5-FU (Fluorouracil)

Last updated: January 2025 | Medical Reviewer: Oncol.net Editorial Board

Overview

5-Fluorouracil, commonly abbreviated as 5-FU, is an antimetabolite chemotherapy drug that disrupts cancer cell growth and division. It is classified as a pyrimidine analog, meaning it mimics natural building blocks of DNA and RNA but contains a fluorine atom that prevents proper cell replication. 5-FU has been in clinical use for over 65 years and continues to be essential in treating multiple cancer types.

The drug can be given as a rapid intravenous push (bolus) or as a continuous infusion over 24-48 hours. Continuous infusion is more common in modern regimens and generally has a different side effect profile compared to bolus administration. 5-FU is rarely given alone; it is almost always combined with other chemotherapy agents and often with leucovorin (folinic acid), which enhances its anti-cancer effects.

How 5-FU Works

Mechanism of Action

• Thymine synthesis inhibition: 5-FU is converted in cells to active metabolites that block thymidylate synthase, an enzyme essential for making thymine (a DNA building block). Without thymine, cells cannot replicate their DNA and divide.
• RNA incorporation: 5-FU metabolites also get mistakenly incorporated into RNA molecules, disrupting RNA function and protein synthesis.
• DNA incorporation: To a lesser extent, 5-FU metabolites are incorporated into DNA, causing strand breaks and dysfunction.
• Cell cycle specificity: 5-FU primarily affects cells in S-phase (DNA synthesis phase), making it most effective against rapidly dividing cancer cells.

Leucovorin Enhancement

Leucovorin (folinic acid) is almost always given with 5-FU because it:

• Stabilizes the bond between 5-FU metabolites and thymidylate synthase
• Increases the duration of enzyme inhibition
• Enhances anti-cancer activity by 3-5 fold
• Does not significantly increase toxicity

Cancer Types Treated with 5-FU

Primary Indications (FDA-Approved)

• Colorectal cancer: Standard component of most regimens (FOLFOX, FOLFIRI, CAPEOX)
  • Adjuvant treatment after surgery
  • First-line treatment for metastatic disease
  • Combination with oxaliplatin or irinotecan
  • 5-FU-based chemotherapy is backbone of colon cancer treatment
• Gastric (stomach) and gastroesophageal junction cancer:
  • Perioperative chemotherapy (before and after surgery)
  • Palliative treatment for advanced disease
  • Often combined with platinum agents (cisplatin, oxaliplatin)
• Pancreatic cancer:
  • Part of FOLFIRINOX regimen (5-FU + leucovorin + irinotecan + oxaliplatin)
  • One of the most effective regimens for metastatic pancreatic cancer
• Breast cancer:
  • Historically part of CMF regimen (cyclophosphamide, methotrexate, 5-FU)
  • Less commonly used now due to more effective newer agents
• Esophageal cancer:
  • Combined with cisplatin and radiation (trimodal therapy)
  • Palliative chemotherapy for advanced disease
• Anal cancer:
  • Combined with mitomycin C and radiation (Nigro protocol)
  • Curative in majority of cases
• Head and neck cancer:
  • Combined with cisplatin and radiation
  • Induction chemotherapy or concurrent with radiation

Other Uses

• Hepatobiliary cancers (biliary tract, gallbladder)
• Cervical cancer
• Skin cancers (topical formulation for actinic keratosis and superficial basal cell carcinoma)

How 5-FU is Given

Route of Administration

• Intravenous (IV): Standard for cancer treatment
  • Through peripheral IV or central line (port, PICC line)
  • Cannot be taken by mouth (oral form is not available for systemic cancer treatment)
• Topical cream: For skin conditions (actinic keratosis), not for internal cancers

Administration Methods

• Bolus injection: Rapid IV push over 1-2 minutes
  • Used in older regimens (Mayo Clinic regimen, Roswell Park regimen)
  • Higher risk of myelosuppression (low blood counts)
  • Less commonly used today
• Continuous infusion: Slow IV infusion over 46-48 hours
  • Most common method in modern regimens (FOLFOX, FOLFIRI)
  • Requires ambulatory infusion pump (small portable pump worn at home)
  • Higher risk of hand-foot syndrome and mucositis
  • Lower risk of severe myelosuppression compared to bolus

Common Regimens

Infusion Pump Management

For continuous infusion regimens:

• Small portable pump (about the size of a pager) worn in a pouch or fanny pack
• Connected to central line (port or PICC)
• Programmed to deliver 5-FU continuously over 46-48 hours
• Patients go home with the pump and return to clinic for disconnection
• Can shower (waterproof pump cover available), but cannot swim or submerge
• Sleep, eat, and perform most daily activities normally
• Keep pump at body temperature (don't expose to extreme heat or cold)

Dosing

Factors Affecting Dose

• Body surface area (BSA): Calculated from height and weight (typical unit: mg/m²)
• Regimen: Dose varies by specific protocol
• Bolus vs infusion: Continuous infusion uses higher total doses but over longer time
• Combination drugs: May require dose adjustments
• Organ function: Kidney and liver function
• Prior toxicity: Doses reduced for significant side effects
• DPD status: Patients with DPD deficiency require major dose reduction or alternative therapy

Typical Doses (Examples)

• FOLFOX/FOLFIRI: 400 mg/m² IV bolus, then 2400-3000 mg/m² continuous infusion over 46 hours
• Bolus regimen: 425-500 mg/m² IV daily for 5 days every 4 weeks (older protocol)
• Weekly regimen: 500-600 mg/m² IV weekly

Side Effects

Side effect profile depends significantly on administration method (bolus vs continuous infusion).

Common Side Effects (Occur in >25% of Patients)

Hand-Foot Syndrome (Palmar-Plantar Erythrodysesthesia)

• More common with continuous infusion (30-40%) than bolus (5-10%)
• Symptoms:
  • Redness, swelling, tingling, or numbness of palms and soles
  • Tenderness and sensitivity to touch
  • Peeling, blistering, or cracking skin in severe cases
  • Difficulty walking, gripping objects, or writing
• Usually appears after 2-3 cycles
• Management:
  • Keep hands and feet cool (avoid hot water, heating pads)
  • Moisturize frequently with thick creams (urea-based or petroleum jelly)
  • Avoid tight shoes and prolonged pressure on hands/feet
  • Pyridoxine (vitamin B6) 100-150 mg daily may help (limited evidence)
  • Dose reduction if severe (Grade 2-3)

Mucositis (Mouth Sores)

• Incidence: 30-40% (higher with bolus dosing)
• Symptoms: Painful sores in mouth and throat, difficulty eating/swallowing
• Onset: Usually 5-10 days after treatment
• Management:
  • Oral cryotherapy (ice chips during bolus infusion): reduces risk by 40-50%
  • Excellent oral hygiene (soft toothbrush, gentle brushing 4× daily)
  • Rinse with salt and baking soda solution every 2-4 hours
  • Avoid spicy, acidic, hot, or rough foods
  • Magic mouthwash for pain relief
  • Prescription analgesics if severe

Diarrhea

• Incidence: 30-50% (especially with FOLFIRI due to irinotecan)
• Can be severe and require hospitalization if not managed promptly
• Management:
  • Start loperamide at first sign (4 mg initially, then 2 mg after each loose stool)
  • BRAT diet (bananas, rice, applesauce, toast)
  • Hydration (replace each stool with 8 oz fluid)
  • Avoid dairy, high-fiber foods, caffeine, alcohol
  • Seek medical attention if >6 stools/day, fever, severe cramping, or blood in stool

Nausea and Vomiting

• Incidence: 30-50%
• 5-FU alone is low-moderate emetogenic (often combined with highly emetogenic drugs like cisplatin)
• Management:
  • Preventive anti-nausea medications (ondansetron, metoclopramide, prochlorperazine)
  • Small, frequent meals
  • Avoid strong odors, greasy or spicy foods
  • Ginger, acupressure, or medical marijuana may help

Fatigue

• Incidence: 40-60%
• Cumulative, worsens with multiple cycles
• Management:
  • Balance rest with light exercise
  • Energy conservation techniques
  • Treat contributing factors (anemia, depression, poor sleep)

Less Common but Serious Side Effects

Myelosuppression (Low Blood Counts)

• More common with bolus than continuous infusion
• Nadir (lowest point): 7-14 days after treatment
• Neutropenia (low white blood cells): Increased infection risk
  • Fever ≥100.4°F requires immediate medical attention
  • G-CSF (Neupogen) may be given if severe or recurrent
• Thrombocytopenia (low platelets): Bleeding/bruising risk
• Anemia (low red blood cells): Fatigue, shortness of breath

Cardiotoxicity

• Rare but potentially life-threatening (incidence: 1-5%)
• More common with continuous infusion and in patients with pre-existing heart disease
• Manifestations:
  • Chest pain (angina) - most common, occurs during or shortly after infusion
  • Arrhythmias (irregular heartbeat)
  • Heart attack (myocardial infarction)
  • Cardiomyopathy (rare)
• Usually reversible if 5-FU is stopped
• Patients with history of coronary artery disease require close monitoring
• If chest pain occurs, 5-FU should be stopped and not restarted

Cerebellar Toxicity (Neurological)

• Rare (<1%) but serious
• Symptoms: Loss of coordination, difficulty walking, slurred speech, tremors
• May be irreversible
• 5-FU must be discontinued permanently if this occurs

Watery Eyes (Excessive Tearing)

• Incidence: 10-20%
• Due to nasolacrimal duct stenosis
• Bothersome but not dangerous
• May improve after treatment ends or may be permanent

Rare Side Effects

• Photosensitivity (increased sun sensitivity)
• Hyperpigmentation of skin or nails
• Nail changes (darkening, lifting, loss)
• Skin rash
• Liver enzyme elevations (usually mild)
• Allergic reactions (very rare)

DPD Deficiency

What is DPD?

Dihydropyrimidine dehydrogenase (DPD) is the enzyme responsible for breaking down 5-FU in the body. Over 80% of administered 5-FU is normally metabolized by DPD. Deficiency in this enzyme leads to toxic accumulation of 5-FU.

Prevalence and Genetics

• Partial DPD deficiency: 3-5% of population (reduced enzyme activity)
• Complete DPD deficiency: 0.1-0.5% (absent or minimal enzyme activity)
• Caused by mutations in DPYD gene (most common: DPYD*2A)
• More common in certain populations

Clinical Consequences

• Complete deficiency: Standard 5-FU doses are potentially fatal
  • Severe mucositis, diarrhea, myelosuppression
  • Mortality rate 20-30% if standard doses given
  • 5-FU should be avoided; alternative chemotherapy required
• Partial deficiency: Increased risk of severe toxicity
  • 50-75% dose reduction recommended based on deficiency severity
  • Close monitoring essential

Testing for DPD Deficiency

• Genetic testing (DPYD genotyping):
  • Detects most common mutations (DPYD*2A, c.1236G>A, c.2846A>T, c.1679T>G)
  • Recommended by some guidelines before starting 5-FU
  • Not yet standard practice in all centers
• Phenotypic testing (uracil blood test):
  • Measures uracil levels in blood (elevated if DPD deficient)
  • Can detect deficiency from any genetic cause, not just common mutations
• Testing is increasingly recommended in Europe and being adopted in US

Monitoring During Treatment

Before Each Treatment Cycle

• Complete blood count (CBC): Check white blood cells, platelets, hemoglobin
  • Treatment may be delayed if counts too low
  • ANC (absolute neutrophil count) should be ≥1500
  • Platelets should be ≥100,000
• Comprehensive metabolic panel: Kidney and liver function, electrolytes
• Assessment of side effects: Hand-foot syndrome, mucositis, diarrhea
• Performance status: Ability to perform daily activities

Dose Modifications

Doses are reduced or treatment delayed based on toxicity:

• Grade 2 hand-foot syndrome: 25% dose reduction
• Grade 3 hand-foot syndrome: Hold until improved to Grade 1, then 50% dose reduction
• Grade 3-4 mucositis or diarrhea: Hold treatment, reduce dose by 25-50% when resumed
• Neutropenic fever: Hold treatment, add G-CSF, reduce dose by 25% when resumed
• Cardiotoxicity: Discontinue 5-FU permanently

Drug Interactions

Significant Interactions

• Leucovorin (folinic acid): Intentional interaction - enhances 5-FU efficacy
• Warfarin: 5-FU increases warfarin effect, increasing bleeding risk
  • Monitor INR closely
  • Warfarin dose may need reduction
• Phenytoin: 5-FU increases phenytoin levels (seizure medication)
  • Monitor phenytoin levels
• Metronidazole: May increase 5-FU toxicity (avoid if possible)
• Allopurinol: May decrease 5-FU effectiveness
• Live vaccines: Should be avoided during 5-FU treatment (immunosuppression risk)

Foods and Supplements

• No specific food restrictions during treatment
• Avoid excessive vitamin B9 (folic acid) supplements (may enhance toxicity)
• Discuss all supplements with oncology team before taking

Pregnancy and Fertility

Pregnancy

• Pregnancy Category D: Can cause fetal harm
• Contraindicated during pregnancy except in life-threatening situations where benefit outweighs risk
• Effective contraception required during treatment and for 3-6 months after
• Both men and women should use contraception

Breastfeeding

• Unknown if 5-FU passes into breast milk, but likely
• Breastfeeding should be discontinued during 5-FU treatment

Fertility

• May cause temporary or permanent infertility in both men and women
• Sperm banking or egg/embryo preservation should be discussed before treatment if fertility is desired
• Risk of permanent infertility increases with cumulative dose and patient age

Frequently Asked Questions

Will I lose my hair from 5-FU?

No. Hair loss is NOT a common side effect of 5-FU when used alone. Hair thinning occurs in about 5-10% of patients, but complete hair loss is rare. However, if 5-FU is combined with other chemotherapy drugs (such as irinotecan or oxaliplatin in FOLFIRI/FOLFOX regimens), those drugs may cause hair loss or thinning.

Can I drink alcohol while receiving 5-FU?

Alcohol should be limited or avoided during 5-FU treatment. Alcohol can worsen side effects like nausea, diarrhea, and mouth sores. It may also increase liver toxicity. If you choose to drink, limit to small amounts and discuss with your healthcare team. Avoid alcohol completely if you have mouth sores or diarrhea.

Why do I need to carry a pump home?

Continuous infusion of 5-FU over 46-48 hours has been shown to be more effective and have fewer severe side effects (especially low blood counts) compared to rapid bolus injections. The portable pump allows you to receive this continuous treatment at home rather than staying in the hospital for 2 days. Most patients adapt well to the pump after the first cycle or two.

What should I do if my pump stops working or alarms?

Check the display for error messages and consult the instructions provided by your infusion center. Common issues include kinked tubing, air bubbles, or low battery. Do NOT try to fix it yourself. Contact your oncology team or infusion pharmacy immediately - most centers have 24/7 hotlines for pump problems. Do not disconnect the pump unless instructed to do so by healthcare professionals.

Can I get the flu or COVID vaccine while on 5-FU?

Yes to inactivated vaccines (flu shot, COVID vaccine). These are recommended and safe during chemotherapy. You should NOT receive live vaccines (such as MMR, varicella, yellow fever, nasal flu vaccine) during 5-FU treatment or for several months after completion. Always inform vaccination providers that you are receiving chemotherapy.

How long will I be on 5-FU?

Treatment duration depends on cancer type and treatment intent. Adjuvant treatment (after surgery) for colon cancer typically lasts 3-6 months (6-12 cycles). For metastatic cancer, treatment may continue as long as it is effective and tolerable, which could be many months to years. Your oncologist will discuss the treatment plan with you.

What if I have severe diarrhea or mouth sores?

Contact your oncology team immediately. Severe diarrhea (>6 stools per day, especially with fever, blood, or severe cramping) can lead to dangerous dehydration and electrolyte imbalances. Severe mouth sores that prevent eating or drinking require immediate attention. These are dose-limiting toxicities - your 5-FU dose will likely be reduced for future cycles, and you may need IV fluids, antibiotics, or hospitalization.

Is hand-foot syndrome dangerous?

Hand-foot syndrome is not dangerous to your health, but it can significantly affect quality of life. Severe cases can make it difficult to walk, work, or perform daily tasks. The good news is that it is completely reversible once treatment is stopped or the dose is reduced. Prevention and early management are key to avoiding severe cases.

Should I be tested for DPD deficiency before starting 5-FU?

This is an evolving area. Testing is increasingly recommended but not yet universally required in all treatment centers. If testing is available, it can identify patients at high risk for severe toxicity and allow for dose adjustments or alternative treatment selection. Discuss testing options with your oncologist, especially if you have a personal or family history of severe reactions to 5-FU or capecitabine.

Can I switch from IV 5-FU to the oral version (capecitabine)?

Capecitabine (Xeloda) is an oral prodrug that is converted to 5-FU in the body. It is sometimes used as an alternative to IV 5-FU in certain regimens (such as CAPEOX instead of FOLFOX for colon cancer). The efficacy is similar, but side effect profiles differ slightly. Capecitabine has higher rates of hand-foot syndrome and may be more convenient (no infusion pump), but requires taking pills twice daily. Discuss with your oncologist whether capecitabine is appropriate for your situation.

Sources and References

• National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology
• American Society of Clinical Oncology (ASCO) Guidelines
• 5-Fluorouracil Prescribing Information (FDA-approved label)
• Diasio RB, Harris BE. Clinical pharmacology of 5-fluorouracil. Clinical Pharmacokinetics. 1989
• European Medicines Agency Guidelines on DPD Testing
• Longley DB, Harkin DP, Johnston PG. 5-fluorouracil: mechanisms of action and clinical strategies. Nature Reviews Cancer. 2003