Randomized Trial of Two Induction Chemotherapy Regimens in Metastatic Colorectal Cancer: An Updated Analysis

• Published in: JNCI : Journal of the National Cancer Institute Vol. 103; no. 1; pp. 21 - 30
• Main Authors: MASI, Gianluca, VASILE, Enrico, FABBRI, Maria Agnese, PUGLISI, Martina, TRENTA, Patrizia, GRANETTO, Cristina, CHIARA, Silvana, FIORETTO, Luisa, ALLEGRINI, Giacomo, CRINO, Lucio, ANDREUCCETTI, Michele, FALCONE, Alfredo, LOUPAKIS, Fotios, CUPINI, Samanta, FORNARO, Lorenzo, BALDI, Giacomo, SALVATORE, Lisa, CREMOLINI, Chiara, STASI, Irene, BRUNETTI, Isa
• Format: Journal Article
• Language: English
• Published: Cary, NC Oxford University Press 05-01-2011; Oxford Publishing Limited (England)
• Subjects: Adult; Aged; Antineoplastic agents; Antineoplastic Combined Chemotherapy Protocols - administration & dosage; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Biological and medical sciences; Camptothecin - administration & dosage; Camptothecin - analogs & derivatives; Chemotherapy; Clinical outcomes; Clinical trials; Colorectal cancer; Colorectal Neoplasms - drug therapy; Colorectal Neoplasms - pathology; Colorectal Neoplasms - surgery; Disease-Free Survival; Female; Fluorouracil - administration & dosage; Follow-Up Studies; Humans; Infusions, Intravenous; Kaplan-Meier Estimate; Leucovorin - administration & dosage; Male; Medical sciences; Middle Aged; Monoclonal antibodies; Multivariate Analysis; Neoplasm Staging; Organoplatinum Compounds - administration & dosage; Pharmacology. Drug treatments; Proportional Hazards Models; Remission Induction; Sample Size; Toxins; Treatment Outcome; Tumors; Antineoplastic agent; Human; Rectal disease; Colorectal cancer; Malignant tumor; Metastasis; Induction treatment; Colonic disease; Chemotherapy; Randomization; Treatment; Cancerology; Digestive diseases; Intestinal disease; Clinical trial; Advanced stage; Therapeutic protocol; Cancer
• ISSN: 0027-8874; 1460-2105
• DOI: 10.1093/jnci/djq456

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).
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.
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.
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%.