Department of Clinical Pharmacy, Catharina Hospital, Eindhoven, the Netherlands; Department of Clinical Pharmacy and Toxicology, Leiden University Medical Center, Leiden, the Netherlands.
Department of Clinical Pharmacy and Toxicology, Leiden University Medical Center, Leiden, the Netherlands; Leiden Network of Personalized Therapeutics, the Netherlands.
Eur J Cancer. 2020 Dec;141:9-20. doi: 10.1016/j.ejca.2020.09.007. Epub 2020 Oct 23.
Pre-therapeutic UGT1A1 genotyping is not yet routinely performed in most hospitals in patients starting irinotecan chemotherapy. The aim of this position paper was to evaluate the available evidence and to assess the potential value of genotyping of UGT1A1∗28 and UGT1A1*6 in patients before starting treatment with irinotecan to reduce the risk of severe toxicity.
The literature was selected and assessed based on five pre-specified criteria: 1) the level of evidence for associations between UGT1A1 polymorphisms and irinotecan-induced severe toxicity, 2) clinical validity and utility of pre-therapeutic genotyping of UGT1A1, 3) safety and tolerability of irinotecan in carriers of UGT1A1 polymorphisms, 4) availability of specific dose recommendations for irinotecan in carriers of UGT1A1 polymorphisms, 5) evidence of cost benefits of pre-therapeutic genotyping of UGT1A1.
On all five criteria, study results were favourable for pre-therapeutic genotyping of UGT1A1. A high level of evidence (level I) was found for a higher incidence of irinotecan-induced severe toxicity in homozygous carriers of UGT1A128 or UGT1A16. The clinical validity and utility of this genetic test proved to be acceptable. Dose-finding studies showed a lower maximum tolerated dose in homozygous variant allele carriers, and most of the drug labels and guidelines recommend a dose reduction of 25-30% in these patients. In addition, pre-therapeutic genotyping of UGT1A1 is likely to save costs.
Pre-therapeutic genotyping of UGT1A1 in patients initiating treatment with irinotecan improves patient safety, is likely to be cost-saving, and should, therefore, become standard of care.
在大多数医院，在开始伊立替康化疗的患者中，并未常规进行治疗前 UGT1A1 基因分型。本立场文件的目的是评估现有证据，并评估在开始伊立替康治疗前对 UGT1A1∗28 和 UGT1A1*6 进行基因分型的潜在价值，以降低严重毒性的风险。
根据五个预先指定的标准选择和评估文献：1）UGT1A1 多态性与伊立替康诱导的严重毒性之间关联的证据水平，2）治疗前 UGT1A1 基因分型的临床有效性和实用性，3）UGT1A1 多态性携带者使用伊立替康的安全性和耐受性，4）UGT1A1 多态性携带者使用伊立替康的特定剂量建议，5）治疗前 UGT1A1 基因分型的成本效益证据。
在所有五个标准上，研究结果均有利于治疗前 UGT1A1 基因分型。发现 UGT1A128 或 UGT1A16 纯合子携带者发生伊立替康诱导的严重毒性的发生率更高，这具有较高的证据水平（一级）。该遗传检测的临床有效性和实用性被证明是可以接受的。剂量确定研究表明，纯合变异等位基因携带者的最大耐受剂量较低，大多数药物标签和指南建议这些患者减少 25-30%的剂量。此外，治疗前 UGT1A1 基因分型可能会节省成本。
在开始伊立替康治疗的患者中进行 UGT1A1 治疗前基因分型可提高患者安全性，可能节省成本，因此应成为护理标准。
