Matheux Alice, Collas Laurine, Grisard Maelle, Goulaieff Léa, Ghiringhelli François, Bengrine-Lefevre Leïla, Vincent Julie, Goirand Francoise, Royer Bernard, Schmitt Antonin
Pharmacology and Toxicology Department, Pharmacology and Toxicology Laboratory, Dijon University Hospital, 2, Rue Angélique Ducoudray, 21000, Dijon, France.
Pharmacy Department, Centre Georges-François Leclerc, Dijon, France.
Cancer Chemother Pharmacol. 2024 Dec 19;95(1):9. doi: 10.1007/s00280-024-04732-x.
The use of plasma uracil measurements to detect dihydropyrimidine dehydrogenase (DPD) deficiency is one of the methods for preventing toxicities associated with fluoropyrimidines, including 5-Fluorouracil (5-FU). Unfortunately, this measurement is subject to variations, that may lead to unnecessary dosage reductions and therefore to a reduced efficacy of treatment. Recently, new factors such as hepatic and renal impairment have been proposed as also influencing uracil concentration. The aim of our study was therefore to study the influence of renal or hepatic function on 5-FU clearance.
This was a retrospective study, using patients treated with 5-FU between September 1, 2018 to December 1, 2022 in a French Clinical Cancer Center. Patients were included after treatment with 5FU and therapeutic monitoring of 5FU concentrations after each course of chemotherapy. For each patient, DPD phenotyping by uracil concentration measurement was determined before the first course of 5FU. Blood samples were then taken the day after the start of the 5-FU infusion, between 8 and 10 am, for the first three cycles of 5-FU. With the exception of uracil concentration, which was determined only once, the various data were recorded for each course of 5FU chemotherapy performed. Patients with incomplete information (missing one of the above parameters) were excluded from the database.
We included 227 patients, corresponding to 227 uracil concentrations and 575 5-FU concentrations. In an original development, our results show for the first time that 5-FU clearance was proportionally correlated with eGFR (calculated according to CKD-EPI formula). Although we failed to demonstrate this hypothesis significantly, we observed that 5-FU clearance may be more dependent on eGFR than on uracil concentration for low uracil concentrations values.
Our study reinforces the still poorly accepted idea of the value of focusing on eGFR in 5-FU dose adjustment.
利用血浆尿嘧啶测量来检测二氢嘧啶脱氢酶（DPD）缺乏是预防与氟嘧啶（包括5-氟尿嘧啶（5-FU））相关毒性的方法之一。不幸的是，这种测量存在差异，可能导致不必要的剂量减少，从而降低治疗效果。最近，诸如肝肾功能损害等新因素也被认为会影响尿嘧啶浓度。因此，我们研究的目的是探讨肾功能或肝功能对5-FU清除率的影响。
这是一项回顾性研究，研究对象为2018年9月1日至2022年12月1日在法国一家临床癌症中心接受5-FU治疗的患者。患者在接受5FU治疗并在每个化疗疗程后对5FU浓度进行治疗监测后被纳入研究。对于每位患者，在第一个5FU疗程之前通过尿嘧啶浓度测量确定DPD表型。然后在5-FU输注开始后的第二天上午8点至10点采集血样，用于5-FU的前三个周期。除仅测定一次的尿嘧啶浓度外，记录每个5FU化疗疗程的各种数据。信息不完整（缺少上述参数之一）的患者被排除在数据库之外。
我们纳入了227例患者，对应227个尿嘧啶浓度和575个5-FU浓度。在一项原创性研究中，我们的结果首次表明5-FU清除率与eGFR（根据CKD-EPI公式计算）成比例相关。尽管我们未能显著证明这一假设，但我们观察到，对于低尿嘧啶浓度值，5-FU清除率可能更依赖于eGFR而非尿嘧啶浓度。
我们的研究强化了在5-FU剂量调整中关注eGFR这一价值仍未被广泛接受的观点。
