Department of Pharmacy, Peter MacCallum Cancer Centre, Locked Bag 1, A'Beckett Street, Melbourne, 8006, Australia.
Department of Pathology, Peter MacCallum Cancer Centre, Melbourne, Australia.
Cancer Chemother Pharmacol. 2018 Nov;82(5):865-876. doi: 10.1007/s00280-018-3679-4. Epub 2018 Sep 3.
5-Fluorouracil (5FU) drug exposure correlates with treatment response and toxicity in cancer patients. Dosing is based upon body surface area which does not correlate with 5FU pharmacokinetics (PK)/pharmacodynamics. Therapeutic drug monitoring has enabled real-time 5FU dose adjustments: reducing toxicity with increased efficacy. The aim of this study was to assess feasibility of a 5FU monitoring service utilising a commercial kit in a quaternary cancer centre and to compare PK parameters to previously published studies.
Cancer patients receiving continuous infusional (CI) 5FU with ECOG PS 0-2, and adequate organ function, were eligible. Patients had blood samples taken at t = 0, mid infusion (if feasible) then 2 h pre infusion end. 5FU levels were measured using a commercial kit (My-5FU PCM™). A feasibility questionnaire was completed by trial nurses and toxicity data were recorded at baseline and at the commencement of the next cycle. 5FU pharmacokinetic exposure parameters were calculated.
Twenty patients (12 male; 8 female), median age 62, (range 37-71) had samples taken. Twenty (100%) feasibility forms were available for assessment. Blood samples were taken at 51/69 (74%) specified time points. Ease of sample processing was recorded as easy in all 20 patients. Patient compliance with scheduled visits was 18/20 (90%). One form noted other difficulties with predicting end of infusion time. 19/20 patients had blood samples analysed. Mean measured 5FU AUC (0-Tlast) for 5FU 1 g/m with platinum: 35.8 h mg/L (range 28.56-44.26), mean Css 372.2 µg/L (range 297.5-461.0); 5FU 600 mg/m with platinum: 12.42 h mg/L (range 6.91-18.29), mean Css 111.0 µg/L (72.0-190.5) and 5FU 2400 mg/m as part of FOLFOX ± bevacizumab: 14.75 h mg/L (range 6.74-22.93), mean Css 320.70 µg/L (range 146.5-498.5). One patient had grade 4 neutropenia and one patient without PK parameters experienced febrile neutropenia (grade 4 neutropenia). Mucositis was observed in two patients: [5FU/platinum (1), grade 1, FOXFOX ± bevacizumab (1) grade 1]. Diarrhoea was reported in three patients [5FU/platinum (2) grade 1-2, FOXFOX ± bevacizumab (1) grade 1].
Therapeutic 5FU drug monitoring was feasible using commercial kits and analysers and hence warrants development as a routine standard of care in cancer patients. The variability in the 5FU exposure parameters is consistent with other studies using the My 5FU PCM kit.
氟尿嘧啶（5FU）药物暴露与癌症患者的治疗反应和毒性相关。剂量基于体表面积，而体表面积与 5FU 药代动力学（PK）/药效动力学不相关。治疗药物监测使实时 5FU 剂量调整成为可能：提高疗效的同时降低毒性。本研究旨在评估在一家四级癌症中心利用商业试剂盒进行 5FU 监测服务的可行性，并将 PK 参数与之前发表的研究进行比较。
符合条件的患者为接受 ECOG PS 0-2 和足够器官功能的连续输注（CI）5FU 的癌症患者。患者在 t = 0、中输注（如果可行）时以及输注前 2 小时时采集血样。使用商业试剂盒（My-5FU PCM™）测量 5FU 水平。试验护士填写可行性问卷，并在基线和下一周期开始时记录毒性数据。计算 5FU 药代动力学暴露参数。
20 名患者（12 名男性；8 名女性），中位年龄 62 岁（范围 37-71 岁），采集了样本。20 份（100%）可行性表格可用于评估。51/69（74%）规定的时间点采集了血样。所有 20 名患者均记录样本处理容易。20 名患者中有 18 名（90%）按计划就诊。一份表格记录了其他预测输注结束时间的困难。19/20 名患者进行了血液样本分析。铂类药物 5FU 1g/m 的 5FU AUC（0-Tlast）平均值为 35.8 h mg/L（范围 28.56-44.26），Css 平均值为 372.2µg/L（范围 297.5-461.0）；铂类药物 600mg/m 的 5FU AUC（0-Tlast）平均值为 12.42 h mg/L（范围 6.91-18.29），Css 平均值为 111.0µg/L（范围 72.0-190.5），5FU 2400mg/m 作为 FOLFOX±bevacizumab 的一部分：14.75 h mg/L（范围 6.74-22.93），Css 平均值为 320.70µg/L（范围 146.5-498.5）。一名患者出现 4 级中性粒细胞减少症，一名无 PK 参数的患者出现发热性中性粒细胞减少症（4 级中性粒细胞减少症）。两名患者观察到粘膜炎：[5FU/platinum（1），1 级，FOXFOX±bevacizumab（1），1 级]。三名患者报告腹泻：[5FU/platinum（2），1-2 级，FOXFOX±bevacizumab（1），1 级]。
使用商业试剂盒和分析仪进行治疗性 5FU 药物监测是可行的，因此值得作为癌症患者常规护理标准进行开发。5FU 暴露参数的变异性与使用 My 5FU PCM 试剂盒的其他研究一致。
