Mick R, Crowley J J, Carroll R J
Department of Biostatistics and Epidemiology, University of Pennsylvania School of Medicine, Philadelphia, PA, USA.
Control Clin Trials. 2000 Aug;21(4):343-59. doi: 10.1016/s0197-2456(00)00058-1.
Phase II evaluation is a critical screening step in the development of new cancer treatments. Historically, anticancer agents have been cytotoxic; they kill existing cells. As such, the primary endpoint for phase II evaluation has been tumor response rate, the percentage of patients whose tumors shrink > 50%. Biotechnology has led to promising new anticancer agents that are cytostatic. In contrast to cytotoxics, these agents modulate tumor environments and/or cellular targets and are expected to delay tumor growth. Phase II evaluation of such agents may instead focus on failure-time endpoints, such as time to disease progression. We examine a phase II trial design that evaluates clinical benefit by comparing sequentially measured paired failure times within each treated patient. Clinical efficacy is defined by a hazard ratio. Assuming patients eligible for a phase II study of a new cytostatic agent have failed previous cancer treatment, their most recent prior time to progression interval, TTP(1), is uncensored. Time to progression after the cytostatic agent, TTP(2), may or may not be censored at analysis. The design is motivated by a "growth modulation index" (TTP(2)/TTP(1)) and the proposition that a cytostatic agent be considered effective if the index is greater than 1.33. A chi(2) test statistic is employed to evaluate the paired failure-time data (TTP(1), TTP(2)). The degree of correlation between the paired failure times is a key feature of this design. Power of the test was evaluated through simulation of trials. Assuming a null hazard ratio equal to 1.0, a trial designed to detect an alternative hazard ratio equal to 1.3, based on accrual of 25 patients/year for 2 years (50 patients total) and with an additional 2 years of follow-up, has 25%, 46%, and 83% power based on correlations of 0.3, 0.5 and 0.7, respectively. These results demonstrate efficiency of the trial design, given moderate to strong correlations between paired failure times.
II期评估是新型癌症治疗药物研发过程中的关键筛选步骤。从历史上看，抗癌药物具有细胞毒性，它们会杀死现存细胞。因此，II期评估的主要终点一直是肿瘤缓解率，即肿瘤缩小超过50%的患者百分比。生物技术带来了前景广阔的新型抗癌药物，这些药物具有细胞生长抑制作用。与细胞毒性药物不同，这些药物可调节肿瘤环境和/或细胞靶点，并有望延缓肿瘤生长。对此类药物的II期评估可能转而关注失败时间终点，如疾病进展时间。我们研究了一种II期试验设计，该设计通过比较每个接受治疗患者序贯测量的配对失败时间来评估临床获益。临床疗效由风险比定义。假设符合新型细胞生长抑制药物II期研究条件的患者之前的癌症治疗失败，他们最近一次的疾病进展时间间隔TTP(1)是未删失的。使用细胞生长抑制药物后的疾病进展时间TTP(2)在分析时可能删失，也可能未删失。该设计的动机是“生长调节指数”（TTP(2)/TTP(1)）以及如果该指数大于1.33，则认为细胞生长抑制药物有效的观点。采用卡方检验统计量来评估配对失败时间数据（TTP(1)，TTP(2)）。配对失败时间之间的相关程度是该设计的一个关键特征。通过试验模拟评估了检验效能。假设无效风险比等于1.0，一项基于每年入组25例患者，持续2年（共50例患者）并额外随访2年的试验，旨在检测替代风险比等于1.3，基于配对失败时间的相关性分别为0.3、0.5和0.7时，其检验效能分别为25%、46%和83%。鉴于配对失败时间之间存在中度至强相关性，这些结果证明了该试验设计的有效性。
