What is the recommended capecitabine (Xeloda) dosing schedule for an adult with metastatic colorectal cancer, including dose adjustments for patients over 65 years old, renal impairment, toxicity monitoring, and alternative options if the drug is not tolerated?

Capecitabine Dosing for Metastatic Colorectal Cancer

Standard Dosing Schedule

The recommended dose of capecitabine for metastatic colorectal cancer is 1250 mg/m² orally twice daily (morning and evening) for 14 days followed by a 7-day rest period, given as 3-week cycles. 1

• Tablets should be swallowed with water within 30 minutes after a meal 1
• The total daily dose is 2500 mg/m² divided into two equal doses approximately 12 hours apart 2
• This intermittent schedule (2 weeks on/1 week off) was established as the optimal regimen based on phase II dose-finding studies 3

Dose Adjustments for Elderly Patients (>65 Years)

No specific starting dose reduction is mandated for elderly patients based solely on age, but close monitoring is essential as North American patients may experience greater toxicity than European patients. 1

• Physicians should exercise caution when monitoring elderly patients on capecitabine 1
• Most safety data were developed in Europe using 1000 mg/m² twice daily; North American patients may require lower doses due to increased fluoropyrimidine sensitivity 4
• Consider starting at 850-1000 mg/m² twice daily in elderly patients, particularly those >75 years 4

Renal Impairment Adjustments

For moderate renal impairment (creatinine clearance 30-50 mL/min), reduce the starting dose to 75% (950 mg/m² twice daily instead of 1250 mg/m²). 1

• Normal or mild renal impairment (CrCl 51-80 mL/min): No dose adjustment required 1
• Moderate renal impairment (CrCl 30-50 mL/min): Start at 950 mg/m² twice daily 1
• Severe renal impairment (CrCl <30 mL/min): Capecitabine is contraindicated 2, 5
• Calculate creatinine clearance using Cockroft-Gault equation: CrCl (male) = (140 - age) × weight(kg) / [72 × serum creatinine(mg/dL)]; for females multiply by 0.85 1

Patients with moderate renal impairment experience higher rates of grade 3-4 toxicities, making dose reduction critical for safety. 5

Toxicity Monitoring and Dose Modifications

Key Toxicities to Monitor

The dose-limiting toxicities requiring vigilant monitoring include:

• Hand-foot syndrome (palmar-plantar erythrodysesthesia): Most common dose-limiting toxicity 2, 5
• Diarrhea: Occurs in approximately 10% at grade 3-4 severity 6, 5
• Hyperbilirubinemia 2
• Myelosuppression (less common than with IV 5-FU/LV) 5

Dose Modification Algorithm for Monotherapy

Grade 1 toxicity: Maintain current dose 1

Grade 2 toxicity:

• First occurrence: Interrupt treatment until resolved to grade 0-1, then resume at 100% dose 1
• Second occurrence: Interrupt until resolved to grade 0-1, then resume at 75% dose 1
• Third occurrence: Interrupt until resolved to grade 0-1, then resume at 50% dose 1
• Fourth occurrence: Discontinue permanently 1

Grade 3 toxicity:

• First occurrence: Interrupt until resolved to grade 0-1, then resume at 75% dose 1
• Second occurrence: Interrupt until resolved to grade 0-1, then resume at 50% dose 1
• Third occurrence: Discontinue permanently 1

Grade 4 toxicity:

• First occurrence: Discontinue permanently, OR if physician deems continuation in patient's best interest, interrupt until resolved to grade 0-1 and resume at 50% dose 1

Critical Safety Considerations

Capecitabine must be discontinued immediately if a patient develops sepsis or severe infection, and should not be restarted until the infection is completely resolved and the patient is clinically stable. 7

• Severe enterocolitis with diarrhea grade 2-4 accompanied by neutropenia, fever/sepsis, or systemic symptoms carries a 1-5% mortality rate in clinical trials, primarily from sepsis or multiorgan failure 7
• Any patient presenting with grade 2-4 diarrhea plus neutropenia, fever/sepsis, reduced oral intake >12 hours, nausea/vomiting, dizziness, dark urine, reduced performance status, weakness, confusion, or rapid/irregular heartbeats requires immediate treatment interruption 7

Once a dose has been reduced for toxicity, it should not be increased at a later time. 1

• Doses missed during a treatment cycle are not replaced 1
• The dose modification scheme effectively reduces recurrence of key toxicities without compromising efficacy—66% of patients in phase III trials did not require dose modification 5

Alternative Options if Capecitabine Not Tolerated

First-Line Alternatives for Metastatic Colorectal Cancer

If capecitabine monotherapy is not tolerated, switch to intravenous 5-FU/leucovorin regimens, which have a different toxicity profile with less hand-foot syndrome but more stomatitis and neutropenia. 4, 5

Simplified biweekly infusional 5-FU/LV (sLV5FU2):

• Leucovorin 400 mg/m² IV over 2 hours on day 1, followed by 5-FU bolus 400 mg/m² then 1200 mg/m²/day × 2 days (total 2400 mg/m² over 46-48 hours) continuous infusion 4
• Repeat every 2 weeks 4

Roswell Park regimen:

• Leucovorin 500 mg/m² IV over 2 hours, followed by 5-FU 500 mg/m² IV bolus 1 hour after start of leucovorin 4
• Given on days 1,8,15,22,29, and 36, repeated every 8 weeks 4

Combination Therapy Alternatives

For patients requiring more aggressive disease control, combination chemotherapy with FOLFOX or FOLFIRI provides higher response rates and longer progression-free survival than fluoropyrimidine monotherapy. 4

FOLFOX regimen:

• Oxaliplatin 85 mg/m² IV over 2 hours on day 1 4
• Leucovorin 400 mg/m² IV over 2 hours on day 1 4
• 5-FU 400 mg/m² IV bolus on day 1, then 1200 mg/m²/day × 2 days continuous infusion 4
• Repeat every 2 weeks 4

FOLFIRI regimen:

• Irinotecan 180 mg/m² IV over 30-90 minutes on day 1 4
• Leucovorin 400 mg/m² IV on day 1 4
• 5-FU 400 mg/m² IV bolus on day 1, then 1200 mg/m²/day × 2 days continuous infusion 4
• Repeat every 2 weeks 4

When to Consider Sequential vs. Combination Therapy

Sequential therapy starting with fluoropyrimidine monotherapy remains valid for selected frail patients, as four randomized studies showed combination chemotherapy was not superior to sequential treatment for overall survival. 4

• Approximately 15% of patients with metastatic colorectal cancer are treated initially with fluoropyrimidine alone 4
• Combination chemotherapy is preferred when: objective tumor response is the primary goal (e.g., for potential surgical resection of metastases or symptomatic metastases requiring rapid control) 4
• Sequential monotherapy is appropriate for: frail patients, those with good performance status but no immediate need for tumor shrinkage, or when quality of life preservation is prioritized 4

Important Tolerability Comparisons

Capecitabine demonstrates superior tolerability compared to IV 5-FU/leucovorin (Mayo Clinic regimen), with significantly lower rates of:

• Diarrhea 5
• Stomatitis 5
• Nausea 5
• Alopecia 5
• Grade 3-4 neutropenia 5
• Neutropenic fever/sepsis 5
• Hospitalizations 5

However, capecitabine causes more hand-foot syndrome than IV 5-FU/LV. 2, 5

Drug Interactions Requiring Dose Adjustments

Capecitabine increases serum phenytoin levels and INR in patients receiving concomitant phenytoin or warfarin—doses of these medications may need reduction. 2

• Monitor phenytoin levels closely and reduce phenytoin dose as needed 2
• Monitor INR frequently (at least weekly initially) in patients on warfarin and adjust warfarin dose accordingly 2