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Comparison of a thymine challenge test and endogenous uracil–dihydrouracil levels for assessment of fluoropyrimidine toxicity risk

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Abstract

Purpose

Standard dosages of fluoropyrimidine chemotherapy result in severe toxicity in a substantial proportion of patients, however, routine pre-therapeutic toxicity prediction remains uncommon. A thymine (THY) challenge test can discriminate risk of severe gastrointestinal toxicity in patients receiving fluoropyrimidine monotherapy. We aimed to measure endogenous plasma uracil (U) and its ratio to dihydrouracil (DHU), and assess the performance of these parameters compared with the THY challenge test to evaluate risk of severe toxicity.

Methods

Plasma samples, previously collected from 37 patients receiving 5-fluorouracil (5-FU) or capecitabine monotherapy for a THY challenge test (ACTRN12615000586516; retrospectively registered), were assessed for endogenous plasma concentrations of U and DHU using a validated LC–MS/MS method. Renal function was estimated from blood creatinine, and patients with ≥ grade 3 toxicity (CTCAE v4.0) were classified as cases.

Results

There were no differences in median endogenous U plasma concentrations or U/DHU ratios between severe toxicity cases and non-cases. Significant differences between cases and non-cases were noted when these measures were normalised to the estimated renal function (CrCL), Unorm p = 0.0004; U/DHUnorm p = 0.0083. These two parameters had a sensitivity of 29%, compared with 57% for the THY challenge test in the same patients. Genotyping for clinically relevant DPYD variants was inferior to either of these pyrimidine phenotyping tests (sensitivity of 14%).

Conclusions

The endogenous uracil-based parameters, adjusted to CrCL, were more predictive of increased risk of severe fluoropyrimidine toxicity than DPYD genotyping. However, endogenous U measurement detected fewer cases of severe toxicity than the THY challenge test.

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References

  1. Ciccolini J, Mercier C, Dahan L, Evrard A, Boyer JC, Richard K, Dales JP, Durand A, Milano G, Seitz JF, Lacarelle B (2006) Toxic death-case after capecitabine + oxaliplatin (XELOX) administration: probable implication of dihydropyrimidine deshydrogenase deficiency. Cancer Chemother Pharmacol 58(2):272–275. https://doi.org/10.1007/s00280-005-0139-8

    Article  CAS  PubMed  Google Scholar 

  2. Maring JG, Van Kuilenburg ABP, Haasjes J, Piersma H, Groen HJM, Uges DRA, Van Gennip AH, De Vries EGE (2002) Reduced 5-FU clearance in a patient with low DPD activity due to heterozygosity for a mutant allele of the DPYD gene. Br J Cancer 86(7):1028–1033. https://doi.org/10.1038/sj.bjc.6600208

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. van Kuilenburg AB, Muller EW, Haasjes J, Meinsma R, Zoetekouw L, Waterham HR, Baas F, Richel DJ, van Gennip AH (2001) Lethal outcome of a patient with a complete dihydropyrimidine dehydrogenase (DPD) deficiency after administration of 5-fluorouracil: frequency of the common IVS14+1G>A mutation causing DPD deficiency. Clin Cancer Res 7(5):1149–1153

    PubMed  Google Scholar 

  4. Meulendijks D, Henricks LM, Sonke GS, Deenen MJ, Froehlich TK, Amstutz U, Largiadèr CR, Jennings BA, Marinaki AM, Sanderson JD (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

    Article  CAS  Google Scholar 

  5. Rosmarin D, Palles C, Church D, Domingo E, Jones A, Johnstone E, Wang H, Love S, Julier P, Scudder C, Nicholson G, Gonzalez-Neira A, Martin M, Sargent D, Green E, McLeod H, Zanger UM, Schwab M, Braun M, Seymour M, Thompson L, Lacas B, Boige V, Ribelles N, Afzal S, Enghusen H, Jensen SA, Etienne-Grimaldi MC, Milano G, Wadelius M, Glimelius B, Garmo H, Gusella M, Lecomte T, Laurent-Puig P, Martinez-Balibrea E, Sharma R, Garcia-Foncillas J, Kleibl Z, Morel A, Pignon JP, Midgley R, Kerr D, Tomlinson I (2014) Genetic markers of toxicity from capecitabine and other fluorouracil-based regimens: investigation in the QUASAR2 study, systematic review, and meta-analysis. J Clin Oncol 32(10):1031–1039. https://doi.org/10.1200/JCO.2013.51.1857

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Ciccolini J, Gross E, Dahan L, Lacarelle B, Mercier C (2010) Routine dihydropyrimidine dehydrogenase testing for anticipating 5-fluorouracil–related severe toxicities: hype or hope? Clin Colorec Cancer 9(4):224–228. https://doi.org/10.3816/ccc.2010.n.033

    Article  CAS  Google Scholar 

  7. Lunenburg C, Henricks LM, Guchelaar HJ, Swen JJ, Deenen MJ, Schellens JHM, Gelderblom H (2016) Prospective DPYD genotyping to reduce the risk of fluoropyrimidine-induced severe toxicity: ready for prime time. Eur J Cancer 54:40–48. https://doi.org/10.1016/j.ejca.2015.11.008

    Article  PubMed  Google Scholar 

  8. Diasio RB, Harris BE (1989) Clinical pharmacology of 5-fluorouracil. Clin Pharmacokinet 16(4):215–237. https://doi.org/10.2165/00003088-198916040-00002

    Article  CAS  PubMed  Google Scholar 

  9. Van Staveren MC, Jan Guchelaar H, Van Kuilenburg ABP, Gelderblom H, Maring JG (2013) Evaluation of predictive tests for screening for dihydropyrimidine dehydrogenase deficiency. Pharmacogenomics J 13(5):389–395. https://doi.org/10.1038/tpj.2013.25

    Article  CAS  PubMed  Google Scholar 

  10. Henricks LM, Jacobs BAW, Meulendijks D, Pluim D, Van Den Broek D, De Vries N, Rosing H, Beijnen JH, Huitema ADR, Guchelaar H-J, Cats A, Schellens JHM (2018) Food-effect study on uracil and dihydrouracil plasma levels as marker for dihydropyrimidine dehydrogenase activity in human volunteers. Br J Clin Pharmacol 84(12):2761–2769. https://doi.org/10.1111/bcp.13719

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Duley JA, Ni M, Shannon C, Norris RL, Sheffield L, Cowley D, Harris M, van Kuilenburg ABP, Helsby N, George R, Charles BG (2018) Preliminary evidence for enhanced thymine absorption: a putative new phenotype associated with fluoropyrimidine toxicity in cancer patients. Ther Drug Monit 40(4):495–502. https://doi.org/10.1097/ftd.0000000000000532

    Article  CAS  PubMed  Google Scholar 

  12. Helsby NA, Duley J, Burns KE, Bonnet C, Jeong SH, Brenman E, Barlow P, Sharples K, Porter D, Findlay M (2020) A case-control study to assess the ability of the thymine challenge test to predict patients with severe to life threatening fluoropyrimidine-induced gastrointestinal toxicity. Br J Clin Pharmacol 86(1):155–164. https://doi.org/10.1111/bcp.14153

    Article  CAS  PubMed  Google Scholar 

  13. Chavani O, Jensen BP, Strother RM, Florkowski CM, George PM (2017) Development, validation and application of a novel liquid chromatography tandem mass spectrometry assay measuring uracil, 5,6-dihydrouracil, 5-fluorouracil, 5,6-dihydro-5-fluorouracil, alpha-fluoro-beta-ureidopropionic acid and alpha-fluoro-beta-alanine in human plasma. J Pharm Biomed Anal 142:125–135. https://doi.org/10.1016/j.jpba.2017.04.055

    Article  CAS  PubMed  Google Scholar 

  14. Duley JA, Ni M, Shannon C, Norris RL, Sheffield L, Harris M, van Kuilenburg AB, Mead S, Cameron A, Helsby N, George R, Charles BG (2016) Towards a test to predict 5-fluorouracil toxicity: pharmacokinetic data for thymine and two sequential metabolites following oral thymine administration to healthy adult males. Eur J Pharm Sci 81:36–41. https://doi.org/10.1016/j.ejps.2015.10.001

    Article  CAS  PubMed  Google Scholar 

  15. Meulendijks D, van Hasselt JGC, Huitema ADR, van Tinteren H, Deenen MJ, Beijnen JH, Cats A, Schellens JHM (2016) 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 54:120–130. https://doi.org/10.1016/j.ejca.2015.10.013

    Article  CAS  PubMed  Google Scholar 

  16. Etienne-Grimaldi M-C, Boyer J-C, Beroud C, Mbatchi L, Van Kuilenburg A, Bobin-Dubigeon C, Thomas F, Chatelut E, Merlin J-L, Pinguet F, Ferrand C, Meijer J, Evrard A, Llorca L, Romieu G, Follana P, Bachelot T, Chaigneau L, Pivot X, Dieras V, Largillier R, Mousseau M, Goncalves A, Roché H, Bonneterre J, Servent V, Dohollou N, Château Y, Chamorey E, Desvignes J-P, Salgado D, Ferrero J-M, Milano G (2017) New advances in DPYD genotype and risk of severe toxicity under capecitabine. PLoS ONE 12(5):e0175998. https://doi.org/10.1371/journal.pone.0175998

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Tafzi N, Woillard J, Fleytoux A, Picard N, Marquet P (2020) Phenotyping of uracil and 5-fluorouracil metabolism using LC-MS/MS for prevention of toxicity and dose adjustment of fluoropyrimidines. Ther Drug Monit. https://doi.org/10.1097/ftd.0000000000000768

    Article  PubMed  Google Scholar 

  18. Sistonen J, Buchel B, Froehlich TK, Kummer D, Fontana S, Joerger M, van Kuilenburg AB, Largiader CR (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

    Article  CAS  PubMed  Google Scholar 

  19. Loriot M-A, Ciccolini J, Thomas F, Barin-Le-Guellec C, Royer B, Milano G, Picard N, Becquemont L, Verstuyft C, Narjoz C, Schmitt A, Bobin-Dubigeon C, Harle A, Paci A, Poinsignon V, Quaranta S, Evrard A, Hennart B, Broly F, Fonrose X, Lafay-Chebassier C, Wozny A-S, Masskouri F, Boyer J-C, Etienne-Grimaldi M-C (2018) Dépistage du déficit en dihydropyrimidine déshydrogénase (DPD) et sécurisation des chimiothérapies à base de fluoropyrimidines : mise au point et recommandations nationales du GPCO-Unicancer et du RNPGx. Bull Cancer 105(4):397–407. https://doi.org/10.1016/j.bulcan.2018.02.001

    Article  PubMed  Google Scholar 

  20. https://www.ema.europa.eu/en/medicines/human/referrals/fluorouracil-fluorouracil-related-substances-capecitabine-tegafur-flucytosine-containing-medicinal

  21. Ni M, Duley J, George R, Charles B, Shannon C, McGeary R, Norris R (2013) Simultaneous determination of thymine and its sequential catabolites dihydrothymine and β-ureidoisobutyrate in human plasma and urine using liquid chromatography–tandem mass spectrometry with pharmacokinetic application. J Pharm Biomed Anal 78–79:129–135. https://doi.org/10.1016/j.jpba.2013.01.038

    Article  CAS  PubMed  Google Scholar 

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Funding

This work was supported by the School of Medicine Foundation (University of Auckland), the Cancer Research Trust New Zealand (formerly Genesis Oncology Trust, GOT 1451-RPG), and the Breast Cancer Foundation New Zealand (F1603).

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Authors and Affiliations

  1. Department of Molecular Medicine and Pathology, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand

    Kathryn E. Burns, Soo Hee Jeong & Nuala A. Helsby

  2. Canterbury Health Laboratories, Christchurch, New Zealand

    Ottiniel Chavani

  3. School of Pharmacy, University of Queensland, Brisbane, Australia

    John A. Duley

  4. Cancer and Blood, Auckland City Hospital, Grafton, Auckland, New Zealand

    David Porter & Michael Findlay

  5. Cancer Trials New Zealand, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand

    Michael Findlay

  6. Department of Oncology, Canterbury District Health Board and Department of Medicine, University of Otago, Christchurch, New Zealand

    R. Matthew Strother

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  1. Kathryn E. Burns
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  2. Ottiniel Chavani
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  8. Nuala A. Helsby
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Correspondence to Nuala A. Helsby.

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All the procedures performed in studies involving human participants were in accordance with the ethical standards of the national research committee (New Zealand Northern A Health and Disability Ethics Committee: 14/NTA/186) and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.

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Burns, K.E., Chavani, O., Jeong, S.H. et al. Comparison of a thymine challenge test and endogenous uracil–dihydrouracil levels for assessment of fluoropyrimidine toxicity risk. Cancer Chemother Pharmacol 87, 711–716 (2021). https://doi.org/10.1007/s00280-021-04240-2

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