@article{Hamzic_Aebi_Joerger_Montemurro_Ansari_Amstutz_Largiadèr_2020, title={Fluoropyrimidine chemotherapy: recommendations for DPYD genotyping and therapeutic drug monitoring of the Swiss Group of Pharmacogenomics and Personalised Therapy}, volume={150}, url={https://smw.ch/index.php/smw/article/view/2899}, DOI={10.4414/smw.2020.20375}, abstractNote={<p><p>Fluoropyrimidines (FPs), mainly 5-fluorouracil (5-FU) and its oral prodrug capecitabine (Cap), remain the backbone of the treatment of many different solid tumors. Despite their broad use in clinical routine, 10–40% of patients experience severe, and in rare cases (0.2–0.5%) even lethal, FP-related toxicity in early chemotherapy cycles. Today, there is a plethora of evidence that genetic variants in the gene encoding for the 5-FU catabolising enzyme dihydropyrimidine dehydrogenase (DPD, encoded by <em>DPYD</em>) are predictive of severe FP-related toxicities, and international clinical practice recommendations for <em>DPYD</em> genotype-guided FP dosing and therapeutic drug monitoring (TDM) are available. In spite of this strong evidence and <em>DPYD</em> genotyping becoming standard practice in other countries, it is has not been widely adopted in Switzerland to date. Here, we discuss current guidelines on genotype-guided FP dosing and TDM, and propose recommendations tailored to the situation in Switzerland to facilitate their clinical uptake for the further individualisation of FP chemotherapy.</p> <p>We recommend preemptive testing of four <em>DPYD</em> variants (c.1905+1G<em>></em>A (rs3918290), c.1679T<em>></em>G (rs55886062), c.2846A<em>></em>T (rs67376798) and c.1129-5923C<em>></em>G (rs75017182, c.1236G<em>></em>A<em>/</em>HapB3)) in patients with an indication for FP-based chemotherapy, with the costs reimbursed through the compulsory health insurance in Switzerland. Carriers of these variants (6.5% in the Swiss population) have a 40–50% risk of developing severe early-onset toxicity when treated with standard FP doses. In these patients, we therefore recommend the use of a reduced starting dose, based on a dose adjustment scheme provided herein. Furthermore, we recommend the use of infusional 5-FU in patients with a <em>DPYD</em> risk genotype in order to enable TDM-based dose escalation. Only if the use of an infusional 5-FU regimen is not feasible should a slow titration of Cap, starting with the recommended reduced dose and basing further doses on monitoring of toxicity, be considered. Given that several studies have shown that TDM in 5-FU treatment improves not only the therapy’s safety, but potentially also its efficacy, we also include detailed TDM-based dosing guidelines and discuss the pre-analytical aspects of 5-FU TDM.</p></p>}, number={4748}, journal={Swiss Medical Weekly}, author={Hamzic, Seid and Aebi, Stefan and Joerger, Markus and Montemurro, Michael and Ansari, Marc and Amstutz, Ursula and Largiadèr, Carlo}, year={2020}, month={Nov.}, pages={w20375} }