The value of screening for DPD activity in all patients treated with fluoropyrimidines.

Fluoropyrimidines (mainly 5-fluorouracil and capecitabine) can cause serious adverse events related to a deficiency of dihydropyrimidine dehydrogenase (DPD), the enzyme that degrades 5-FU to an inactive metabolite. This study presents the case of a patient being managed for a relapse of breast cancer, for whom treatment with capecitabine (pro-drug of 5-FU) at standard dose (2000mg/m²/d) was prescribed. As she had tolerated well the FEC-100 protocol 5-FU (500mg/m² infusion over 15 min) that she had received at the time of her initial management, she was considered not to be DPD deficient. However, from the first cycle of treatment, the patient experienced severe adverse events, which were resolved by discontinuation of the treatment. Phenotypic and genotypic analysis of DPD revealed that the patient had a partial deficiency due to a mutation in the DPYD gene and was unable to clear the molecule properly, putting her at increased risk of toxicity. The treatment with a 50% dose reduction could be resumed with good tolerance. The difference in tolerance between the two chemotherapy protocols (FEC-100 and continuous capecitabine) is explained by the much higher dose-intensity of 5-FU in continuous capecitabine treatment, which leads to saturation of the DPD.

This case highlights the importance of assessing DPD activity by simple phenotyping in all patients who are to receive fluoropyrimidines (5-fluorouracil or capecitabine), including those who have previously received and tolerated a lower dose-intensity fluoropyrimidine. It also indicates that the magnitude of the recommended dose concessions in deficient patients should take into account the dose-intensity of the protocol: it should be greater for high fluoropyrimidine intensity protocols such as continuous capecitabine or protocols used in digestive cancers (e.g. FOLFIRI or FOLFOX) than for protocols using lower doses of 5-FU administered as a short infusion.

Collaborations and acknowledgements

• Medical Oncology Department of the Claudius Regaud Institute
• Pharmacology Laboratory of the Claudius Regaud Institute
• Team 14, DIAD Dose-Individualization of Anti-cancer Drugs, CRCT