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Purpose <p>Inherited dihydropyrimidine dehydrogenase (DPD) deficiency is a risk factor for severe 5-fluorouracil toxicity. We report a phenotyping approach (thymine challenge test) to prospectively determine DPD activity and the association with severe adverse events.</p> Methods <p>The primary aim of this prospective study was to determine whether a thymine challenge test could prospectively identify patients at risk of severe toxicity from treatment with 5-fluorouracil/capecitabine in combination chemotherapy schedules or monotherapy. The focus was prediction of those at risk of ≥ grade 3 gastrointestinal toxicity. DPD activity was determined from the thymine/dihydrothymine (THY/DHT) ratio measured in a urine sample after a thymine test dose (250&#xa0;mg, oral).</p> Results <p>Of the 166 patients, 11.7% had severe diarrhoea/mucositis. The THY/DHT ratio was not significantly different in these individuals compared to those with minimal toxicity. However, <i>post hoc</i> analysis found decreased DPD activity in those who had non-gastrointestinal toxicity, most notably grade ≥ 2 Hand-Foot syndrome (<i>p</i> = 0.001).</p> Conclusion <p>The data do not support our primary hypothesis that this phenotyping approach would discriminate those at risk of severe/life-threatening gastrointestinal toxicity. The clinical factors which influence gastrointestinal toxicity, particularly in patients receiving CAPOX require further investigation.</p> Clinical trial registration <p>ACTRN 12,617,001,109,392 registered 28/07/2017.</p>

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A thymine-challenge test to prospectively evaluate dihydropyrimidine dehydrogenase activity for risk of severe 5-fluorouracil-induced gastrointestinal toxicity

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年8月18日

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  • Nuala Helsby,
  • Katrina Sharples,
  • Yu Jin Kim,
  • David Porter,
  • Kathryn Burns,
  • Soo Hee Jeong,
  • Sarah Benge,
  • Sanjeev Deva,
  • Ben Lawrence,
  • Christopher Jackson,
  • Richard North,
  • R. Matthew Strother,
  • John Duley,
  • Michael Findlay

摘要

Purpose

Inherited dihydropyrimidine dehydrogenase (DPD) deficiency is a risk factor for severe 5-fluorouracil toxicity. We report a phenotyping approach (thymine challenge test) to prospectively determine DPD activity and the association with severe adverse events.

Methods

The primary aim of this prospective study was to determine whether a thymine challenge test could prospectively identify patients at risk of severe toxicity from treatment with 5-fluorouracil/capecitabine in combination chemotherapy schedules or monotherapy. The focus was prediction of those at risk of ≥ grade 3 gastrointestinal toxicity. DPD activity was determined from the thymine/dihydrothymine (THY/DHT) ratio measured in a urine sample after a thymine test dose (250 mg, oral).

Results

Of the 166 patients, 11.7% had severe diarrhoea/mucositis. The THY/DHT ratio was not significantly different in these individuals compared to those with minimal toxicity. However, post hoc analysis found decreased DPD activity in those who had non-gastrointestinal toxicity, most notably grade ≥ 2 Hand-Foot syndrome (p = 0.001).

Conclusion

The data do not support our primary hypothesis that this phenotyping approach would discriminate those at risk of severe/life-threatening gastrointestinal toxicity. The clinical factors which influence gastrointestinal toxicity, particularly in patients receiving CAPOX require further investigation.

Clinical trial registration

ACTRN 12,617,001,109,392 registered 28/07/2017.