Implementing routine pre-emptive DPD testing with adaptive dosing to secure 5-FU administration: Performance in digestive and head-and-neck cancer patients

Introduction: Fluoropyrimidines are a mainstay in the treatment of numerous solid tumors. Most of the administered 5-FU dose will undergo extensive liver catabolism driven by dihydropyrimidine dehydrogenase (DPD). Drug dosing... [ view full abstract ]

Introduction: Fluoropyrimidines are a mainstay in the treatment of numerous solid tumors. Most of the administered 5-FU dose will undergo extensive liver catabolism driven by dihydropyrimidine dehydrogenase (DPD). Drug dosing is particularly high in some settings such as digestive or head-and-neck cancers. DPD-deficient patients are likely to experience life-threatening toxicities. Those are now a rising issue regarding pre-emptive strategies to be undertaken to improve safety. 5-FU usually claims 20-40% of severe toxicities and up to 1% of toxic deaths.

Material and Methods: Prospective DPD testing was performed in 59 digestive and 240 head-and-neck cancer patients treated at La Timone University Hospital of Marseille. DPD status determination was performed on a phenotyping basis (i.e., UH2/U ratio measurement in plasma). Doses were tailored prospectively according to the recorded DPD status using an empirical geometric scale with reduction from 20 to 100% of standard 5-FU dosing. Toxicities were graded following CTCAE 2.0., efficacy following Recist criteria.

Results: DPD deficiency (PM patients) was suspected in 25% of digestive patients and 6% of head-and-neck patients. 5-FU dosing was subsequently cut by an average 35% and 20% in PM patients (2390±1225 mg vs 3653±1371 mg, p=0.003* in digestive cancer and 2102±254 mg/m² vs 2577±353mg/m², p<0.0001* in head-and-neck cancer). Overall, 10-12% of severe toxicities were reported, a value markedly lower than usually described with 5-FU. No early severe toxicities was observed in PM patients. Delayed severe toxicities were not significantly different between PM and non-DPD deficient (EM) (7% vs 7% in digestive cancer; 11% vs 13% in head-and- cancer). Of note, despite the reduction in dosing, no significant difference was observed between PM and EM in terms of efficacy (p=0.0893 in digestive cancer; p=0.2774 in head-and-neck cancer).

Discussion/Conclusion: This work demonstrates that basic DPD-based adaptive dosing of 5-FU achieves better efficacy–toxicity balance in patients with solid tumors. Of note, reducing 5-FU dosing in PM patients does not hinder treatment efficacy, while helps to avoid severe toxicities. Developing a proper PK/PD/PGx model should help in the future to tailor more precisely 5-FU dosing, so as to achieve a better optimization of the efficacy–toxicity balance of 5-FU.