Does 5-FU Cause Neuropathy?
5-Fluorouracil (5-FU) rarely causes peripheral neuropathy as a direct effect, with an incidence of only 0.2% when used alone, but neurotoxicity can occur, particularly in patients with dihydropyrimidine dehydrogenase (DPD) deficiency or when combined with other neurotoxic agents like oxaliplatin. 1
Incidence and Clinical Context
The MOSAIC trial definitively established that 5-FU/leucovorin alone causes grade 3 peripheral sensory neuropathy in only 0.2% of patients, compared to 12.4% when combined with oxaliplatin in FOLFOX regimens. 1 This demonstrates that neuropathy attributed to 5-FU-containing regimens is almost always due to oxaliplatin, not the fluoropyrimidine itself.
Types of 5-FU-Associated Neurotoxicity
Acute Central Neurotoxicity (More Common)
- Acute cerebellar syndrome with ataxia, dysarthria, and gait disturbances 2, 3
- Encephalopathy with confusion and cognitive disturbances 3
- Seizures (rare) 3
- These typically occur with high-dose bolus regimens or continuous infusions 4, 5
Peripheral Neuropathy (Rare)
- Sensorimotor polyneuropathy with distal sensory loss and weakness 4, 5
- Foot drop has been reported 4
- Paresthesias in extremities 4
- This occurs most often with intermittent high-dose bolus or 24-48 hour infusions 4
High-Risk Populations
Patients with DPD deficiency are at dramatically increased risk for severe neurotoxicity. 6, 7 The FDA label specifically warns that "rarely, life-threatening toxicities such as stomatitis, diarrhea, neutropenia, and neurotoxicity have been reported with intravenous administration of fluorouracil in patients with DPD enzyme deficiency." 6
Two case reports documented profound neurotoxicity (drowsiness, acute confusion, dysarthria, seizures, metabolic encephalopathy) in patients with DPD deficiency receiving standard 5-FU doses. 7 Both patients had elevated uracil-to-dihydrouracil ratios confirming DPD deficiency. 7
Mechanism and Contributing Factors
The neurotoxicity likely results from 5-FU itself or its active metabolite fluoro-beta-alanine. 4, 5 Contributing factors include:
- DPD deficiency leading to 5-FU overexposure 7
- High-dose or prolonged infusion schedules 4, 5
- Combination with other neurotoxic agents (cisplatin) 2
- Possible alcohol abuse as a cofactor 2
Clinical Management
If peripheral neuropathy develops during 5-FU therapy:
- Immediately discontinue 5-FU 4
- Evaluate for DPD deficiency retrospectively 7
- Rule out other causes (CNS lesions, other medications, metabolic disorders) 4, 5
- Perform electromyography and nerve conduction studies to confirm peripheral neuropathy 4, 5
- Symptoms typically stabilize or improve after dose reduction or discontinuation 4, 5
- Resolution may take 4 weeks or longer 4
- If rechallenge is necessary, reduce dose by 20-40% 4
Important Caveats
The vast majority of neuropathy in patients receiving FOLFOX or similar regimens is attributable to oxaliplatin, not 5-FU. 1 In the PROSPECT trial comparing FOLFOX to 5-FU-based chemoradiation, severe neuropathy during neoadjuvant treatment was significantly more frequent with FOLFOX (19% presurgery) versus 5-FU chemoradiation (5% presurgery). 1 However, at 12 months post-surgery, severe neuropathy was paradoxically higher in the 5-FU chemoradiation group (8% vs 3%), likely because 78% of that group received adjuvant oxaliplatin-containing chemotherapy. 1
For patients with pre-existing neuropathy or neurological disorders, 5-FU alone is generally safe, but oxaliplatin-containing regimens should be avoided. 1 The ASCO guideline for anal cancer specifically states that "cisplatin is not recommended for patients with renal dysfunction, significant neuropathy, or hearing loss," implicitly suggesting that 5-FU-based regimens without platinum agents are acceptable alternatives in these populations. 1