IFCT-0002 : Early results (ASCO 2007)

Transcription

Phase III Study Comparing a Preoperative
(PRE) and a Perioperative (PERI)
Chemotherapy with Two Different CT
Regimens in Resectable Non-small Cell Lung
Cancer (NSCLC): Early Results (IFCT 0002)
B. Milleron, E. Quoix, V. Westeel, M. Puyraveau, D. Braun, J.L. Breton, L. Bigay-Game, J.L.Pujol,
F. Morin, A. Depierre,
On Behalf of the “Intergroupe Francophone de Cancérologie Thoracique”
Rationale (1)
Cisplatin-based adjuvant chemotherapy
Pignon JP et al, J Clin Oncol 2006; 24 , 18S Part I of II : 366s
Rationale (2)
Meta-analysis Group, MRC Clinical Trials Unit
S Burdett et al, Journal of Thoracic Oncology • Volume 1, Number 7, September 2006
End Points
Main objective : to define the best timing of CT (all before
surgery (PRE) versus perioperative (PERI),
Secondary objectives :
To compare response rates with CDDP -GEM and
CBDCA-PAC,
To compare CDDP-GEM- and CBDCA-PAC toxicity ,
To compare TTP and sites of relapse in each arm,
To compare quality of life,
To assess predictive and pronostic factors with
biological markers.
CDDP-GEM (A, B)

Study design
CADDP-PAC (C, D)

Week
1
3
Arm
PRE
(A+C)
Cycle 1 Cycle 2
Arm
PERI
(B-D)
6
7
E
V
A
L
U
A
T
I
O
N
GEM : 1250 mg/m2, J1-J8
CDDP : 75 mg/m2, J1
PAC : 200 mg/m2, J1
CADDP : AUC 6, J1
9
11
Cycle 3 + Cycle 4
(in responders)
Surgery
Surgery
Cycle 3 + Cycle 4
(in responders)
Statistical considerations
Open, multicentric, randomized study,
Stratification by center, histology, clinical
stage,
Comparison of overall survival in arms PRE
(A+C) vs PERI (B+D),
Benefit expected for 3-year survival rate in the
PRE arms : 20%, (60 to 72%),
522 patients (alpha 5 % and beta 20 %),
Interim analyses planned after inclusion of 175
and 350 patients.
Inclusion criteria
Histological or cytological
proof of NSCLC,
cTNM stage : I or II,
With at least 1 mesurable or
evaluable lesion,
OMS ≤ 2,
Age ≤ 75 years,
Fit to receive chemotherapy,
Written informed consent.
Exclusion criteria
Mediastinal lymph nodes ≥ 1
cm,
Previous history of cancer,
Creatinine ≥ 120 µol/l,
PNN < 1500 /mm3,
Platelets < 100 000 / mm3,
Bilirubine > 25 µol/l,
Peripheral neuropathy.
Early Results (at 21 weeks)
Efficacy :
Clinical response,
Pathological response (PCR, tumoral necrosis, lymphatic
and vessels invasion) :
In PRE and PERI arms,
In GEM-DDP and PAC-CADDP arms.
Tolerance of treatment :
Toxicity of chemotherapy,
Feasibility of surgery and adjuvant chemotherapy,
Post-operative mortality.
Patients Characteristics
Total (%)
Arm A
Arm B
Arm C
Arm D
Sex
M/F
427/101 (80.9)
114/20
108/24
101/32
104/25
Stage
IA
92 (17.4)
20
27
22
23
IB
248 (47)
55
64
73
56
IIA
21 (4)
7
7
3
4
IIB
150 (28.4)
48
31
31
40
Other (ineligible)
17 (3.2)
4
3
4
6
0
419 (79.4)
102
107
102
108
1
106 (20.1)
31
24
31
20
2
3 (0.6)
1
1
0
1
Squamous
231 (43.7)
58
59
57
57
Adenocarcinoma
201 (38.1)
57
51
46
47
Other
96 (18.2
19
22
30
25
PS
Histology
Pre vs Peri results :
1- Chemotherapy compliance
N° cycle
% of patients receiving cycles
p
PRE
PERI
(CDDP-GEM and
CADDP-PAC)
(CDDP-GEM and
CADDP-PAC)
1 and 2
96.6
93.8
ns
3 and 4 (responders only)
90.4
75.2
0.0011
PRE: cycles 3-4 administered before surgery
PERI: cycles 3-4 administered after surgery
Pre vs Peri results (2)
Surgery
Total (%)
PRE
PERI
(CDDP-GEM and
CADDP-PAC)
(CDDP-GEM and
CADDP-PAC)
N
528
267
261
Lobectomy
354 (67.0)
182 (68.1)
172 (65.9)
Pneumonectomy
115 (21.7)
54 (20.2)
61 (23.3)
Other
36 (6.8)
19 (7.1)
17 (6.5)
No surgery
21 (4)
10 (3.7)
11 (4.2)
Pre vs Peri results (3): Toxicity
PRE
PERI
(CDDP-GEM and
CADDP-PAC)
(CDDP-GEM and CADDPPAC)
p
Grade III-IV Toxicity
% cycles
% patients
% cycles
% patients
Neutropenia
31.5
41.2
30.4
36
ns
Febrile neutropenia
1.3
3.7
1.3
3.7
ns
Thrombopenia
4.3
10.5
6.9
11.5
ns
Nausea/Vomiting
1.6
3.7
2.2
5
ns
11.7
ns
Neuropathy
at 6 months (all grades)
12.2
Mortality
Pre-operative /chemo
mortality (%)
2/1 (0.74 /0.37)
2/0 (0.76 /0)
ns
Post-operative mortality (%)
8 (3 )
8 (3.1 )
ns
Pré vs Peri results (4): Pathologic results
Total
PRE
PERI
(CDDP-GEM and
CADDP-PAC)
(CDDP-GEM and
CADDP-PAC)
p
pT0N0
38
22 (8.6)
16 (6.4)
ns
Peri T vascular invasion
36
20 (7.8)
16 (6.4)
ns
Peri T lymphatic
invasion
84
41 (16)
43 (17.2)
ns
Visceral pleura
involvement
106
54 (21)
52 (20.8)
ns
Necrosis
264
126 (49.6)
138 (55.6)
ns
DDP-GEM vs CADDP-PAC
Clinical (after 2 cycles) an Pathological Response
Total (%)
CDDP-GEM (%)
CADDP-PAC (%)
n
528
266
262
CR
14 (2.6)
10 (3.8)
4 (1.5)
PR
254 (48.1)
129 (48.5)
125 (47.7)
OR
268 (50.7)
139 (52.3)
129 (49.2)
NC
223 (42.6)
111
112
PD
17 (3.2)
5
12
NE
20 (3.8)
11
9
pT0N0
38
17
21
DDP-GEM vs CADDP-PAC (2) :
Chemotherapy compliance
% of patients receiving
cycles
N° cycle
p
CDDP-GEM
CADDP-PAC
1 and 2
93.2
97.3
ns
3 and 4 (responders
only)
79.9
86
ns
DDP-GEM vs CADDP-PAC (3) :
Toxicity (WHO grade 3-4)
CDDP-GEM
CADDP-PAC
p
% cycles
% patients
% cycles
% patients
Neutropenia
28.9
36.1
33
41.2
ns
Febrile neutropenia
1.7
4.1
1
2.7
ns
Thrombopenia
9.7
18.4
1.4
3.4
0.0001
Nausea/Vomiting
3.4
7.5
0.4
1.1
0.0003
19
<0.0001
Neuropathy
at 6 months (all
grades)
5.1
DDP-GEM vs CADDP-PAC (4)
Relation between response, chemotherapy, stage
and histology
Factors
Group
Stage
Histology
Odds Ratio
GEM-DDP
1
PAC-CAR
0.846
I
1
Other
1.081
Squamous
1
Other
0.263
95% CI
p
0.589-1.216
0.3669
0.740-1.581
0.6865
0.182-0.381
<0.0001
Bio-IFCT 0002
Goals: to assess predictive and prognostic value of
biological markers in IFCT 0002 cohort :
Molecular markers,
IHC putative markers of Chemo Resistance,
250 snap-frozen surgical post-chemo specimens (DNA and
RNA extraction),
499 paraffin-embedded surgical post-chemo specimens.
G. Zalcman (PI) and M Beau-Faller, E. Brambilla, MC Favrot, P. Hainaut, JC Soria
PNES Poumon / National Program of Scientific Excellency- Lung
Conclusion
Administration of four cycles of CT before surgery is
feasible,
Post operative mortality is low in both preoperative and
perioperative arms,
After 2 cycles of CT, compliance to 2 additional cycles in
responders is better before than after surgery,
No significant difference in terms of pathological
response was observed after 2 or 4 cycles,
Higher response rates were observed in squamous cell
cancers than in other histological subtypes,
Gemcitabine-Cisplatin and Paclitaxel-Carboplatine are
effective and safe, with no difference in response rates
but a different toxicity profile.
DEPIERRE A
WESTEEL V
Besançon
MILLERON B
LAVOLÉ A
Paris - Tenon
QUOIX E
MENECIER B
Strasbourg
BRAUN D
BRETON JL
Briey
Belfort
CARLES P
Toulouse
PUJOL JL
Montpellier
OZENNE G
Bois-Guillaume
RIVIERE A
Caen
DOUILLARD JY
LEBEAU B
DEBIEUVRE D
POUDENX M
DAVID Ph
DUCOLONE A
LEBAS FX
Nantes
LEMARIÉ E
Tours
TANGUY B
MONNET I
Créteil
VAYLET F
SOUQUET PJ
FOURNEL P
St Denis La Réunion
Clamart - Percy
Lyon
MENARD O
Vandoeuvre
Saint-Etienne
OSTER JPh
Colmar
CREQUIT J
Beauvais
MAURY B
Cholet
DUHAMEL JP
Harfleur
FRIARD S
Suresnes - Foch
MORO-SIBILOT D
Grenoble
PEROL M
Lyon
JANICOT H
HERMANN J
Clermont-Ferrand
Metz-Belle-Isle
LEVEL MC
OLIVIERO G
Verdun
Longjumeau
PAILLOT N
Metz
THIBERVILLE L
DANSIN E
Lille
GOUVA S
Vesoul
BENICHOU M
Pau
MONTCHATRE M
Nice-CAC
BLANCHON F
Meaux
AZARIAN R
Versailles
Marseille -CAC
Paris - SaintAntoine
Rouen
Brest
Ermont
Elbeuf
MORERE JF
Bobigny
VIALLAT JR
Strasbourg
MORNET M
Bourges
BOMBARON P
ROSSIGNOLI N
Mâcon
LE GROUMELLEC A
Vannes
Le Mans
COETMEUR D
St Brieuc
ZALCMAN G
Caen -
TREDANIEL J
Paris - Saint-Louis
HERMAN D
Nevers
RODIER JM
LAUWERIER C
Paris - Bichat
St Omer
TERRIOUX Ph
Mulhouse
Coulommiers