Clinical application of the AUC-guided dosage adjustment of docetaxel-based chemotherapy for patients with solid tumours: a single centre, prospective and randomised control study
Clinical application of the AUC-guided dosage adjustment of docetaxel-based chemotherapy for patients with solid tumours: a single centre, prospective and randomised control study
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DOI：
10.1186/s12967-020-02394-w
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发表时间：
2020-06-08
影响因子：
7.4
通讯作者：
Zhang, Yan
中科院分区：
文献类型：
--
作者：
Sun, Ning;Shen, Bo;Zhang, Yan
背景多西他赛（DTX）是一种广泛使用的抗肿瘤药物，其剂量仅由体表面积（BSA）决定。由于患者的药代动力学（PK）和药效学差异，可能会发生不良事件，如中性粒细胞减少或疗效不满意。因此，需要一种可行的剂量调整方法。方法将209例患者随机分为两组，分别接受BSA和PK指导的MTX化疗剂量调整（3周/周期）。测定DTX的AUC，确定中国患者的治疗窗。评价了治疗窗内的患者比例。按照世界卫生组织建议的毒性分级标准进行中性粒细胞检查。根据实体瘤缓解评价标准第1.1版评估肿瘤缓解。主要终点为中性粒细胞减少的发生率，次要终点为疾病控制率（DCR）和3年生存率。结果中国患者的治疗窗为1.7- 2.5mg中心点·h/L。第6个周期试验组和对照组治疗窗内患者比例分别为63.89%和28.33%（P < 0.0001），中性粒细胞减少发生率分别为68.33%和38.89%（P = 0.001）。对照组和实验组的DCR分别为72%和85%（P = 0.018）。PK组3年生存率明显高于BSA组（P = 0.034）。结论PK指导下的DTX剂量调整可显著提高治疗窗内患者比例，降低中性粒细胞减少发生率，提高DCR和3年生存率。基于AUC动态监测的PK指导剂量调整可能是肿瘤学家改善个体化治疗选择、优化药物疗效和降低药物毒性的有用方法。
Background Docetaxel (DTX) is a widely used anti-tumour drug, and its dosage is solely determined by body surface area (BSA). Adverse events, such as neutropenia or unsatisfied efficacy, likely occur because of differences in the pharmacokinetics (PK) and pharmacodynamics of patients. Thus, a feasible dosage adjustment method is needed. Methods A total of 209 eligible patients who provided consent were enrolled and randomised into two groups to receive the BSA- and PK-guided dosage adjustments of DTX-based chemotherapy (3 weeks per cycle). The AUC of DTX was detected, and the therapeutic window for Chinese patients was determined. The proportion of patients within the therapeutic window was evaluated. Neutropenia was examined in accordance with the toxicity grading standard suggested by the World Health Organisation. Tumour response was assessed in accordance with Response Evaluation Criteria in Solid Tumors version 1.1. The primary endpoint was the incidence of neutropenia, and the secondary endpoints were disease control rate (DCR) and 3-year survival rate. Results The therapeutic window for Chinese patients was 1.7-2.5 mg center dot h/L. The proportion of patients within the therapeutic window was 63.89% versus 28.33% (P < 0.0001), and the incidence of neutropenia was 68.33% versus 38.89% (P = 0.001) in the experimental group versus the control group in the sixth cycle, respectively. DCR was 72% versus 85% (P = 0.018) in the control group versus the experimental group. The 3-year survival rate of the PK group was significantly higher than that of the BSA group (P = 0.034). Conclusions The PK-guided dosage adjustment of DTX could significantly increase the proportion of patients within the therapeutic window, decrease the incidence of neutropenia and increase the DCR and the 3-year survival rate. The PK-guided dosage adjustment based on the dynamic monitoring of AUC could be a useful method for oncologists to improve individualised treatment options, optimise drug efficacy and reduce drug toxicity.