Detecting an Overall Survival Benefit that Is Derived From Progression-Free Survival

被引:405
作者
Broglio, Kristine R. [2 ]
Berry, Donald A. [1 ]
机构
[1] Univ Texas MD Anderson Canc Ctr, Dept Biostat, Div Quantitat Sci, Houston, TX 77230 USA
[2] Texas A&M Univ, Dept Stat, College Stn, TX 77843 USA
来源
JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE | 2009年 / 101卷 / 23期
关键词
METASTATIC BREAST-CANCER; SURROGATE END-POINTS; COLORECTAL-CANCER;
D O I
10.1093/jnci/djp369
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Whether progression-free survival (PFS) or overall survival (OS) is the more appropriate endpoint in clinical trials of metastatic cancer is controversial. In some disease and treatment settings, an improvement in PFS does not result in an improved OS. We partitioned OS into two parts and expressed it as the sum of PFS and survival postprogression (SPP). We simulated randomized clinical trials with two arms that had respective medians for PFS of 6 and 9 months. We assumed no treatment difference in median SPP. We found the probability of a statistically significant benefit in OS for various median SPP and observed P values for PFS. We compared the sample sizes required for PFS vs OS for various median SPP. We compare our results with the literature regarding surrogacy of PFS for OS by use of the correlation between hazard ratios for PFS and OS. All statistical tests were two-sided. For a trial with observed P value for improvement in PFS of .001, there was a greater than 90% probability for statistical significance in OS if median SPP was 2 months but less than 20% if median SPP was 24 months. For a trial requiring 280 patients to detect a 3-month difference in PFS, 350 and 2440 patients, respectively, were required to have the same power for detecting a real difference in OS that is carried over from the 3-month benefit in PFS when the median SPP was 2 and 24 months. Addressing SPP is important in understanding treatment effects. For clinical trials with a PFS benefit, lack of statistical significance in OS does not imply lack of improvement in OS, especially for diseases with long median SPP. Although there may be no treatment effect on SPP, its variability so dilutes the OS comparison that statistical significance is likely lost. OS is a reasonable primary endpoint when median SPP is short but is too high a bar when median SPP is long, such as longer than 12 months.
引用
收藏
页码:1642 / 1649
页数:8
相关论文
共 15 条
[1]  
ALBAIN KS, 2008, 2008 AM SOC CLIN ONC
[2]   Trouble at the office [J].
Allison, Malorye .
NATURE BIOTECHNOLOGY, 2008, 26 (09) :967-969
[3]  
[Anonymous], 2006, R LANG ENV STAT COMP
[4]  
Berry D. A., 2008, 2008 AM SOC CLIN ONC
[5]   The relationship between progression-free and post-progression survival in treating four types of metastatic cancer [J].
Bowater, Russell J. ;
Bridge, Luke J. ;
Lilford, Richard J. .
CANCER LETTERS, 2008, 262 (01) :48-53
[6]   Evaluation of tumor response, disease control, progression-free survival, and time to progression as potential surrogate end points in metastatic breast cancer [J].
Burzykowski, Tomasz ;
Buyse, Marc ;
Piccart-Gebhart, Martine J. ;
Sledge, George ;
Carmichael, James ;
Lueck, Hans-Joachim ;
Mackey, John R. ;
Nabholtz, Jean-Marc ;
Paridaens, Robert ;
Biganzoli, Laura ;
Jassem, Jacek ;
Bontenbal, Marijke ;
Bonneterre, Jacques ;
Chan, Stephen ;
Basaran, Gul Atalay ;
Therasse, Patrick .
JOURNAL OF CLINICAL ONCOLOGY, 2008, 26 (12) :1987-1992
[7]   Exploring and validating surrogate endpoints in colorectal cancer [J].
Burzykowski, Tomasz ;
Buyse, Marc ;
Yothers, Greg ;
Sakamoto, Junichi ;
Sargent, Dan .
LIFETIME DATA ANALYSIS, 2008, 14 (01) :54-64
[8]   Prediction of survival benefits from progression-free survival in patients with advanced non small cell lung cancer: Evidence from a pooled analysis of 2,838 patients randomized in 7 trials [J].
Buyse, M. E. ;
Squifflet, P. ;
Laporte, S. ;
Fossella, F. V. ;
Georgoulias, V. ;
Pujol, J. ;
Kubota, K. ;
Monnier, A. ;
Kudoh, S. ;
Douillard, J. .
JOURNAL OF CLINICAL ONCOLOGY, 2008, 26 (15)
[9]   Progression-free survival is a surrogate for survival in advanced colorectal cancer [J].
Buyse, Marc ;
Burzykowski, Tomasz ;
Carroll, Kevin ;
Michiels, Stefan ;
Sargent, Daniel J. ;
Miller, Langdon L. ;
Elfring, Gary L. ;
Pignon, Jean-Pierre ;
Piedbois, Pascal .
JOURNAL OF CLINICAL ONCOLOGY, 2007, 25 (33) :5218-5224
[10]   Use of progression-free survival as a surrogate marker in oncology trials: some regulatory issues [J].
Chakravarty, Aloka ;
Sridhara, Rajeshwari .
STATISTICAL METHODS IN MEDICAL RESEARCH, 2008, 17 (05) :515-518