EPU: 'SOIREE DIGESTIVE de SAINT JOSEPH' le Mardi 23 mai 2017. Comment prendre en charge les formes localisées de cancer du pancréas. Cette présentation fait état de l'histoire de la maladie tumorale et discute de l'importance des traitements néo-adjuvants par chimiothérapie chez les patients opérables d'emblée et chez ceux à la limite de la chirurgie (borderline).
3. Le cancer du pancréas
Le cancer du pancréas (adénocarcinome) est
au 10ème rang des cancers les plus fréquents
et garde un mauvais pronostic le plaçant au
5ème rang des causes de décès par cancer
L’incidence du cancer du pancréas est en
forte augmentation. Chez l’homme, le taux
d’incidence annuel standardisé (100 000
homme-années) est passé de 4,9 cas à 9,5 cas
entre 1980 et 2015 et chez la femme de 2,0 cas
à 6,3 cas sur la même période
Il s’agit d’un cancer agressif souvent d’emblée
métastatique et provoquant rapidement une
jaunisse, des douleurs et une altération
importante de l’état général avec fatigue,
amaigrissement et perte d’appétit. Il
s’accompagne fréquemment de complications
thromboemboliques, inflammatoires,
métaboliques et immunologiques jouant un rôle
important dans l’évolution des malades
7. Le cancer du pancréas est tardivement pris en charge et d’autant plus
difficile à traiter
14. Oberstein 2013. Therapeutic advances in gastroenterology. Pancreatic cancer: why is it so hard to treat
Les symptômes sont peu spécifiques et retardent souvent le diagnostic
Il n’existe pas de biomarqueur, de gène ou de nouvelle technique d’imagerie
diagnostique
La tumeur est souvent mal située au confluent de nombreuses structures
anatomiques
Les métastases sont précoces mais difficiles à identifier
L’évolution est rapide et le diagnostique souvent fait à un stade avancé
Les altérations géniques sont sévères et fréquentes
La chirurgie curative ne peut concerner qu’un nombre limité de patients
Les résistances spontanées ou acquises aux chimiothérapies et à la radiothérapie
sont fréquentes
Diagnostic tardif/ pas de
dépistage
Difficultés de
traitement
9. Métastatique Survie 8-12 mois
Localement avancé Survie 12-15 mois
Localisé opérable Survie 15-20 mois
60%
30%
10%
Degré d’extension et pronostic des
cancers du pancréas au diagnostic
(dont 10% ‘bordeline’)
15. Opérable radiologiquement, mais physiquement?
• Grand âge
• Anorexie
• Perte de poids
• Hypo-albuminémie
• Amyotrophie
• Anémie inflammatoire
• Douleurs
• Ictère
• Occlusion haute
• Altération de l’état général
• Syndrome dépressif
• Thromboses veineuses et EP
• Diabète
• Comorbidités du tabac
Nécessite une remise en
condition physique
préalable à la chirurgie
Pré-habilitation
systématique pour
limiter les risques per et
post-opératoires
SMARTH-HAB
24. Phase III Gemcitabine Monotherapy in
Advanced Pancreatic Cancer: Study Design
• Primary endpoint: improvement in specific disease-related signs and
symptoms (clinical benefit), including pain and KPS
• Secondary endpoint: weight change
• Other endpoints: ORR, survival, time to progressive disease
24Burris III HA, et al. J Clin Oncol. 1997;15:2403-2413.
5-FU, 5-fluorouracil; IV, intravenous; KPS, Karnofsky performance status; ORR, overall response rate; qw, weekly; qw ¾, first 3 of 4 weeks;
qw 7/8, first 7 of 8 weeks.
26. Intent-to-Treat Gem
(n = 63)
5-FU
(n = 63)
P Value
Clinical benefit, %
Time to clinical benefit, median, weeks
Duration of clinical benefit, mean,
weeks
23.8
7
18
4.8
3
13
0.0022
OS, median, months
OS rate, %
6 months
9 months
12 months
5.65
46
24
18
4.41
31
6
2
0.0025
PFS rate, %
6 months
9 months
12 months
22
9
9
5
5
5
Time to progression, median, months 2.33 0.92 0.0002
ORR, %
PR
SD
n = 56
5.4
39
n = 57
0
19
NS
5-FU, 5-fluorouracil; Gem, gemcitabine; NS, not significant; ORR, overall response rate; OS, overall survival; PFS, progression-free survival;
PR, progressive disease; SD, stable disease.
26Burris III HA, et al. J Clin Oncol. 1997;15:2403-2413.
Phase III Gemcitabine Monotherapy in Advanced
Pancreatic Cancer: Efficacy Outcomes
27. Chauffert B, Ann Oncol 2008
Gem
Gem
CRT
CRT
Chemotherapy or chemo-radiotherapy (C-RT)
Huguet F, J Clin Oncol 2007
Front line C-RT Chemotherapy then C-RT
Chemo then CRT
Chemo alone
Chemo then CRT
Chemo alone
28. PAC
Locally
advanced,
M0
N=449 Gem 2 months
RCT
R2
Gemcitabine
+ Erlotinib
Gemcitabine
R1
Erlotinib : 100 mg avec gemzar ; 150 mg en mono. Maintenu jusqu’à progression
RCT : RT 54 Gy (6 semaines) + Capecitabine 1600 mg/m2
Patients who not
progressed at 4 months
F. Huguet et al., ASCO 2014, A 4001
N=269
LAP07 :
Impact of C-RT on local control?
l No overall benefits of RCT (Hammel ASCO 2013 LBA4003)
à Overall survival (15,2 vs 16,4 mois, p=0,82)
à Profression-free survival (12,5 vs 11,8: p=0,21)
l Acceptable safety of RCT (more nausea grade 3-4: 5,9% vs 0)
29. Probabilityof LPFS
100
0 6
50 HR (95% CI) : 0,78 (0,61-1,01)
Log-rank : p=0,055
Time from the first randomization (month)
136
133
Nb at risk patients
0
Local progression-free
survival
3 9 12 15 18 21 24 27 30 33 36 39 42
136
133
113
117
61
76
35
45
21
30
12
21
7
11
3
8
1
7
1
4
1
4
1
4
1
4
1
4
CT
RCT
N Events LPFS (mois)
CT 136 125 8,4
RCT 133 122 9,9
F. Huguet et al., ASCO 2014, A 4001
LAP07 :
Impact of C-RT on local control?
30. Sites of a progression
l Patients at 2nd randomization
l Progression : 236/269 pts (88%)
à Local progression only: 93 (39%)
à Metastatic progression (± local) : 122 (52%)
à Progression at unknown site : 21 (9%)
F. Huguet et al., ASCO 2014, A 4001
Chemo
(n=125)
Local Metastatic Unknown
RCT
(n=111)
46% 44% 10%
60%32% 8%
p=0.035
LAP07 :
Impact of C-RT on local control?
32. CA19-9, carbohydrate antigen 19-9; CT, computed tomography; HR, hazard ratio; IV, intravenous; KPS, Karnofsky performance status; NCI
CTCAE, National Cancer Institute Common Terminology Criteria for Adverse Events; MRI, magnetic resonance imaging; ORR, overall
response rate; OS, overall survival; PFS, progression-free survival; qw 3/4, first 3 of 4 weeks; qw 7/8, first 7 of 8 weeks; RECIST, Response
Evaluation Criteria In Solid Tumors; ULN, upper limit of normal.
• Primary endpoint
– OS
• Secondary endpoints
– PFS and ORR by independent
review (RECIST v1.0)
• Safety and tolerability
– By NCI CTCAE v3.0
• With 608 events, 90% power to detect OS
HR = 0.769 (2-sided α = 0.049)
• Treat until progression or unacceptable toxicity
• Spiral CT or MRI scans every 8 weeks
• CA19-9 measurements at baseline and every
8 weeks
Von Hoff DD, et al. N Engl J Med. 2013 Oct 16. [Epub ahead of print]. 32
Phase III Gemcitabine + nab-Paclitaxel in
Metastatic Pancreatic Cancer: Study Design
33. a The 75th percentile represents the time point at which 25% of patients were alive.
Gem, gemcitabine; HR, hazard ratio; nab-P, nab-paclitaxel; OS, overall survival; pt, patient.
Von Hoff DD, et al. N Engl J Med. 2013;369(18):1691-1703. 33
Phase III Gemcitabine + nab-Paclitaxel in
Metastatic Pancreatic Cancer: Overall Survival
35. CA046 (Lopez-Martín): Subgroup Analysis of Outcomes
of the MPACT Trial Based on Primary Tumor Location
Efficacy by Primary Tumor Location Summary
Efficacy Parameter
nab-P + Gem
n = 431
Gem
n = 430
HR or RRR P Value
Tumor location: head
n (%) 191 (44) 180 (42) —
OS, median, months 9.3 6.5 0.59 < 0.001
PFS, median, months 5.5 3.7 0.53 < 0.001
ORR, % 25.0 5.0 5.03 < 0.001
Tumor location: other
n (%)a 237 (55) 246 (57) —
OS, median, months 8.1 6.9 0.80 0.033
PFS, median, months 5.4 3.7 0.74 0.013
ORR, % 21.0 9.0 2.36 < 0.001
a n values different from at-risk populations in the previous slides because of differences in the analysis populations.
Gem, gemcitabine; HR, hazard ratio; nab-P, nab-paclitaxel; ORR, overall response rate; OS, overall survival; PFS, progression-free survival; RRR,
response rate ratio.
Lopez-Martín J, Ma WW, Balcke P, et al. nab®-Paclitaxel plus gemcitabine vs gemcitabine alone for patients with metastatic pancreatic cancer: influence of
primary pancreatic tumor location on efficacy and treatment exposure in the MPACT phase III trial. Poster presented at: 16th World Congress on
Gastrointestinal Cancer; June 25 - 28, 2014; Barcelona, Spain [abstract P-0029].
35
36. Phase II/III FOLFIRINOX in Metastatic
Pancreatic Cancer: Study Design
Conroy T, et al. N Engl J Med. 2011;364:1817-1825.
5-FU, 5-fluorouracil; ECOG, Eastern Cooperative Oncology Group; IV, intravenous; OS, overall survival; PFS, progression-free survival;
PS, performance status; q2w, every 2 weeks, qw 3/4, first 3 of 4 weeks; qw 7/8, first 7 of 8 weeks.
Phase II
§ Primary endpoint: tumor response
§ Secondary end point: safety
Phase III
• Primary endpoint: OS
• Secondary endpoints: PFS, tumor response, safety, quality of life
36
37. FOLFIRINOX, 5-fluorouracil, leucovorin, irinotecan, and oxaliplatin; Gem, gemcitabine; HR, hazard ratio; OS, overall survival; Pts, patients.
• Subsequent therapy: 80 patients for FOLFIRINOX and 85 for Gem
• Median survival was 4.4 months in both groups from the time of secondary therapy
Phase II/III FOLFIRINOX in Metastatic Pancreatic
Cancer: Overall Survival
37
Conroy T, et al. N Engl J Med. 2011;364:1817-1825.
38. Intent-to-Treat FOLFIRINOX
(n = 171)
Gem
(n = 171)
HR (95% CI) P Value
OS, median, months
OS rate, %
6 months
12 months
18 months
11.1
75.9
48.4
18.6
6.8
57.6
20.6
6.0
0.57
(0.45 - 0.73)
< 0.001
PFS, median, months
PFS rate, %
6 months
12 months
18 months
6.4
52.8
12.1
3.3
3.3
17.2
3.5
0
0.47
(0.37 - 0.59)
< 0.001
ORR, % 31.6 9.4 NA < 0.001
DCR, % 70.2 50.9 NA < 0.001
Response duration,
median, months 5.9 3.9 NA 0.57
Conroy T, et al. N Engl J Med. 2011;364:1817-1825.
DCR, disease control rate; FOLFIRINOX, 5-fluorouracil, leucovorin, irinotecan, and oxaliplatin; Gem, gemcitabine; HR, hazard ratio; NA, not
available; ORR, overall response rate; OS, overall survival; PFS, progression-free survival.
Phase II/III FOLFIRINOX in Metastatic Pancreatic
Cancer: Efficacy Outcomes
38
However, no data in the
NEJM paper on the local
pancreatic tumor mass
control rate
39. First
Author
No. of Pts
with
Metastatic
Disease
FOLFIRINOX Regimen/Deliverya5
Efficacyb Safety
OS
mos
PFS
mos
ORR
%
Select Grade ≥3 AEs,g
(%)
Gunturu1 19c Same starting dose used as reported by
Conroy et al.5 All pts received pegfilgrastim;
Lower median relative dose intensities vs
Conroy et al5 for irinotecan (64% vs 81%)
and bolus 5-FU (66% vs 82%)
11.2 9.9 47 Neutropenia (11.4),
fatigue (5.7), diarrhea,
(2.9),febrile neutropenia
(2.9)
Lowery2 61d Median starting dose was 80% as reported
by Conroy et al5; prophylactic growth factor
was given in 84% of pts
12.5 NR 40 Neuropathy (15),
myelosuppression (7)
Mahaseth3 28 Omitted bolus 5-FU, included mandatory G-
CSF
NRf NRf 21 Fatigue (11), diarrhea
(11), neuropathy (4),
neutropenia (4)
Vaccaro4 36e Starting dose undefined; 58% received
prophylactic G-CSF; FOLFIRINOX dose
was reduced to 75% in 23% of cycles
NA 8g 25g Neutropenia (16.6)
Modified FOLFIRINOX in Advanced Pancreatic
Cancer: Retrospective Analysis
1. Gunturu KS, et al. Med Oncol. 2013;30:361. 2. Lowery MA, et al. J Poster presented at: ASCO 2012. [abstract 4057]. 3. Mahaseth H, et al.
Abstract presented at: ASCO 2012. [abstract e14614]. 4. Vaccaro V, et al. Abstract presented at: ASCO 2012. [abstract e14661]. 5. Conroy T, et al. N
Engl J Med. 2011;364:1817-1825.
5-FU, 5-fluorouracil; AE, adverse event; DCR, disease control rate; FOLFIRINOX, 5-fluorouracil, leucovorin, irinotecan, and oxaliplatin;
G-CSF, granulocyte colony-stimulating factor; mos, months; NA, not available; NR, not reached; ORR, overall response rate; OS, overall
survival; PFS, progression-free survival; pts, patients.
a Modified based on Conroy study regimen; b OS and PFS given as median; outcomes for pts with metastatic disease only unless otherwise
indicated; c Of the 35 pts were treated, 19 had metastatic disease and 17 pts were evaluable for efficacy; d Of the 80 pts enrolled, 61 had
metastatic disease; e Identified as advanced, inoperable pancreatic cancer; 26 pts had metastatic disease. PFS and ORR apply to all 36 pts; f
Median OS and PFS were NR after median 5.5 months follow-up; g In all treated pts.
39
40. First
Author
No. of Pts
with
Metastatic
Disease
FOLFIRINOX Regimen/Deliverya4
Efficacyb Safety
OS
mos
PFS
mos
ORR
%
Select Grade ≥3
AEs,g (%)
Peddi1 38c FOLFIRINOX5 regimen modified in 51% of
pts; 22 pts did not receive 5-FU; irinotecan
DR required in 22 pts; 67% of pts received
G-CSF starting in cycle 1
1 yr
OS:
42%
NA 18 Neutropenia (19.7),
abdominal pain,
(8.2), fatigue (4.9),
febrile neutropenia
(4.9), diarrhea (3.3)
Ginocchi2 17d No bolus 5-FU and lower dose of irinotecan
(150 mg/m2 q2w); modified dose of
infusional 5-FU (2800 mg/m2 over 48 hours
q2w). 18% pts received G-CSF
14.8 8.4 33 Neutropenia (35.9),
neuropathy (5.1),
diarrhea (5.5),
fatigue (2.6)
Alessandretti3 19e No bolus 5-FU and DR of at least 1 agent
at cycle 1. 73% of pts received prophylactic
G-CSF . Median DR cycle 1: 23% for
oxaliplatin, 25% irinotecan, and 21% 5-FU
NRf NRf 32g Neutropenia (21%),
fatigue (15.7%),
diarrhea (5.2),
febrile neutropenia
(15.6%)
Modified FOLFIRINOX in Advanced Pancreatic
Cancer: Retrospective Analysis (cont)
1. Peddi PF, et al. JOP. 2012;13:497-501. 2. Ginocchi L, et al. Presented at ESMO 2012. [abstract 714P]. 3. Alessandretti , et al. Abstract presented at
: ASCO 2013. [abstract e15176]. 4. Conroy T, et al. N Engl J Med. 2011;364:1817-1825.
5-FU, 5-fluorouracil; DCR, disease control rate; FOLFIRINOX, 5-fluorouracil, leucovorin, irinotecan, and oxaliplatin; G-CSF, granulocyte
colony-stimulating factor; mos, months; NA, not available; NR, not reached; ORR, overall response rate; OS, overall survival; PFS,
progression-free survival; pt, patients; q2w, every other week.
40
a Modified based on Conroy study regimen; b OS and PFS given as median; outcomes for pts with metastatic disease only unless otherwise
indicated; c Of the 35 pts were treated, 19 had metastatic disease and 17 pts were evaluable for efficacy; d Of the 80 pts enrolled, 61 had
metastatic disease; e Identified as advanced, inoperable pancreatic cancer; 26 pts had metastatic disease. PFS and ORR apply to all 36 pts; f
Median OS and PFS were NR after median 5.5 months follow-up; g In all treated pts.
41. First
Author
No. of Pts
with
Metastatic
Disease
FOLFIRINOX Regimen/Deliverya6
Efficacyb Safety
OS
mos
PFS
mos
ORR
%
Select
Grade ≥3 Aes,g (%)
Lorgis1 42 Standard FOLFIRINOX6
9 NA NA
Neutropenia (57), diarrhea
(30),
neuropathy (25), febrile
neutropenia (14)
Metges2 79 FOLFIRINOX regimen undefined;
during treatment, 75% of pts had a
dose adjustment
10.2 5.7 37 Total (28)
Faris3 26c FOLFIRINOX regimen undefined
NA NA 33
Neutropenia (32), febrile
neutropenia (16)
Arlen4 ≈ 93d,e FOLFIRINOX regimen undefined 8.4 NA NA NA
Cartwright5 522 FOLFIRINOX regimen undefined 10.2f NA NA NA
Modified FOLFIRINOX in Advanced Pancreatic
Cancer: Retrospective Analysis (cont)
1. Lorgis V, et al. Anticancer Res. 2012;32:4125-4130. 2. Metges J-P, et al. Poster presentation at: ASCO 2012. [abstract 248]. 3. Faris JE, et al.
Abstract presented at: ASCO 2012. [abstract e14615]. 4. Arlen AG, et al. Abstract presented at: ASCO 2012. [abstract e16536]. 5. Cartwright TH, et
al. Poster presented at: ASCO 2013. [abstract 6607]. 6. Conroy T, et al. N Engl J Med. 2011;364:1817-1825.
DCR, disease control rate; FOLFIRINOX, 5-fluorouracil, leucovorin, irinotecan, and oxaliplatin; KPS, Karnofsky performance score;
mos, months; NA, not available; ORR, overall response rate; OS, overall survival; PFS, progression-free survival; pts, patients.
41
a Modified based on Conroy study regimen; b OS and PFS given as median; outcomes for pts with metastatic disease only unless otherwise
indicated; c Of the 35 pts were treated, 19 had metastatic disease and 17 pts were evaluable for efficacy; d Of the 80 pts enrolled, 61 had
metastatic disease; e Identified as advanced, inoperable pancreatic cancer; 26 pts had metastatic disease. PFS and ORR apply to all 36 pts; f
Median OS and PFS were NR after median 5.5 months follow-up; g In all treated pts.