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Background <p>Fluoropyrimidines (e.g., 5-fluorouracil, capecitabine) are antineoplastic agents commonly used in the setting of gastrointestinal cancer. Dihydropyridine dehydrogenase (DPD), encoded by the <i>DPYD</i> gene, is the enzyme responsible for up to 85% of 5-FU catabolism into inactive metabolites. Decreased or no function genetic variations in <i>DPYD</i> are rare but increase risk of potentially fatal adverse effects (e.g., myelosuppression) due to decreased metabolism of 5-FU. The extent of which DPD enzyme activity is impaired varies among individual decreased function DPYD variants.</p> Case presentation <p>A 75-year-old female was diagnosed with stage III squamous cell carcinoma of the anal canal. She was scheduled to receive therapy consisting of mitomycin C (8&#xa0;mg/m2) administered over 30&#xa0;min and continuous infusion 5-FU (4000&#xa0;mg/m2) over 96&#xa0;h for 2 cycles with concurrent radiotherapy. Prior to treatment, the patient underwent DPYD genotyping which revealed she was a heterozygous carrier of the decreased function allele, c.2846&#xa0;A &gt; T. In accordance with Clinical Pharmacogenomics Implementation Consortium (CPIC) guideline recommendations, the dose of 5-FU for cycle 1 was reduced by 50%. Despite the dose reduction, she still experienced mucositis (G3), neutropenia (G3), diarrhea (G2), nausea and vomiting (G2), and dyspnea (G2).</p> Conclusion <p>This case report supports the clinical utility of pre-emptive DPYD genotyping to guide initial 5-FU dosing in intermediate metabolizers, and it suggests that all patients still require close monitoring and some (particularly carriers of c.2846&#xa0;A &gt; T) may require an initial dose reduction greater than the recommended 50% to prevent severe toxicity.</p>

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Severe toxicity following genotype-guided reduced 5-FU dose in a heterozygous DPYD c.2846A>T carrier with stage III anal carcinoma: A case report

  • 期刊论文

  • 发表日期：

    2025年11月21日

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  • Madeline L. Norris,
  • David L. DeRemer,
  • Julio D. Duarte,
  • George P. Kim,
  • Thomas J. George

摘要

Background

Fluoropyrimidines (e.g., 5-fluorouracil, capecitabine) are antineoplastic agents commonly used in the setting of gastrointestinal cancer. Dihydropyridine dehydrogenase (DPD), encoded by the DPYD gene, is the enzyme responsible for up to 85% of 5-FU catabolism into inactive metabolites. Decreased or no function genetic variations in DPYD are rare but increase risk of potentially fatal adverse effects (e.g., myelosuppression) due to decreased metabolism of 5-FU. The extent of which DPD enzyme activity is impaired varies among individual decreased function DPYD variants.

Case presentation

A 75-year-old female was diagnosed with stage III squamous cell carcinoma of the anal canal. She was scheduled to receive therapy consisting of mitomycin C (8 mg/m2) administered over 30 min and continuous infusion 5-FU (4000 mg/m2) over 96 h for 2 cycles with concurrent radiotherapy. Prior to treatment, the patient underwent DPYD genotyping which revealed she was a heterozygous carrier of the decreased function allele, c.2846 A > T. In accordance with Clinical Pharmacogenomics Implementation Consortium (CPIC) guideline recommendations, the dose of 5-FU for cycle 1 was reduced by 50%. Despite the dose reduction, she still experienced mucositis (G3), neutropenia (G3), diarrhea (G2), nausea and vomiting (G2), and dyspnea (G2).

Conclusion

This case report supports the clinical utility of pre-emptive DPYD genotyping to guide initial 5-FU dosing in intermediate metabolizers, and it suggests that all patients still require close monitoring and some (particularly carriers of c.2846 A > T) may require an initial dose reduction greater than the recommended 50% to prevent severe toxicity.