Journal of the National Cancer Institute Advance Access published online on November 9, 2009
JNCI Journal of the National Cancer Institute, doi:10.1093/jnci/djp369
© The Author 2009. Published by Oxford University Press. All rights reserved.
ARTICLE |
Detecting an Overall Survival Benefit that Is Derived From Progression-Free Survival
Affiliations of authors: Department of Statistics, Texas A&M University, College Station, TX (KRB); Department of Biostatistics, Division of Quantitative Sciences, University of Texas M. D. Anderson Cancer Center, Houston, TX (DAB)
Correspondence to: Donald A. Berry, PhD, Department of Biostatistics, University of Texas M. D. Anderson Cancer Center, PO Box 301402, Houston, TX 77230-1402 (e-mail: dberry{at}mdanderson.org).
Background: 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.
Methods: 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.
Results: 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.
Conclusions: 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.
| CONTEXT AND CAVEATS Prior knowledge It is still controversial as to whether progression-free survival (PFS) or overall survival (OS) is the most appropriate endpoint in clinical trials of metastatic cancer. Study design Clinical trials with two arms having respective medians for PFS of 6 and 9 months were simulated. OS was the sum of PFS and survival postprogression (SPP). Probabilities of a benefit in OS were determined for various median SPP, by assuming no treatment-related difference in SPP, and for observed P values for PFS. Sample sizes required for various PFS and OS values were determined. Contribution OS was a reasonable primary endpoint when median SPP was short but was too high a bar when median SPP was long (eg, longer than 12 months). Implications As therapies for metastatic cancer improve, SPP would be expected to increase, which may decrease the utility of OS as a clinical endpoint. Limitations Simulations considered a specific difference in median PFS, accrual rate, and follow-up time. PFS and SPP were assumed to follow exponential distributions. The assumption that there was no difference in SPP may not be correct in a particular circumstance. From the Editors
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Manuscript received April 7, 2009; revised August 31, 2009; accepted September 18, 2009.