What dose adjustments are recommended for fluoropyrimidines (e.g. capecitabine, 5-fluorouracil (5-FU)) in patients with hepatic dysfunction?

Fluoropyrimidine Dose Adjustments in Hepatic Dysfunction

For patients with mild to moderate hepatic dysfunction due to liver metastases, no dose adjustment of fluoropyrimidines (capecitabine, 5-FU) is necessary, but careful monitoring is recommended. Patients with severe hepatic dysfunction should avoid fluoropyrimidines if possible.

Assessment of Hepatic Function

• Hepatic dysfunction should be categorized based on:
  • Laboratory parameters (bilirubin, AST/ALT, alkaline phosphatase)
  • Etiology (metastatic disease vs. primary liver disease)
  • Severity (mild, moderate, severe)

Specific Dosing Recommendations

Capecitabine

• Mild to moderate hepatic dysfunction:

  • No starting dose adjustment required 1
  • Careful monitoring for toxicity is essential 1
  • Although plasma concentrations of capecitabine may be higher in patients with liver dysfunction, these effects are not clinically significant 2

• Severe hepatic dysfunction:

  • No formal recommendations exist as these patients have not been adequately studied 1
  • Consider alternative treatment options when possible

5-Fluorouracil (5-FU)

• Mild to moderate hepatic dysfunction:

  • Continuous-infusion 5-FU appears to be relatively well tolerated 3
  • No specific dose adjustments are recommended, but careful monitoring is essential

• Severe hepatic dysfunction:

  • Limited data available
  • 5-FU is primarily metabolized by dihydropyrimidine dehydrogenase (DPD) rather than hepatic metabolism 4
  • Consider alternative treatment options when possible

Special Considerations

DPYD Genetic Variants

• Patients with DPYD gene variants are at higher risk for fluoropyrimidine toxicity regardless of hepatic function 4
• For patients with identified DPYD variants:
  • Intermediate metabolizers (heterozygous for DPYD decreased/no function variants): Reduce starting dose by 25-50% depending on the specific variant 4
  • Poor metabolizers: Avoid fluoropyrimidines 4
  • Monitor closely and adjust doses in subsequent cycles based on toxicity 4

Cardiac Toxicity Risk

• Fluoropyrimidines can cause myocardial ischemia (incidence up to 10%) 4
• Mechanisms include coronary vasospasm and endothelial injury 4
• Monitor for chest pain and ECG changes, which typically occur at rest within days of administration 4

Monitoring Recommendations

• Assess liver function tests before each treatment cycle

• Monitor for signs of toxicity:

  • Hand-foot syndrome
  • Diarrhea
  • Mucositis
  • Myelosuppression
  • Cardiac symptoms (chest pain, ECG changes)

• For grade 2 toxicity:

  • Interrupt treatment until resolved to grade 0-1
  • Resume at 100% for first occurrence, 75% for second occurrence, 50% for third occurrence 1

• For grade 3 toxicity:

  • Interrupt treatment until resolved to grade 0-1
  • Resume at 75% for first occurrence, 50% for second occurrence 1
  • Discontinue after third occurrence 1

Management of Severe Toxicity

• Uridine triacetate is FDA approved for emergency treatment of early-onset, severe or life-threatening fluoropyrimidine toxicity 4
• Must be administered within 96 hours of the completion of fluoropyrimidine administration 4
• 96% of patients treated with uridine triacetate survived and exhibited rapid reversal of severe cardiac and neurologic toxicities 4

Clinical Pearls and Pitfalls

• Pitfall: Assuming hepatic dysfunction always requires dose reduction. For mild-moderate hepatic dysfunction due to liver metastases, fluoropyrimidines can often be given at standard doses.

• Pitfall: Overlooking DPYD variants. Consider testing for DPYD variants in patients with unexplained severe toxicity from standard doses.

• Pitfall: Delaying treatment of severe toxicity. Uridine triacetate must be administered within 96 hours of fluoropyrimidine administration to be effective.

• Pearl: Case reports suggest that capecitabine has been successfully used even in patients with severe hyperbilirubinemia (12 mg/dL) 5, though this should be approached with extreme caution and is not officially recommended.