Cargando…
The case against censoring of progression-free survival in cancer clinical trials – A pandemic shutdown as an illustration
BACKGROUND: Missing data may lead to loss of statistical power and introduce bias in clinical trials. The Covid-19 pandemic has had a profound impact on patient health care and on the conduct of cancer clinical trials. Although several endpoints may be affected, progression-free survival (PFS) is of...
Autores principales: | , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BioMed Central
2022
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9532825/ https://www.ncbi.nlm.nih.gov/pubmed/36199019 http://dx.doi.org/10.1186/s12874-022-01731-5 |
_version_ | 1784802205181673472 |
---|---|
author | Jamoul, Corinne Collette, Laurence Coart, Elisabeth D’Hollander, Koenraad Burzykowski, Tomasz Saad, Everardo D. Buyse, Marc |
author_facet | Jamoul, Corinne Collette, Laurence Coart, Elisabeth D’Hollander, Koenraad Burzykowski, Tomasz Saad, Everardo D. Buyse, Marc |
author_sort | Jamoul, Corinne |
collection | PubMed |
description | BACKGROUND: Missing data may lead to loss of statistical power and introduce bias in clinical trials. The Covid-19 pandemic has had a profound impact on patient health care and on the conduct of cancer clinical trials. Although several endpoints may be affected, progression-free survival (PFS) is of major concern, given its frequent use as primary endpoint in advanced cancer and the fact that missed radiographic assessments are to be expected. The recent introduction of the estimand framework creates an opportunity to define more precisely the target of estimation and ensure alignment between the scientific question and the statistical analysis. METHODS: We used simulations to investigate the impact of two basic approaches for handling missing tumor scans due to the pandemic: a “treatment policy” strategy, which consisted in ascribing events to the time they are observed, and a “hypothetical” approach of censoring patients with events during the shutdown period at the last assessment prior to that period. We computed the power of the logrank test, estimated hazard ratios (HR) using Cox models, and estimated median PFS times without and with a hypothetical 6-month shutdown period with no patient enrollment or tumor scans being performed, varying the shutdown starting times. RESULTS: Compared with the results in the absence of shutdown, the “treatment policy” strategy slightly overestimated median PFS proportionally to the timing of the shutdown period, but power was not affected. Except for one specific scenario, there was no impact on the estimated HR. In general, the pandemic had a greater impact on the analyses using the “hypothetical” strategy, which led to decreased power and overestimated median PFS times to a greater extent than the “treatment policy” strategy. CONCLUSION: As a rule, we suggest that the treatment policy approach, which conforms with the intent-to-treat principle, should be the primary analysis to avoid unnecessary loss of power and minimize bias in median PFS estimates. |
format | Online Article Text |
id | pubmed-9532825 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-95328252022-10-05 The case against censoring of progression-free survival in cancer clinical trials – A pandemic shutdown as an illustration Jamoul, Corinne Collette, Laurence Coart, Elisabeth D’Hollander, Koenraad Burzykowski, Tomasz Saad, Everardo D. Buyse, Marc BMC Med Res Methodol Research BACKGROUND: Missing data may lead to loss of statistical power and introduce bias in clinical trials. The Covid-19 pandemic has had a profound impact on patient health care and on the conduct of cancer clinical trials. Although several endpoints may be affected, progression-free survival (PFS) is of major concern, given its frequent use as primary endpoint in advanced cancer and the fact that missed radiographic assessments are to be expected. The recent introduction of the estimand framework creates an opportunity to define more precisely the target of estimation and ensure alignment between the scientific question and the statistical analysis. METHODS: We used simulations to investigate the impact of two basic approaches for handling missing tumor scans due to the pandemic: a “treatment policy” strategy, which consisted in ascribing events to the time they are observed, and a “hypothetical” approach of censoring patients with events during the shutdown period at the last assessment prior to that period. We computed the power of the logrank test, estimated hazard ratios (HR) using Cox models, and estimated median PFS times without and with a hypothetical 6-month shutdown period with no patient enrollment or tumor scans being performed, varying the shutdown starting times. RESULTS: Compared with the results in the absence of shutdown, the “treatment policy” strategy slightly overestimated median PFS proportionally to the timing of the shutdown period, but power was not affected. Except for one specific scenario, there was no impact on the estimated HR. In general, the pandemic had a greater impact on the analyses using the “hypothetical” strategy, which led to decreased power and overestimated median PFS times to a greater extent than the “treatment policy” strategy. CONCLUSION: As a rule, we suggest that the treatment policy approach, which conforms with the intent-to-treat principle, should be the primary analysis to avoid unnecessary loss of power and minimize bias in median PFS estimates. BioMed Central 2022-10-05 /pmc/articles/PMC9532825/ /pubmed/36199019 http://dx.doi.org/10.1186/s12874-022-01731-5 Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/ (https://creativecommons.org/publicdomain/zero/1.0/) ) applies to the data made available in this article, unless otherwise stated in a credit line to the data. |
spellingShingle | Research Jamoul, Corinne Collette, Laurence Coart, Elisabeth D’Hollander, Koenraad Burzykowski, Tomasz Saad, Everardo D. Buyse, Marc The case against censoring of progression-free survival in cancer clinical trials – A pandemic shutdown as an illustration |
title | The case against censoring of progression-free survival in cancer clinical trials – A pandemic shutdown as an illustration |
title_full | The case against censoring of progression-free survival in cancer clinical trials – A pandemic shutdown as an illustration |
title_fullStr | The case against censoring of progression-free survival in cancer clinical trials – A pandemic shutdown as an illustration |
title_full_unstemmed | The case against censoring of progression-free survival in cancer clinical trials – A pandemic shutdown as an illustration |
title_short | The case against censoring of progression-free survival in cancer clinical trials – A pandemic shutdown as an illustration |
title_sort | case against censoring of progression-free survival in cancer clinical trials – a pandemic shutdown as an illustration |
topic | Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9532825/ https://www.ncbi.nlm.nih.gov/pubmed/36199019 http://dx.doi.org/10.1186/s12874-022-01731-5 |
work_keys_str_mv | AT jamoulcorinne thecaseagainstcensoringofprogressionfreesurvivalincancerclinicaltrialsapandemicshutdownasanillustration AT collettelaurence thecaseagainstcensoringofprogressionfreesurvivalincancerclinicaltrialsapandemicshutdownasanillustration AT coartelisabeth thecaseagainstcensoringofprogressionfreesurvivalincancerclinicaltrialsapandemicshutdownasanillustration AT dhollanderkoenraad thecaseagainstcensoringofprogressionfreesurvivalincancerclinicaltrialsapandemicshutdownasanillustration AT burzykowskitomasz thecaseagainstcensoringofprogressionfreesurvivalincancerclinicaltrialsapandemicshutdownasanillustration AT saadeverardod thecaseagainstcensoringofprogressionfreesurvivalincancerclinicaltrialsapandemicshutdownasanillustration AT buysemarc thecaseagainstcensoringofprogressionfreesurvivalincancerclinicaltrialsapandemicshutdownasanillustration AT jamoulcorinne caseagainstcensoringofprogressionfreesurvivalincancerclinicaltrialsapandemicshutdownasanillustration AT collettelaurence caseagainstcensoringofprogressionfreesurvivalincancerclinicaltrialsapandemicshutdownasanillustration AT coartelisabeth caseagainstcensoringofprogressionfreesurvivalincancerclinicaltrialsapandemicshutdownasanillustration AT dhollanderkoenraad caseagainstcensoringofprogressionfreesurvivalincancerclinicaltrialsapandemicshutdownasanillustration AT burzykowskitomasz caseagainstcensoringofprogressionfreesurvivalincancerclinicaltrialsapandemicshutdownasanillustration AT saadeverardod caseagainstcensoringofprogressionfreesurvivalincancerclinicaltrialsapandemicshutdownasanillustration AT buysemarc caseagainstcensoringofprogressionfreesurvivalincancerclinicaltrialsapandemicshutdownasanillustration |