Can Leucovorin (folinic acid) cause neuropathy in patients, especially those with a history of cancer receiving chemotherapy?

Does Leucovorin Cause Neuropathy?

Leucovorin (folinic acid) does not cause peripheral neuropathy. The neuropathy observed in cancer patients receiving leucovorin-containing regimens is caused by the neurotoxic chemotherapy agents (oxaliplatin, cisplatin, or taxanes) administered alongside leucovorin, not by leucovorin itself.

Evidence from Chemotherapy Regimens

FOLFOX Regimen (Fluorouracil, Leucovorin, Oxaliplatin)

• Oxaliplatin is the sole neurotoxic agent in FOLFOX regimens, with grade 3 peripheral sensory neuropathy occurring in 12.4% of patients receiving FOLFOX compared to only 0.2% in patients receiving 5-FU/leucovorin alone 1
• The MOSAIC trial demonstrated that neuropathy persisted in 15.4% of patients at 4 years after FOLFOX treatment, confirming oxaliplatin-induced neuropathy may not be completely reversible 1
• When comparing FOLFOX to 5-FU/leucovorin without oxaliplatin, the dramatic difference in neuropathy rates (12.4% vs 0.2%) definitively establishes oxaliplatin as the causative agent 1

Fluorouracil and Leucovorin Alone

• Studies comparing different doses of leucovorin (175 mg vs 25 mg, 500 mg/m² vs 20 mg/m², and 200 mg/m² vs 20 mg/m²) with bolus 5-FU showed no difference in toxicity profiles, including no mention of neuropathy as a side effect 1
• The QUASAR study and multiple other trials using 5-FU/leucovorin combinations without platinum agents or taxanes did not report peripheral neuropathy as a significant adverse event 1

Other Leucovorin-Containing Regimens

• In pancreatic cancer patients receiving leucovorin, 5-FU, and cisplatin, 21% developed grade 2 peripheral neuropathy—this was attributed to cisplatin, a known neurotoxic platinum agent 2
• High-dose methotrexate with leucovorin rescue protocols reported peripheral neuropathy only when vincristine was co-administered, with the neuropathy attributed to vincristine (a known neurotoxic vinca alkaloid), not leucovorin 3

Mechanism and Clinical Context

Leucovorin's Role

• Leucovorin functions as a reduced folate that bypasses dihydrofolate reductase inhibition and enhances fluoropyrimidine efficacy 4
• It serves as a rescue agent to prevent methotrexate toxicity (leucopenia, mucositis, hepatotoxicity) but does not cause or prevent neuropathy 5, 4
• Leucovorin is used in autism spectrum disorder and folate metabolism disorders without reports of neuropathy as an adverse effect 6

Identifying the True Culprits

When evaluating neuropathy in patients receiving leucovorin-containing chemotherapy regimens, the neurotoxic agents responsible are:

• Oxaliplatin: Causes acute cold-induced dysesthesias and chronic cumulative sensory neuropathy 1
• Cisplatin: Produces dose-dependent sensory neuropathy 1
• Taxanes (paclitaxel, docetaxel): Result in sensory-predominant peripheral neuropathy 1
• Vincristine: Causes sensory and motor neuropathy 3

Clinical Implications

• The 66.2% incidence of chemotherapy-induced peripheral neuropathy (CIPN) in colorectal cancer patients receiving FOLFOX was entirely attributable to oxaliplatin, as evidenced by the characteristic cold-related symptoms and cumulative dose-dependent pattern 7
• Cross-study comparisons consistently show neuropathy rates of <1% with 5-FU/leucovorin regimens versus 10-15% when oxaliplatin is added 1
• ASCO guidelines for CIPN prevention and management focus exclusively on neurotoxic chemotherapy agents (platinum compounds, taxanes, vinca alkaloids) and make no mention of leucovorin as a neuropathy-causing agent 1

Common Clinical Pitfall

Do not attribute neuropathy to leucovorin when patients are receiving combination chemotherapy regimens. The neuropathy is caused by the neurotoxic chemotherapy agents (oxaliplatin, cisplatin, taxanes, or vinca alkaloids) in these regimens. Leucovorin can be safely continued or dose-adjusted based on other toxicities without concern for causing or worsening peripheral neuropathy 1.