Proportional Hazards Violations in Phase III Cancer Clinical Trials: A Potential Source of Trial Misinterpretation.

Autor:	Lin TA; Division of Radiation Oncology, Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.; Department of Radiation Oncology and Molecular Radiation Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland., McCaw ZR; Insitro, South San Francisco, California.; Department of Biostatistics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina., Koong A; Division of Radiation Oncology, Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas., Lin C; Division of Radiation Oncology, Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas., Abi Jaoude J; Division of Radiation Oncology, Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.; Department of Radiation Oncology, Stanford Medicine, Palo Alto, California., Patel R; Division of Radiation Oncology, Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.; Department of Radiation Oncology, Memorial-Sloan Kettering Cancer Center, New York, New York., Kouzy R; Division of Radiation Oncology, Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas., El Alam MB; Division of Radiation Oncology, Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas., Sherry AD; Division of Radiation Oncology, Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas., Noticewala SS; Division of Radiation Oncology, Department of Gastrointestinal Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas., Fuller CD; Division of Radiation Oncology, Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas., Thomas CR Jr; Department of Radiation Oncology and Applied Sciences, Dartmouth Cancer Center, Geisel School of Medicine, Lebanon, New Hampshire., Sun R; Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, Texas., Lee JJ; Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, Texas., Lin R; Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, Texas., Yuan Y; Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, Texas., Shyr Y; Department of Biostatistics, Vanderbilt University Medical Center, Nashville, Tennessee., Meirson T; Davidoff Cancer Center, Rabin Medical Center-Beilinson Hospital, Petach Tikva, Israel., Ludmir EB; Division of Radiation Oncology, Department of Gastrointestinal Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.; Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Jazyk:	angličtina
Zdroj:	Clinical cancer research : an official journal of the American Association for Cancer Research [Clin Cancer Res] 2024 Oct 15; Vol. 30 (20), pp. 4791-4799.
DOI:	10.1158/1078-0432.CCR-24-0566
Abstrakt:	Purpose: Survival analyses of novel agents with long-term responders often exhibit differential hazard rates over time. Such proportional hazards violations (PHV) may reduce the power of the log-rank test and lead to misinterpretation of trial results. We aimed to characterize the incidence and study attributes associated with PHVs in phase III oncology trials and assess the utility of restricted mean survival time and maximum combination test as additional analyses. Experimental Design: Clinicaltrials.gov and PubMed were searched to identify two-arm, randomized, phase III superiority-design cancer trials with time-to-event primary endpoints and published results through 2020. Patient-level data were reconstructed from published Kaplan-Meier curves. PHVs were assessed using Schoenfeld residuals. Results: Three hundred fifty-seven Kaplan-Meier comparisons across 341 trials were analyzed, encompassing 292,831 enrolled patients. PHVs were identified in 85/357 [23.8%; 95% confidence interval (CI), 19.7%, 28.5%] comparisons. In multivariable analysis, non-overall survival endpoints [OR, 2.16 (95% CI, 1.21, 3.87); P = 0.009] were associated with higher odds of PHVs, and immunotherapy comparisons [OR 1.94 (95% CI, 0.98, 3.86); P = 0.058] were weakly suggestive of higher odds of PHVs. Few trials with PHVs (25/85, 29.4%) prespecified a statistical plan to account for PHVs. Fourteen trials with PHVs exhibited discordant statistical signals with restricted mean survival time or maximum combination test, of which 10 (71%) reported negative results. Conclusions: PHVs are common across therapy types, and attempts to account for PHVs in statistical design are lacking despite the potential for results exhibiting nonproportional hazards to be misinterpreted. (©2024 American Association for Cancer Research.)
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu