Babb J, Rogatko A, Zacks S
Fox Chase Cancer Center, Department of Biostatistics, Cheltenham, PA 19012, USA.
Stat Med. 1998 May 30;17(10):1103-20. doi: 10.1002/(sici)1097-0258(19980530)17:10<1103::aid-sim793>3.0.co;2-9.
We describe an adaptive dose escalation scheme for use in cancer phase I clinical trials. The method is fully adaptive, makes use of all the information available at the time of each dose assignment, and directly addresses the ethical need to control the probability of overdosing. It is designed to approach the maximum tolerated dose as fast as possible subject to the constraint that the predicted proportion of patients who receive an overdose does not exceed a specified value. We conducted simulations to compare the proposed method with four up-and-down designs, two stochastic approximation methods, and with a variant of the continual reassessment method. The results showed the proposed method effective as a means to control the frequency of overdosing. Relative to the continual reassessment method, our scheme overdosed a smaller proportion of patients, exhibited fewer toxicities and estimated the maximum tolerated dose with comparable accuracy. When compared to the non-parametric schemes, our method treated fewer patients at either subtherapeutic or severely toxic dose levels, treated more patients at optimal dose levels and estimated the maximum tolerated dose with smaller average bias and mean squared error. Hence, the proposed method is promising alternative to currently used cancer phase I clinical trial designs.
我们描述了一种用于癌症I期临床试验的自适应剂量递增方案。该方法是完全自适应的，利用每次剂量分配时可用的所有信息，并直接满足控制过量用药概率的伦理需求。它旨在在预测接受过量用药的患者比例不超过指定值的约束下，尽可能快地接近最大耐受剂量。我们进行了模拟，将所提出的方法与四种上下设计、两种随机逼近方法以及连续重新评估方法的一种变体进行比较。结果表明，所提出的方法作为控制过量用药频率的一种手段是有效的。相对于连续重新评估方法，我们的方案使过量用药的患者比例更小，毒性更少，并且以相当的准确性估计最大耐受剂量。与非参数方案相比，我们的方法在亚治疗或严重毒性剂量水平下治疗的患者更少，在最佳剂量水平下治疗的患者更多，并且以更小的平均偏差和均方误差估计最大耐受剂量。因此，所提出的方法是目前用于癌症I期临床试验设计的有前景的替代方案。
