Fluorouracil

Fluorouracil, a so called pyrimidine analogue, with the molecular formula: C4H3FN2O2 , is a heterocyclic organic compound which is a derivative of the nucleic base uracil (uracil is one of the four most important nucleic bases in RNA, together with adenine, cytosine and guanine). Pyrimidine analogues belong to the large group of non-selective cytotoxic chemotherapeutics. These are substances from different drug classes that have an antineoplastic effect. The average half-life of 5-fluorouracil is about 0.25 h.

5-FU is incorporated into RNA or DNA as the wrong building block(antimetabolite) due to its structural similarity to the pyrimidine bases cytosine and thymine (DNA nucleotides) or uracil (RNA nucleotide). In detail, the enzyme UMP pyrophosphorylase converts 5-fluorouracil into 5-fluoro-UMP. 5-fluoro-UMP is further phosphorylated to 5-fluoro-UTP and then incorporated into the RNA. This causes the synthesis of a defective RNA. The protein biosynthesis is inhibited. Furthermore, 5-fluoro-DUMP also inhibits thymidylate synthase. These mechanisms lead to a disturbance of DNA synthesis and ultimately to an inhibition of cell division.

5-fluorouracil is degraded by the enzyme dihydropyrimidine dehydrogenase. Therefore, it must not be taken at the same time as the nucleoside analogues brivudine and sorivudine. This could lead to an increase in the plasma concentration of fluorouracil and thus to an increase in toxicity

Fluorouracil is used for the treatment of various types of tumors (especially colorectal cancer and breast cancer) as well as certain precancerous and non-melanoma malignancies (e.g. basal cell carcinoma) of the skin. In combination with salicylic acid, 5-fluoruracil is also used for the local treatment of vulgar warts.

5-Fluorouracil can be genetically harmful!

5-Fluorouracil must not be used during pregnancy and lactation. Women of childbearing age should ensure effective contraception during chemotherapy and up to 6 months afterwards. 5-Fluorouracil can have a genetic damage effect. Men treated with 5-fluorouracil are therefore advised not to conceive a child during treatment and up to 6 months afterwards.

Breastfeeding is not allowed during the treatment.

As monochemotherapy or as part of polychemotherapy in daily individual doses of 370 - 600 mg/m2 body surface area (KOF) as an i.v. bolus injection or 200 - 750 mg/m2 KOF as an i.v. continuous infusion.

Advanced stomach cancer: As monochemotherapy or as part of polychemotherapy in individual daily doses of 500 - 600 mg/m2 KOF as an i.v. bolus injection.

Advanced pancreatic carcinoma: As monochemotherapy in individual daily doses of 400 - 500 mg/m2 KOF as an intravenous bolus injection or 1,000 mg/m2 KOF as an intravenous continuous infusion.

Metastasized breast carcinoma: Applied as part of polychemotherapy in daily doses of 500 - 600 mg/m2 KOF i.v. (e.g. CMF, FAC).

Dermatological applications: see below Fluorouracil/Dermatology

Blood and hematopoietic system

• Myelosuppression occurs frequently and is one of the dose-limiting adverse reactions
• Neutropenias and thrombocytopenias of mild to severe severity, agranulocytosis, anemia, and pancytopenia have been described.
• The extent (NCI grade I-IV) of myelosuppression depends on the mode of administration (i.v. bolus injection or i.v. continuous infusion) and dosage. Neutropenia occurs after each treatment course with i.v. bolus injections at adequate dosing (Nadir: 9th - 14th - 20th day of treatment,

Digestive:

• Gastrointestinal UAW (common): Mucositis (stomatitis, esophagitis, proctitis), watery diarrhea, nausea and vomiting of mild to severe degree, and stoneless cholecystitis have been described
• The severity (NCI grade I-IV) of gastrointestinal adverse events is dependent on dosage and route of administration. With i.v. continuous infusion, stomatitis rather than myelosuppression proves to be dose-limiting.
• Dehydration, sepsis, and gastrointestinal ulceration and bleeding are rarely observed.
• Liver cell damage is rare, and in isolated cases hepatic necrosis with lethal outcome.

Immunological UAW:

• Anaphylactic reactions: Generalized allergic reactions up to anaphylactic shock may occur.

Cardiovascular UAW:

• Cardiotoxic adverse reactions usually occur during or a few hours after the first cycle of use. ECG frequently shows ischemia-like changes. Angina pectoris-like chest pain occasionally occurs. Rarely, arrhythmias, myocardial infarction, myocarditis, heart failure, dilated cardiomyopathy, and cardiogenic shock have been observed, as well as cardiac arrest and sudden cardiac death in isolated cases. Patients with pre-existing coronary artery disease or cardiomyopathy are at increased risk of developing cardiotoxic adverse events. The occurrence of thrombophlebitis is rare.

Nervous System and Sensory Organs:

• Nystagmus, headache, dizziness,
• Parkinsonian symptoms, pyramidal tract signs, and euphoria may rarely occur.
• In isolated cases, encephalopathies with symptoms such as ataxia, speech disorders, confusion, disorientation, muscle weakness, aphasia, seizures, or coma may occur after infusion of high doses of 5-fluorouracil or in patients with dihydropyrimidine dehydrogenase (leuko) deficiency.

Ophthalmic UAW:

• Excessive lacrimation, blurred vision, ocular motility disorders, optic neuritis,
• Diplopia, visual acuity reduction, photophobia, conjunctivitis, blepharitis, scarring-induced
• Ectropion, and fibrosis of the lacrimal duct may rarely occur.

Skin and skin appendages:

• The so-called "hand-footsyndrome"with dysesthesias as well as redness, swelling, pain and desquamation of the skin on palms and soles occurs more frequently after i.v. continuous infusion than after i.v. bolus injections.

5-Fluorouracil must not be used:

• in case of hypersensitivity to 5-fluorouracil or any of the other components
• for bone marrow depression
• for severe blood count changes
• for severe liver dysfunction
• in acute infections
• for patients in poor general condition

Note: 5-Fluorouracil (5-FU) must not be taken or used together with Brivudine, Sorivudine and analogues. Brivudine, sorivudine and analogues are potent inhibitors of the 5-FU-degrading enzyme dihydropyrimidine dehydrogenase (DPD).

Fluorouracil-GRY® 50 mg/ml solution for injection; topical agents: Verrumal® Emra solution; Efudix® 5 % cream; Actikerall® 5 mg/g + 100 mg/g solution for application on the skin.

Cave: Patients with partial or complete dihydropyrimidine dehydrogenase (DPD) deficiency have an increased risk of severe toxicity when treated with fluoropyrimidines including 5-fluorouracil (5-FU) and its prodrugs capecitabine and tegafur. The following instructions should therefore be observed: Before starting treatment with fluoropyrimidines, the phenotype and/or genotype should be determined.

Treatment with drugs containing 5-FU, capecitabine or tegafur is contraindicated in patients with known complete DPD deficiency.

A reduced starting dose should be considered in patients with identified partial DPD deficiency.

In patients receiving continuous 5-fluorouracil infusions, therapeutic drug monitoring (TDM) of 5-fluorouracil may improve clinical outcomes.

1. Diasio RB et al (1989) Clinical pharmacology of 5-fluorouracil. Clin Pharmacokinet 16:215-237.
2. Freeman NJ et al. (1088) 5-fluorouracil-associated cardiotoxicity. Cancer 61:36-45.
3. Lemaitre F et al (2018) Suivi thérapeutique pharmacologique du 5-fluorouracile: mise au point et recommandations du groupe STP-PT de la SFPT et du GPCO-Unicancer [5-fluorouracil therapeutic drug monitoring: Update and recommendations of the STP-PT group of the SFPT and the GPCO-Unicancer]. Bull Cancer 105:790-803.