可能是药物分发不良导致 PRECISE 试验的结果。

Poor drug distribution as a possible explanation for the results of the PRECISE trial.

机构信息

Division of Neurosurgery, Department of Surgery, Duke University, Durham, North Carolina, USA.

出版信息

J Neurosurg. 2010 Aug;113(2):301-9. doi: 10.3171/2009.11.JNS091052.

DOI:10.3171/2009.11.JNS091052

PMID:20020841

Abstract

OBJECT

Convection-enhanced delivery (CED) is a novel intracerebral drug delivery technique with considerable promise for delivering therapeutic agents throughout the CNS. Despite this promise, Phase III clinical trials employing CED have failed to meet clinical end points. Although this may be due to inactive agents or a failure to rigorously validate drug targets, the authors have previously demonstrated that catheter positioning plays a major role in drug distribution using this technique. The purpose of the present work was to retrospectively analyze the expected drug distribution based on catheter positioning data available from the CED arm of the PRECISE trial.

METHODS

Data on catheter positioning from all patients randomized to the CED arm of the PRECISE trial were available for analyses. BrainLAB iPlan Flow software was used to estimate the expected drug distribution.

RESULTS

Only 49.8% of catheters met all positioning criteria. Still, catheter positioning score (hazard ratio 0.93, p = 0.043) and the number of optimally positioned catheters (hazard ratio 0.72, p = 0.038) had a significant effect on progression-free survival. Estimated coverage of relevant target volumes was low, however, with only 20.1% of the 2-cm penumbra surrounding the resection cavity covered on average. Although tumor location and resection cavity volume had no effect on coverage volume, estimations of drug delivery to relevant target volumes did correlate well with catheter score (p < 0.003), and optimally positioned catheters had larger coverage volumes (p < 0.002). Only overall survival (p = 0.006) was higher for investigators considered experienced after adjusting for patient age and Karnofsky Performance Scale score.

CONCLUSIONS

The potential efficacy of drugs delivered by CED may be severely constrained by ineffective delivery in many patients. Routine use of software algorithms and alternative catheter designs and infusion parameters may improve the efficacy of drugs delivered by CED.

摘要

目的

脑室内药物输注（CED）是一种新型的颅内药物输送技术，具有在中枢神经系统内输送治疗剂的巨大潜力。尽管有这种潜力，但采用 CED 的 III 期临床试验未能达到临床终点。尽管这可能是由于无效的药物或未能严格验证药物靶点，但作者之前已经证明，导管定位在使用该技术进行药物分布方面起着重要作用。本研究的目的是回顾性分析 PRECISE 试验 CED 臂的导管定位数据，预测药物的预期分布。

方法

对所有随机分配到 PRECISE 试验 CED 臂的患者的导管定位数据进行分析。使用 BrainLAB iPlan Flow 软件估计预期的药物分布。

结果

仅有 49.8%的导管符合所有定位标准。尽管如此，导管定位评分（风险比 0.93，p = 0.043）和最佳定位导管数量（风险比 0.72，p = 0.038）对无进展生存期有显著影响。然而，相关靶区的覆盖范围估计较低，平均仅覆盖切除腔周围 2cm 半影的 20.1%。尽管肿瘤位置和切除腔体积对覆盖体积没有影响，但对相关靶区的药物输送估计与导管评分密切相关（p < 0.003），最佳定位的导管具有更大的覆盖体积（p < 0.002）。调整患者年龄和 Karnofsky 表现量表评分后，只有经验丰富的研究者的总生存期（p = 0.006）更高。