Treating patients with dihydropyrimidine dehydrogenase (DPD) deficiency with fluoropyrimidine chemotherapy since the onset of routine prospective testing—The experience of a large oncology center in the United Kingdom

IF 3 3区 医学 Q2 ONCOLOGY
Lei Wang, Sarah Howlett, Sharadah Essapen
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引用次数: 4

Abstract

Background

Fluoropyrimidine chemotherapy is used across many tumor types and settings. The incidence of severe adverse events (SAEs) is around 20%. Mortality is 0.5%-1%. Dihydropyrimidine dehydrogenase (DPD) plays a key role in fluoropyrimidine inactivation. Key DPYD mutations are linked to a high risk of SAEs. Pretreatment DPD screening was mandated by EMA guidelines in April 2020 and widely adopted thereafter. Uncertainty remains regarding optimal dosing practice.

Methods

We retrospectively examined records of all 23 patients with DPYD mutation who started chemotherapy between April and November 2020. Our center tests for the mutations considered clinically actionable by Clinical Pharmacogenetics Implementation Consortium and uses the Gene Activity Score (GAS) to guide dose reduction.

Results

Most patients started on a 50% dose. One started on 100% and experienced mild diarrhea after cycle 2; DPD was tested belatedly, subsequent cycles were reduced to 50% and he remained well. Three patients receiving chemo-radiotherapy started on 76% dose; 50% was felt to be subtherapeutic. One of them had no toxicities; another had grade 2 nausea and a hospital attendance with non-neutropenic fever; the third was admitted for 6 weeks with pancolitis. Seven patients did not have toxicities above grade 1 and no hospital attendances. Five patients had further dose reductions. None had dose escalation.

Conclusion

As our experience shows, patients with DPD deficiency are heterogeneous. Worryingly, SAEs occur despite dose reduction according to GAS. Others had minimal toxicity and may be under-dosed by GAS. There are clearly many factors at play other than the 4 DPYD variants. The DPD result must be available and inform first cycle dosing. Dose should be cautiously titrated up if tolerated; this was not done at our center due to clinician caution. Further research is needed to guide this. Patients should be reviewed frequently, counselled regarding their DPD status, and empowered to seek advice promptly when they feel unwell.

自常规前瞻性检测开始用氟嘧啶化疗治疗二氢嘧啶脱氢酶(DPD)缺乏症患者——英国某大型肿瘤中心的经验
背景氟嘧啶化疗用于许多肿瘤类型和设置。严重不良事件(sae)的发生率约为20%。死亡率为0.5%-1%。二氢嘧啶脱氢酶(DPD)在氟嘧啶失活过程中起关键作用。关键的DPYD突变与SAEs的高风险有关。预处理DPD筛查于2020年4月被EMA指南强制要求,此后被广泛采用。关于最佳给药方法的不确定性仍然存在。方法回顾性分析2020年4月至11月期间开始化疗的所有23例DPYD突变患者的记录。我们的中心对临床药物遗传学实施联盟认为具有临床可操作性的突变进行测试,并使用基因活性评分(GAS)来指导减少剂量。结果大多数患者开始时的剂量为50%。一名患者开始服用100%,在第2周期后出现轻度腹泻;DPD检测较晚,随后的周期减少到50%,患者保持良好。3例化疗起始剂量为76%;50%被认为是亚治疗。其中一种没有毒性;另一人有2级恶心,因非中性粒细胞减少症发烧住院;第三例患者因结肠炎住院6周。7例患者没有1级以上的毒性,没有住院治疗。5名患者进一步减少了剂量。没有剂量递增。结论我们的经验表明,DPD缺乏症患者具有异质性。令人担忧的是,尽管根据GAS减少了剂量,仍会发生SAEs。其他的毒性很小,可能是气体剂量不足。显然,除了4 DPYD变体之外,还有许多因素在起作用。DPD结果必须可用,并通知第一周期给药。如果耐受,剂量应谨慎滴定;由于临床医生的谨慎,我们中心没有进行这项研究。这需要进一步的研究来指导。患者应经常接受检查,了解他们的DPD状态,并有权在感到不适时及时寻求建议。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Seminars in oncology
Seminars in oncology 医学-肿瘤学
CiteScore
6.60
自引率
0.00%
发文量
58
审稿时长
104 days
期刊介绍: Seminars in Oncology brings you current, authoritative, and practical reviews of developments in the etiology, diagnosis and management of cancer. Each issue examines topics of clinical importance, with an emphasis on providing both the basic knowledge needed to better understand a topic as well as evidence-based opinions from leaders in the field. Seminars in Oncology also seeks to be a venue for sharing a diversity of opinions including those that might be considered "outside the box". We welcome a healthy and respectful exchange of opinions and urge you to approach us with your insights as well as suggestions of topics that you deem worthy of coverage. By helping the reader understand the basic biology and the therapy of cancer as they learn the nuances from experts, all in a journal that encourages the exchange of ideas we aim to help move the treatment of cancer forward.
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