Page 139 - Personalised medicine of fluoropyrimidines using DPYD pharmacogenetics Carin Lunenburg

Literature
1. 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.
2. 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.
3. 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.
4. SPC Efudix crème and Fluorouracil PCH.
DPD gene act. 1: 5-fluorouracil (5-FU)/capecitabine 4
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 50% 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.
NB1: The dose reduction described here is well substantiated for *1/*2A and 1236A/1236A. The dose reduction for patients with 2846T (2846T/2846T or 1236A/2846T) is based on, among other factors, the dose reductions identified for *1/2846T.
NB2: If a patient has two different genetic variations that result in a partially functional DPD enzyme (e.g. 2846T and 1236A), this recommendation applies if the variations are on a different allele. If both variations are on the same allele, the gene activity score is between 1 and 1.5, depending on whether and how the two gene variations influence each other and on other factors that influence the DPD activity. Whether a gene activity score of 1 or 1.5 needs to be assigned in the case of two different genetic variations can only be determined by measuring 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 1: see the general background information about DPD on the KNMP Knowledge Bank or on www.knmp.nl (search for DPD).
Clinical consequences:
7 of the 10 studies and two meta-analyses found an increased risk of grade ≥ 3 toxicity. Increased grade ≥ 3 toxicity: OR = 4.67-24.9; RR = 4.40-9.76. The highest ORs were found for haematological toxicity. There was a 74- 793% increase in the percentage of patients with grade ≥ 3 toxicity. Out of 48 patients with genotype *1/*2A in published cohort studies, 73% developed grade ≥ 3 toxicity. The allele frequency of *2A in a group with grade III/ IV toxicity was 1548-2879% higher. Toxicity generally occurred in the first cycle. Six patients died due to toxicity, including two that had used capecitabine.
No association with grade ≥ 3 toxicity was found for breast cancer patients receiving adjuvant/neoadjuvant therapy with 5-fluorouracil, epirubicin and cyclophosphamide in a phase II study that showed 94% grade ≥ 3 toxicity and in a small study of 21 patients with grade ≥ 3 toxicity. 5-Fluorouracil toxicity is not common in breast cancer patients treated with this combination therapy.
A large study found that the *2A allele only increased the risk of grade ≥ 3 toxicity in men (OR = 41.8) and not in women. Other studies did not find any differences between men and women.
When the dose was guided by toxicity, the average dose in the sixth cycle was 56% of the standard dose in 7 *1/*2A. Dose reduction down to 40% or 50% of the standard dose was not adequate in two *1/*2A patients in another study. There was no difference in grade ≥ 3 toxicity between 18 *1/*2A at ≤ 50% of the standard
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