Page 224 - Personalised medicine of fluoropyrimidines using DPYD pharmacogenetics Carin Lunenburg

Chapter 8
(e.g., TYMS) have been associated with fluoropyrimidine-induced toxicity with conflicting results. However, testing for these SNPs holds the potential to increase sensitivity.23 Even though DPYD screening cannot prevent all fluoropyrimidine-related toxicity, we feel that the available evidence strongly supports implementation in clinical practice and can prevent fluoropyrimidine-induced deaths.8,11,24
The presence of one of the four DPYD variants that were pre-emptively tested resulted in a recommendation to the oncologist to reduce the initial dose of 5-FU or capecitabine by 25–50% depending on the identified variant. In February 2015 the recommended dose reduction for c.2846A>T was changed from 50 to 25%, following the updated guidelines of the DPWG.25,26
One patient (Table 4, patient 13) received full capecitabine dose, since the treating oncologist argued that she was afraid of under dosing the patient as the dosage of capecitabine in chemoradiation schemes is already lower compared with other treatments and there is less opportunity to increase the dose in subsequent treatment cycles. The patient developed severe toxicity illustrating that the recommended dose reductions should also be applied to lower capecitabine doses used in chemoradiation, despite lack of published data about capecitabine toxicity during chemoradiation therapy.
Conclusion
This study for the first time shows that systematic prospective DPYD screening can be implemented successfully in real world daily clinical practice. The applied 25–50% dose reduction for patients with a DPYD variant resulted in absence of toxicity. However, a more active follow-up of adherence to provided dose recommendations might improve patient safety even further.
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