What is the Folfiri (fluorouracil, leucovorin, irinotecan) chemotherapy regimen?

FOLFIRI Chemotherapy Regimen

Regimen Definition and Components

FOLFIRI is a combination chemotherapy regimen consisting of leucovorin calcium (folinic acid), fluorouracil (5-FU), and irinotecan hydrochloride, administered as a biweekly infusional protocol for colorectal cancer treatment. 1

Standard Dosing Schedule

The established FOLFIRI protocol administered every 2 weeks includes: 1

• Irinotecan 180 mg/m² IV infusion over 90 minutes on day 1 1, 2
• Leucovorin 400 mg/m² IV (or 200 mg/m² if using levo-leucovorin) as a 2-hour infusion on day 1 1, 3
• 5-FU 400 mg/m² IV bolus immediately following leucovorin on day 1 1
• 5-FU 2,400 mg/m² continuous infusion over 46-48 hours (prescribe as 1,200 mg/m²/day × 2 days to minimize medication errors) 1, 3

Clinical Indications

FOLFIRI serves multiple roles in colorectal cancer management:

• First-line therapy for metastatic colorectal cancer, providing equivalent efficacy to FOLFOX with different toxicity profiles 1
• Second-line therapy after failure of oxaliplatin-based regimens (FOLFOX/CAPOX) 1
• Conversion therapy for initially unresectable metastatic disease to achieve resectability 1

Efficacy Profile

FOLFIRI demonstrates superior outcomes compared to fluoropyrimidine monotherapy: 1

• Higher response rates (approximately 40-45%) 1, 4
• Longer progression-free survival (5-9 months) 1, 5, 4
• Improved overall survival when all three cytotoxics (fluoropyrimidine, oxaliplatin, irinotecan) are used sequentially 1
• Median overall survival approaching 24-30 months when combined with targeted biologics 1

Toxicity Profile

FOLFIRI exhibits a distinct toxicity pattern compared to FOLFOX, with more alopecia and diarrhea but less polyneuropathy. 1

Common grade 3-4 adverse events include: 6, 5, 7

• Neutropenia (36-52%) 6, 5
• Diarrhea (5-20%) 6, 5
• Leucopenia (15-18%) 6, 5
• Mucositis (less common but notable) 6

Critical safety consideration: Recent evidence suggests single-agent irinotecan may provide similar efficacy with reduced toxicity compared to full FOLFIRI in the second-line setting after oxaliplatin failure, though this remains controversial and FOLFIRI remains the guideline-recommended standard. 6

Comparison with Alternative Regimens

FOLFIRI and FOLFOX demonstrate equivalent activity as first-line therapy, making the choice dependent on toxicity considerations and planned treatment sequencing. 1

• FOLFIRI preferred when avoiding cumulative neurotoxicity is priority 1
• FOLFOX preferred when diarrhea risk must be minimized 1
• Both serve as appropriate partners for biologic agents (bevacizumab, anti-EGFR antibodies) 1

The triplet regimen FOLFOXIRI (adding oxaliplatin to FOLFIRI) shows improved outcomes in selected patients but remains controversial due to increased toxicity. 1

Administration Considerations

Infusional 5-FU regimens are less toxic than bolus regimens and should be preferentially used. 1

Key practical points: 3, 7

• Requires central venous access for continuous infusion 5
• Chemotherapy orders must specify 24-hour units (1,200 mg/m²/day, NOT 2,400 mg/m² over 48 hours) to prevent medication errors 3
• Never confuse leucovorin 400 mg/m² with levo-leucovorin 200 mg/m² dosing 3
• Modified regimens with lower leucovorin doses (20 mg/m²) show similar efficacy with acceptable tolerability 7

Treatment Duration and Monitoring

Treatment continues until disease progression, unacceptable toxicity, or achievement of treatment goals (resectability). 1

• Consider treatment interruptions or de-escalation to fluoropyrimidine monotherapy if cumulative toxicity develops and disease control is achieved 1
• Sequential therapy starting with fluoropyrimidine alone remains valid for frail patients (approximately 15% of patients), though combination therapy is preferred when objective response is the goal 1
• Monitor complete blood counts, liver function, and renal function before each cycle 3