FOLFIRI vs 5FU in metastatic CRC

Background

Phase III randomized trial in 387 patients with previously untreated advanced/metastatic colorectal cancer. Tested whether adding irinotecan to infusional 5-FU/leucovorin (FOLFIRI) improves response and survival as first-line therapy; weekly and every-2-week schedules permitted.

Interventions and follow up

Arm A: Irinotecan plus 5-FU/folinic acid (FOLFIRI); weekly (irinotecan 80 mg/m2, 5-FU 2300 mg/m2 24-h, folinate 500 mg/m2) or every 2 weeks (irinotecan 180 mg/m2, 5-FU 400 mg/m2 bolus then 600 mg/m2 22-h x2 days, folinate 200 mg/m2)
Arm B: 5-FU/folinic acid alone, matching weekly or every-2-week schedule
Primary endpoint: Response rate

Results

Response rate: 49% vs 31%, FOLFIRI vs 5-FU/LV (P<.001)
Median time to progression: 6.7 mo vs 4.4 mo (P<.001)
Median OS: 17.4 mo vs 14.1 mo (P=.031)

Adverse events

Hematologic (grade ≥3): Neutropenia 28.8% vs 2.4% (P=.001); leukopenia 20.4% vs 2.4% (P=.009)
GI (grade ≥3): Diarrhea 44.4% vs 25.6% (P=.055)
Other: Asthenia 42.6%, acute cholinergic syndrome 20.4% (irinotecan-specific)

Conclusions

FOLFIRI improved response rate, time to progression, and overall survival versus 5-FU/leucovorin as first-line therapy for metastatic colorectal cancer, establishing irinotecan-containing regimens as a first-line standard.

Key Limitations

Predates routine biomarker testing and modern biologic combinations; benefit was achieved at the cost of substantially higher grade 3-4 diarrhea and neutropenia. Two different schedules pooled, introducing heterogeneity.

Clinical Context

This landmark trial helped establish irinotecan/5-FU (FOLFIRI) as a first-line backbone for mCRC and supported broad regulatory approval of irinotecan in colorectal cancer. FOLFIRI remains an ESMO-endorsed chemotherapy doublet, typically combined with a biologic (anti-EGFR or bevacizumab) by RAS status and sidedness.

References