Texier Matthieu, Rotolo Federico, Ducreux Michel, Bouché Olivier, Pignon Jean-Pierre, Michiels Stefan
Biostatistics and Epidemiology Unit, Gustave Roussy, Université Paris-Saclay, 94805 Villejuif, France.
CESP INSERM U1018, Paris-Sud University, 94805 Villejuif, France.
Comput Math Methods Med. 2018 Jan 11;2018:1672176. doi: 10.1155/2018/1672176. eCollection 2018.
In early phase clinical trials of cytotoxic drugs in oncology, the efficacy is typically evaluated based on the tumor shrinkage. However, this criterion is not always appropriate for more recent cytostatic agents, and alternative endpoints have been proposed. The growth modulation index (GMI), defined as the ratio between the times to progression in two successive treatment lines, has been proposed for a single-arm phase II trials. The treatment effect is evaluated by estimating the rate of patients having a GMI superior to a given threshold. To estimate this rate, we investigated a parametric method based on the distribution of the times to progression and a nonparametric one based on a midrank estimator. Through simulations, we studied their operating characteristics and the impact of different design parameters (censoring, dependence, and distribution) on them. In these simulations, the nonparametric estimator slightly underestimated the rate and had slightly overconservative confidence intervals in some cases. Conversely, the parametric estimator overestimated the rate and had anticonservative confidence intervals in some cases. The nonparametric method appeared to be more robust to censoring than the parametric one. In conclusion, we recommend the nonparametric method, but the parametric method can be used as a supplementary tool.
在肿瘤学中细胞毒性药物的早期临床试验中，疗效通常根据肿瘤缩小情况进行评估。然而，该标准并不总是适用于最近的细胞生长抑制剂，因此有人提出了替代终点。生长调节指数（GMI）定义为两个连续治疗阶段进展时间的比值，已被用于单臂II期试验。通过估计GMI高于给定阈值的患者比例来评估治疗效果。为了估计这个比例，我们研究了一种基于进展时间分布的参数方法和一种基于中秩估计量的非参数方法。通过模拟，我们研究了它们的操作特性以及不同设计参数（删失、相关性和分布）对它们的影响。在这些模拟中，非参数估计量在某些情况下略微低估了比例，并且置信区间略微过于保守。相反，参数估计量在某些情况下高估了比例，并且置信区间过于宽松。非参数方法似乎比参数方法对删失更具稳健性。总之，我们推荐使用非参数方法，但参数方法可作为一种补充工具。
