联合肿瘤缓解和无进展生存期作为晚期结直肠癌总生存期的替代终点
Combining tumour response and progression free survival as surrogate endpoints for overall survival in advanced colorectal cancer
摘要：
已将无进展生存期（PFS）和肿瘤缓解（TR）作为晚期结直肠癌（aCRC）总生存期（OS）的替代终点进行了研究，但其有效性显示为次优。近年来，已经提出了允许联合使用多个替代终点的荟萃分析方法。本研究的目的是评估联合使用PFS和TR作为OS的替代终点是否可以提高其预测价值。数据来自于一项随机对照试验的系统性综述，该试验研究了不同药物治疗对aCRC的有效性：全身化疗、抗表皮生长因子受体治疗、抗血管生成药物、其他多靶向抗叶酸治疗和肝内动脉化疗。采用多变量荟萃分析对替代终点（PFS、TR）的处理效应与最终结局（OS）之间的关联模式进行建模。对33项报告了对所有三种结局的处理效应的试验进行的分析显示，对PFS和OS的处理效应之间存在相当强的相关性。对TR和OS的处理效应之间存在较弱的替代关系。对两个替代终点TR和PFS进行建模，联合作为OS的预测因子，在交叉试验中，无论是代孕模式还是预测处理效应的精度都没有显著改善。验证程序。当研究治疗亚组时，在研究抗血管生成治疗的研究中，仅注意到预测处理效应对最终结局的精确度略有改善。总体而言，两个替代终点的同时建模并未改善aCRC中替代终点和最终终点的处理效应之间的相关性。
英文摘要：
Progression free survival (PFS) and tumour response (TR) have been investigated as surrogate endpoints for overall survival (OS) in advanced colorectal cancer (aCRC), however their validity has been shown to be suboptimal. In recent years, meta-analytic methods allowing for use of multiple surrogate endpoints jointly have been proposed. The aim of this research was to assess if PFS and TR used jointly as surrogate endpoints to OS improve their predictive value. Data were obtained from a systematic review of randomised controlled trials investigating effectiveness of different pharmacological therapies in aCRC: systemic chemotherapies, anti-epidermal growth factor receptor therapies, anti-angiogenic agents, other multi-targeted antifolate treatments and intra-hepatic arterial chemotherapy. Multivariate meta-analysis was used to model the association patterns between treatment effects on the surrogate endpoints (PFS, TR) and the final outcome (OS). Analysis of 33 trials which reported treatment effects on all three outcomes showed reasonably strong association between treatment effects on PFS and OS. A weak surrogate relationship was noted between the treatment effects on TR and OS. Modelling the two surrogate endpoints, TR and PFS, jointly as predictors of OS gave no marked improvement in neither surrogacy patterns nor the precision of predicted treatment effect in the cross-validation procedure. When investigating subgroups of therapy, only small improvement in precision of predicted treatment effects on the final outcome in studies investigating anti-angiogenic therapy was noted. Overall, the simultaneous modelling of two surrogate endpoints did not lead to improvement in association between treatment effects on surrogate and final endpoints in aCRC.
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