FOLFOX4 (12 cycles) versus sequential dose-dense FOLFOX7 (6 cycles) followed by FOLFIRI (6 cycles)...
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Transcript of FOLFOX4 (12 cycles) versus sequential dose-dense FOLFOX7 (6 cycles) followed by FOLFIRI (6 cycles)...
FOLFOX4 (12 cycles) versus sequential dose-dense FOLFOX7 (6 cycles) followed by FOLFIRI (6 cycles) in
patients with initially resectable metastatic colorectal cancer. A GERCOR Randomized Phase III study (MIROX)
M. Hebbar, B. Chibaudel, T. André, L. Mineur, D. Smith, C. Louvet, J.L. Dutel, M. Ychou, J.L. Legoux, M. Mabro, R. Faroux, D. Auby,
D. Brusquant, A. Khalil, S. Truant, A. Hadengue, F. Bonnetain, FR. Pruvot, C. Dalban, A. de Gramont
CONFLICT OF INTEREST DISCLOSURE
No conflict of interest to declare
Liver is the main metastatic site in patients with colorectal cancerMetastases are initially resectable in 15-20 % patientsPerioperative FOLFOX chemotherapy is active (EORTC study)
RATIONALE
Nordlinger B, et al. Lancet 2008, 371:1007-16
HR= 0.73[CI: 0.55-0.97]
P=0.025
Surgery only
Periop FOLFOX4
33.2%
42.4%
(years)0 1 2 3 4 5 6
0
10
20
30
40
50
60
70
80
90
100
PF
S in
res
ecte
d pa
tient
s (%
)
3-yr PFS + 9.2%
Role of Irinotecan ?
Ychou M, et al. Ann Oncol 2009, 20:1964-70
FOLFIRI x12cy
postop
LV5FU2 x12cy
postop
RANDOMIZATION
DFS
OS
RATIONALE
Two questions
May sequential administration of FOLFOX followed by FOLFIRI improve results ?
Why should the chronology be imposed ?
RATIONALE
MIROX strategy for resectable metastases
6FOLFOX7 (oxa. 130mg/m²) followed by 6FOLFIRI To reduce occurrence of oxaliplatin-related neuropathy, To increase efficacy (absence of cross resistance)
Perioperative OR postoperative chemotherapy Personalized strategy To limit selection bias
Prior phase II study in patients with resectable MCRC N=47 (periop, N=22 ; postop, N=25) No grade 3 neurotoxicity Survivals : 2-yr DFS 47%, and 2-yr OS 89%
Taïeb J, et al. J Clin Oncol 2005, 23:502-9
RATIONALE
DESIGN OF THE PHASE III STUDY
FOLFOX7 – FOLFIRI (N=142)
FOLFOX4 (N=142)
RANDOMIZATION
4-6 preop cycles recommended
Surgery Surgery
N=284From May 2004 to June 2010
N=284From May 2004 to June 2010
INCLUSION CRITERIA
Histologically documented colorectal adenocarcinoma
Resected or resectable metastases
Only one metastatic site: liver, lung, ovary, or peritoneum
Age : 18-75
PS: 0-2
In case of prior adjuvant FOLFOX after resection of the primary:
interval > 12 months required
Primary endpoint :
Disease-free survival (DFS)
Secondary endpoints :–Overall survival–Objective response rate with perioperative chemotherapy,–Resection rate (R0, R1, R2) with perioperative chemotherapy,–Safety (NCI CTC v2)–Health related Quality of Life (EORTC QLQ C-30)
Sample Size
- Superiority study, power of 80%, 2-sided test = 0.05,
- Δ 2-yr DFS rate : from 30% (FOLFOX4) to 45% (FOLFOX7-FOLFIRI)
• 284 patients to be enrolled
• 188 events required
ENDPOINTS
STRATIFICATION CRITERIA
Periop vs. postop chemotherapy
Surgery alone vs. radiofrequency ablation +/- surgery
Blumgart’s score (0-1 vs. 2-3 vs. 4-5)
Disease-free interval (months) <12 ≥12
Primary tumor N+ N0
Number of metastase(s) ≥1 1
Largest met. size (cm) >5 ≤5
Preop CEA level >200 ≤200
Fong Y, et al. Ann Surg 1999, 3:309-21
CONSORT DIAGRAM
FOLFOX4 arm
Randomized: N=284
Treatment allocation
Median follow-up : 50.4 months
FOLFOX7 – FOLFIRI arm
N=142N=142
Treated N=140N=142
ITT analysis N=140N=142
PATIENT’S CHARACTERISTICSFOLFOX4(N=142)
FOLFOX7-FOLFIRI(N=142)
Age <70, % 77 82
Male, % 64 70
ECOG PS 0-1, % 93 93
Liver met. Site, % 83 84
One metatasis, % 51 52
Largest met. Size <5cm, % 86 85
Synchronous met., % 55 59
Primary : node positive, % 58 57
Prior adjuvant chemo, % 23 28
Preop CEA level, mean ratio (V/ULN) 9.9 8.1
TREATMENTSFOLFOX4(N=142)
FOLFOX7-FOLFIRI(N=142)
Treated patient 142 140
Median oxaliplatin dose (mg) 1385 1218
Median oxaliplatin or irinotecan-base cycles 9 12
Peri-operative chemotherapy, n (%) 85 (60) 83 (58)
Response rate after pre-operative chemo, n (%) 42 (49) 41 (50)
Met. Surgery after pre-operative chemo, n % 68 (80) 73 (88)
R0 resection after pre-operative chemo, n % 61 (90) 61 (84)
TOXICITYNCI CTCAE v2, grade 3-4 (%) FOLFOX4
(N=142)FOLFOX7-FOLFIRI
(N=142)
Neutropenia 32 22
Anemia 2 0
Thrombocytopenia 5 9
Febrile neutropenia 2 <1
Nausea 3 9
Vomiting 2 2
Mucositis / Stomatitis 1 2
Diarrhea 10 21*
Cutaneous 0 <1
Alopecia (Gr. 2) 6 6
Neurotoxicity 24 16
Arm 2-yr rate,%
Median[95% CI]
HR[95% CI]
P value
FOLFOX4 48.2 22.4[17.9-36.2]
FOLFOX7-FOLFIRI 49.3 23.0[19.7-35.6]
0.97[0.72-1.31]
0.856
DFS
DISEASE-FREE SURVIVAL
Arm 2-yr rate,%
Median[95% CI]
HR[95% CI]
P value
FOLFOX4 87.5 NR
FOLFOX7-FOLFIRI 90.2 NR 1.07[0.68-1.70]
0.764
OS
NR, not reached
OVERALL SURVIVAL
Arm 2-yr rate,%
Median[95% CI]
Postoperative 60.5 39.9[26.9-NR]
Perioperative 40.3 23.0[15.2-22.4]
DFS
NR, not reached
DFS POSTOP VS PERIOP
Arm 2-yr rate,%
Median[95% CI]
Postoperative 60.5 39.9[26.9-NR]
Perioperative 40.3 23.0[15.2-22.4]
DFS
NR, not reached
DFS POSTOP VS PERIOP
Populations not comparable
39.6% synchronous mets
66.0% synchronous mets
MIROX strategy is not superior to FOLFOX4.
Results in both arms were better than expected, with a 2y-DFS
over 45%, and a 4-yr survival over 70%.
Survival difference between perioperative and postoperative
schedules mainly explained by differences in patient’s profiles.
Planned:
Multivariate analysis focusing on known prognostic factors, and
chronology of chemotherapy.
Overall survival update.
CONCLUSIONS
AcknowlegmentsPATIENTS AND THEIR FAMILIES,
INVESTIGATORSAVIGNON: Laurent MineurBEAUVAIS: Jean-Yves DutelBORDEAUX: Denis SmithBRIEY: Patrick BruckerCALAIS: Zoher MeradDIJON: Michel FleschLA ROCHE/YON: Roger FarouxLIBOURNE: Dominique AubyLILLE: Mohamed Hebbar, Eric Vaillant, Philippe Martin, Stéphanie Truant, François-René Pruvot, Christophe Mariette, Jean-Pierre TribouletMONTPELLIER: Marc Ychou, Eric AssenatPARIS: Aimery de Gramont, Thierry André, Christophe Louvet, Christophe Tournigand, Frédérique Maindrault-Goëbel, Mostepha Bennamoun, Ahmed Khalil, Julien TaïebPESSAC: Jean-Louis LegouxSENLIS: Elisabeth CarolaSURESNES: May Mabro
BIOSTATISTICIANS : CGFL (Dijon)Cécile Dalban, Franck Bonnetain
GERCOR (Paris)Benoist Chibaudel, David Brusquant, Alexandra Hadengue, Dominique Notelet …
SANOFI-AVENTIS Youssef Yataghene