Quantification of overdiagnosis in randomised trials of cancer screening: an overview and re-analysis of systematic reviews

1Introduction

Overdiagnosis of cancer is the diagnosis of indolent neoplastic pathology that would never progress to cause symptoms and/or death during an individual´s lifetime [1] and it is the most serious harm of cancer screening. 234 If cancer is detected, clinicians cannot know which individuals that are overdiagnosed as it is not possible to know how the cancer would have evolved in the absence of screening. Therefore all patients are offered treatment or routine observation. [56] Overdiagnosed individuals are thus needlessly diagnosed, subsequently overtreated, and thereby harmed. For this reason, it is critical to know the extent of overdiagnosis in cancer screening to enable informed decisions about screening, e.g. whether to participate as an individual or whether to provide a given screening programme on a national level such as prostate cancer screening. [78] .

In theory, the most robust method to estimate overdiagnosis is to use data from RCTs with life-long follow-up of all participants and no contamination of the control group nor the intervention group, i.e. without screening of the two trial arms during and after the end of the study. [59] At the end of the active screening phase, an excess of cancers in the screened population is expected because screening should advance the time of diagnosis (lead time). [5] If there was no overdiagnosis, these excess cancers should be compensated over time because they would all progress to cancer that would be detected clinically after the active screening phase. Thus, a persistent excess in the cumulative incidence of cancers in the screened population after a sufficient follow-up time to account for lead time is high-quality evidence of overdiagnosis. [5810] .

The purpose of this overview and re-analysis of systematic reviews of RCTs of cancer screening was to assess the extent of design limitations and bias in the included RCTs for quantifying overdiagnosis and, if possible, to estimate the probability that cancer detected by screening was overdiagnosed for the most widespread cancer screening programmes. Many, if not all types of cancer screening, might lead to overdiagnosis. To our knowledge, we are the first to compile the evidence for overdiagnosis across screening for different cancers. For this paper, we chose to focus on the most widely offered cancer screening programmes.