The degree of overdiagnosis in common cancer screening trials is uncertain due to inadequate design of trials, varying definition and methods used to estimate overdiagnosis. Therefore, we aimed to quantify the risk of overdiagnosis for the most widely implemented cancer screening programmes and assess the implications of design limitations and biases in cancer screening trials on the estimates of overdiagnosis by conducting an overview and re-analysis of systematic reviews of cancer screening. We searched PubMed and the Cochrane Library from their inception dates to November 29, 2021. Eligible studies included systematic reviews of randomised trials comparing cancer screening interventions to no screening, which reported cancer incidence for both trial arms. We extracted data on study characteristics, cancer incidence and assessed the risk of bias using the Cochrane Collaboration’s risk of bias tool. We included 19 trials described in 30 articles for review, reporting results for the following types of screening: mammography for breast cancer, chest X-ray or low-dose CT for lung cancer, alpha-foetoprotein and ultrasound for liver cancer, digital rectal examination, prostate-specific antigen, and transrectal ultrasound for prostate cancer, and CA-125 test and/or ultrasound for ovarian cancer. No trials on screening for melanoma were eligible. Only one trial (5%) had low risk in all bias domains, leading to a post-hoc meta-analysis, excluding trials with high risk of bias in critical domains, finding the extent of overdiagnosis ranged from 17% to 38% across cancer screening programmes. We conclude that there is a significant risk of overdiagnosis in the included randomised trials on cancer screening. We found that trials were generally not designed to estimate overdiagnosis and many trials had high risk of biases that may draw the estimates of overdiagnosis towards the null. In effect, the true extent of overdiagnosis due to cancer screening is likely underestimated.
- • Randomised cancer screening trials are rarely designed for estimating overdiagnosis.
- • Many trials were biased towards underestimating the degree of overdiagnosis.
- • Overdiagnosis was revealed in screening for lung, breast and prostate cancer.
- • The first overview and re-analysis of overdiagnosis in cancer screening trials.
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 and it is the most serious harm of cancer screening. 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. 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. .
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. 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). 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. .
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.