What are the indications, mechanism of action, efficacy, and adverse effects of leucovorin (folinic acid)?

Leucovorin: Indications, Mechanism of Action, Efficacy, and Adverse Effects

Indications

Leucovorin (folinic acid) is FDA-approved for four primary indications: rescue therapy after high-dose methotrexate in osteosarcoma, treatment of methotrexate toxicity, megaloblastic anemia when oral therapy is not feasible, and combination therapy with 5-fluorouracil for advanced colorectal cancer. 1, 2

Approved Indications:

• Methotrexate rescue: Following high-dose methotrexate therapy (≥3-8 g/m²) in osteosarcoma to prevent life-threatening toxicity 1, 2
• Methotrexate toxicity management: To diminish toxicity and counteract effects of impaired methotrexate elimination or inadvertent overdosage of folic acid antagonists 1, 2
• Megaloblastic anemia: Treatment of folic acid deficiency when oral therapy is not feasible 1, 2
• Colorectal cancer: Combination with 5-fluorouracil to prolong survival in palliative treatment of advanced colorectal cancer 1, 2

Specific Dosing Regimens in Colorectal Cancer:

• FOLFOX regimen: Leucovorin 400 mg/m² IV over 2 hours on day 1, followed by 5-FU bolus and continuous infusion, repeated every 2 weeks 3
• FOLFIRI regimen: Leucovorin 400 mg/m² IV infusion matching irinotecan duration, with 5-FU bolus and continuous infusion, repeated every 2 weeks 3
• Roswell-Park regimen: Leucovorin 500 mg/m² IV over 2 hours on days 1,8,15,22,29, and 36, repeated every 8 weeks 3
• Weekly regimen: Leucovorin 20 mg/m² IV over 2 hours followed by 5-FU bolus 3

Important note: Leucovorin 400 mg/m² is equivalent to levo-leucovorin 200 mg/m² 3

Mechanism of Action

Leucovorin bypasses methotrexate's inhibition of dihydrofolate reductase by providing reduced folates directly to cells, allowing DNA synthesis to resume in normal cells while maintaining selective toxicity in tumor cells with impaired folate transport. 4, 5

Biochemical Basis:

• Folate pathway rescue: Leucovorin is a reduced folate that does not require conversion by dihydrofolate reductase, unlike folic acid 6
• Selective cellular uptake: High-dose methotrexate enters tumor cells (such as osteosarcoma) only by passive diffusion, while leucovorin in low doses enters normal cells via active transport, creating selective antitumor effect 5
• Competitive inhibition: Leucovorin and its metabolites compete with methotrexate at dihydrofolate reductase and other folate-dependent enzymes 7
• Folate pool restoration: Leucovorin restores intracellular folate pools (tetrahydrofolate, 10-formyl tetrahydrofolate, 5-methyl tetrahydrofolate, 5,10-methylene tetrahydrofolate) that are depleted by methotrexate 7

5-Fluorouracil Synergy:

• Enhanced cytotoxicity: In colorectal cancer, leucovorin stabilizes the binding of 5-FU metabolites to thymidylate synthase, enhancing 5-FU's cytotoxic effect 3

Critical caveat: Leucovorin should never be mixed in the same infusion as 5-fluorouracil because a precipitate may form 1, 2

Efficacy

Methotrexate Rescue:

• High-dose methotrexate toxicity: High-dose leucovorin (0.24 to 8 g/day) as sole therapy successfully rescued 13 patients with severe methotrexate intoxication (MTX levels >100 micromol/L at 24 hours) without need for hemodialysis or other extracorporeal removal 8
• Rescue formula for critical cases: When methotrexate elimination is retarded, leucovorin dose (mg) = 10 × MTX (mg/L) × 0.76 × body weight (kg) 5
• Timing matters: Leucovorin rescue must be initiated while methotrexate serum concentration is ≥10⁻⁶ M, as standard doses are insufficient for effective bone marrow rescue at higher concentrations 5

Low-Dose Methotrexate Toxicity:

• Mortality remains high: In severe low-dose methotrexate toxicity (WBC ≤2×10⁹/L or platelets ≤50×10⁹/L), 30-day mortality was 42-47% regardless of leucovorin dose (15 mg vs 25 mg every 6 hours), with serum albumin being the only predictor of survival 9
• No dose advantage: There was no significant difference in survival or hematological recovery between usual-dose (15 mg) and high-dose (25 mg) leucovorin given every 6 hours 9

Colorectal Cancer:

• Survival benefit: FOLFOX and FOLFIRI regimens containing leucovorin with 5-FU are standard first-line therapies for advanced colorectal cancer, prolonging survival compared to 5-FU alone 3, 1
• Adjuvant therapy: In stage III colon cancer, leucovorin-containing regimens (FOLFOX, 5-FU/leucovorin) are standard adjuvant treatments 3

Murine Tumor Models:

• Optimal scheduling: Delayed "low-dose" leucovorin rescue (12 mg/kg starting 16-20 hours after methotrexate 400 mg/kg) achieved 2-fold (L1210 leukemia) and 4-fold (Sarcoma 180) greater antitumor effects than maximally tolerated methotrexate alone 10

Adverse Drug Effects

Leucovorin itself has minimal toxicity, with allergic reactions being the primary concern; however, when combined with 5-fluorouracil for colorectal cancer, significant hematologic and gastrointestinal toxicity occurs. 2

Leucovorin-Specific Adverse Effects:

• Allergic reactions: Allergic sensitization, including anaphylactoid reactions and urticaria, reported with both oral and parenteral administration 2
• No other direct toxicity: No other adverse reactions have been attributed to leucovorin per se 2

Leucovorin/5-FU Combination Toxicity (Advanced Colorectal Cancer):

Data from 316 patients treated with leucovorin/5-FU combinations versus 70 patients on 5-FU alone 2:

Hematologic Toxicity:

• Leukopenia (any grade): 69-83% with leucovorin/5-FU vs 93% with 5-FU alone 2
• Leukopenia (grade 3+): 14-23% with leucovorin/5-FU vs 48% with 5-FU alone 2
• Thrombocytopenia (any grade): 8% with leucovorin/5-FU vs 18% with 5-FU alone 2

Gastrointestinal Toxicity:

• Stomatitis (any grade): 75-84% with leucovorin/5-FU vs 59% with 5-FU alone 2
• Stomatitis (grade 3+): 27-29% with leucovorin/5-FU vs 16% with 5-FU alone 2
• Diarrhea (any grade): 66-67% with leucovorin/5-FU vs 43% with 5-FU alone 2
• Diarrhea (grade 3+): 14-18% with leucovorin/5-FU vs 11% with 5-FU alone 2
• Nausea (any grade): 74-80% with leucovorin/5-FU vs 60% with 5-FU alone 2
• Vomiting (any grade): 44-46% with leucovorin/5-FU vs 40% with 5-FU alone 2

Other Toxicities:

• Alopecia (any grade): 42-43% with leucovorin/5-FU vs 37% with 5-FU alone 2
• Dermatitis (any grade): 21-25% with leucovorin/5-FU vs 13% with 5-FU alone 2
• Hospitalization for toxicity: 5-15% with leucovorin/5-FU vs 7% with 5-FU alone 2

Critical interpretation: The increased toxicity with leucovorin/5-FU combinations reflects enhanced 5-FU efficacy rather than leucovorin toxicity, as leucovorin potentiates 5-FU's mechanism of action 2

Methotrexate Rescue Outcomes:

• Neutropenia: Occurred in 8/13 patients (neutrophil count <1,000/μL) lasting 1-5 days despite high-dose leucovorin rescue 8
• Thrombocytopenia: Occurred in 7/13 patients (platelet count <100,000/μL) lasting 5-10 days 8
• Mucositis and diarrhea: Variable degrees observed, but all patients recovered 8

Monitoring Recommendations:

• Complete blood count: Regular monitoring essential for early detection of hematologic toxicity 11
• Liver and renal function: Monitor during therapy to detect early signs of toxicity 11
• Methotrexate levels: When using leucovorin for methotrexate rescue, monitor MTX levels to guide leucovorin dosing 4