What are the recommended dose reductions for capecitabine (capecitabine) based on DYPD (dihydropyrimidine dehydrogenase) testing results?

DPYD Testing Levels and Capecitabine Dose Reductions

For patients with heterozygous DPYD mutations (intermediate metabolizers), start capecitabine at 50% dose reduction for the first cycle; for homozygous DPYD mutations (poor metabolizers), avoid fluoropyrimidines completely. 1

DPYD Metabolizer Categories and Dosing

Poor Metabolizers (Homozygous DPYD Variants)

• Avoid fluoropyrimidines entirely - these patients have complete or near-complete DPD deficiency and face life-threatening toxicity risk 1, 2
• Treatment-related mortality reaches 2.3% in patients with known DPYD variants versus only 0.1% in those without variants, representing a 25.6-fold increased risk 1, 2
• Consider alternative non-fluoropyrimidine chemotherapy regimens 2

Intermediate Metabolizers (Heterozygous DPYD Variants)

• Reduce starting dose by 50% for the first cycle 1, 2
• The Clinical Pharmacogenetics Implementation Consortium (CPIC) recommends 25-50% dose reduction depending on the specific variant 1
• Monitor closely during the first two cycles for signs of toxicity including bone marrow suppression, mucositis, palmar-plantar syndrome, and diarrhea 1, 2
• After demonstrating tolerability in cycle 1, cautious dose escalation may be considered based on toxicity profile 2

Normal Metabolizers (Wild-Type DPYD)

• Standard dosing: 1,000-1,250 mg/m² orally twice daily for 14 days, repeated every 3 weeks 3
• North American patients may require the lower end of this range (850-1,000 mg/m²) due to higher toxicity rates compared to European patients 3

Key DPYD Variants to Test

The four most clinically significant variants that should be tested include 1:

• DPYD*2A (c.1905+1G>A): Most well-established pathogenic variant, found in 39% of DPD-deficient patients in one study, with 13% showing homozygosity 4
• DPYD*13 (c.1679T>G): Associated with reduced DPD activity 1
• D949V (c.2846A>T): Can cause profound DPD deficiency even with heterozygous status 5
• HapB3 (c.1236G>A): May affect progression-free survival more significantly with dose reduction 2

Evidence Supporting Dose Reduction Efficacy

Prospective data demonstrates that dose reduction in DPYD variant carriers significantly reduces severe toxicity without compromising survival in most cases:

• In a study of 22 patients with DPYD*2A variant receiving 50% dose-reduced fluoropyrimidine, grade ≥3 toxicity occurred in only 28% versus 73% in historic controls (P <0.001) 1, 2
• Zero treatment-related deaths occurred in the dose-reduced group compared to 10% mortality in historical controls 1, 2
• For most DPYD variant carriers, progression-free survival and overall survival were not significantly affected by lower doses, though efficacy concerns may be greater in adjuvant versus metastatic settings 1, 2

Clinical Implementation Algorithm

1. Consider upfront DPYD genotyping for at minimum the 4 most common variants, particularly in patients where severe toxicity would be catastrophic or in adjuvant therapy where efficacy is paramount 1
2. If homozygous variant detected: Avoid fluoropyrimidines; select alternative chemotherapy regimen 1, 2
3. If heterozygous variant detected: Start at 50% dose reduction, monitor intensively during first two cycles 1, 2
4. If wild-type: Use standard dosing with close monitoring, recognizing that 23% of wild-type patients still experience grade 3 toxicities 6

Critical Pitfalls to Avoid

• Do not assume prior 5-FU tolerance predicts capecitabine safety: A fatal case occurred in a patient who tolerated low-dose 5-FU (500 mg/m²) in FEC100 protocol but died from capecitabine toxicity due to higher cumulative dosing, despite having the same underlying DPYD deficiency 5
• Do not ignore any grade 3 toxicity as a warning signal: Even non-life-threatening toxicities with low-dose protocols should raise suspicion for underlying DPD deficiency 5
• Do not assume all DPYD variants behave identically: The c.1236G>A variant showed shorter progression-free survival with reduced doses (HR 1.43; 95% CI 1.10-1.86; P=0.007), suggesting variant-specific considerations 2
• Recognize that DPYD testing does not eliminate all risk: In one implementation study, 23% of wild-type patients still experienced grade 3 toxicities, though none required hospitalization 6

Guideline Positions on Universal Testing

While the NCCN does not currently mandate universal pretreatment DPYD genotyping, they acknowledge that patients with DPYD variants should receive dose reductions or alternative non-fluoropyrimidine regimens 1. The CPIC provides standardized dosing recommendations based on genotype 1. The European Society for Medical Oncology recommends germline variant testing for DPD deficiency before capecitabine treatment is initiated 2.