Manon Launay1,2,3, Joseph Ciccolini1,3, Claire Fournel4, Carmelo Blanquicett5, Charlotte Dupuis4, Nicolas Fakhry6, Florence Duffaud4, Sébastien Salas4, Bruno Lacarelle1,3. 1. Laboratoire de Pharmacocinétique Clinique, La Timone University Hospital of Marseille, APHM Marseille France. 2. Laboratoire de Pharmacologie, European Hospital Georges Pompidou, APHP Paris France. 3. SMARTc Unit, Inserm S_911 CRO2, Aix Marseille Univ, Marseille France. 4. Medical Oncology Unit, La Timone University hospital of Marseille, APHM Marseille France. 5. Emory University School of Medicine and Atlanta VA Medical Center, USA. 6. Head-and-Neck Surgery Unit, La Conception University Hospital of Marseille, Marseille France.
Abstract
BACKGROUND: Upfront screening for dihydropyrimidine dehydrogenase (DPD) deficiency in patients scheduled for 5-FU should help reduce the risk of toxicities by preventive adaptive dosing. Our group has developed a simple functional testing categorizing patients upon their DPD status, i.e. extensive metabolizer (EM) or poor metabolizer (PM) patients, using UH2/U ratio measurement in plasma as a surrogate for DPD activity. 5-FU dosing can then be tailored according to DPD deficiency status. OBJECTIVES: We present here an observational study of this strategy implemented in routine clinical practice when treating head-and-neck cancer patients. RESULTS: A total of 218 evaluable adult patients were treated with a 5-FU-regimen, with DPD-based adaptive dosing. Among them, 20 (9%) were identified as PM and received subsequently a 20-50% reduced dosing of 5-FU as compared with EM patients (2102 ±254 mg VS. 2577 ±353mg, p<0.001 ttest). Gender (Female) was associated with higher risk for being PM (p=0.01, Pearson's Chi squared test). Overall, early severe toxicities were seen only in 5% of patients, all being EM with standard dosing. Similarly, overall severe toxicities were observed in 12.8% of patients only, both figures being markedly lower than usually reported with standard 5-FU. Despite the average -20% reduction in 5-FU dosing between PM and EM patients, clinical efficacy was not statistically different between the two groups (p = 0.2774, chi-square test). CONCLUSION: This study shows that 5-FU-related toxicities can be greatly reduced in routine clinical practice by the upfront detection of DPD deficient patients with simple adaptive dosing strategy.
BACKGROUND: Upfront screening for dihydropyrimidine dehydrogenase (DPD) deficiency in patients scheduled for 5-FU should help reduce the risk of toxicities by preventive adaptive dosing. Our group has developed a simple functional testing categorizing patients upon their DPD status, i.e. extensive metabolizer (EM) or poor metabolizer (PM) patients, using UH2/U ratio measurement in plasma as a surrogate for DPD activity. 5-FU dosing can then be tailored according to DPD deficiency status. OBJECTIVES: We present here an observational study of this strategy implemented in routine clinical practice when treating head-and-neck cancer patients. RESULTS: A total of 218 evaluable adult patients were treated with a 5-FU-regimen, with DPD-based adaptive dosing. Among them, 20 (9%) were identified as PM and received subsequently a 20-50% reduced dosing of 5-FU as compared with EM patients (2102 ±254 mg VS. 2577 ±353mg, p<0.001 ttest). Gender (Female) was associated with higher risk for being PM (p=0.01, Pearson's Chi squared test). Overall, early severe toxicities were seen only in 5% of patients, all being EM with standard dosing. Similarly, overall severe toxicities were observed in 12.8% of patients only, both figures being markedly lower than usually reported with standard 5-FU. Despite the average -20% reduction in 5-FU dosing between PM and EM patients, clinical efficacy was not statistically different between the two groups (p = 0.2774, chi-square test). CONCLUSION: This study shows that 5-FU-related toxicities can be greatly reduced in routine clinical practice by the upfront detection of DPD deficient patients with simple adaptive dosing strategy.
Entities:
Keywords:
5-FluoroUracil; DPD deficiency; adaptive dosing; dihydropyrimidine dehydrogenase; efficacy; head and neck cancer; toxicity
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