What are the most common and clinically important side effects of 5‑fluorouracil (5‑FU) in adult patients?

Side Effects of 5-Fluorouracil (5-FU)

The most clinically important side effects of 5-FU are gastrointestinal toxicity (diarrhea, mucositis, stomatitis), myelosuppression, hand-foot syndrome, and cardiotoxicity manifesting as coronary vasospasm with chest pain—with the specific toxicity profile depending critically on whether bolus or infusional schedules are used. 1, 2

Gastrointestinal Toxicity

• Diarrhea is one of the most common and potentially life-threatening side effects, occurring more frequently with bolus administration than continuous infusion, and can be watery or bloody 1
• The disruption of intestinal lining integrity allows enteric organisms to access the bloodstream, creating risk for overwhelming sepsis, particularly when granulocyte nadir coincides with diarrhea 1
• Mucositis and stomatitis are frequent dose-limiting toxicities, especially with bolus schedules that include leucovorin 2
• Risk factors for severe diarrhea include unresected primary tumor, previous episodes of chemotherapy-induced diarrhea, and female sex 1

Dermatologic Toxicity

• Hand-foot syndrome (palmar-plantar erythrodysesthesia) occurs more commonly with infusional schedules 2, 3
• Local skin reactions when used topically include burning, crusting, allergic contact dermatitis, pruritus, scarring, rash, soreness, ulceration, blistering, and desquamating dermatitis 4, 5
• Infusional schedules are associated with more gastrointestinal and skin toxicity compared to bolus regimens 2

Hematologic Toxicity

• Myelosuppression is the most frequent hematological side effect with bolus schedules, while infusional schedules cause less myelotoxicity 4, 2
• Leukocytosis is the most frequent hematologic finding, though leukopenia, thrombocytopenia, eosinophilia, and toxic granulation can occur 4
• Prolonged myelosuppression requiring months of hospitalization has been reported in patients with dihydropyrimidine dehydrogenase (DPD) deficiency 5

Cardiotoxicity

• Coronary vasospasm and myocardial ischemia are the primary cardiac manifestations, not congestive heart failure 1, 6
• Angina-like chest pain is the most frequent cardiac symptom, with incidence ranging from 1-68% depending on monitoring intensity 1, 6
• Ischemic ECG changes occur in 68% of patients experiencing cardiac events, while cardiac biomarker elevations occur in only 43% 1
• Cardiac events typically manifest within 2-5 days after initiation of 5-FU and are usually short-lasting (up to 48 hours) 7, 6
• Silent myocardial ischemia has been detected in 6-7% of patients when stress testing is performed, suggesting clinical underestimation 7, 6

Neurotoxicity

• Acute leukoencephalopathy is a rare but severe complication, with median time to onset of symptoms being 3 days (range 2-4 days) from initiation 8
• Presenting symptoms include confusion, ataxia, altered mental status, and can progress to require intensive care unit admission 5, 8
• Hyperammonemic encephalopathy is a rare but recognized complication that can occur during 5-FU infusion 3
• Neurologic toxicity can vary from mild to severe and prolonged, with complete recovery typically occurring within 4 months after drug withdrawal 5, 8

Schedule-Dependent Toxicity Patterns

• Bolus schedules cause myelotoxicity as the predominant toxicity 2
• Bolus schedules with leucovorin are associated with diarrhea, mucositis, and myelosuppression 2
• Infusional schedules have less myelosuppression but more gastrointestinal and skin toxicity 2

High-Risk Populations

• Patients above age 70 years and female patients experience relatively increased drug toxicity 2
• Patients with DPD deficiency (prevalence ~3%) can develop severe, life-threatening toxicities including prolonged mucositis, desquamating dermatitis, myelosuppression, and neurotoxicity 5, 9
• Patients with prior coronary vasospasm are at substantially elevated risk for recurrent cardiac events and should generally avoid 5-FU 7

Drug Interactions

• Warfarin interaction is clinically significant: 5-FU causes INR increases >1.5 in 33-50% of patients, with INR >3.0 in 19%, leading to major hemorrhages in 3.2-8% of cases 10
• The combination of low-dose warfarin with 5-FU may be harmful due to INR elevation and consequent bleeding risk 10

Critical Management Considerations

• When used topically for actinic keratosis, side effects include soreness, redness, and possible crusting, which can be minimized through reduction in frequency of application or short breaks in therapy 10
• Application of weak topical steroid can be used if the reaction is excessive 10
• Use at poor healing sites such as the lower leg should always be undertaken with caution and may need supervision 10
• Maximum recommended treatment area is 500 cm² for 5-FU 5% based on toxicity concerns 10

Less Common Side Effects

• Central nervous system: emotional upset, insomnia, irritability 4
• Gastrointestinal: medicinal taste 4
• Special senses: conjunctival reaction, corneal reaction, lacrimation, nasal irritation 4
• Miscellaneous: herpes simplex, alopecia, telangiectasia 4