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
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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.
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.