Interpretability of Cancer Clinical Trial Results Using Restricted Mean Survival Time as an Alternative to the Hazard Ratio

被引:190
作者
Pak, Kyongsun [2 ]
Uno, Hajime [3 ]
Kim, Dae Hyun [4 ,5 ]
Tian, Lu [6 ]
Kane, Robert C. [7 ]
Takeuchi, Masahiro [2 ]
Fu, Haoda [8 ]
Claggett, Brian [9 ]
Wei, Lee-Jen [1 ]
机构
[1] Harvard TH Chan Sch Publ Hlth, Dept Biostat, 655 Huntington Ave, Boston, MA 20115 USA
[2] Kitasato Univ, Sch Pharm, Dept Clin Med Biostat, Minato Ku, Tokyo 1080072, Japan
[3] Dana Farber Canc Inst, Dept Med Oncol, Div Populat Sci, Boston, MA 02115 USA
[4] Brigham & Womens Hosp, Dept Med, Div Pharmacoepidemiol & Pharmacoecon, 75 Francis St, Boston, MA 02115 USA
[5] Beth Israel Deaconess Med Ctr, Dept Med, Div Gerontol, Boston, MA 02215 USA
[6] Stanford Univ, Sch Med, Dept Hlth Res & Policy, Palo Alto, CA 94304 USA
[7] OPinions, Hematol Oncol, Nokomis, FL USA
[8] Eli Lilly & Co, Indianapolis, IN 46285 USA
[9] Harvard Med Sch, Brigham & Womens Hosp, Div Cardiovasc Med, Boston, MA USA
关键词
CELL LUNG-CANCER; NIVOLUMAB;
D O I
10.1001/jamaoncol.2017.2797
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
IMPORTANCE In a comparative clinical study with progression-free survival (PFS) or overall survival (OS) as the end point, the hazard ratio (HR) is routinely used to design the study and to estimate the treatment effect at the end of the study. The clinical interpretation of the HR may not be straightforward, especially when the underlying model assumption is not valid. A robust procedure for study design and analysis that enables clinically meaningful interpretation of trial results is warranted. OBJECTIVE To discuss issues of conventional trial design and analysis and to present alternatives to the HR using a recent immunotherapy study as an illustrative example. DESIGN, SETTING, AND PARTICIPANTS By comparing 2 groups in a survival analysis, we discuss issues of using the HR and present the restricted mean survival time (RMST) as a summary measure of patients' survival profile over time. We show how to use the difference or ratio in RMST between 2 groups as an alternative for designing and analyzing a clinical study with an immunotherapy study as an illustrative example. MAIN OUTCOMES AND MEASURES Overall survival or PFS. Group contrast measures included HR, RMST difference or ratio, and the event rate difference. RESULTS For the illustrative example, the HR procedure indicates that nivolumab significantly prolonged patient OS and was numerically better than docetaxel for PFS. However, the median PFS time of docetaxel was significantly better than that of nivolumab. Therefore, it may be difficult to use median OS and/or PFS to interpret of the HR value clinically. On the other hand, using RMST difference, nivolumab was significantly better than docetaxel for both OS and PFS. We also provide details regarding design of a future study with RMST-based measures. CONCLUSIONS AND RELEVANCE The design and analysis of a conventional cancer clinical trial can be improved by adopting a robust statistical procedure that enables clinically meaningful interpretations of the treatment effect. The RMST-based quantitativemethod may be used as a primary tool for future cancer trials or to help us to better understand the clinical interpretation of the HR even when its model assumption is plausible.
引用
收藏
页码:1692 / 1696
页数:5
相关论文
共 15 条
[1]   Restricted Mean Survival Time: An Obligatory End Point for Time-to-Event Analysis in Cancer Trials? [J].
A'Hern, Roger P. .
JOURNAL OF CLINICAL ONCOLOGY, 2016, 34 (28) :3474-+
[2]  
[Anonymous], 2012, GUIDANCE IND ENRICHM
[3]   Nivolumab versus Docetaxel in Advanced Nonsquamous Non-Small-Cell Lung Cancer [J].
Borghaei, H. ;
Paz-Ares, L. ;
Horn, L. ;
Spigel, D. R. ;
Steins, M. ;
Ready, N. E. ;
Chow, L. Q. ;
Vokes, E. E. ;
Felip, E. ;
Holgado, E. ;
Barlesi, F. ;
Kohlhaeufl, M. ;
Arrieta, O. ;
Burgio, M. A. ;
Fayette, J. ;
Lena, H. ;
Poddubskaya, E. ;
Gerber, D. E. ;
Gettinger, S. N. ;
Rudin, C. M. ;
Rizvi, N. ;
Crino, L. ;
Blumenschein, G. R. ;
Antonia, S. J. ;
Dorange, C. ;
Harbison, C. T. ;
Finckenstein, F. Graf ;
Brahmer, J. R. .
NEW ENGLAND JOURNAL OF MEDICINE, 2015, 373 (17) :1627-1639
[4]   First-Line Nivolumab in Stage IV or Recurrent Non-Small-Cell Lung Cancer [J].
Carbone, D. P. ;
Reck, M. ;
Paz-Ares, L. ;
Creelan, B. ;
Horn, L. ;
Steins, M. ;
Felip, E. ;
van den Heuvel, M. M. ;
Ciuleanu, T. -E. ;
Badin, F. ;
Ready, N. ;
Hiltermann, T. J. N. ;
Nair, S. ;
Juergens, R. ;
Peters, S. ;
Minenza, E. ;
Wrangle, J. M. ;
Rodriguez-Abreu, D. ;
Borghaei, H. ;
Blumenschein, G. R. ;
Villaruz, L. C. ;
Havel, L. ;
Krejci, J. ;
Corral Jaime, J. ;
Chang, H. ;
Geese, W. J. ;
Bhagavatheeswaran, P. ;
Chen, A. C. ;
Socinski, M. A. .
NEW ENGLAND JOURNAL OF MEDICINE, 2017, 376 (25) :2415-2426
[5]   Describing Differences in Survival Curves [J].
Chappell, Rick ;
Zhu, Xiaotian .
JAMA ONCOLOGY, 2016, 2 (07) :906-907
[6]  
COX DR, 1972, J R STAT SOC B, V34, P187
[7]   Enhanced secondary analysis of survival data: reconstructing the data from published Kaplan-Meier survival curves [J].
Guyot, Patricia ;
Ades, A. E. ;
Ouwens, Mario J. N. M. ;
Welton, Nicky J. .
BMC MEDICAL RESEARCH METHODOLOGY, 2012, 12
[8]   A Predictive Enrichment Procedure to Identify Potential Responders to a New Therapy for Randomized, Comparative Controlled Clinical Studies [J].
Li, Junlong ;
Zhao, Lihui ;
Tian, Lu ;
Cai, Tianxi ;
Claggett, Brian ;
Callegaro, Andrea ;
Dizier, Benjamin ;
Spiessens, Bart ;
Ulloa-Montoya, Fernando ;
Wei, Lee-Jen .
BIOMETRICS, 2016, 72 (03) :877-887
[9]   A RESAMPLING METHOD BASED ON PIVOTAL ESTIMATING FUNCTIONS [J].
PARZEN, MI ;
WEI, LJ ;
YING, Z .
BIOMETRIKA, 1994, 81 (02) :341-350
[10]   The Net Chance of a Longer Survival as a Patient-Oriented Measure of Treatment Benefit in Randomized Clinical Trials [J].
Peron, Julien ;
Roy, Pascal ;
Ozenne, Brice ;
Roche, Laurent ;
Buyse, Marc .
JAMA ONCOLOGY, 2016, 2 (07) :901-905