School of Medicine, University of California, San Francisco, San Francisco, CA, USA.
Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, CA, USA.
Nat Rev Clin Oncol. 2023 Dec;20(12):885-895. doi: 10.1038/s41571-023-00823-5. Epub 2023 Oct 12.
Composite outcome measures such as progression-free survival and disease-free survival are increasingly used as surrogate end points in oncology research, frequently serving as the primary end point of pivotal trials that form the basis for FDA and EMA approvals. Such outcome measures combine two or more distinct events (for example, tumour (re)growth, new lesions and/or death) into a single, time-to-event end point. The use of a composite end point can increase the statistical power of a clinical trial and decrease the follow-up period required to demonstrate efficacy, thus lowering costs; however, these end points have a number of limitations. Composite outcomes are often vaguely defined, with definitions that vary greatly between studies, complicating comparisons of results across trials. Altering the makeup of events included in a composite outcome can alter study conclusions, including whether treatment effects are statistically significant. Moreover, the events included in a composite outcome often vary in clinical significance, reflect distinct biological pathways and/or are affected differently by treatment. Therefore, knowing the precise breakdown of the component events is essential to accurately interpret trial results and gauge the true benefit of an intervention. In oncology clinical trials, however, such information is rarely provided. In this Perspective, we emphasize this deficiency through a review of 50 studies with progression-free survival as an outcome published in five top oncology journals, discuss the advantages and challenges of using composite end points, and highlight the need for transparent reporting of the component events.
复合结局指标，如无进展生存期和无病生存期，越来越多地被用作肿瘤学研究中的替代终点指标，通常作为关键性试验的主要终点指标，这些试验是 FDA 和 EMA 批准的基础。这些结局指标将两个或多个不同的事件（例如肿瘤（再）生长、新病灶和/或死亡）组合成一个单一的、时间相关的终点指标。复合终点指标的使用可以提高临床试验的统计学功效，并减少证明疗效所需的随访时间，从而降低成本；然而，这些终点指标有许多局限性。复合结局通常定义模糊，在不同的研究之间定义差异很大，使得跨试验的结果比较变得复杂。改变复合结局中包含的事件组合可以改变研究结论，包括治疗效果是否具有统计学意义。此外，复合结局中包含的事件在临床意义上往往不同，反映不同的生物学途径，并且受到治疗的影响也不同。因此，准确解读试验结果并评估干预措施的真实获益，了解复合结局中各个组成部分的具体情况至关重要。然而，在肿瘤学临床试验中，很少提供此类信息。在这篇观点文章中，我们通过回顾在五个顶级肿瘤学期刊上发表的 50 项以无进展生存期为结局的研究，强调了这一缺陷，讨论了使用复合终点指标的优点和挑战，并强调了透明报告组成部分事件的必要性。
