PRIMUM NON NOCERE: now and again an echo of DPD with capecitabine

Excerpt

In a recent clinical report, Meulendjiks et al. have underlined how plasma uracil level performed better than other parameters as predictive marker of severe toxicities upon fluoropyrimidines intake [1]. Of note, their data fully confirm our own findings regarding how monitoring uracilemia could help securing the administration of capecitabine in advanced breast cancer patients [2]. Interestingly, a same cut-off value in uracil plasma concentration (i.e., 16 ng/ml) has been identified by the two groups, after independent studies conducted by different investigators in different settings and using different methodologies. This uracil threshold value remains to be confirmed by other groups and constitutes a good starting point in terms of detection of patients at risk. It is clear that upfront detection of DPD deficiency still remains an ongoing challenge with lack of clear consensus regarding the best strategy to anticipate drug-related toxicities. Even if measurement of uracil in plasma has probably several caveats (e.g., factors introducing inter-study variability like bioanalytical issues, possible influence of food habits, and surrogate marker providing only indirect insight on actual DPD activity), as of today, it certainly offers the most simple, rapid, and widely applicable test meeting the requirements of routine screening with such widely prescribed anticancer drug. There is rising concern now among patient’s community, media, and medical groups regarding the life-threatening toxicities associated with the administration of chemotherapeutic agents. The canonical Primum Non Nocere medical concern is particularly true with fluoropyrimidine drugs (i.e., 5-FU and capecitabine) which claim elevated number of severe side effects, including toxic-deaths, every year. It is now widely admitted that most of these side effects are related to DPD deficiency and thus could be prevented, provided that a suitable tool for detection is available [3]. Once again, Uracilemia as demonstrated by the Meulendjiks study and by our own group does meet these requirements. In this context, capecitabine patients should be particularly under scrutiny. Indeed, DPD activity has a strong impact on the fate of intracellular 5-FU generated from capecitabine, both in tumor and in healthy cells [4]—subsequently, DPD deficiency will trigger severe toxicities because of intracellular accumulation of 5-FU in non-cancerous tissues. In addition, capecitabine being widely prescribed in breast cancer, it is well known now that women are more at risk with an increased incidence and subsequent life-threatening toxicities with fluoropyrimidine drugs as compared to men [5]. In this respect, upfront DPD testing should be a priority in this category of patients. Of note, Xeloda® leaflet currently indicates that capecitabine is formally contraindicated “in case of known DPD deficiency”, but to date, no health authorities have taken a step yet to oblige capecitabine prescribers to request DPD testing to actually know whether or not a patient is deficient or not prior to starting the administration. In this respect, this leaflet warning is not legally binding, and by consequence useless for the patient. In the light or the rising number of clinical reports demonstrating that fluoropyrimidine-related toxicities are not a fatality and should be successfully anticipated using suitable tools, we call here for a clear and univoqual position from regulatory agencies to secure the use of capecitabine through upfront and mandatory detection of DPD deficiency. …