2. CAPÍTULO SEGUNDO: UNA EXPLICACION DEL PERFIL ENCONTRADO
2.4. EL PRIMER CONCURSO PARA JUECES
• 5-fluorouracil (5-FU) is a common, broad-spectrum chemotherapeutic agent.1,2 • Dihydropyrimidine dehydrogenase (DPD) is the enzyme involved in the first step
of the breakdown of 5-fluorouracil (5-FU), to 5-fluoro-5, 6-dihydro-fluorouracil (FUH2).3-5
• More than 80% of a dose of 5-fluorouracil is metabolized by DPD to FUH2. This metabolite has much lower toxicity than 5-FU.4
• A small percentage (≤10%) of 5-FU patients develop grade III-IV toxicity (neutropenia, nausea, vomiting, severe diarrhea, stomatitis, mucosistitis, and neuropathy)6,7, which can be life-threatening.
• One primary cause for toxicity is DPD deficiency.4,6,7
An estimated 0.1-3% of the population has DPD deficiency, caused by variants in the dihydropyrimidine dehydrogenase (DPYD) gene.5,8 In particular, about 1% of the population has the DPYD IVS14 +1G>A variant (also called DPYD*2A) that is found to be
associated with a seven-fold increased risk for grade III/IV 5-FU toxicity.9-11 • Individuals found to have a DPYD genetic variant require lowered drug doses or
alternative therapies.7,9
• Testing may also be used to investigate a possible cause of toxicity if a person experiences adverse effects while on a 5-FU based therapy.6
Test Information
• Testing for the DPYD variant IVS14+1G>A should be considered prior to initiating treatment with 5-fluorouracil and capecitabine for most patients. • Testing is widely available and highly accurate for this variant (>99% detection
rate). Testing does not look for any other variants in the DPYD gene.
Guidelines and Evidence
• The FDA has acknowledged DPD deficiency as a risk factor for 5-FU related toxicity on multiple drug inserts. However, testing is not explicitly recommended or required prior to treatment initiation.
o FDA updated the drug insert for Xeloda®12 in 2003, listing DPD deficiency as a contraindication.
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o Carac® Cream13 and Efudex® topical solutions and cream14 also carry a warning for patients with known or suspected DPD deficiency.
o DPYD variant testing is listed by the FDA as a valid biomarker in the context of approved drug labeling.15
• Though not specified in professional guidelines or otherwise, there is general consensus that given the large number of patients treated each year with 5-FU, and the human and economical cost of severe toxic side effects, pre-therapeutic detection of DPD deficiency should be considered.7,16,17
Criteria
DPD deficiency testing by DPYD IVS14+1G>A variant analysis is indicated in individuals considering or currently on therapy with any 5-FU containing drug:
• 5-fluorouracil (Fluorouracil®
, Adrucil®) • Capecitabine (Xeloda®
)
• Fluorouracil topical formulations (Carac®
, Efudex®, Fluoroplex®)
References
1. van Kuilenburg AB, Maring JG, Schalhorn A, et al. Pharmacokinetics of 5-fluorouracil in patients heterozygous for the IVS14+1G > A mutation in the dihydropyrimidine
dehydrogenase gene. Nucleosides Nucleotides Nucleic Acids. 2008;27(6):692-8. 2. Lim W-T, McLeod HL. Should screening for DPD deficiency be mandatory before 5-FU
exposure? [Editorial]Onkologie. 2004;27:531-3.
3. Capecitabine (Xeloda) Prescribing Information. Nutley, NJ: Roche Laboratories, November 2000.
4. Schwab M, Zanger UM, Marx C, et al. Role of genetic and non-genetic factors for fluorouracil treatment-related severe toxicity: A prospective clinical trial by German 5-FU Toxicity Study Group. J Clin Oncol. 2008;26:2131-8.
5. Yen JL, McLeod HL. Should DPD analysis be required prior to prescribing fluoropyrimidines? Eur J Cancer. 1007;43:1011-16.
6. Halmos B, Krishnamurthi SS. Enterotoxicity of chemotherapeutic agents. UpToDate, database online v. 17.3.
7. Lazar A, Jetter A. [Pharmacogenetics in oncology: 5-fluorouracil and the dihydropyrimidine dehydrogenase]. Dtsch Med Wochenschr. 2008;133(28-29):1501-4.
8. Genetics Home Reference. Genes: DPYD. Available at http://ghr.nlm.nih.gov/gene/DPYD. 9. Raida M, Schwabe W, Häusler P, et al. Prevalence of a common point mutation in the
dihydropyrimidine dehydrogenase (DPD) gene within the 5'-splice donor site of intron 14 in patients with severe 5-fluorouracil (5-FU)- related toxicity compared with controls. Clin
Cancer Res. 2001;7(9):2832-9.
10. van Kuilenburg AB, Muller EW, Haasjes J, et al. 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. 2001;7(5):1149-53.
11. Van Kuilenburg AB. Dihydropyrimidine dehydrogenase and the efficacy and toxicity of 5- fluorouracil. Eur J Cancer. May 2004;40(7):939-50.
12. Xeloda® (capecitabine tablet) package insert. Roche Pharmaceuticals. Available at: http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?id=17339.
13. CARAC® (fluorouracil cream) package insert. Dermik Laboratories. Available at: http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?id=8871.
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14. Efudex® (fluorouracil) Topical Solutions and Cream package insert. ICN Pharmaceuticals, Inc. Available at:
15. FDA Table of valid genomic biomarkers in the context of approved drug labels. Available at: http://www.fda.gov/ohrms/dockets/dockets/04p0557/04p-0557-cp00001-02- Tab-A-vol1.pdf.
http://www.fda.gov/Drugs/ScienceResearch/ResearchAreas/Pharmacogenetics/ucm083378.h tm.
16. Morel A, Boisdron-Celle M, Fey L, et al. Clinical relevance of different dihydropyrimidine dehydrogenase gene single nucleotide polymorphisms on 5-fluorouracil tolerance. Mol
Cancer Ther. 2006;5:2895-2904.
17. Van Kuilenburg AB, De Abreu RA, van Gennip AH. Pharmacogenetic and clinical aspects of dihydropyrimidine dehydrogenase deficiency. Ann Clin Biochem. 2003;40(pt1):41-5.
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