Paclitaxel Plasma Concentration after the First Infusion Predicts Treatment-Limiting Peripheral Neuropathy.
Paclitaxel Plasma Concentration after the First Infusion Predicts Treatment-Limiting Peripheral Neuropathy.
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DOI：
10.1158/1078-0432.ccr-18-0656
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发表时间：
2018-08-01
期刊：
影响因子：
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通讯作者：
Henry NL
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作者：
Hertz DL;Kidwell KM;Vangipuram K;Li F;Pai MP;Burness M;Griggs JJ;Schott AF;Van Poznak C;Hayes DF;Lavoie Smith EM;Henry NL
紫杉醇暴露，特别是最大浓度（Cmax）和浓度保持在0.05 μM以上的时间（Tc>0.05）与紫杉醇诱导的周围神经病变（PN）的发生有关。本研究的目的是验证紫杉醇暴露与PN之间的关系。接受紫杉醇80 mg/m2 × 12周剂量的乳腺癌患者被纳入一项观察性临床研究（NCT02338115）。第一次给药结束时及第一次给药后16 ~ 26 h测定紫杉醇血药浓度，估算Cmax和Tc>0.05。在每个剂量下，通过CIPN20收集患者报告的PN，并使用8项感觉量表（CIPN8）进行初步分析，以检验其与Tc bb0 0.05的相关性。使用Cmax作为替代暴露参数进行二次分析，并以发生pn诱导的治疗中断的次要终点对这两个参数进行测试。在纳入分析的60名受试者中，治疗期间CIPN8的增加与基线CIPN8、累积剂量和相对剂量强度相关（p<0.05），但与Tc>0.05 （p=0.27）和Cmax （p=0.99）无关。在次要终点的分析中，累积剂量(优势比（OR)=1.46, 95%可信区间（CI）： 1.18-1.80, p=0.0008）和Tc >.05 （OR=1.79, 95% CI: 1.06-3.01, p=0.029）或Cmax （OR=2.74, 95% CI: 1.45-5.20, p=0.002）与pn诱导的治疗中断相关。紫杉醇暴露可预测每周接受紫杉醇治疗的乳腺癌患者发生治疗限制性PN。有必要进行研究，以确定暴露引导剂量是否能提高这些患者的治疗效果和/或预防PN。
Paclitaxel exposure, specifically the maximum concentration (Cmax) and amount of time the concentration remains above 0.05 μM (Tc>0.05), have been associated with the occurrence of paclitaxel-induced peripheral neuropathy (PN). The objective of this study was to validate the relationship between paclitaxel exposure and PN. Patients with breast cancer receiving paclitaxel 80 mg/m2 × 12 weekly doses were enrolled in an observational clinical study (NCT02338115). Paclitaxel plasma concentration was measured at the end of, and 16–26 hours after, the first infusion to estimate Cmax and Tc>0.05. Patient-reported PN was collected via CIPN20 at each dose, and an 8-item sensory subscale (CIPN8) was used in the primary analysis to test for an association with Tc>0.05. Secondary analyses were conducted using Cmax as an alternative exposure parameter and testing either parameter with a secondary endpoint of the occurrence of PN-induced treatment disruption. In the sixty subjects included in the analysis, the increase in CIPN8 during treatment was associated with baseline CIPN8, cumulative dose, and relative dose intensity (p<0.05), but neither Tc>0.05 (p=0.27) nor Cmax (p=0.99). In analyses of the secondary endpoint, cumulative dose (odds ratio (OR)=1.46, 95% confidence interval (CI): 1.18–1.80, p=0.0008) and Tc>0.05 (OR=1.79, 95% CI: 1.06–3.01, p=0.029) or Cmax (OR=2.74, 95% CI: 1.45–5.20, p=0.002) were associated with PN-induced treatment disruption. Paclitaxel exposure is predictive of the occurrence of treatment-limiting PN in patients receiving weekly paclitaxel for breast cancer. Studies are warranted to determine whether exposure-guided dosing enhances treatment effectiveness and/or prevents PN in these patients.