The fluoropyrimidine anticancer drugs, especially 5-fluorouracil (5-FU) and capecitabine, are frequently prescribed for several types of cancer, including breast, colorectal, head and neck and gastric cancer. In the current drug labels of 5-FU and capecitabine in the European Union and the United States, no adaptive dosing strategies are incorporated for polymorphic metabolism of 5-FU. Although treatment with fluoropyrimidines is generally well tolerated, a major clinical limitation is that a proportion of the treated population experiences severe, sometimes life-threatening, fluoropyrimidine-related toxicity. This toxicity is strongly affected by interindividual variability in activity of dihydropyrimidine dehydrogenase (DPD), the main metabolic enzyme for inactivation of fluoropyrimidines, with an estimated 3%-8% of the population being partially DPD deficient. A reduced functional or abrogated DPD enzyme is often caused by genetic polymorphisms in DPYD, the gene encoding for DPD, and heterozygous carriers of such DPYD polymorphisms have a partial DPD deficiency. When these partially DPD deficient patients are treated with a full dose of fluoropyrimidines, they are generally exposed to toxic levels of 5-FU and its metabolites, and the risk of developing severe treatment-related toxicity is therefore significantly increased.Currently, functional and clinical validity is well established for four DPYD variants (DPYD*2A, c.2846A>T, c.1679T>G and c.1236G>A), as those variants have retrospectively and in a large population study prospectively been shown to be associated with increased risk of fluoropyrimidine-associated toxicity. Patient safety of fluoropyrimidine treatment can be significantly improved by pre-emptive screening for DPYD genotype variants and dose reductions in heterozygous DPYD variant allele carriers, thereby normalizing 5-FU exposure. Based on the critical appraisal of currently available data, adjusting the labels of capecitabine and 5-FU by including recommendations on pre-emptive screening for DPYD variants and DPYD genotype-guided dose adjustments should be the new standard of care.

中文翻译：

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DPYD基因型指导的剂量个体化，以提高氟嘧啶治疗的患者安全性：呼吁更新药物标签。

氟嘧啶类抗癌药物，尤其是5-氟尿嘧啶（5-FU）和卡培他滨，经常用于几种类型的癌症，包括乳腺癌，结肠直肠癌，头颈癌和胃癌。在欧盟和美国当前的5-FU和卡培他滨的药物标签中，没有为5-FU的多态性代谢采用适应性给药策略。尽管通常对氟嘧啶的治疗耐受性良好，但主要的临床局限性是一部分被治疗的人群遭受了严重的，有时甚至威胁生命的氟嘧啶相关的毒性。氢氟嘧啶失活的主要代谢酶二氢嘧啶脱氢酶（DPD）的个体间差异会严重影响这种毒性。估计有3％-8％的人口部分缺乏DPD。DPD酶的遗传多态性通常导致功能性或废除的DPD酶降低，该基因编码DPD，而此类DPYD多态性的杂合子携带者具有部分DPD缺陷。当这些部分DPD缺陷的患者接受全剂量的氟嘧啶治疗时，通常会暴露于5-FU及其代谢产物的毒性水平，因此显着增加发生与治疗相关的严重毒性的风险。四个DPYD变体（DPYD * 2A，c.2846A> T，c.1679T> G和c.1236G> A）的有效性已经很好地确立，因为这些变体已经过回顾性研究，并且在大量人群研究中前瞻性显示与氟嘧啶相关的毒性风险增加有关。可以通过预先筛选DPYD基因型变异体和减少杂合DPYD变异体等位基因载体的剂量来显着提高氟嘧啶治疗的患者安全性，从而使5-FU暴露正常化。根据对当前可用数据的严格评估，通过包括对DPYD变体和DPYD基因型指导的剂量调整进行优先筛查的建议，调整卡培他滨和5-FU的标签应成为新的治疗标准。从而使5-FU暴露正常化。根据对当前可用数据的严格评估，通过包括对DPYD变体和DPYD基因型指导的剂量调整进行优先筛查的建议，调整卡培他滨和5-FU的标签应成为新的治疗标准。从而使5-FU暴露标准化。根据对当前可用数据的严格评估，通过包括对DPYD变体和DPYD基因型指导的剂量调整进行优先筛查的建议，调整卡培他滨和5-FU的标签应成为新的治疗标准。