Wu Angela, Anderson Helen, Hughesman Curtis, Young Sean, Lohrisch Caroline, Ross Colin J D, Carleton Bruce C
Department of Experimental Medicine, University of British Columbia, Vancouver, BC, Canada.
BC Children's Hospital Research Institute, Vancouver, BC, Canada.
Front Pharmacol. 2023 Sep 8;14:1257745. doi: 10.3389/fphar.2023.1257745. eCollection 2023.
Fluoropyrimidine toxicity is often due to variations in the gene () encoding dihydropyrimidine dehydrogenase (DPD). genotyping can be used to adjust doses to reduce the likelihood of fluoropyrimidine toxicity while maintaining therapeutically effective drug levels. A multiplex QPCR assay was locally developed to allow genotyping for six variants. The test was offered prospectively for all patients starting on fluoropyrimidines at the BC Cancer Centre in Vancouver and then across B.C., Canada as well as retrospectively for patients suspected to have had an adverse reaction to therapy. Dose adjustments were made for variant carriers. The incidence of toxicity in the first three cycles was compared between variant allele carriers and non-variant carriers. Subsequent to an initial implementation phase, this test was made available province-wide. In 9 months, 186 patients were tested and 14 were found to be heterozygous variant carriers. Fluoropyrimidine-related toxicity was higher in variant carriers. Of 127 non-variant carriers who have completed chemotherapy, 18 (14%) experienced severe (grade ≥3, Common Terminology Criteria for Adverse Events version 5.0). Of note, 22% (3 patients) of the variant carriers experienced severe toxicity even after -guided dose reductions. For one of these carriers who experienced severe thrombocytopenia within the first week, testing likely prevented lethal toxicity. In variant carriers who tolerate reduced doses, a later 25% increase led to chemotherapy discontinuation. As a result, a recommendation was made to clinicians based on available literature and expert opinion specifying that variant carriers who tolerated two cycles without toxicity can have a dose escalation of only 10%. -guided dose reductions were a feasible and acceptable method of preventing severe toxicity in variant carriers. Even with dose reductions, there were variant carriers who still experienced severe fluoropyrimidine toxicity, highlighting the importance of adhering to guideline-recommended dose reductions. Following the completion of the pilot phase of this study, genotyping was made available province-wide in British Columbia.
氟嘧啶毒性通常归因于编码二氢嘧啶脱氢酶（DPD）的基因（）的变异。基因分型可用于调整剂量，以降低氟嘧啶毒性的可能性，同时维持治疗有效的药物水平。当地开发了一种多重定量聚合酶链反应（QPCR）检测方法，用于对6种变异进行基因分型。该检测方法前瞻性地应用于温哥华不列颠哥伦比亚癌症中心所有开始使用氟嘧啶的患者，随后推广至加拿大不列颠哥伦比亚省全境，同时也对疑似有治疗不良反应的患者进行回顾性检测。对变异携带者进行了剂量调整。比较了变异等位基因携带者和非变异携带者在前三个周期的毒性发生率。在初始实施阶段之后，该检测在全省范围内可用。在9个月内，对186名患者进行了检测，发现14名是杂合变异携带者。变异携带者中与氟嘧啶相关的毒性更高。在127名完成化疗的非变异携带者中，18名（14%）经历了严重（≥3级，不良事件通用术语标准第5.0版）毒性反应。值得注意的是，即使在进行了基因指导的剂量减少后，22%（3名患者）的变异携带者仍经历了严重毒性反应。对于其中一名在第一周内出现严重血小板减少症的携带者，基因检测可能预防了致命毒性。在能够耐受降低剂量的变异携带者中，随后剂量增加25%导致化疗中断。因此，根据现有文献和专家意见向临床医生提出了一项建议，明确指出在两个周期内无毒性的变异携带者剂量仅可增加10%。基因指导的剂量减少是预防变异携带者严重毒性的一种可行且可接受的方法。即使进行了剂量减少，仍有变异携带者经历严重的氟嘧啶毒性反应，这凸显了遵循指南推荐的剂量减少的重要性。在本研究试点阶段完成后，基因分型在不列颠哥伦比亚省全省范围内可用。
