Piantadosi S, Fisher J D, Grossman S
Johns Hopkins Oncology Center, Baltimore, Maryland, USA.
Cancer Chemother Pharmacol. 1998;41(6):429-36. doi: 10.1007/s002800050763.
We describe a practical, reliable, efficient dose-finding design for cytotoxic drugs applied in a multi-institutional setting.
The continual reassessment method (CRM) was modified for use in phase I trials conducted through the New Approaches to Brain Tumor Therapy (NABTT) Consortium. Our implementation of the CRM uses (1) a simple dose-toxicity model to guide data interpolation, (2) groups of three patients to minimize calculations and stabilize estimates, (3) investigators' clinical knowledge or opinion in the form of data to make the process easier to understand, and (4) a flexible computer program and interface to facilitate calculations.
The modified CRM was used in two dose-finding trials of 9-aminocamptothecin in patients with newly diagnosed and recurrent glioblastoma who were taking anticonvulsant medication. The CRM located the maximum tolerated dose (MTD) efficiently in both trials. Compared to conventional designs, the CRM required slightly more than half the number of patients expected, did not greatly overshoot the MTD (i.e. no patients were treated at dangerously high doses), and did not underestimate the MTD.
Our experience demonstrates the feasibility of implementing this design in multi-institutional trials and the possibility of performing dose-finding studies that require fewer patients than conventional methods.
我们描述了一种适用于多机构环境中细胞毒性药物的实用、可靠且高效的剂量探索设计。
对连续重新评估法（CRM）进行了修改，以用于通过脑肿瘤治疗新方法（NABTT）联盟开展的I期试验。我们实施的CRM采用了以下方法：（1）使用简单的剂量-毒性模型来指导数据内插；（2）每组三名患者，以尽量减少计算并稳定估计值；（3）以数据形式纳入研究者的临床知识或观点，使过程更易于理解；（4）使用灵活的计算机程序和界面来方便计算。
修改后的CRM用于两项9-氨基喜树碱的剂量探索试验，受试患者为新诊断和复发的胶质母细胞瘤患者且正在服用抗惊厥药物。在两项试验中，CRM均有效地确定了最大耐受剂量（MTD）。与传统设计相比，CRM所需患者数量略多于预期数量的一半，未大幅超过MTD（即没有患者接受危险的高剂量治疗），也未低估MTD。
我们的经验证明了在多机构试验中实施该设计的可行性，以及开展所需患者数量比传统方法少的剂量探索研究的可能性。
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