Can 5-fluorouracil (5-FU) cause peripheral neuropathy?

5-Fluorouracil Can Cause Peripheral Neuropathy, Though It Is Rare

5-FU can cause peripheral neuropathy, but this is an uncommon adverse effect compared to its more frequent toxicities like cardiotoxicity, mucositis, and hand-foot syndrome. The evidence demonstrates that both systemic and topical formulations have been associated with neuropathic complications, though the incidence is significantly lower than with other chemotherapy agents like oxaliplatin.

Evidence from Systemic 5-FU Administration

The peripheral neurotoxicity from systemic 5-FU is well-documented in case reports and clinical trials, though it remains rare:

• Isolated case reports describe patients developing mild axonal sensorimotor neuropathy following 5-FU therapy for rectal cancer 1
• One case documented 5-FU-induced peripheral neuropathy in metastatic colorectal carcinoma, with recommendations to discontinue therapy when neurotoxicity occurs 2
• The FDA drug label acknowledges that "rarely, life-threatening toxicities such as stomatitis, diarrhea, neutropenia, and neurotoxicity have been reported with intravenous administration" 3

Evidence from Topical 5-FU

Surprisingly, even topical 5-FU can cause neurologic complications through systemic absorption:

• A 2024 case report described focal neurotoxicity (supraorbital neuralgia with frontalis muscle paralysis) following topical 5-FU 5% cream application to the scalp, with symptoms persisting 4 months after cessation 4
• A 2006 case documented exacerbation of pre-existing peripheral neuropathy after 21 days of topical 5-FU for actinic keratosis, which resolved upon discontinuation 5
• A 2018 review identified multiple systemic reactions to topical 5-FU including "neurologic conditions (such as acute cerebellar syndrome, headaches, and peripheral neuropathy exacerbation)" 6

Comparison to FOLFOX Regimens

The neuropathy risk profile changes dramatically when 5-FU is combined with oxaliplatin:

In FOLFOX regimens, the neuropathy is primarily attributable to oxaliplatin, not 5-FU:

• The MOSAIC trial showed grade 3 peripheral sensory neuropathy occurred in 12.4% of FOLFOX patients versus only 0.2% of 5-FU/LV patients 7
• At 4-year follow-up, neuropathy persisted in 15.4% of FOLFOX patients (mostly grade 1), demonstrating that oxaliplatin-induced neuropathy may not be completely reversible 7
• The NSABP C-07 trial comparing FLOX to 5-FU/LV showed grade 3 neurotoxicity was higher with FLOX 7

Risk Factors and Mechanism

Dihydropyrimidine dehydrogenase (DPD) deficiency is the critical risk factor:

• DPD is responsible for 80% of 5-FU degradation 4
• Patients with DPD deficiency can develop toxic levels of unmetabolized 5-FU, leading to severe systemic toxicity including neurotoxicity 3, 6
• One documented case of life-threatening systemic toxicity (including potential neurotoxic effects) occurred with topical 5-FU in a DPD-deficient patient 3
• However, one case report showed neuropathy exacerbation even with normal DPD activity 5

Clinical Implications

When prescribing 5-FU, clinicians should:

• Counsel patients that peripheral neuropathy is a possible but rare adverse effect
• Monitor for neurologic symptoms including paresthesias, pain, sensory changes, or motor weakness
• Immediately discontinue 5-FU if peripheral neuropathy develops 2
• Consider DPD deficiency testing in patients who develop severe or unexpected toxicity, though this is not routinely performed 6
• Avoid re-challenge with 5-FU in patients who have experienced neurotoxicity 5

Important Caveats

• The incidence of 5-FU-induced peripheral neuropathy may be underreported 6
• When neuropathy occurs in FOLFOX regimens, it is overwhelmingly due to oxaliplatin rather than 5-FU 7
• Topical 5-FU can cause systemic absorption sufficient to produce neurotoxicity, particularly through ulcerated or inflamed skin 3
• The 2014 ASCO guideline on chemotherapy-induced peripheral neuropathy prevention focused primarily on taxanes, platinum agents, and other neurotoxic chemotherapies, but did not identify 5-FU as a major causative agent 8

Bottom line: While 5-FU can cause peripheral neuropathy, this remains a rare complication. The far more common and serious concern with 5-FU is cardiotoxicity (myocardial ischemia and arrhythmias), which requires immediate discontinuation and avoidance of future 5-FU therapy 9.