What is the recommended dose of FOLFIRI (Irinotecan, Fluorouracil, Folinic acid) + Bevacizumab for a patient with metastatic colorectal cancer?

FOLFIRI + Bevacizumab Dosing for Metastatic Colorectal Cancer

The recommended dose is FOLFIRI (irinotecan 180 mg/m² IV over 30-90 minutes day 1, leucovorin 400 mg/m² IV over 2 hours day 1,5-FU 400 mg/m² IV bolus day 1 followed by 1,200 mg/m²/day continuous infusion over 2 days for a total of 2,400 mg/m² over 46-48 hours) plus bevacizumab 5 mg/kg IV every 2 weeks, repeated every 2 weeks until disease progression or unacceptable toxicity. 1

Standard Dosing Components

FOLFIRI Chemotherapy Backbone

• Irinotecan: 180 mg/m² IV infusion over 30-90 minutes on day 1 1
• Leucovorin (or levoleucovorin 200 mg/m²): 400 mg/m² IV infusion over 2 hours on day 1, matching the duration of irinotecan infusion 1
• 5-Fluorouracil: 400 mg/m² IV bolus on day 1, immediately followed by 1,200 mg/m²/day continuous infusion over 2 days (total dose 2,400 mg/m² over 46-48 hours) 1
• Cycle frequency: Repeat every 2 weeks 1

Bevacizumab Dosing

• Standard dose: 5 mg/kg IV infusion every 2 weeks when combined with FOLFIRI 1, 2
• Bevacizumab is administered on day 1 of each cycle, typically before chemotherapy 1

Treatment Duration and Continuation

Continue FOLFIRI plus bevacizumab until disease progression or unacceptable toxicity. 1, 2 Unlike oxaliplatin-based regimens, irinotecan lacks cumulative toxicity, so full-dose therapy should continue without planned interruption. 1

Critical Dosing Considerations

Infusional vs. Bolus 5-FU

• Infusional 5-FU is mandatory when combining with irinotecan; bolus 5-FU regimens are inappropriate and not recommended due to increased toxicity and lack of efficacy. 1
• The NCCN recommends limiting chemotherapy orders to 24-hour units (1,200 mg/m²/day, NOT 2,400 mg/m² over 46 hours) to minimize medication errors. 1

Patient Selection Criteria

• This regimen is appropriate for patients with good performance status (ECOG 0-2) who can tolerate combination chemotherapy. 1
• RAS wild-type right-sided tumors: FOLFIRI plus bevacizumab is the preferred first-line option over anti-EGFR antibodies. 1
• RAS-mutant tumors (any location): FOLFIRI plus bevacizumab is standard first-line therapy. 1

Important Safety Modifications

Hepatic Impairment

• Irinotecan should be used with caution and decreased doses in patients with Gilbert's disease or elevated serum bilirubin. 1
• Patients with baseline bilirubin 1.0-2.0 mg/dL have significantly greater risk of grade 3-4 neutropenia (50% vs. 18%). 3
• Do not use in patients with bilirubin >2.0 mg/dL or transaminases >3× upper limit of normal (>5× if liver metastases present). 3

UGT1A1 Testing

• A commercially available test for UGT1A1 exists, but guidelines for routine clinical use have not been established. 1
• Consider dose reduction in patients with known UGT1A1*28 homozygosity due to increased risk of severe neutropenia. 3

Common Pitfalls to Avoid

Dosing Errors

• Never use bolus 5-FU schedules (such as Mayo Clinic or Roswell Park regimens) with irinotecan—only infusional 5-FU is appropriate. 1
• Do not combine bevacizumab with anti-EGFR antibodies (cetuximab or panitumumab)—this combination is not recommended. 1

Inappropriate Discontinuation

• Do not stop irinotecan early for maintenance therapy as you would with oxaliplatin; continue full-dose FOLFIRI until progression due to lack of cumulative toxicity. 1
• If maintenance is needed after initial treatment, bevacizumab can be continued with a fluoropyrimidine, but this is less commonly done with FOLFIRI than with FOLFOX. 1

Bevacizumab-Specific Precautions

• Wound healing: Discontinue bevacizumab at least 28 days before elective surgery and do not resume until wound is fully healed. 2
• Gastrointestinal perforation risk: Monitor for abdominal pain, constipation, and vomiting—occurs in approximately 0.3-2.4% of patients. 2
• Hemorrhage: Bevacizumab increases bleeding risk; avoid in patients with recent hemoptysis or significant bleeding. 2

Alternative Dosing in Specific Contexts

Second-Line Setting

• When FOLFIRI plus bevacizumab is used as second-line therapy (after oxaliplatin-based first-line), the same dosing applies: irinotecan 180 mg/m², bevacizumab 5 mg/kg every 2 weeks. 1, 4
• Consider aflibercept or ramucirumab instead of bevacizumab in second-line FOLFIRI for potentially superior efficacy. 1

Reduced-Intensity Regimen

• For elderly or frail patients, consider irinotecan 150 mg/m² with bevacizumab 10 mg/kg every 2 weeks as an alternative schedule. 5
• Single-agent bevacizumab with fluoropyrimidine (without irinotecan) may be appropriate for patients with significant comorbidities. 1

Monitoring Requirements

• Complete blood counts: Before each cycle to assess for neutropenia, anemia, and thrombocytopenia. 3
• Liver function tests: Monitor transaminases and bilirubin, especially in patients with baseline hepatic impairment. 3
• Blood pressure: Monitor regularly due to bevacizumab-associated hypertension (grade 3-4 in approximately 5-11% of patients). 6, 7
• Proteinuria: Dipstick urinalysis before each bevacizumab dose; if ≥2+, obtain 24-hour urine collection. 2