Abstract
Background
Pretherapeutic screening for dihydropyrimidine dehydrogenase (DPD) deficiency is recommended prior to the administration of fluoropyrimidine-based chemotherapy. However, the best strategy to identify DPD deficiency in End Stage Renal Disease (ESRD) patients is unknown.
Methods
We assessed the characteristics of both DPD phenotypes and DPYD genotypes in 20 dialyzed patients before and after dialysis session. The extent to which the concentrations of uracil [U] and dihydrouracil [UH2] were affected by dialysis was evaluated.
Results
Mean [U] was 14 ± 3.3 ng/ml before the dialysis session, and 7.9 ± 2.7 ng/ml after. Notably, mean [U] in 119 non-ESRD patients during the same timeline was 8.7 ± 3.9 ng/ml, which is similar to [U] values after dialysis session (p = 0.38). [U] values > 16 ng/ml were measured in 4 ESRD patients (20%), whereas the rate was 3.3% in the non-ESRD cohort. Whole gene sequencing did not reveal DPYD deleterious allelic variants in the 4 ESRD patients with [U] values > 16 ng/ml. The profile of [UH2] values during dialysis was similar to that of [U]: 385 ± 86 ng/ml before, and 185 ± 62 ng/ml after (mean reduction rate 42.5%). Thus, [UH2]:[U] ratio remained unaffected by dialysis, and was similar to the values in non-ESRD patients (22.4 ± 7.1).
Conclusion
Phenotyping based on measuring plasma [U] before a dialysis sessions in ESRD patients is associated with an unacceptable high rate of false positives. The optimal strategy for the identification of patients with DPD deficiency in this population would be the monitor the [UH2]:[U] ratio, which remains unaffected.
References
Butler AM, Olshan AF, Kshirsagar AV et al (2015) Cancer incidence among US medicare ESRD patients receiving hemodialysis, 1996–2009. Am J Kidney Dis 65(5):763–772. https://doi.org/10.1053/j.ajkd.2014.12.013
Janus N, Launay-Vacher V, Thyss A et al (2013) Management of anticancer treatment in patients under chronic dialysis: results of the multicentric CANDY (CANcer and DialYsis) study. Ann Oncol 24(2):501–507. https://doi.org/10.1093/annonc/mds344
Andre T, Colin P, Louvet C et al (2003) Semimonthly versus monthly regimen of fluorouracil and leucovorin administered for 24 or 36 weeks as adjuvant therapy in stage II and III colon cancer: results of a randomized trial. J Clin Oncol 21(15):2896–2903. https://doi.org/10.1200/JCO.2003.10.065
van Kuilenburg ABP (2004) Dihydropyrimidine dehydrogenase and the efficacy and toxicity of 5-fluorouracil. Eur J Cancer 40(7):939–950. https://doi.org/10.1016/j.ejca.2003.12.004
Meulendijks D, Henricks LM, Sonke GS et al (2015) 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 16(16):1639–1650. https://doi.org/10.1016/S1470-2045(15)00286-7
Amstutz U, Henricks LM, Offer SM et al (2018) Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for Dihydropyrimidine Dehydrogenase Genotype and Fluoropyrimidine Dosing: 2017 Update. Clin Pharmacol Ther 103(2):210–216. https://doi.org/10.1002/cpt.911
Meulendijks D, Henricks LM, Jacobs BAW et al (2017) Pretreatment serum uracil concentration as a predictor of severe and fatal fluoropyrimidine-associated toxicity. Br J Cancer 116(11):1415–1424. https://doi.org/10.1038/bjc.2017.94
Boisdron-Celle M, Remaud G, Traore S et al (2007) 5-Fluorouracil-related severe toxicity: a comparison of different methods for the pretherapeutic detection of dihydropyrimidine dehydrogenase deficiency. Cancer Lett 249(2):271–282. https://doi.org/10.1016/j.canlet.2006.09.006
Sistonen J, Büchel B, Froehlich TK et al (2014) Predicting 5-fluorouracil toxicity: DPD genotype and 5,6-dihydrouracil:uracil ratio. Pharmacogenomics 15(13):1653–1666. https://doi.org/10.2217/pgs.14.126
Launay M, Dahan L, Duval M et al (2016) Beating the odds: efficacy and toxicity of dihydropyrimidine dehydrogenase-driven adaptive dosing of 5-FU in patients with digestive cancer. Br J Clin Pharmacol 81(1):124–130. https://doi.org/10.1111/bcp.12790
Loriot M-A, Ciccolini J, Thomas F et al (2018) Dihydropyrimidine déhydrogenase (DPD) deficiency screening and securing of fluoropyrimidine-based chemotherapies: Update and recommendations of the French GPCO-Unicancer and RNPGx networks. Bull Cancer 105(4):397–407. https://doi.org/10.1016/j.bulcan.2018.02.001
Barnes KJ, Rowland A, Polasek TM, Miners JO (2014) Inhibition of human drug-metabolising cytochrome P450 and UDP-glucuronosyltransferase enzyme activities in vitro by uremic toxins. Eur J Clin Pharmacol 70(9):1097–1106. https://doi.org/10.1007/s00228-014-1709-7
Pedrazzoli P, Silvestris N, Santoro A et al (2017) Management of patients with end-stage renal disease undergoing chemotherapy: recommendations of the Associazione Italiana di Oncologia Medica (AIOM) and the Società Italiana di Nefrologia (SIN). ESMO Open 2(3):e000167. https://doi.org/10.1136/esmoopen-2017-000167
Janus N, Thariat J, Boulanger H, Deray G, Launay-Vacher V (2010) Proposal for dosage adjustment and timing of chemotherapy in hemodialyzed patients. Ann Oncol 21(7):1395–1403. https://doi.org/10.1093/annonc/mdp598
Funakoshi T, Horimatsu T, Nakamura M et al (2018) Chemotherapy in cancer patients undergoing haemodialysis: a nationwide study in Japan. ESMO Open 3(2):e000301. https://doi.org/10.1136/esmoopen-2017-000301
Ozaki Y, Imamaki H, Ikeda A et al (2020) Successful management of hyperammonemia with hemodialysis on day 2 during 5-fluorouracil treatment in a patient with gastric cancer: a case report with 5-fluorouracil metabolite analyses. Cancer Chemother Pharmacol 86(5):693–699. https://doi.org/10.1007/s00280-020-04158-1
Pallet N, Hamdane S, Garinet S et al (2020) A comprehensive population-based study comparing the phenotype and genotype in a pretherapeutic screen of dihydropyrimidine dehydrogenase deficiency. Br J Cancer 123(5):811–818. https://doi.org/10.1038/s41416-020-0962-z
Funding
None declared.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of interest
The authors have no conflict of interest to disclose.
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
About this article
Cite this article
Gaible, C., Narjoz, C., Loriot, MA. et al. Pretherapeutic screening for Dihydropyrimidine deshydrogenase deficiency in measuring uracilemia in dialysis patients leads to a high rate of falsely positive results. Cancer Chemother Pharmacol 88, 1049–1053 (2021). https://doi.org/10.1007/s00280-021-04354-7
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00280-021-04354-7