Poor correlation between progression-free and overall survival in modern clinical trials: Are composite endpoints the answer?
Poor correlation between progression-free and overall survival in modern clinical trials: Are composite endpoints the answer?
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DOI：
10.1016/j.ejca.2011.10.028
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发表时间：
2012-02-01
影响因子：
8.4
通讯作者：
Ocana, Alberto
中科院分区：
文献类型：
--
作者：
Amir, Eitan;Seruga, Bostjan;Ocana, Alberto
很难确定准确反映转移性实体瘤患者获益的终点。总生存期（OS）是金标准，尽管无进展生存期（PFS）有时被用作OS的替代指标。统计建模表明，在进展后生存期（SPP）较长的疾病中，OS和PFS之间的相关性变得较弱。为了评估这些统计学假设，我们确定了过去10年中进行的随机试验的对照组和实验组中PFS和OS之间的关系，这些试验导致了药物的批准。我们的数据证实，当SPP较长时，PFS是OS的不良替代指标，但当SPP较短时，PFS是更好的替代指标。在SPP较短的癌症中，设计试验以显示OS获益是可行的，因此仍然是首选方法。在SPP较长的肿瘤中，PFS没有临床意义，除非它也与患者报告的结局（如生活质量）改善相关。肿瘤学界应考虑进一步开发和验证复合终点，包括不同疾病部位的患者报告结局和PFS。这些终点在过去已成功用于癌症试验。随着治疗方法的改进和许多癌症患者生存期的延长，以及医疗保健支付者越来越大的压力，以证明治疗会给患者带来益处，临床试验的最佳终点选择越来越重要。包括患者报告结局和中间终点（如PFS）的复合指标可能是解决方案，应进一步研究。(C)2011爱思唯尔有限公司保留所有权利。
It can be difficult to identify endpoints that accurately reflect patient benefit in metastatic solid tumors. Overall survival (OS) is the gold standard although progression-free survival (PFS) is sometimes used as a surrogate for OS. Statistical modelling has suggested that the association between OS and PFS becomes weaker in diseases with longer survival post-progression (SPP). To evaluate these statistical hypotheses we determined the relationship between PFS and OS in control and experimental arms of randomised trials conducted in the last 10 years, which have led to drug approval. Our data confirm that PFS is a poor surrogate for OS when SPP is long, but it is a better surrogate where SPP is short. In cancers with short SPP designing trials to show OS benefit is feasible and, therefore, remains the preferred approach. In tumours with long SPP, PFS is not clinically meaningful unless it is also associated with improvement in patient reported outcomes such as quality of life. The oncology community should consider the further development and validation of composite endpoints including patient reported outcomes and PFS across different disease sites. Such endpoints have been successfully used in cancer trials in the past. With improvements in therapy and prolonged survival of patients with many cancers, and with increasing pressure from healthcare payers to prove that treatment leads to patient benefit, the choice of optimal endpoints for clinical trials is increasingly important. Composite measures comprising patient reported outcomes and intermediate endpoints such as PFS may be the solution and should be investigated further. (C) 2011 Elsevier Ltd. All rights reserved.