Introduction
Capecitabine is an oral chemotherapeutic agent classified as a prodrug of 5-fluorouracil (5-FU). It belongs to the antimetabolite class of anticancer drugs and is specifically designed to be converted to its active form preferentially in tumor tissue, potentially minimizing systemic toxicity while maintaining antitumor efficacy.
Mechanism of Action
Capecitabine undergoes a three-step enzymatic conversion to its active form, 5-fluorouracil (5-fluorouracil). The final conversion step is catalyzed by thymidine phosphorylase, which is significantly more active in tumor tissues compared to normal tissues. 5-fluorouracil is then metabolized to two active metabolites: fluorodeoxyuridine monophosphate (FdUMP) and fluorouridine triphosphate (FUTP).
FdUMP inhibits thymidylate synthase, disrupting DNA synthesis by reducing thymidine production. FUTP incorporates into RNA, interfering with RNA processing and protein synthesis. This dual mechanism results in cytotoxic effects preferentially in rapidly dividing cancer cells.
Indications
- Metastatic colorectal cancer: First-line treatment as monotherapy or in combination regimens
- Adjuvant treatment of colon cancer: Following complete resection of primary tumor
- Metastatic breast cancer: Monotherapy after failure of taxane and anthracycline chemotherapy, or in combination with docetaxel after failure of prior anthracycline-containing chemotherapy
- Gastric cancer: Often used in combination regimens
- Pancreatic cancer: Frequently used in combination therapy (e.g., with gemcitabine)
Dosage and Administration
Standard dosing: 1250 mg/m² orally twice daily (total daily dose 2500 mg/m²) for 14 days followed by a 7-day rest period, repeated every 21 days Dose modifications: Required based on toxicity, renal function, and performance status Special populations:- Renal impairment: Reduce dose in patients with CrCl 30-50 mL/min; contraindicated if CrCl <30 mL/min
- Hepatic impairment: Use with caution in patients with hepatic dysfunction
- Elderly patients: Increased incidence of grade 3-4 adverse reactions; consider dose reduction
Pharmacokinetics
- Absorption: Readily absorbed from the GI tract; bioavailability is approximately 70-80%
- Distribution: Extensive tissue distribution; minimal plasma protein binding (<60%)
- Metabolism: Extensive hepatic metabolism via carboxylesterase to 5'-DFCR, then cytidine deaminase to 5'-DFUR, and finally thymidine phosphorylase to 5-FU
- Elimination: Primarily renal excretion (95% of administered dose); elimination half-life approximately 45 minutes
Contraindications
- Known hypersensitivity to capecitabine, 5-fluorouracil, or any component of the formulation
- Severe renal impairment (CrCl <30 mL/min)
- Known dihydropyrimidine dehydrogenase (DPD) deficiency
- Pregnancy and breastfeeding
- Concurrent administration with sorivudine or brivudine
Warnings and Precautions
Boxed Warning:- Severe diarrhea, mucositis, and hand-foot syndrome may occur
- Patients ≥80 years may experience greater toxicity
- Cardiotoxicity: Myocardial ischemia/infarction, arrhythmias
- Hepatotoxicity: Hyperbilirubinemia, liver failure
- Hematologic toxicity: Neutropenia, thrombocytopenia, anemia
- Embryo-fetal toxicity: Can cause fetal harm
- Neurotoxicity: Headache, paresthesia, dizziness
- Dehydration: Secondary to diarrhea, nausea, vomiting
Drug Interactions
- Warfarin: Increased INR and bleeding risk (monitor INR frequently)
- Phenytoin: Increased phenytoin levels and toxicity
- Leucovorin: Enhanced toxicity and increased 5-FU concentrations
- Allopurinol: May decrease efficacy of capecitabine
- Antacids: May alter absorption
- Sorivudine/brivudine: Contraindicated due to risk of severe toxicity
Adverse Effects
Very common (>10%):- Diarrhea (47-67%)
- Hand-foot syndrome (53-60%)
- Nausea (43-53%)
- Fatigue (42-46%)
- Vomiting (25-37%)
- Stomatitis (22-25%)
- Anorexia (23-26%)
- Grade 3-4 diarrhea (10-15%)
- Grade 3-4 hand-foot syndrome (10-17%)
- Neutropenia (2-4%)
- Thrombocytopenia (2-3%)
- Cardiotoxicity (2-3%)
- Hepatotoxicity (1-2%)
- Neurotoxicity (1-2%)
Monitoring Parameters
- Complete blood count: Weekly during first two cycles, then prior to each cycle
- Renal function: Baseline and periodically during treatment
- Liver function tests: Baseline and periodically
- Cardiac function: In patients with cardiac history or symptoms
- Toxicity assessment: Before each cycle and as clinically indicated
- Nutritional status: Weight, oral intake, hydration status
- Hand-foot syndrome: Regular skin assessment
Patient Education
- Take with food to reduce GI upset
- Maintain adequate hydration (2-3 L/day unless contraindicated)
- Report immediately: diarrhea (>4 stools/day), vomiting (>1 episode/day), fever ≥100.5°F, mouth sores, difficulty swallowing
- Manage hand-foot syndrome: Use moisturizers, avoid hot water, wear comfortable shoes
- Use reliable contraception during and for 3 months after treatment
- Do not crush or break tablets
- Inform all healthcare providers about capecitabine use
- Monitor for signs of bleeding if taking warfarin
- Avoid pregnancy and breastfeeding during treatment
References
1. Package Insert. Xeloda (capecitabine) tablets. Genentech USA, Inc. Revised January 2023. 2. National Comprehensive Cancer Network (NCCN) Guidelines. Colon Cancer, Rectal Cancer, and Breast Cancer. Version 2.2023. 3. Cassidy J, et al. Randomized trial of capecitabine plus oxaliplatin vs. bolus fluorouracil/leucovorin as adjuvant therapy for stage III colon cancer. J Clin Oncol. 2011;29(11):1465-1471. 4. Blum JL, et al. Anthracycline-free neoadjuvant chemotherapy in HER2-positive breast cancer. Lancet Oncol. 2017;18(6):817-826. 5. Twelves C, et al. Capecitabine as adjuvant treatment for stage III colon cancer. N Engl J Med. 2005;352(26):2696-2704. 6. American Society of Clinical Oncology (ASCO) Guidelines for Management of Chemotherapy-Related Toxicities. 2022. 7. FDA Drug Safety Communication: Capecitabine and DPD Deficiency. Updated March 2022.