Postprogression therapy and confounding for the estimated treatment effect on overall survival in phase III oncology trials
Objective Estimations of the treatment effect on overall survival (OS) may be influenced by post-progression therapies (PPTs). It is unclear how often OS analyses account for PPT effects. The purpose of this cross-sectional analysis was to determine the prevalence of OS analyses accounting for PPT e...
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| Format: | Article |
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BMJ Publishing Group
2024-07-01
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| Series: | BMJ Oncology |
| Online Access: | https://bmjoncology.bmj.com/content/3/1/e000322.full |
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| author | Pavlos Msaouel Ramez Kouzy Joseph Abi Jaoude Ethan B Ludmir Alexander D Sherry Timothy A Lin Esther J Beck Avital M Miller Adina H Passy Gabrielle S Kupferman Eugene J Koay Clifton David Fuller Charles R Thomas Zachary R McCaw |
| author_facet | Pavlos Msaouel Ramez Kouzy Joseph Abi Jaoude Ethan B Ludmir Alexander D Sherry Timothy A Lin Esther J Beck Avital M Miller Adina H Passy Gabrielle S Kupferman Eugene J Koay Clifton David Fuller Charles R Thomas Zachary R McCaw |
| author_sort | Pavlos Msaouel |
| collection | DOAJ |
| description | Objective Estimations of the treatment effect on overall survival (OS) may be influenced by post-progression therapies (PPTs). It is unclear how often OS analyses account for PPT effects. The purpose of this cross-sectional analysis was to determine the prevalence of OS analyses accounting for PPT effects in phase III oncology trials.Methods and analysis We screened two-arm, superiority design, phase III, randomised, oncology trials reporting OS from ClinicalTrials.gov. The primary outcome was the frequency of OS analyses adjusting for PPT confounding. Logistic regressions computed ORs for the association between trial-level covariates and the outcome.Results A total of 334 phase III trials enrolling 265 310 patients were included, with publications between 2004 and 2020. PPTs were reported in 47% of trials (157 of 334), and an analysis accounting for PPTs was performed in only 12% of trials (N=41). PPT adjustments were often prespecified (N=23, 56%), and appeared to be more likely in cross-over studies (OR 5.04, 95% CI 2.42 to 10.38) and studies with discordant surrogate-OS findings (OR 2.26, 95% CI 1.16 to 4.38). In key subgroup analyses, PPT analyses were infrequent, including 8% of trials among those studying locoregional/first-line therapy and 11% of trials among those powered for OS.Conclusions Although time on PPTs is an important component of OS, PPTs are rarely considered in OS analyses, which may introduce confounding on estimates of the treatment effect on OS. PPTs and methods to account for their effects on OS estimates should be considered at the time of trial design and reporting. |
| format | Article |
| id | doaj-art-284718e1663b466c99a570c4fdc80d03 |
| institution | Kabale University |
| issn | 2752-7948 |
| language | English |
| publishDate | 2024-07-01 |
| publisher | BMJ Publishing Group |
| record_format | Article |
| series | BMJ Oncology |
| spelling | doaj-art-284718e1663b466c99a570c4fdc80d032025-01-30T06:40:10ZengBMJ Publishing GroupBMJ Oncology2752-79482024-07-013110.1136/bmjonc-2024-000322Postprogression therapy and confounding for the estimated treatment effect on overall survival in phase III oncology trialsPavlos Msaouel0Ramez Kouzy1Joseph Abi Jaoude2Ethan B Ludmir3Alexander D Sherry4Timothy A Lin5Esther J Beck6Avital M Miller7Adina H Passy8Gabrielle S Kupferman9Eugene J Koay10Clifton David Fuller11Charles R Thomas12Zachary R McCaw13Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA1The University of Texas MD Anderson Cancer Center, Houston, TX, USADepartment of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USAThe University of Texas MD Anderson Cancer Center, Houston, TX, USAThe University of Texas MD Anderson Cancer Center, Houston, TX, USADepartment of Radiation Oncology and Molecular Radiation Sciences, Johns Hopkins Medicine, Baltimore, Maryland, USADepartment of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USADepartment of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USADepartment of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USADepartment of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USADepartment of Gastrointestinal Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USADepartment of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USADepartment of Radiation Oncology and Applied Sciences, Dartmouth College Geisel School of Medicine, Lebanon, New Hampshire, USADepartment of Biostatistics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USAObjective Estimations of the treatment effect on overall survival (OS) may be influenced by post-progression therapies (PPTs). It is unclear how often OS analyses account for PPT effects. The purpose of this cross-sectional analysis was to determine the prevalence of OS analyses accounting for PPT effects in phase III oncology trials.Methods and analysis We screened two-arm, superiority design, phase III, randomised, oncology trials reporting OS from ClinicalTrials.gov. The primary outcome was the frequency of OS analyses adjusting for PPT confounding. Logistic regressions computed ORs for the association between trial-level covariates and the outcome.Results A total of 334 phase III trials enrolling 265 310 patients were included, with publications between 2004 and 2020. PPTs were reported in 47% of trials (157 of 334), and an analysis accounting for PPTs was performed in only 12% of trials (N=41). PPT adjustments were often prespecified (N=23, 56%), and appeared to be more likely in cross-over studies (OR 5.04, 95% CI 2.42 to 10.38) and studies with discordant surrogate-OS findings (OR 2.26, 95% CI 1.16 to 4.38). In key subgroup analyses, PPT analyses were infrequent, including 8% of trials among those studying locoregional/first-line therapy and 11% of trials among those powered for OS.Conclusions Although time on PPTs is an important component of OS, PPTs are rarely considered in OS analyses, which may introduce confounding on estimates of the treatment effect on OS. PPTs and methods to account for their effects on OS estimates should be considered at the time of trial design and reporting.https://bmjoncology.bmj.com/content/3/1/e000322.full |
| spellingShingle | Pavlos Msaouel Ramez Kouzy Joseph Abi Jaoude Ethan B Ludmir Alexander D Sherry Timothy A Lin Esther J Beck Avital M Miller Adina H Passy Gabrielle S Kupferman Eugene J Koay Clifton David Fuller Charles R Thomas Zachary R McCaw Postprogression therapy and confounding for the estimated treatment effect on overall survival in phase III oncology trials BMJ Oncology |
| title | Postprogression therapy and confounding for the estimated treatment effect on overall survival in phase III oncology trials |
| title_full | Postprogression therapy and confounding for the estimated treatment effect on overall survival in phase III oncology trials |
| title_fullStr | Postprogression therapy and confounding for the estimated treatment effect on overall survival in phase III oncology trials |
| title_full_unstemmed | Postprogression therapy and confounding for the estimated treatment effect on overall survival in phase III oncology trials |
| title_short | Postprogression therapy and confounding for the estimated treatment effect on overall survival in phase III oncology trials |
| title_sort | postprogression therapy and confounding for the estimated treatment effect on overall survival in phase iii oncology trials |
| url | https://bmjoncology.bmj.com/content/3/1/e000322.full |
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