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DPD Ultra-Rapid Metabolizer Status and Efficacy of 5-Fluorouracil Treatment: A Real-World Study
Govind Kallee1,2, Gérard Milano3, Florence Duffaud4
1PRISM, Biogenopôle La Timone University Hospital of Marseille, Marseille, France.
Background:
Anticancer drug 5FU is extensively metabolized by dihydropyrimidine dehydrogenase (DPD), an enzyme with high interindividual variability. Poor metabolizer (PM, i.e., DPD deficient) patients are at risk of life-threatening toxicities. Whether ultra-rapid metabolizer (UM) status could conversely compromise 5FU efficacy remains to be investigated.
Methods:
In this real-world study, 352 adult patients treated with a 5FU-containing regimen were screened. Patients were classified as normal (extensive metabolizer, EM), PM, or UM on DPD function based upon baseline plasma uracil monitoring. The impact of DPD status on efficacy and safety endpoints was investigated.
Results:
Patients were categorized on DPD as UM (11.9%), EM (75.9%), and PM (12.2%). The response rate was 54.5%, with median PFS and OS of 13.9 and 19 months, respectively. PM patients were treated with an average 13% lower 5FU starting dose. There was no statistical difference in efficacy between UM and other patients. Severe toxicities were observed in less than 5% of patients, an incidence significantly lower than commonly reported with 5FU-containing regimen and was comparable between UM, EM, and PM patients. Our observations suggest that UM status is not associated with the lack of efficacy of 5FU. In addition, upfront DPD testing with adaptive dosing helps to reduce the incidence of severe toxicities, as PM patients on reduced doses did not have more severe toxicities than other patients treated with standard doses, while exhibiting similar efficacy in terms of response rate and survival.
Conclusion:
When upfront DPD screening with adaptive dosing is performed, no difference is observed between UM, EM, and PM patients in terms of efficacy and safety.
Trial Registration:
#PADSA3GKW7.
Insights
Upfront dihydropyrimidine dehydrogenase (DPD) screening and adaptive dosing of 5-fluorouracil (5FU) ensure comparable efficacy and safety across all patient metabolizer types, including ultra-rapid metabolizers (UM). This approach mitigates toxicity risks for poor metabolizers (PM) without compromising treatment outcomes.
Area of Science:
- Pharmacogenomics
- Oncology
- Drug Metabolism
Background:
- 5-fluorouracil (5FU) is a cornerstone anticancer drug with significant inter-individual variability in metabolism due to dihydropyrimidine dehydrogenase (DPD).
- DPD deficiency (poor metabolizers, PM) is linked to severe 5FU toxicities, while the impact of ultra-rapid metabolizer (UM) status on efficacy is less understood.
Purpose of the Study:
- To investigate the impact of DPD metabolizer status (PM, normal/extensive metabolizer (EM), and UM) on the efficacy and safety of 5FU-containing regimens.
- To evaluate the effectiveness of upfront DPD screening with adaptive dosing in managing 5FU therapy.
Main Methods:
- A real-world study screened 352 adult patients receiving 5FU-based chemotherapy.
- DPD function was assessed via plasma uracil monitoring, classifying patients into EM, PM, or UM groups.
- Efficacy (response rate, progression-free survival, overall survival) and safety endpoints were analyzed based on DPD status.
Main Results:
- The study population comprised 11.9% UM, 75.9% EM, and 12.2% PM patients.
- No significant differences in efficacy (response rate, PFS, OS) were observed between UM and other patient groups.
- Severe toxicities were infrequent (<5%) and comparable across all DPD metabolizer groups, with PM patients receiving reduced doses showing similar safety and efficacy outcomes.
Conclusions:
- Upfront DPD screening and adaptive dosing enable safe and effective 5FU treatment across all metabolizer phenotypes.
- UM status does not appear to compromise 5FU efficacy.
- Adaptive dosing strategies effectively reduce severe toxicities in PM patients without sacrificing therapeutic benefit.
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