Ciani Oriana, Buyse Marc, Garside Ruth, Peters Jaime, Saad Everardo D, Stein Ken, Taylor Rod S
Institute of Health Research, University of Exeter Medical School, Veysey Building, Salmon Pool Lane, Exeter EX2 4SG, UK; Centre for Research on Health and Social Care Management, Bocconi University, via Rontgen, 1, Milan 20141, Italy.
Interuniversity Institute for Biostatistics and Statistical Bioinformatics (I-BioStat), Hasselt University, Universitaire Campus, 3590 Diepenbeek, Belgium; International Drug Development Institute (IDDI), 185 Alewife Brook Parkway, Suite 410, Cambridge, MA 02138, USA.
J Clin Epidemiol. 2015 Jul;68(7):833-42. doi: 10.1016/j.jclinepi.2015.02.016. Epub 2015 Mar 6.
To quantify and compare the treatment effects on three surrogate end points, progression-free survival (PFS), time to progression (TTP), and tumor response rate (TR) vs. overall survival (OS) based on a meta-analysis of randomized controlled trials (RCTs) of drug interventions in advanced colorectal cancer (aCRC).
We systematically searched for RCTs of pharmacologic therapies in aCRC between 2003 and 2013. Trial characteristics, risk of bias, and outcomes were recorded based on a predefined form. Univariate and multivariate random-effects meta-analyses were used to estimate pooled summary treatment effects. The ratio of hazard ratios (HRs)/odds ratios (ORs) and difference in medians were used to quantify the degree of difference in treatment effects on the surrogate end points and OS. Spearman ρ, surrogate threshold effect (STE), and R(2) were also estimated across predefined trial-level covariates.
We included 101 RCTs. In univariate and multivariate meta-analyses, we found larger treatment effects for the surrogates than for OS. Compared with OS, treatment effects were on average 13% higher when HRs were measured and 3% to 45% higher when ORs were considered; differences in median PFS/TTP were higher than on OS by an average of 0.5 month. Spearman ρ ranged from 0.39 to 0.80, mean R(2) from 0.06 to 0.65, and STE was 0.8 for HRPFS, 0.64 for HRTTP, or 0.28 for ORTR. The stratified analyses revealed high variability across all strata.
None of the end points in this study were found to achieve the level of evidence (ie, mean R(2)trial > 0.60) that has been set to select high or excellent correlation levels by common surrogate evaluation tools. Previous surrogacy relationships observed between PFS and TTP vs. OS in selected settings may not apply across other classes or lines of therapy.
基于对晚期结直肠癌（aCRC）药物干预随机对照试验（RCT）的荟萃分析，对无进展生存期（PFS）、疾病进展时间（TTP）和肿瘤缓解率（TR）这三个替代终点与总生存期（OS）的治疗效果进行量化和比较。
我们系统检索了2003年至2013年间aCRC药物治疗的RCT。根据预定义表格记录试验特征、偏倚风险和结果。采用单变量和多变量随机效应荟萃分析来估计汇总治疗效果。风险比（HRs）/优势比（ORs）的比值以及中位数差异用于量化替代终点和OS治疗效果的差异程度。还在预定义的试验水平协变量中估计了Spearman ρ、替代阈值效应（STE）和R(2)。
我们纳入了101项RCT。在单变量和多变量荟萃分析中，我们发现替代终点的治疗效果大于OS。与OS相比，测量HRs时治疗效果平均高13%，考虑ORs时高3%至45%；PFS/TTP中位数差异比OS平均高0.5个月。Spearman ρ范围为0.39至0.80，平均R(2)为0.06至0.65，HRPFS的STE为0.8，HRTTP为0.64，ORTR为0.28。分层分析显示所有层的变异性都很高。
本研究中没有一个终点达到常见替代评估工具设定的选择高或优秀相关性水平的证据水平（即平均R(2)试验>0.60）。先前在特定环境中观察到的PFS和TTP与OS之间的替代关系可能不适用于其他治疗类别或治疗线。
