The primary endpoint of this trial was time to progression of disease after second-line therapy. Previous phase III studies had demonstrated the superiority of 5-fluorouracil-folinic acid combined with either irinotecan or oxaliplatin over 5-fluorouracil-folinic acid alone. The current trial set out to determine which if either sequence of the two combination treatments was more effective.

Patients were selected on the basis of a history of metastatic colorectal cancer and no prior chemotherapy except for adjuvant therapy ending at least 6 months prior to the trial. After randomization, 109 patients in arm A received a median of 13 cycles of FOLFIRI, after which 81 received a median of 8 cycles of FOLFOX. In the second arm (B), 111 patients were given FOLFOX for a median of 12 cycles, and 69 of this group received a median of 6 cycles of FOLFIRI following progression.

The dosing regimen for FOLFIRI was as follows: every 2 weeks, on day 1, 180 mg/m2 irinotecan; 200 mg/m2 L-folinic acid; 5FU bolus 400 mg/m2; followed by 5FU 46 hours continuous infusion 2.4 to 3 g/m2 (=simplified LV5FU2 schedule). For FOLFOX, dosage was every 2 weeks, oxaliplatin on day 1, followed by the same LV5FU2 regimen. Eight patients had a complete surgical resection of metastasis with FOLFIRI first, whereas 20 patients had FOLFOX first.

Response rates were 57.5% with FOLFIRI in the first line and 21% with FOLFOX in second line compared with 56% with FOLFOX in the first line and 7% with FOLFIRI second. Progression-free survival time in the first line was 8.6 months in the FOLFIRI arm and 8.9 months in the FOLFOX arm. In the second line, the survival time was 2.5 months and 4.1 months, respectively.

Neutropenia was greater with FOLFOX in the first line, and grade 3 peripheral neuropathy was sufficiently higher in the FOLFIRI group that treatment was stopped early for some patients in order to avoid progression of neurologic symptoms.

Although there was no significant difference in response rates between FOLFOX and FOLFIRI when used as first line treatment, Dr. Tournigand said longer follow up will be needed to assess long-term survival between these two sequences.