1. Clinical Overview
Fluorouracil (5-FU) is a fluorinated pyrimidine antimetabolite and a cornerstone chemotherapeutic agent. It is a cell cycle-specific agent, primarily active in the S-phase, used extensively in the treatment of various solid tumors. In the Indian context, it is a widely available, cost-effective chemotherapy option, often used in combination regimens for gastrointestinal, breast, and head & neck cancers. Its mechanism involves inhibition of thymidylate synthase and incorporation into RNA and DNA, leading to faulty nucleic acid synthesis and cell death.
| Onset | Duration | Bioavailability |
|---|---|---|
| Following intravenous administration, the onset of cytotoxic action is rapid, with cellular effects beginning within hours. Clinical tumor response, however, may take several weeks to become evident. | The cytotoxic effect is prolonged due to its incorporation into RNA and DNA. The plasma half-life is short (10-20 minutes), but its active metabolites (FdUMP) can inhibit thymidylate synthase for prolonged periods (hours to days). | Oral bioavailability is highly variable and unpredictable (0-80%) due to extensive first-pass metabolism by dihydropyrimidine dehydrogenase (DPD) in the gut and liver. Therefore, it is almost exclusively administered via intravenous routes (bolus or infusion) in clinical practice. |
2. Mechanism of Action
Fluorouracil is a prodrug that requires intracellular activation to exert its cytotoxic effects. Its primary mechanism is the inhibition of thymidylate synthase (TS) by its active metabolite, fluorodeoxyuridine monophosphate (FdUMP), in the presence of a folate cofactor (5,10-methylenetetrahydrofolate). This inhibition blocks the conversion of deoxyuridylic acid (dUMP) to deoxythymidylic acid (dTMP), thereby depleting intracellular thymidine triphosphate (dTTP) pools, which is essential for DNA synthesis and repair. Additionally, fluorouracil is metabolized to fluorouridine triphosphate (FUTP), which is incorporated into RNA, disrupting normal RNA processing and function. A third metabolite, fluorodeoxyuridine triphosphate (FdUTP), can be misincorporated into DNA, leading to DNA strand breaks and cell death.
3. Indications & Uses
- Adenocarcinoma of the colon and rectum (adjuvant and palliative treatment)
- Adenocarcinoma of the stomach (gastric cancer)
- Adenocarcinoma of the pancreas
- Carcinoma of the breast (advanced stage)
- Carcinoma of the head and neck (squamous cell carcinoma)
4. Dosage & Administration
Adult Dosage: Dose varies drastically based on regimen, cancer type, and combination therapy. Common regimens: 1) Bolus: 370-425 mg/m² IV daily for 5 days, repeated every 4-5 weeks. 2) Continuous Infusion (common in India for GI cancers): 1000 mg/m²/day IV as a continuous infusion over 24 hours for 4-5 days, repeated every 3-4 weeks. 3) Weekly Bolus: 500-600 mg/m² IV once weekly. Dose MUST be calculated using Body Surface Area (BSA).
Administration: For 250mg vial: Reconstitute with sterile water for injection or other specified diluent as per manufacturer's instructions. Administer as a slow intravenous push (bolus) over 1-5 minutes or dilute in compatible IV fluid (e.g., 0.9% NaCl, 5% Dextrose) for infusion as per protocol. EXTRAVASATION CAN CAUSE SEVERE LOCAL TISSUE DAMAGE. Ensure patent IV line. Continuous infusion requires a central venous line or a well-secured peripheral line with an infusion pump. NEVER administer intrathecally - FATAL.
5. Side Effects
Common side effects may include:
- Nausea and vomiting (moderate)
- Diarrhea (early or late onset)
- Stomatitis/Mucositis (oral ulcers)
- Myelosuppression: Leukopenia, Neutropenia (nadir at 9-14 days), Thrombocytopenia, Anemia
- Alopecia (reversible)
- Anorexia
- Hyperpigmentation of skin/nails/veins
6. Drug Interactions
| Drug | Effect | Severity |
|---|---|---|
| Leucovorin (Calcium Folinate) | Potentiates the cytotoxicity and toxicity of fluorouracil by stabilizing the ternary complex with thymidylate synthase. Requires careful dose monitoring. | Major |
| Cimetidine | May increase plasma concentrations of fluorouracil by inhibiting its metabolism, potentially increasing toxicity. | Moderate |
| Metronidazole | May increase toxicity of fluorouracil by reducing its clearance. Avoid combination. | Major |
| Warfarin | Fluorouracil may enhance the anticoagulant effect of warfarin, increasing INR and risk of bleeding. Monitor INR closely. | Major |
| Phenytoin | Fluorouracil may decrease phenytoin levels, potentially leading to loss of seizure control. | Moderate |
| Live Vaccines (e.g., BCG, MMR, Varicella) | Risk of disseminated infection due to immunosuppression. Contraindicated. | Major |
| Other Myelosuppressive Agents (e.g., Clozapine, Azathioprine) | Additive risk of severe bone marrow suppression. | Major |
7. Patient Counselling
- DO report any fever, chills, sore throat, or signs of infection immediately.
- DO maintain meticulous oral hygiene (soft toothbrush, non-alcoholic mouthwash) to reduce mucositis risk.
- DO drink plenty of fluids (2-3 liters/day) unless contraindicated.
- DO use sunscreen (SPF 30+) and protective clothing due to photosensitivity risk.
- DO inform all treating doctors and dentists about your chemotherapy.
- DONT take any over-the-counter medications, herbal supplements (e.g., St. John's Wort), or vaccines without consulting your oncologist.
- DONT become pregnant or father a child during and for at least 6 months after treatment. Use effective contraception.
- DONT breastfeed during treatment.
- DONT consume alcohol as it can worsen mouth sores and stomach upset.
8. Toxicology & Storage
Overdose: Manifestations of severe, acute toxicity: Profound myelosuppression (neutropenic fever, sepsis), severe hemorrhagic enterocolitis with explosive diarrhea, dehydration, electrolyte imbalance, severe mucositis/esophagitis/pharyngitis, cerebellar ataxia, confusion, and death.
Storage: Store unopened vials at controlled room temperature (15-25°C), protected from light. Do not freeze. Reconstituted solutions are chemically stable for up to 24 hours at room temperature (15-25°C) or 48 hours under refrigeration (2-8°C). However, due to microbiological risk, it is recommended to use immediately after reconstitution/dilution. Discard any unused portion. Follow strict cytotoxic drug handling guidelines during preparation and administration.