FOLFOX4 versus sequential dose-dense FOLFOX7 followed by FOLFIRI in patients with resectable metastatic colorectal cancer (MIROX): a pragmatic approach to chemotherapy timing with perioperative or postoperative chemotherapy from an open-label, randomized phase III trial.
BACKGROUND
Perioperative FOLFOX4 (oxaliplatin plus 5-fluorouracil/leucovorin) chemotherapy is the current standard in patients with resectable metastases from colorectal cancer (CRC). We aimed to determine whether a sequential chemotherapy with dose-dense oxaliplatin (FOLFOX7) and irinotecan (FOLFIRI; irinotecan plus 5-fluorouracil/leucovorin) is superior to FOLFOX4. The chemotherapy timing was not imposed, and was perioperative or postoperative.


METHODS
In this open-label, phase III trial, patients with resectable or resected metastases were randomly assigned either to 12 cycles of FOLFOX4 (oxaliplatin 85 mg/m(2)) or 6 cycles of FOLFOX7 (oxaliplatin 130 mg/m(2)) followed by 6 cycles of FOLFIRI (irinotecan 180 mg/m(2)). Randomization was done centrally, with stratification by chemotherapy timing, type of local treatment (surgery versus radiofrequency ablation with/without surgery), and Fong's prognostic score. The primary end point was 2-year disease-free survival (DFS).


RESULTS
A total of 284 patients were randomized, 142 in each treatment group. Chemotherapy was perioperative in 168 (59.2%) patients and postoperative in 116 (40.8%) patients. Perioperative chemotherapy was preferentially proposed for synchronous metastases, whereas postoperative chemotherapy was more frequently used for metachronous metastases. Two-year DFS was 48.5% in the FOLFOX4 group and 50.0% in the FOLFOX7-FOLFIRI group. In the multivariable analysis, more than one metastasis [hazard ratio (HR) = 2.15] and synchronous metastases (HR = 1.63) were independent prognostic factors for shorter DFS. Five-year overall survival (OS) rate was 69.5% with FOLFOX4 versus 66.6% with FOLFOX7-FOLFIRI.


CONCLUSIONS
FOLFOX7-FOLFIRI is not superior to FOLFOX4 in patients with resectable metastatic CRC. Five-year OS rates observed in both groups are the highest ever reported in this setting, possibly reflecting the pragmatic approach to chemotherapy timing.


BACKGROUND
NCT00268398.
Department of Medical Oncology, University Hospital, Lille mohamed.hebbar@chru-lille.fr.
M
M
Hebbar
Department of Medical Oncology, Hospital Saint-Antoine, Paris.
B
B
Chibaudel
Department of Medical Oncology, Hospital Saint-Antoine, Paris.
T
T
André
Department of Radiotherapy, Institute Sainte-Catherine, Avignon.
L
L
Mineur
Department of Medical Oncology and Radiotherapy, Hospital Saint-André, Bordeaux.
D
D
Smith
Department of Oncology, Institute Mutualiste Montsouris, Paris.
C
C
Louvet
Department of Medical Oncology, Radiotherapy Service, Hospital Centre Beauvais, Beauvais.
J L
JL
Dutel
Regional Centre against Cancer, Val d'Aurelle-Paul Lamarque, Montpellier.
M
M
Ychou
Department of Hepatology and Gastroenterology, Hospital de Haut-Lévêque, Pessac.
J L
JL
Legoux
Department of Medical Oncology, Hospital Foch, Suresnes.
M
M
Mabro
Department of Gastroenterology, Hospital La Roche-sur-Yon, La Roche-sur-Yon.
R
R
Faroux
Department of Medicine, Hospital Libourne, Libourne.
D
D
Auby
GERCOR, Paris.
D
D
Brusquant
Department of Medical Oncology, Hospital Tenon, Paris.
A
A
Khalil
Department of Digestive Surgery and Transplantation, University Hospital, Lille.
S
S
Truant
GERCOR, Paris.
A
A
Hadengue
Methodology and Quality of Life in Oncology Department EA 3181, Hospital Besançon, Besançon.
C
C
Dalban
Department of Surgery, Institute Mutualiste Montsouris, Paris.
B
B
Gayet
Department of Digestive Surgery, Hospital Saint-Antoine, Paris.
F
F
Paye
Department of Digestive Surgery and Transplantation, University Hospital, Lille.
F R
FR
Pruvot
Methodology and Quality of Life in Oncology Department EA 3181, Hospital Besançon, Besançon.
F
F
Bonnetain
Department of Gastroenterology and Digestive Oncology, Hôpital Européen Georges Pompidou, Université Paris Descartes, Paris.
J
J
Taieb
Department of Gastroenterology, Centre hospitalier François Maillot, Briey.
P
P
Brucker
Department of Hepatogastroenterology and Digestive Oncology, Hôpital Européen Georges Pompidou Service Hépato-gastroentérologie; Paris.
B
B
Landi
Department of Medical Oncology, Clinique Clément Drevon, Dijon.
M
M
Flesch
Department of Medical Oncology, Centre Hospitalier, Senlis.
E
E
Carola
Department of Cancerology, Centre Bourgogne, Lille.
P
P
Martin
Department of Gastroenterology, Clinique Ambroise Paré, Lille, France.
E
E
Vaillant
Department of Medical Oncology, Hospital Saint-Antoine, Paris.
A
A
de Gramont
D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage*; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives*; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000401:mortality; D018572:Disease-Free Survival; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage; D006801:Humans; D053208:Kaplan-Meier Estimate; D002955:Leucovorin / Q000008:administration & dosage; D008297:Male; D008875:Middle Aged; D009944:Organoplatinum Compounds / Q000008:administration & dosage; D016016:Proportional Hazards Models
D009944:Organoplatinum Compounds; D002955:Leucovorin; D005472:Fluorouracil; D002166:Camptothecin
chemotherapy; colorectal cancer; irinotecan; metastases; oxaliplatin; resection