Capecitabine: Comprehensive Clinical Guide

Indications

Capecitabine is FDA-approved for metastatic colorectal cancer as first-line therapy when single-agent fluoropyrimidine is preferred, and for metastatic breast cancer either as monotherapy after anthracycline/paclitaxel resistance or combined with docetaxel after anthracycline failure. 1

Colorectal Cancer Applications

Adjuvant therapy for stage III colon cancer: Capecitabine 1,250 mg/m² twice daily days 1-14 every 3 weeks for 24 weeks is equivalent to bolus 5-FU/leucovorin 2
Stage III disease: Capecitabine appears equivalent to bolus 5-FU/leucovorin based on randomized trials 2
Metastatic disease: Capecitabine 850-1,250 mg/m² twice daily days 1-14 every 3 weeks as monotherapy or in combination regimens 2
High-risk stage II disease: May be considered, though benefit is limited (1-2% absolute improvement) 2

Breast Cancer Applications

Metastatic breast cancer resistant to anthracyclines and taxanes 1, 3
Combination with docetaxel after anthracycline failure 3

Standard Dosing Schedules

Monotherapy Dosing

The FDA-approved dose is 1,250 mg/m² orally twice daily for 14 days, repeated every 3 weeks. 1, 4

Adjuvant colon cancer: 1,250 mg/m² twice daily days 1-14 every 3 weeks for 8 cycles (24 weeks total) 2
Metastatic colorectal cancer: 850-1,250 mg/m² twice daily days 1-14 every 3 weeks 2

Combination Regimens

CapeOX (XELOX) - Preferred Adjuvant Regimen

Oxaliplatin: 130 mg/m² IV over 2 hours, day 1 2
Capecitabine: 1,000 mg/m² twice daily days 1-14 2
Cycle: Repeat every 3 weeks for 8 cycles 2

Critical consideration: Most safety data developed in Europe used 1,000 mg/m² twice daily; North American patients may experience greater toxicity and require lower starting doses 2, 5

Duration Modifications

Standard duration: 6 months of adjuvant therapy 2
Shortened duration: High-risk stage II and low-risk stage III patients (T1-3N1) may consider 3-month CapeOX based on IDEA study 2
Oxaliplatin discontinuation: Stop after 3-4 months to prevent cumulative neurotoxicity while maintaining capecitabine until progression 6

Administration Instructions

Timing and Food Effects

Capecitabine must be taken within 30 minutes after a meal, as food significantly affects absorption. 1

Food reduces Cmax by 60% and AUC by 35% 1
Peak capecitabine levels occur at 1.5 hours, with 5-FU peaks at 2 hours 1
Doses should be separated by approximately 12 hours 4

Practical Administration

Swallow tablets whole with water 1
Take morning and evening doses within 30 minutes after meals 1
Do not crush or split tablets 1

Common Toxicities

Dose-Limiting Toxicities

Hand-foot syndrome is the most characteristic adverse effect, occurring in up to 73% of patients (11% grade 3). 5

Frequency of Major Toxicities

Hand-foot syndrome: 31-73% (grade 3: 11%) 5, 6
Diarrhea: 10-28% of patients 6
Peripheral sensory neuropathy: 85% (when combined with oxaliplatin) 6
Hyperbilirubinemia: Common dose-limiting toxicity 4
Lymphopenia and anemia: >25% incidence 3

Comparative Toxicity Profile

Capecitabine causes significantly less stomatitis, alopecia, and neutropenia than IV 5-FU/leucovorin, but more hand-foot syndrome. 7, 8

Lower with capecitabine: Stomatitis (P<0.00001), neutropenia (P<0.00001), neutropenic fever/sepsis, alopecia 7, 8
Higher with capecitabine: Hand-foot syndrome (P<0.00001), uncomplicated hyperbilirubinemia (P<0.0001) 8

Special Population Risks

Patients over 65 years have 34% risk of grade 3 or higher toxicity, including treatment-related deaths. 5

Monitoring Parameters

First Cycle Monitoring Protocol

Close monitoring during the first treatment cycle is essential, with particular attention to hand-foot syndrome, diarrhea, and coagulation parameters in anticoagulated patients. 5

Monitor for toxicity development throughout first cycle 5
Assess for hand-foot syndrome, diarrhea, and hematologic toxicity 5
For grade 1 toxicity: Continue treatment with close monitoring 5

Ongoing Monitoring

Imaging: CT scan with contrast or MRI to monitor treatment progress 5, 6
Do NOT use PET/CT for monitoring therapy progress 5, 6
Coagulation monitoring: Closely monitor INR in patients on warfarin (see Drug Interactions) 1
Renal function: Monitor creatinine clearance, especially in elderly patients 1

Laboratory Monitoring

Complete blood count for neutropenia and thrombocytopenia 5
Liver function tests for hyperbilirubinemia 4
Renal function (creatinine clearance) 1

Contraindications

Absolute Contraindications

Capecitabine is contraindicated in patients with creatinine clearance <30 mL/min. 1, 4

Severe renal impairment: CrCl <30 mL/min 1, 4
Known DPD deficiency: 3-5% of population at risk for life-threatening toxicity 5
Hypersensitivity to capecitabine or 5-FU 1

Relative Contraindications and Cautions

Moderate hepatic dysfunction: Use with caution; AUC and Cmax increased by 60% 1
Severe hepatic dysfunction: Effect unknown, use with extreme caution 1
Concurrent warfarin therapy: Requires intensive INR monitoring (see Drug Interactions) 1

Dose Adjustment Guidelines

Renal Impairment Adjustments

Patients with moderate renal impairment (CrCl 30-50 mL/min) require 75% dose reduction. 1, 4

CrCl 30-50 mL/min: Reduce starting dose to 75% (approximately 950 mg/m² twice daily) 1, 4
CrCl <30 mL/min: Contraindicated 1, 4
Rationale: Moderate impairment increases FBAL exposure by 85% and 5'-DFUR by 42% 1

Toxicity-Based Dose Modifications

Hand-Foot Syndrome

Grade 1: Continue at same dose with close monitoring 5
Grade 2 (first occurrence): Interrupt until resolved to grade 0-1, then resume at same dose 1
Grade 2 (second occurrence): Interrupt until resolved, then resume at 75% of original dose 1
Grade 3: Interrupt until resolved to grade 0-1, then resume at 50% of original dose 1

Diarrhea

Grade 2: Interrupt until resolved to grade 0-1, then resume at same dose 1
Grade 3-4: Interrupt until resolved to grade 0-1, then resume at 75% of original dose 1

Hematologic Toxicity

Grade 3-4 neutropenia or thrombocytopenia: Interrupt until resolved, then resume at 75% of original dose 1

Age-Related Adjustments

Consider starting dose of 1,000 mg/m² twice daily in elderly patients due to 20% increase in FBAL exposure with age. 5, 1

Geographic Considerations

North American patients may require lower starting doses (1,000 mg/m² vs 1,250 mg/m²) due to greater toxicity compared to European patients. 2, 5, 6

Critical Drug Interactions

Warfarin Interaction - BOXED WARNING

Capecitabine increases S-warfarin AUC by 57% and INR by 2.8-fold, with maximum INR increased by 91%. 1

Monitor INR frequently and adjust warfarin dose accordingly 1
Baseline corrected AUC of INR increased 2.8-fold in clinical studies 1
Risk of bleeding complications significantly elevated 1

Phenytoin Interaction

Capecitabine increases serum phenytoin levels. 4

Monitor phenytoin levels closely 4
Adjust phenytoin dose as needed 4

No Significant Interactions

Docetaxel: No effect on pharmacokinetics of either agent 1

Mechanism of Action

Enzymatic Conversion Pathway

Capecitabine is a prodrug converted to 5-FU preferentially in tumor tissue through three-step enzymatic cascade. 1

Hepatic conversion: Carboxylesterase converts capecitabine to 5'-deoxy-5-fluorocytidine (5'-DFCR) 1
Tissue conversion: Cytidine deaminase converts 5'-DFCR to 5'-deoxy-5-fluorouridine (5'-DFUR) 1
Tumor activation: Thymidine phosphorylase (expressed 2.9-fold higher in colorectal tumors) converts 5'-DFUR to active 5-FU 1

Cytotoxic Mechanisms

Thymidylate synthase inhibition: FdUMP blocks DNA synthesis 1
RNA incorporation: FUTP mistakenly incorporated into RNA, interfering with processing and protein synthesis 1

Pharmacokinetics

Absorption and Distribution

Bioavailability: Approximately 100% 4
Tmax: 1.5 hours for capecitabine, 2 hours for 5-FU 1
Protein binding: <60%, primarily albumin (35%) 1
Food effect: Reduces Cmax by 60% and AUC by 35% 1

Metabolism and Elimination

Primary route: Renal excretion (95.5% of dose) 1
Major urinary metabolite: FBAL (57% of administered dose) 1
Unchanged drug in urine: 3% 1
Half-life: Approximately 45 minutes for both capecitabine and 5-FU 1

Special Population Pharmacokinetics

Japanese vs Caucasian patients: 36% lower Cmax and 24% lower AUC for capecitabine in Japanese patients 1
Age effect: 20% increase in age results in 15% increase in FBAL AUC 1
Hepatic impairment: 60% increase in capecitabine AUC and Cmax with mild-moderate dysfunction 1

Common Pitfalls and Caveats

Critical Errors to Avoid

Do NOT assume European dosing is appropriate for North American patients - toxicity profiles differ significantly 2, 5, 6
Do NOT use PET/CT for monitoring therapy progress - use CT with contrast or MRI instead 5, 6
Do NOT continue oxaliplatin beyond 3-4 months if significant neurotoxicity develops 6, 9
Do NOT ignore renal function - failure to dose-reduce in moderate impairment (CrCl 30-50 mL/min) leads to severe toxicity 1, 7
Do NOT overlook warfarin interactions - can cause life-threatening bleeding 1

High-Risk Scenarios

DPD deficiency (3-5% of population): May experience life-threatening toxicity including severe diarrhea 5
Elderly patients (≥65 years): 34% risk of grade 3+ toxicity, consider lower starting dose 5
Moderate renal impairment: Higher toxicity incidence, mandatory 75% dose reduction 1, 7

Dose Modification Principles

The majority of patients (66%) do not require dose modification, and efficacy is not compromised in those requiring dose reduction. 7

Dose-modification scheme reduces toxicity recurrence without compromising efficacy 7
58% of 5-FU/leucovorin patients also required dose reduction 7

What are the indications, dosing schedule, administration instructions, common toxicities, monitoring parameters, contraindications, and dose‑adjustment guidelines for capecitabine?

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