 :
EVALUATION
EVALUATION : non progressive
Arm A1 :
EVALUATION : non progressive
Locally Advanced cancer of Pancreas study LAP 07
Until
progression
CRT
R2
3 perfusions of gemcitabine (1000 mg/m2)
Erlotinib
100 mg/d when combined to Gem
150 mg/d as single agent
capecitabine
irradiation
Secondary surgery allowed in each arm at any time
Conventional
No Nodal RT
How to move on ?
1-
Better knowledege on :
pancreatic cancer cells
relationships between tumoral, endothelial and stromal cells
pancreatic 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 cells
relationships between tumoral, endothelial and stromal cells
pancreatic 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/Capecitabine
Gem ± 5FU bolus (Berlin, 2002)
Gem ± Capecitabine (Herrmann, 2005)
Gem ± 5FU/LV (Riess, 2005)
Gem ± Capecitabine (Cunningham, 2005)
3.4
4.8
4.9
NA
6.7
8.4
5.9
7.4
362
319
466
533
Gem ± Platinum-analogs
Gem ± Cisplatin (Heinemann, 2003)
Gem ± Oxaliplatin (Louvet, 2004)
5.3
5.8
7.5
9.0
190
313
Gem ± erlotinib
Gem ± Erlotinib (Moore, 2005)
3.7
6.4
530
Need more than 500 pts to demonstrate survival advantage
Gemcitabine-based Combinations
evidence from randomised trials
Regimen
GemOx vs Gem
GemPlat vs Gem
Gem + Capecitabine
vs Gem
Gem + Erlotinib
vs Gem
n
313
190
OR
(%)
PFS
(mo)
Survival
(mo)
28* vs 16 5.7* vs 3.7 9.0 vs 7.1
12 vs 10 5.3* vs 3.1 7.5 vs 6.0
533
14*
7
-
7.4*
6.0
530
8
8.6
3.75*
3.55
6.4*
5.9
*significant
Gemcitabine-based Combinations
evidence from randomised trials
Regimen
Gem + Platinum-Analog
vs Gem
Gem + Capecitabine
vs Gem
Gem + Erlotinib
vs Gem
n
OR
(%)
PFS
(mo)
Survival
(mo)
503
22*
14
5.5*
3.45
8.3*
6.7*
533
14
7
-
7.4*
6.0
530
8
8.6
3.75*
3.55
6.4*
5.9
*significant
Gemcitabine-based Combinations
evidence from randomised trials
Regimen
Gem + Platinum-Analog
vs Gem
Gem + Capecitabine
vs Gem
Gem + Erlotinib
vs Gem
n
Survival
(mo)
HR
p
503
8.3*
6.7*
0.77
0.031*
533
7.4*
6.0
0.80
0.026
530
6.4*
5.9
0.81
0.034
*significant
How to move on ?
1-
Better knowledege on :
pancreatic cancer cells
relationships between tumoral, endothelial and stromal cells
pancreatic 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 ?
#4519
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
Overall Survival by Treatment Arm - E8200
1.0
0.9
Survival Probability
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
0
5
10
15
20
25
30
Overall Survival T ime in Months
Treatment Arm
A
B
TOTAL
43
43
DEAD
37
40
ALIVE
6
3
MEDIAN
6.5
5.3
35
#4516
RANDOMIZED PHASE II TRIAL COMPARING FOLFIRINOX
(5FU/LEUCOVORIN, IRINOTECAN
AND OXALIPLATIN) VS GEMCITABINE
AS 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
3. Institut Claudius Regaud, Toulouse
5. Centre Hospitalier R. Debré, Reims
7. Centre Oscar Lambret, Lille
9. Centre Alexis Vautrin, Nancy, FRANCE
2. Centre Léon Bérard, Lyon
4. Institut Gustave Roussy, Villejuif
6. Institut Bergonié, Bordeaux
8. FNCLCC, Paris
Results – Efficacy
Investigators Response Rate* (ITT Population)
Complete Response (CR)
Partial Response (PR)
[ 95 % IC ]
FOLFIRINOX (A)
n = 44
Gemcitabine (B)
n = 44
0
0
14 (31.8 %)
[18.6-47.6 %]
5 (11.4 %)
[3.8-24.6 %]
Stable Disease (SD)
12 (27.3 %)
9 (20.4 %)
Progressive Disease (PD)
15 (34.1 %)
27 (61.4 %)
3 (6.8 %)
3 (6.8 %)
Non Evaluable (NE)**
* Panel confirmed 15 PR in arm A and 2
in arm B
** 2 non treated and 4 ineligible
How to move on ?
1-
Better knowledege on :
pancreatic cancer cells
relationship between tumoral, endothelial and stroma cells
pancreatic 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.
#4521
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
Among K-ras WT:
gem + T > or = to gem
expected
Fish neg (53% of pts) better than Fish pos
expected
Among Fish pos, gem + T = gem
unexpected
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 chemoradiation
neoadjuvant treatment ?
•
Locally-advanced disease :
chemotherapy (± biotherapy) followed by chemoradiation
secondary resection ?
•
Metastatic disease :
chemotherapy (doublets ?) (± biotherapy ?)
investigational new drugs ; gemcitabine-free regimens ? ; tailored choice of treatment
according to molecular issues ?

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