Page 141 - Personalised medicine of fluoropyrimidines using DPYD pharmacogenetics Carin Lunenburg

21. Van Kuilenburg AB et al. High prevalence of the IVS14 + 1G>A mutation in the dihydropyrimidine dehydrogenase gene of patients with severe 5-fluorouracil-associated toxicity. Pharmacogenetics 2002;12:555-8.
22. Raida M 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;7:2832-9.
23. van Kuilenburg AB et al. Clinical implications of dihydropyrimidine dehydrogenase (DPD) deficiency in patients with severe 5-fluorouracil-associated toxicity: identification of new mutations in the DPD gene. Clin Cancer Res 2000;6:4705-12.
24. SPCs Efudix crème and Fluorouracil PCH. 4
DPD gene act. 1.5: 5-fluorouracil (5-FU)/capecitabine
Pharmacist text / Hospital text / Prescriber text
Genetic variation increases the risk of severe, potentially fatal toxicity. A reduced conversion of 5-fluorouracil/ capecitabine to inactive metabolites means that the normal dose is an overdose.
Recommendation:
•- Start with 75% of the standard dose or choose an alternative.
Adjustment of the initial dose should be guided by toxicity and effectiveness. Tegafur is not an alternative, as this is also metabolised by DPD.
Background information
Mechanism:
5-Fluorouracil and its prodrug capecitabine are mainly converted by dihydropyrimidine dehydrogenase (DPD) to inactive metabolites. Genetic variations result in reduced DPD activity and thereby to reduced conversion of 5-fluorouracil to inactive metabolites. As a result, the intracellular concentration of the active metabolite of 5-fluorouracil can increase, resulting in severe, potentially fatal toxicity.
For more information about the phenotype gene activity score 1.5: see the general background information about DPD on the KNMP Knowledge Bank or on www.knmp.nl (search for DPD).
Clinical consequences:
4 of the 5 studies and one meta-analysis found an increased risk of grade ≥ 3 toxicity. Increased grade ≥ 3 toxicity: OR = 4.42-9.35. The percentage of patients with grade ≥ 3 toxicity was 109-1175% higher. One patient (*1/496G) died due to toxicity.
No association with grade ≥ 3 toxicity was found in one small study of 21 patients with grade ≥ 3 toxicity.
When the dose for 8 *1/2846T was guided by toxicity, the average dose in the sixth cycle was 76% of the standard dose. 5 patients with genotype *1/1236A did not develop grade ≥ 3 toxicity at 75 % of the standard dose. The two patients for who the dose was then increased tolerated the standard dose. One patient with genotype *1/1236A, who was started at the standard dose, developed grade 3-4 toxicity in the first cycle.
Kinetic consequences:
40-58% decrease in clearance.
Literature
1. Rosmarin D et al. Genetic markers of toxicity from capecitabine and other fluorouracil-based regimens:
investigation in the QUASAR2 study, systematic review, and meta-analysis. J Clin Oncol 2014; 32:1031-9.
2. Terrazzino S et al. DPYD IVS14+1 G>A and 2846A>T genotyping for the prediction of severe
fluoropyrimidine-related toxicity: a meta-analysis. Pharmacogenomics2013; 14:1255-72.
3. Deenen MJ et al. Relationship between single nucleotide polymorphisms and haplotypes in DPYD and
toxicity and efficacy of capecitabine in advanced colorectal cancer. Clin Cancer Res 2011; 17:3455-68.
4. Kristensen MH et al. Variants in the dihydropyrimidine dehydrogenase, methylenetetrahydrofolate
reductase and thymidylate synthase genes predict early toxicity of 5-fluorouracil in colorectal cancer
patients. J Int Med Res 2010; 38:870-83.
5. Gross E et al. Strong association of a common dihydropyrimidine dehydrogenase gene polymorphism with
fluoropyrimidine-related toxicity in cancer patients. PLoS ONE 2008;3:e4003.
6. Capitain O et al. The influence of fluorouracil outcome parameters on tolerance and efficacy in patients
with advanced colorectal cancer. Pharmacogenomics J 2008;8:256-67.
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