Leucovorin Dosing Recommendations
The recommended dose of leucovorin varies by clinical indication: 400 mg/m² IV over 2 hours for FOLFOX/FOLFIRI regimens in colorectal cancer, 20 mg/m² IV for Mayo Clinic regimen, 500 mg/m² IV weekly for Roswell Park regimen, and 15 mg every 6 hours for methotrexate rescue. 1, 2
Colorectal Cancer Chemotherapy Regimens
FOLFOX and FOLFIRI Protocols
- Leucovorin 400 mg/m² IV over 2 hours on day 1 is the standard dose for mFOLFOX6 and FOLFIRI regimens, repeated every 2 weeks 1
- This dose applies whether leucovorin is used alone or combined with bevacizumab, cetuximab, or panitumumab 1
- Important equivalency: Levoleucovorin dose is 200 mg/m², which equals 400 mg/m² of standard leucovorin 1
Mayo Clinic Regimen
- Leucovorin 20 mg/m² IV followed immediately by 5-FU 425 mg/m² daily for 5 consecutive days, repeated every 4 weeks 2
- Alternative dosing: Leucovorin 200 mg/m² IV by slow injection over minimum 3 minutes, followed by 5-FU 370 mg/m² daily for 5 days 2
- Critical safety consideration: This regimen carries 13% hospitalization rate for severe toxicity, with 2% treatment-related mortality, particularly in elderly patients (≥70 years) and females 3
Roswell Park Regimen
- Leucovorin 500 mg/m² IV over 2 hours on days 1,8,15,22,29, and 36 1
- 5-FU 500 mg/m² IV bolus given 1 hour after start of leucovorin infusion 1
- Repeated every 8 weeks 1
Rectal Cancer Adjuvant Therapy
- Postoperative regimen: Leucovorin 20 mg/m² IV on days 1-5 with 5-FU 380 mg/m²/day, repeated every 28 days for 4 cycles 1
- Weekly regimen: Leucovorin 500 mg/m² IV over 2 hours once weekly for 6 weeks, followed by 2 weeks rest 1
- Concurrent with radiation: Leucovorin 20 mg/m² IV bolus with 5-FU 400 mg/m² for 4 days during weeks 1 and 5 of radiation therapy 1
Methotrexate Rescue Dosing
Standard Rescue Protocol
- Leucovorin 15 mg (approximately 10 mg/m²) IV every 6 hours for 10 doses, starting 24 hours after methotrexate infusion begins 2
- Continue until methotrexate level falls below 5 × 10⁻⁸ M (0.05 micromolar) 2
Delayed Elimination Adjustments
- For delayed late elimination (methotrexate >0.2 micromolar at 72 hours): Continue 15 mg every 6 hours until level <0.05 micromolar 2
- For delayed early elimination (methotrexate ≥50 micromolar at 24 hours or ≥5 micromolar at 48 hours): Increase to 150 mg IV every 3 hours until level <1 micromolar, then 15 mg every 3 hours until <0.05 micromolar 2
Evidence on Rescue Dosing
- A 2023 randomized trial comparing 15 mg versus 25 mg every 6 hours for severe low-dose methotrexate toxicity found no survival difference between doses (42% vs 47% mortality, p=0.74), suggesting standard 15 mg dosing is adequate 4
Key Clinical Considerations
Dose Equivalency and Safety
- Never confuse leucovorin with levoleucovorin: The active isomer (levoleucovorin) requires half the dose 1
- Limit chemotherapy orders to 24-hour units (e.g., 1200 mg/m²/day NOT 2400 mg/m²/day over 46 hours) to minimize medication errors 1
High-Risk Populations
- Elderly patients (≥70 years) and females experience higher toxicity rates with Mayo Clinic regimen (24% vs 7% severe toxicity in elderly) 3
- Consider dose reduction for first cycle in high-risk patients, as 56% of severe toxicity and 80% of toxic deaths occur after the first cycle 3
Comparative Efficacy Data
- A randomized trial showed no superiority of high-dose leucovorin (500 mg/m²) versus low-dose (20 mg/m²) when combined with weekly 5-FU 500 mg/m² (response rates 21.6% vs 17.5%, p=NS), but high-dose caused significantly more grade III/IV diarrhea 5
- Weekly high-dose 5-FU with oral leucovorin (60 mg every 6 hours) achieved 37.5% response rate but did not appear superior to 5-FU alone at higher doses 6