Randomized trial of two induction chemotherapy regimens in metastatic colorectal cancer: an updated analysis.
BACKGROUND
In a randomized trial with a median follow-up of 18.4 months, 6 months of induction chemotherapy with a three-drug regimen comprising 5-fluorouracil (by continuous infusion)-leucovorin, irinotecan, and oxaliplatin (FOLFOXIRI) demonstrated statistically significant improvements in response rate, radical surgical resection of metastases, progression-free survival, and overall survival compared with 6 months of induction chemotherapy with fluorouracil-leucovorin and irinotecan (FOLFIRI).


METHODS
From November 14, 2001, to April 22, 2005, we enrolled 244 patients with metastatic colorectal cancer. To evaluate if the superiority of FOLFOXIRI is maintained in the long term, we updated the overall and progression-free survival data to include events that occurred up to February 12, 2009, with a median follow-up of 60.6 months. We performed a subgroup and a risk-stratified analysis to examine whether outcomes differed in specific patient subgroups, and we analyzed the results of treatment after progression. Survival curves were estimated by the Kaplan-Meier method. Multivariable Cox regression models were fit to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). All statistical tests were two-sided.


RESULTS
FOLFOXIRI demonstrated statistically significant improvements in median progression-free survival (9.8 vs 6.8 months, HR for progression = 0.59, 95% CI = 0.45 to 0.76, P < .001) and median overall survival (23.4 vs 16.7 months, HR for death = 0.74, 95% CI = 0.56 to 0.96, P = .026) with a 5-year survival rate of 15% (95% CI = 9% to 23%) vs 8% (95% CI = 4% to 14%). The improvements in progression-free survival and, to a lesser extent, in overall survival were evident even when the analysis excluded patients who received radical resection of metastases. With regard to the risk-stratified analysis, FOLFOXIRI results in longer progression-free survival and overall survival than FOLFIRI in all risk subgroups.


CONCLUSIONS
Six months of induction chemotherapy with FOLFOXIRI is associated with a clinically significant improvement in the long-term outcome compared with FOLFIRI with an absolute benefit in survival at 5 years of 7%.
U.O. Oncologia Medica 2 Universitaria - Polo Oncologico, Azienda Ospedaliero-Universitaria Pisana, Via Roma, 67 - 56126 Pisa, Italy. a.falcone@med.unipi.it
Gianluca
G
Masi
Enrico
E
Vasile
Fotios
F
Loupakis
Samanta
S
Cupini
Lorenzo
L
Fornaro
Giacomo
G
Baldi
Lisa
L
Salvatore
Chiara
C
Cremolini
Irene
I
Stasi
Isa
I
Brunetti
Maria Agnese
MA
Fabbri
Martina
M
Puglisi
Patrizia
P
Trenta
Cristina
C
Granetto
Silvana
S
Chiara
Luisa
L
Fioretto
Giacomo
G
Allegrini
Lucio
L
Crinò
Michele
M
Andreuccetti
Alfredo
A
Falcone
D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000627:therapeutic use*; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000473:pathology* / Q000601:surgery; D018572:Disease-Free Survival; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage; D005500:Follow-Up Studies; D006801:Humans; D007262:Infusions, Intravenous; D053208:Kaplan-Meier Estimate; D002955:Leucovorin / Q000008:administration & dosage; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D009367:Neoplasm Staging; D009944:Organoplatinum Compounds / Q000008:administration & dosage; D016016:Proportional Hazards Models; D012074:Remission Induction; D018401:Sample Size; D016896:Treatment Outcome
D009944:Organoplatinum Compounds; D002955:Leucovorin; D005472:Fluorouracil; D002166:Camptothecin