Knikman Jonathan E, de With Mirjam, Heersche Niels, Lopez-Yurda Marta, Baars Arnold, Creemers Geert-Jan, Droogendijk Helga J, Fiets Edward, Imholz Alexander L T, Iersel Liselot Valkenburg-van, Mandigers Caroline M P W, van de Vendel Alina J, Jeurissen Frank J F, Nieboer Peter, Deenen Maarten J, van de Poel Marlène H W, Wymenga Machteld N M, van Schaik Ron H N, van den Bosch Bianca J C, Hoop Esther Oomen-de, Rosing Hilde, Swen Jesse J, Gelderblom Hans, Schellens Jan H M, Beijnen Jos H, Mathijssen Ron H J, Guchelaar Henk-Jan, Cats Annemieke
Div. of Pharmacology, The Netherlands Cancer Institute, Amsterdam, the Netherlands; Dept. of Pharmacy & Pharmacology, The Netherlands Cancer Institute, Amsterdam, the Netherlands.
Dept. of Medical Oncology, Erasmus MC Cancer Institute, Erasmus University Medical Centre, Rotterdam, the Netherlands; Dept. of Clinical Chemistry, Erasmus University Medical Centre, Rotterdam, the Netherlands.
Eur J Cancer. 2025 Jun 25;224:115483. doi: 10.1016/j.ejca.2025.115483. Epub 2025 Apr 30.
BACKGROUND: DPYD-guided dosing enhances safety of fluoropyrimidine-based chemotherapy. However, approximately 23 % of patients still experience severe toxicity unexplained by the four commonly tested DPYD-variant alleles. Elevated pre-treatment uracil levels have been proposed as a surrogate marker for reduced DPD activity and an independent predictor of toxicity. This prospective study evaluated whether uracil-guided dose individualisation can reduce severe fluoropyrimidine-induced toxicity in DPYD wild-type patients. METHODS: Pre-treatment plasma uracil levels were quantified in patients scheduled to receive fluoropyrimidine-based therapy. DPYD wild-type individuals with uracil concentrations > 16 ng/mL (DPYD/U) received a 50 % dose reduction, in accordance with French RNPGx guidelines. The incidence of grade ≥ 3 fluoropyrimidine-related toxicity was compared between dose-reduced DPYD/U patients, DPYD patients with uracil ≤ 16 ng/mL (DPYD/U), and a historical cohort of DPYD/U patients treated at full dose. Pharmacokinetic data were compared to a second historical cohort. RESULTS: Among 612 evaluable patients, 22 were DPYD/U. The incidence of severe toxicity in the dose-reduced group was significantly lower than in historical full-dose DPYD/U patients (20 % vs 43 %, P = 0.03) and comparable during the first 2 treatment cycles to DPYD/U patients (10 % vs 11 %). However, 5-fluorouracil exposure was markedly reduced in nineteen dose-reduced DPYD/U patients (177 vs 381 ngh/mL), while five subsequently treated fully dosed DPYD/U patients exhibited comparable exposure to historical wild-type controls (456 vs 381 ngh/mL). No correlation was found between uracil levels and DPD enzyme activity (R=-0.006, P = 0.98). CONCLUSION: Uracil-guided dosing of fluoropyrimidines may reduce toxicity risk but leads to subtherapeutic 5-fluorouracil exposure in DPYD wild-type patients. This indicates that these patients are treated sub-optimally and that uracil is not a reliable predictor of DPD deficiency in DPYD wild-type patients.
背景：二氢嘧啶脱氢酶（DPYD）指导下的给药可提高基于氟嘧啶的化疗的安全性。然而，约23%的患者仍会出现严重毒性反应，而这无法用四种常见检测的DPYD变异等位基因来解释。预处理时尿嘧啶水平升高已被提议作为二氢嘧啶脱氢酶（DPD）活性降低的替代标志物以及毒性的独立预测指标。这项前瞻性研究评估了尿嘧啶指导下的剂量个体化是否能降低DPYD野生型患者中严重的氟嘧啶诱导的毒性。 方法：对计划接受基于氟嘧啶治疗的患者的预处理血浆尿嘧啶水平进行定量。根据法国RNPGx指南，尿嘧啶浓度>16 ng/mL的DPYD野生型个体（DPYD/U）接受50%的剂量减少。比较剂量减少的DPYD/U患者、尿嘧啶≤16 ng/mL的DPYD患者（DPYD/U）以及历史上全剂量治疗的DPYD/U患者队列中≥3级氟嘧啶相关毒性的发生率。将药代动力学数据与第二个历史队列进行比较。 结果：在612例可评估患者中，22例为DPYD/U。剂量减少组中严重毒性的发生率显著低于历史上全剂量的DPYD/U患者（20%对43%，P = 0.03），并且在前两个治疗周期中与DPYD/U患者相当（10%对11%）。然而，19例剂量减少的DPYD/U患者中5-氟尿嘧啶暴露显著降低（177对381 ngh/mL），而随后接受全剂量治疗的5例DPYD/U患者的暴露与历史野生型对照相当（456对381 ngh/mL）。未发现尿嘧啶水平与DPD酶活性之间存在相关性（R = -0.006，P = 0.98）。 结论：尿嘧啶指导下的氟嘧啶给药可能降低毒性风险，但会导致DPYD野生型患者中5-氟尿嘧啶暴露低于治疗水平。这表明这些患者的治疗并非最佳，并且尿嘧啶不是DPYD野生型患者中DPD缺乏的可靠预测指标。
Cochrane Database Syst Rev. 2017-7-28
Cochrane Database Syst Rev. 2018-2-6
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