Fluorouracil: Effects in Oncology and Dermatology

Fluorouracil, abbreviated 5-FU (brand names Fluorouracil Hexal, Efudix topical, and numerous generics), is a pyrimidine analog and one of the oldest and most important cytostatic agents in oncology. The substance has been in use since the 1960s, particularly for colorectal carcinoma, gastric carcinoma, pancreatic carcinoma, breast carcinoma, and squamous cell carcinomas in the head and neck area. In dermatology, fluorouracil is used topically for treatment of actinic keratosis, superficial basal cell carcinomas, and Bowen's disease. Intravenous administration is a central component of modern chemotherapy regimens such as FOLFOX and FOLFIRI.

Fluorouracil is a classic antimetabolite cytostatic with a complex efficacy profile. Intravenous administration occurs in specialized oncology centers; topical administration can be performed at home after appropriate counseling but requires discipline due to intense skin reactions. Careful evaluation of possible metabolic abnormalities such as dihydropyrimidine dehydrogenase deficiency (DPD deficiency) is necessary before systemic therapy, as DPD deficiency significantly increases the risk of severe toxicity.

Mechanism of Action

Fluorouracil is a pyrimidine analog that is converted into several active metabolites within the cell. The most important mechanism is inhibition of thymidylate synthase by the metabolite 5-FdUMP, which stops thymine synthesis and thus DNA replication. Additionally, fluorouracil metabolites are incorporated into RNA and DNA, leading to defective nucleic acids and cellular dysfunction. The interaction of these effects has the greatest impact on rapidly proliferating cells such as tumor cells, bone marrow cells, and gastrointestinal mucosa.

The pharmacokinetics are complex. Approximately 80 percent of intravenously administered fluorouracil is metabolized by the enzyme dihydropyrimidine dehydrogenase (DPD) to inactive metabolites. In patients with DPD deficiency (complete or partial), the substance can accumulate toxically, which is why DPD testing before therapy has been established in recent years. In high-risk profiles, dose reduction or switching to alternative therapy is indicated.

When applied topically, fluorouracil is absorbed by the skin and exerts its effect specifically on preneoplastic or superficially tumorous cells. Resorption is limited; systemic effects rarely occur with proper application. The typical skin reaction with redness, erosion, and crust formation is a desired therapeutic sign.

Indications

• Colorectal carcinoma, in adjuvant and palliative situations, especially as part of FOLFOX (with oxaliplatin) and FOLFIRI (with irinotecan) regimens
• Gastric and esophageal carcinoma, often in combination with platinum compounds
• Pancreatic carcinoma, in combinations such as FOLFIRINOX
• Breast carcinoma in specific regimens, especially in non-endocrine sensitive tumors
• Squamous cell carcinomas in the head and neck area, often in combination with platinum and cetuximab
• Actinic keratosis topically, frequently 4 weeks therapy with 5 percent cream
• Superficial basal cell carcinomas when contraindicated for operative therapy
• Bowen's disease in suitable locations

Fluorouracil is not first-line therapy for nodular basal cell carcinomas or deeply infiltrating skin tumors; operative therapy is established here. In many breast cancer forms, modern agents such as taxanes and HER2-targeted therapies are now dominant.

Dosage and Administration

Intravenous therapy: 400 to 600 mg per square meter body surface area as a bolus, followed by continuous infusion 2400 mg per square meter over 46 hours in regimens such as mFOLFOX6. Exact dose and schedule depend on indication, tolerability, and comedication.

DPD test: strongly recommended before therapy start, as DPD deficiency can lead to life-threatening toxicity. Genotyping or determination of phenotype (uracil in plasma) are available.

Topical application 5 percent cream: once to twice daily on affected areas over 2 to 6 weeks, depending on indication. Application according to skin reaction: initially redness, then erosion and crust formation, followed by healing. Therapy may be paused if reaction is very severe.

Renal insufficiency: typically no dose adjustment needed as hepatic metabolism is dominant. With severe renal insufficiency, individual assessment is required. Hepatic insufficiency: with impaired function, cautious use, possibly dose reduction.

Duration of therapy: in oncology over several months, in regimens with breaks. Topically typically two to six weeks, followed by a recovery phase.

Adverse Effects

Very frequent (intravenous): mucositis, stomatitis, nausea, vomiting, diarrhea, bone marrow suppression with leukopenia, thrombocytopenia and anemia, hand-foot syndrome (palmoplantar erythrodysesthesia syndrome).

Frequent: fatigue, hyperpigmentation, alopecia, conjunctivitis, lacrimal duct stenosis, cardiac toxicity with vasospasm or angina pectoris, especially with continuous infusion.

With DPD deficiency: enhanced and prolonged toxicity with severe mucositis, diarrhea, bone marrow suppression, sepsis, cardiac complications. With complete DPD deficiency, fluorouracil is contraindicated.

Topical application: redness, burning, pain, erosion, crust formation at application site, pruritus. These reactions are desired and part of therapy. With very severe reaction, therapy pause.

Severe and rare adverse effects: encephalopathy, seizures, Stevens-Johnson syndrome, acute pancreatitis, cardiac ischemia to myocardial infarction.

Drug Interactions

• Folinic acid (leucovorin): enhancement of antitumor effect, intentional in many regimens.
• Brivudin and sorivudin: irreversible DPD inhibition, life-threatening fluorouracil toxicity, contraindicated.
• Methotrexate: combined in specific regimens, clinically synergistic effect possible.
• Vitamin K antagonists: increased INR and bleeding risk, regular monitoring.
• Phenytoin: increased phenytoin levels with neurotoxic symptoms.
• Other cytostatic agents: carefully coordinated in combination regimens, mutual toxicity enhancement possible.
• Live vaccines: contraindicated during therapy due to immunosuppression.

Special Precautions

Pregnancy: Fluorouracil is teratogenic and contraindicated in pregnancy. Women of childbearing age must use reliable contraception during therapy and for several months afterward. Men with desire for children should consider sperm cryopreservation before therapy start, as spermatogenesis can be temporarily or permanently impaired. Breast feeding: Breast feeding during therapy is not permitted.

Children and adolescents: Use in pediatric tumors in specialized centers.

Elderly patients: increased toxicity and susceptibility to adverse effects. Low doses, individual support.

Before therapy start: complete blood count, liver function tests, kidney function tests, bilirubin, ECG, DPD test (genotype or uracil level), pregnancy test. Counseling on toxicity, warning signs, sun protection, oral hygiene, hand-foot care.

Topical application: patients require detailed counseling about expected skin reactions. Sun protection consistently, as photosensitivity exists. Application with gloves, as hands should not be treated if there is no indication there. With eye contact, rinse immediately.

Hand-foot syndrome: upon occurrence, pain, swelling, redness on palms and soles. Care with urea-containing creams, avoidance of friction and pressure, cool baths. With severe form, therapy adjustment.

Mucositis prophylaxis: good oral hygiene, possibly ice chewing during short bolus administration, rinses with mild solutions, observation for fungal infections.

Fitness to drive: with fatigue, dizziness, or neurotoxic symptoms, restricted, to be assessed individually.

You Might Also Be Interested In

• Methotrexate, another classic antimetabolite cytostatic
• Cisplatin, platinum compound in many combination regimens
• Oxaliplatin, platinum compound in gastrointestinal oncology
• Imiquimod, another topical therapy option for actinic keratosis
• Hydroxycarbamide, oral cytostatic with application in hematology and oncology

Frequently Asked Questions

Sources

• Gelbe Liste, Fluorouracil Active Substance Profile
• BfArM, Federal Institute for Drugs and Medical Devices
• AWMF, Oncological Guidelines
• ESMO, European Society for Medical Oncology