Cancer chemotherapy and pharmacology · 2025
A thymine-challenge test to prospectively evaluate dihydropyrimidine dehydrogenase activity for risk of severe 5-fluorouracil-induced gastrointestinal toxicity.
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Helsby Nuala, Sharples Katrina, Kim Yu Jin, Porter David, Burns Kathryn, Jeong Soo Hee, Benge Sarah, Deva Sanjeev, Lawrence Ben, Jackson Christopher, North Richard, Strother R Matthew, Duley John, Findlay Michael
Аннотация
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.
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.