Plasma Clearance of 5-fluorouracil is More Influenced by Variations in Glomerular Filtration Rate Than by Uracil Concentration

Overview

Journal Cancer Chemother Pharmacol

Specialty Oncology

Date 2024 Dec 20

PMID 39702680

Authors

Alice Matheux

Laurine Collas

Maelle Grisard

Lea Goulaieff

Francois Ghiringhelli

Leila Bengrine-Lefevre

Julie Vincent

Francoise Goirand

Bernard Royer

Antonin Schmitt

Affiliations

Soon will be listed here.

Abstract

Objectives: 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.

Patients And Methods: 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.

Results: 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.

Conclusion: Our study reinforces the still poorly accepted idea of the value of focusing on eGFR in 5-FU dose adjustment.

References

Longley D, Harkin D, Johnston P . 5-fluorouracil: mechanisms of action and clinical strategies. Nat Rev Cancer. 2003; 3(5):330-8. DOI: 10.1038/nrc1074. View

Milano G . Clinical pharmacokinetics of 5-fluorouracil with consideration of chronopharmacokinetics. Chronobiol Int. 2002; 19(1):177-89. DOI: 10.1081/cbi-120002597. View

Mercier C, Ciccolini J . Profiling dihydropyrimidine dehydrogenase deficiency in patients with cancer undergoing 5-fluorouracil/capecitabine therapy. Clin Colorectal Cancer. 2007; 6(4):288-96. DOI: 10.3816/CCC.2006.n.047. View

van Kuilenburg A, van Lenthe H, Wanders R, van Gennip A . Subcellular localization of dihydropyrimidine dehydrogenase. Biol Chem. 1997; 378(9):1047-53. DOI: 10.1515/bchm.1997.378.9.1047. View

Meulendijks D, Henricks L, Sonke G, Deenen M, Froehlich T, Amstutz U . Clinical relevance of DPYD variants c.1679T>G, c.1236G>A/HapB3, and c.1601G>A as predictors of severe fluoropyrimidine-associated toxicity: a systematic review and meta-analysis of individual patient data. Lancet Oncol. 2015; 16(16):1639-50. DOI: 10.1016/S1470-2045(15)00286-7. View

Cheung W, Renfro L, Kerr D, De Gramont A, Saltz L, Grothey A . Determinants of Early Mortality Among 37,568 Patients With Colon Cancer Who Participated in 25 Clinical Trials From the Adjuvant Colon Cancer Endpoints Database. J Clin Oncol. 2016; 34(11):1182-9. PMC: 4933130. DOI: 10.1200/JCO.2015.65.1158. View

Laures N, Konecki C, Brugel M, Giffard A, Abdelli N, Botsen D . Impact of Guidelines Regarding Dihydropyrimidine Dehydrogenase (DPD) Deficiency Screening Using Uracil-Based Phenotyping on the Reduction of Severe Side Effect of 5-Fluorouracil-Based Chemotherapy: A Propension Score Analysis. Pharmaceutics. 2022; 14(10). PMC: 9610761. DOI: 10.3390/pharmaceutics14102119. View

de With M, Knikman J, de Man F, Lunenburg C, Henricks L, van Kuilenburg A . Dihydropyrimidine Dehydrogenase Phenotyping Using Pretreatment Uracil: A Note of Caution Based on a Large Prospective Clinical Study. Clin Pharmacol Ther. 2022; 112(1):62-68. PMC: 9322339. DOI: 10.1002/cpt.2608. View

10.

Maillard M, Launay M, Royer B, Guitton J, Gautier-Veyret E, Broutin S . Quantitative impact of pre-analytical process on plasma uracil when testing for dihydropyrimidine dehydrogenase deficiency. Br J Clin Pharmacol. 2022; 89(2):762-772. PMC: 10092089. DOI: 10.1111/bcp.15536. View

11.

Gaible C, Narjoz C, Loriot M, Roueff S, Pallet N . Pretherapeutic screening for Dihydropyrimidine deshydrogenase deficiency in measuring uracilemia in dialysis patients leads to a high rate of falsely positive results. Cancer Chemother Pharmacol. 2021; 88(6):1049-1053. DOI: 10.1007/s00280-021-04354-7. View

12.

Launay M, Guitton J, Balluet R, Moreau A, Phelip J, Tholance Y . Clinical considerations for DPD deficiency testing in advanced cancer patients: tumor lysis syndrome should be considered as a major interference. Ann Oncol. 2022; 33(8):850-852. DOI: 10.1016/j.annonc.2022.04.073. View

13.

Meulendijks D, van Hasselt J, Huitema A, van Tinteren H, Deenen M, Beijnen J . Renal function, body surface area, and age are associated with risk of early-onset fluoropyrimidine-associated toxicity in patients treated with capecitabine-based anticancer regimens in daily clinical care. Eur J Cancer. 2016; 54:120-130. DOI: 10.1016/j.ejca.2015.10.013. View

14.

Callon S, Brugel M, Botsen D, Royer B, Slimano F, Feliu C . Renal impairment and abnormal liver function tests in pre-therapeutic phenotype-based DPD deficiency screening using uracilemia: a comprehensive population-based study in 1138 patients. Ther Adv Med Oncol. 2023; 15:17588359221148536. PMC: 9837271. DOI: 10.1177/17588359221148536. View

15.

Narjoz C, Nadour Z, Zaanan A, Taieb J, Loriot M, Pallet N . Screening for dihydropyrimidine dehydrogenase deficiency by measuring uracilemia in chronic kidney disease patients is associated with a high rate of false positives. Clin Chim Acta. 2023; 543:117326. DOI: 10.1016/j.cca.2023.117326. View

16.

Morawska K, Goirand F, Marceau L, Devaux M, Cueff A, Bertaut A . 5-FU therapeutic drug monitoring as a valuable option to reduce toxicity in patients with gastrointestinal cancer. Oncotarget. 2018; 9(14):11559-11571. PMC: 5837758. DOI: 10.18632/oncotarget.24338. View

17.

Loriot M, Ciccolini J, Thomas F, Barin-Le-Guellec C, Royer B, Milano G . [Dihydropyrimidine déhydrogenase (DPD) deficiency screening and securing of fluoropyrimidine-based chemotherapies: Update and recommendations of the French GPCO-Unicancer and RNPGx networks]. Bull Cancer. 2018; 105(4):397-407. DOI: 10.1016/j.bulcan.2018.02.001. View

18.

Tron C, Lemaitre F, Boisteau E, Sourd S, Lievre A . When helping the minority of patients may hurt the majority: The case for DPD phenotyping and 5-fluorouracil therapeutic drug monitoring. Dig Liver Dis. 2020; 53(2):258-260. DOI: 10.1016/j.dld.2020.11.004. View

19.

Cassidy J, Twelves C, Van Cutsem E, Hoff P, Bajetta E, Boyer M . First-line oral capecitabine therapy in metastatic colorectal cancer: a favorable safety profile compared with intravenous 5-fluorouracil/leucovorin. Ann Oncol. 2002; 13(4):566-75. DOI: 10.1093/annonc/mdf089. View

20.

Poole C, Gardiner J, Twelves C, Johnston P, Harper P, Cassidy J . Effect of renal impairment on the pharmacokinetics and tolerability of capecitabine (Xeloda) in cancer patients. Cancer Chemother Pharmacol. 2002; 49(3):225-34. DOI: 10.1007/s00280-001-0408-0. View

21.

Fleming G, Schilsky R, Schumm L, Meyerson A, Hong A, Vogelzang N . Phase I and pharmacokinetic study of 24-hour infusion 5-fluorouracil and leucovorin in patients with organ dysfunction. Ann Oncol. 2003; 14(7):1142-7. DOI: 10.1093/annonc/mdg302. View