Sequential versus combination chemotherapy for the treatment of advanced colorectal cancer (FFCD 2000-05): an open-label, randomised, phase 3 trial.

Background The optimum use of cytotoxic drugs for advanced colorectal cancer has not been defined. Our aim was to investigate whether combination treatment is better than the sequential administration of the same drugs in patients with advanced colorectal cancer. Methods In this open-label, randomised, phase 3 trial, we randomly assigned patients (1:1 ratio) with advanced, measurable, non-resectable colorectal cancer and WHO performance status 0-2 to receive either first-line treatment with bolus (400 mg/m(2)) and infusional (2400 mg/m(2)) fluorouracil plus leucovorin (400 mg/m(2)) (simplified LV5FU2 regimen), second-line LV5FU2 plus oxaliplatin (100 mg/m(2)) (FOLFOX6), and third-line LV5FU2 plus irinotecan (180 mg/m(2)) (FOLFIRI) or first-line FOLFOX6 and second-line FOLFIRI. Chemotherapy was administered every 2 weeks. Randomisation was done centrally using minimisation (minimisation factors were WHO performance status, previous adjuvant chemotherapy, number of disease sites, and centre). The primary endpoint was progression-free survival after two lines of treatment. Analyses were by intention-to-treat. This trial is registered at ClinicalTrials. gov, NCT00126256. Findings 205 patients were randomly assigned to the sequential group and 205 to the combination group. 161 (79%) patients in the sequential group and 161 (79%) in the combination group died during the study. Median progression-free survival after two lines was 10.5 months (95% CI 9.6-11.5) in the sequential group and 10.3 months (9.0-11.9) in the combination group (hazard ratio 0.95, 95% CI 0.77-1.16; p=0.61). All six deaths caused by toxic effects of treatment occurred in the combination group. During first-line chemotherapy, significantly fewer severe (grade 3-4) haematological adverse events (12 events in 203 patients in sequential group vs 83 events in 203 patients in combination group; p<0.0001) and non-haematological adverse events (26 events vs 186 events; p<0.0001) occurred in the sequential group than in the combination group. Interpretation Upfront combination chemotherapy is more toxic and is not more effective than the sequential use of the same cytotoxic drugs in patients with advanced, non-resectable colorectal cancer. Funding Sanofi-Aventis France.