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

BackgroundDuring 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. MethodsWe wrote to 12 experts in statistics/epidemiology/screening-trials, setting out current evidence, importance of pre-specification, 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 (C)all data(2001-2020) using a test that allows for delayed effects. ResultsOf 11 respondents, eight supported changing the 2014-approach to allow for a potential delayed effect (optionC), suggesting various tests while three favoured retaining the Cox-model (optionA). 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. ConclusionsThe 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. Trial registration: (ISRCTN22488978, Registration date: 6/4/2000)