UKCTOCS update: applying insights of delayed effects in cancer screening trials to the long-term follow-up mortality analysis

摘要

During trials that span decades, new evidence including progress in statistical methodology, may require revision of original assumptions. An example is the continued use of a constant-effect approach to analyse the mortality reduction which is often delayed in cancer-screening trials. The latter led us to re-examine our approach for the upcoming primary mortality analysis (2020) of long-term follow-up of the United Kingdom Collaborative Trial of Ovarian Cancer Screening (LTFU UKCTOCS), having initially (2014) used the proportional hazards?(PH) Cox?model. We wrote to 12 experts in statistics/epidemiology/screening?trials, setting out current evidence, the?importance of pre-specification, our?previous mortality analysis (2014) and three possible choices for the follow-up analysis (2020) of the mortality outcome:?(A) all data (2001–2020) using the Cox?model (2014), (B) new data (2015–2020) only and (C) all data (2001–2020) using a test that allows for delayed effects. Of 11 respondents, eight supported changing the 2014 approach to allow for a potential delayed effect (option C), suggesting various tests while three favoured retaining the Cox?model (option A). Consequently, we opted for the Versatile test introduced in 2016 which maintains good power for early, constant or delayed effects. We retained the Royston-Parmar model to estimate absolute differences in disease-specific mortality at 5, 10, 15 and 18?years. The decision to alter the follow-up analysis for the primary outcome on the basis of new evidence and using new statistical methodology for long-term follow-up is novel and has implications beyond UKCTOCS. There is an urgent need for consensus building on how best to design, test, estimate and report mortality outcomes from long-term randomised cancer screening trials. ISRCTN22488978 . Registered on 6 April 2000.