Abstract 3892: Upfront DPD screening with adaptive dosing to secure 5-FU administration in head and neck cancer patients
Authors: Ciccolini Joseph , Launay Manon , Dupuis Charlotte , Duffaud Florence , Lacarelle Bruno , Salas Sébastien 
Published: August 2018

Abstract
Upfront screening for dihydropyrimidine dehydrogenase (DPD) deficiency in patients scheduled for 5-FU-based protocols should reduce the risk of treatment-related toxicities by preventive adaptive dosing. Our group has developed a simple, rapid and cheap functional testing that helps categorizing patients on their DPD status and detecting poor metabolizer (PM) patients, using UH2/U ratio measurement in plasma as a surrogate for DPD activity. 5-FU dosing can be next tailored using a geometric scale, according to the level of DPD deficiency. We report here the performances of this adaptive dosing strategy implemented in routine clinical practice in head and neck cancer patients. A total of 218 evaluable adult patients were scheduled for a 5-FU-regimen (mostly TPF protocol), with prospective search for DPD deficiency and, if required, tailored dosing. Overall, 20 patients (9%) were identified as PM and received subsequently an average 20-50% reduced dose of 5-FU as compared with extensive metabolizer (EM) patients (2102 ± 254 mg VS. 2577 ±353mg, p&lt;0.001 t-test). Gender (Female) was associated with higher risk for being PM (p=0.01, Pearson's Chi-square test), whereas age was not. Early severe toxicities were seen only in 5% of patients, a figure markedly lower than the one usually reported with 5-FU-based regimen in head-and-neck cancer patients. Similarly, all severe toxicities (i.e; including now the delayed or cumulative ones) were observed in 12.8% of patients only. No statistical difference was evidenced in overall toxicities between PM patients with adapted dosing (10%) and EM patients with standard dosing (13%, p=0.7014, Chi-square test), suggesting that being DPD-deficient is not anymore a risk for severe or life-threatening toxicities with 5-FU, provided that corrective action is undertaken. As for early toxicities, incidence of global toxicities was lower than the 30-40% usually described with 5-FU in this setting. Finally, despite an average -20% reduction in 5-FU dosing between PM and EM patients, clinical efficacy was not statistically different between the two groups (CR+PR: 56% VS. 40%, SD: 11% VS. 5%, PD: 22% VS. 43%, p = 0.2774, chi-square test), thus demonstrating how cutting 5-FU dose in PM patients does not hinder treatment efficacy. In conclusion, this study shows that 5-FU-related toxicities can be avoided at low cost by the upfront detection of DPD deficient patients with simple adaptive dosing strategies. Of note, reducing 5-FU dosing in PM patients did not affect negatively treatment efficacy, while limiting the incidence of treatment-related toxicities, thus improving the efficacy/toxicity balance of this drug.
Citation Format: Joseph Ciccolini, Manon Launay, Charlotte Dupuis, Florence Duffaud, Bruno Lacarelle, Sébastien Salas. Upfront DPD screening with adaptive dosing to secure 5-FU administration in head and neck cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3892.