Usage
- This combination, known as S-1 or Teysuno, is an oral chemotherapy regimen indicated for the treatment of advanced gastric cancer in combination with cisplatin. It is also used in metastatic colorectal cancer, sometimes combined with oxaliplatin, irinotecan, and/or bevacizumab, particularly in patients who cannot tolerate other fluoropyrimidines. It has shown efficacy in other cancers like head and neck, non-small-cell lung, breast, pancreatic, and biliary tract cancers. In some regions, it’s used as adjuvant therapy after surgery for gastric cancer.
- Pharmacological classification: Antineoplastic agent, antimetabolite, pyrimidine analog.
- Mechanism of Action: Tegafur is a prodrug of 5-fluorouracil (5-FU). Gimeracil inhibits dihydropyrimidine dehydrogenase (DPD), the enzyme responsible for 5-FU degradation, thus increasing 5-FU bioavailability. Oteracil inhibits orotate phosphoribosyltransferase (OPRT), reducing the gastrointestinal toxicity of 5-FU.
Alternate Names
How It Works
- Pharmacodynamics: 5-FU, the active metabolite of tegafur, inhibits thymidylate synthase, disrupting DNA and RNA synthesis, leading to cell death. Gimeracil increases 5-FU concentration in tumor tissues. Oteracil preferentially accumulates in the gastrointestinal tract, protecting it from 5-FU’s toxicity.
- Pharmacokinetics: Tegafur is well-absorbed orally. All three components are primarily metabolized in the liver. Tegafur converts to 5-FU, then further metabolized to active metabolites, primarily FdUMP. Elimination is mainly through renal excretion. Gimeracil is primarily excreted unchanged in urine and oteracil is partially metabolized with some renal excretion.
- Mode of Action: Inhibition of thymidylate synthase, leading to impaired DNA/RNA synthesis.
- Receptor Binding/Enzyme Inhibition: Inhibition of thymidylate synthase by FdUMP (5-FU metabolite), inhibition of DPD by gimeracil, and inhibition of OPRT by oteracil.
- Elimination Pathways: Primarily renal excretion.
Dosage
Standard Dosage
Adults:
- Advanced Gastric Cancer (with cisplatin): 25 mg/m² (tegafur equivalent) twice daily for 21 days followed by a 7-day rest period, repeated every 4 weeks. Cisplatin is typically administered on day 1 of the cycle.
- Metastatic Colorectal Cancer (monotherapy or with other agents): Dosages vary based on combination regimens (e.g., with oxaliplatin, irinotecan, bevacizumab) and can range from 25 mg/m² twice daily for 14 days followed by a 7-day rest period, repeated every 3 weeks. Lower doses are used when combined with oxaliplatin and irinotecan.
- Adjuvant Therapy for Gastric Cancer: Dosages vary based on BSA and treatment protocols.
Children:
- Not recommended for use in children under 18 years due to a lack of safety and efficacy data.
Special Cases:
- Elderly Patients: Careful monitoring is recommended, with potential dose adjustments based on tolerability and organ function.
- Patients with Renal Impairment: Dose reductions are necessary in moderate to severe renal impairment. Not recommended for patients with end-stage renal disease requiring dialysis.
- Patients with Hepatic Dysfunction: Not recommended in severe hepatic impairment. Caution is advised in mild to moderate impairment.
- Patients with Comorbid Conditions: Careful consideration of potential drug interactions and overlapping toxicities is crucial, especially in patients with cardiovascular disease, diabetes, and bone marrow suppression.
Clinical Use Cases
The provided sources focus on dosages for the treatment of advanced gastric and metastatic colorectal cancers and do not include specific dosage recommendations for intubation, surgical procedures, mechanical ventilation, ICU use, or emergency situations. Dosage in these settings should be individualized based on patient needs and overseen by a specialist.
Dosage Adjustments
- Dose modifications are based on creatinine clearance, liver function, myelosuppression, other toxicities, and patient tolerance.
- Genetic polymorphisms affecting DPD activity should be considered; testing for DPD deficiency is recommended before initiating therapy. Dose reductions or avoidance are crucial in patients with partial or complete DPD deficiency.
Side Effects
Common Side Effects
- Nausea, vomiting, diarrhea, constipation, anorexia, fatigue, stomatitis, hand-foot syndrome (palmar-plantar erythrodysesthesia), rash, leukopenia, neutropenia, anemia, thrombocytopenia.
Rare but Serious Side Effects
- Severe myelosuppression, acute renal failure, Stevens-Johnson syndrome, toxic epidermal necrolysis, interstitial pneumonitis, cardiotoxicity, hepatic dysfunction.
Long-Term Effects
- Chronic myelosuppression, secondary malignancies, cardiac dysfunction.
Adverse Drug Reactions (ADR)
- Severe neutropenia, febrile neutropenia, severe thrombocytopenia with bleeding, severe diarrhea, dehydration, acute renal failure, severe hepatic dysfunction, allergic reactions.
Contraindications
- Hypersensitivity to any component, severe bone marrow suppression, severe renal impairment requiring dialysis, severe hepatic impairment, complete DPD deficiency, pregnancy, breastfeeding.
Drug Interactions
- Interactions with other myelosuppressive agents, anticoagulants (increased bleeding risk), CYP2A6 inhibitors (increased 5-FU levels). Sorivudine and its analogs are contraindicated due to severe drug interactions leading to life-threatening toxicity. Caution with drugs metabolized by CYP2A6.
Pregnancy and Breastfeeding
- Pregnancy Safety Category: Contraindicated (teratogenic).
- Breastfeeding: Contraindicated (drug is excreted in breast milk).
Drug Profile Summary (See above sections for details).
Popular Combinations
- Cisplatin (for advanced gastric cancer)
- Oxaliplatin, irinotecan, bevacizumab (for metastatic colorectal cancer)
Precautions (See above sections for details).
FAQs (Frequently Asked Questions)
Q1: What is the recommended dosage for Gimeracil + Oteracil + Tegafur?
A: See the detailed Dosage section above.
Q2: What are the most common side effects?
A: Nausea, vomiting, diarrhea, anorexia, fatigue, and myelosuppression.
Q3: Is this drug safe for use during pregnancy or breastfeeding?
A: No, it’s contraindicated due to potential harm to the fetus and neonatal exposure.
Q4: What is DPD deficiency, and why is it important?
A: DPD deficiency can lead to severe toxicity with this drug. Testing is recommended before initiating therapy.
Q5: What are the key monitoring parameters during treatment?
A: Complete blood counts, renal and liver function tests, and monitoring for other side effects.
Q6: What are the signs of acute 5-FU toxicity?
A: Severe myelosuppression, mucositis, diarrhea, and hand-foot syndrome.
Q7: Can S-1 be used in combination with other chemotherapeutic agents?
A: Yes, it can be combined with cisplatin, oxaliplatin, irinotecan, and bevacizumab, depending on the cancer being treated.
Q8: How should S-1 be administered?
A: Orally, with water, at least one hour before or after meals. Do not crush, chew, or break capsules.
Q9: Are there any drug interactions I should be particularly aware of?
A: Sorivudine and its analogs are strictly contraindicated. Caution is advised with coumarin anticoagulants and clozapine. Interactions with CYP2A6 substrates should be considered.
