Page 138 - Personalised medicine of fluoropyrimidines using DPYD pharmacogenetics Carin Lunenburg

Chapter 4
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. 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.
3. Boisdron-Celle M et al. 5-Fluorouracil-related severe toxicity: a comparison of different methods for the pretherapeutic detection of dihydropyrimidine dehydrogenase deficiency. Cancer Lett 2007;249:271-82.
4. Morel A et al. Clinical relevance of different dihydropyrimidine dehydrogenase gene single nucleotide polymorphisms on 5-fluorouracil tolerance. Mol Cancer Ther 2006;5:2895-904.
5. 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.
6. 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.
7. 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.
8. Johnson MR et al. Life-threatening toxicity in a dihydropyrimidine dehydrogenase-deficient patient after treatment with topical 5-fluorouracil. Clin Cancer Res 1999;5:2006-11.
9. SPC Carac cream (VS) en Efudix crème.
DPD gene act. 0.5: 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 25% 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.
NOTE: This recommendation only applies if the two genetic variations are on a different allele. If both variations are on the same allele, this patient has gene activity score 1 and the recommendation
for that gene activity score should be followed. These two situations can only be distinguished by determining the enzyme activity (phenotyping).
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 0.5: see the general background information about DPD on the KNMP Knowledge Bank or on www.knmp.nl (search for DPD).
Clinical consequences:
Clinical consequences are only known for 3 patients (all genotype *2A/2846T). The first patient developed grade III/IV toxicity and died due to toxicity. The second patient developed grade V toxicity and tolerated only one cycle of FOLFOX plus cetuximab. The third patient received half the standard dose, but despite this the fluoropyrimidine therapy was stopped after the first cycle due to side effects (≤ grade 3).
Kinetic consequences:
Clearance decreased by almost 100% in one patient with gene activity score 0.5 (*2A/2846T). Extrapolation of the dose reductions identified for *1/*2A, *1/2846T and *1/1236A would, however, lead to a dose reduction by 75%.
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