Page 80 - Personalised medicine of fluoropyrimidines using DPYD pharmacogenetics Carin Lunenburg

Chapter 4
c.2846A global toxicity
>T and
*13
c.1236A global toxicity
>G gastrointestinal toxicity
haematological toxicity hospitalisation
increase (p=0.094) 3.0 (1.05- 8.77) (S)
NS
NS
NS
NS, trend for an increase (p=0.069)
ref. 4 – FU/CAP, mono/comb Kodali S et al. Capecitabine- induced severe toxicity secondary to DPD deficiency and successful treatment with low dose 5-fluorouracil. J Gastrointest Cancer 2017;48:66- 69. PubMed PMID: 26744322.
ref. 5 – CAP, mono/comb Meulendijks D et al. Patients homozygous for DPYD
Level of evidence score: 2
gene act. 1: CTC- AE 4
For the 3 gene variants combined, sensitivity was 6%, specificity 95%, positive predictive value 13% and negative predictive value 88% for prediction of global toxicity grade ≥ 3 in the first cycle.
NOTE: No association was found for the gene variants *4 (84 carriers), except for a trend for gastrointestinal toxicity. However, most studies including a meta- analysis (Meulendijks 2015) do not show an association of this gene variant with toxicity. In addition, results regarding the effect on DPD activity are inconsistent.
A 51-year old male developed severe colitis with mucous stools (grade 4 toxicity) and neutropenic fever (neutrophils 0.18x109/L) on day 21 of neoadjuvant treatment with standard dose capecitabine (825 mg/m2 twice daily) and radiotherapy. His genotype was *1/*2A.
The patient tolerated adjuvant therapy with 5-FU 300 mg/m2 per day as a continuous intravenous infusion (25% of the standard dose) and without bolus injections of 5-fluorouracil very well. Higher doses were not attempted, because they were judged not to influence recurrence or survival.
Authors’ conclusion: ‘The utility of pharmacokinetic- based dosing remains questionable as patients experienced toxicity even with 50% dose reduction of 5-FU, as recommended by current consortium guidelines. We therefore suggest that dosing of 5-FU should be customized in patients with DPD deficiency based on clinical judgment taking into account the severity of toxicity from initial exposure.’
Authors’ conclusion: ‘The presented functional and clinical data indicate that the c.1129-5923 C>G variant is both functionally and
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Level of evidence score: 2
gene act. 1: CTC- AE 2
Three patients treated with capecitabine containing chemotherapy were retrospectively determined to have genotype c.1236A>G/c.1236A>G. Gene variants *2A, *13 and c.2846A>T were not present in these patients. More than 4 weeks after the last treatment with fluoropyrimidines, DPD enzyme activity in
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