Effect of Screening on Breast Cancer Mortality
Randomized Controlled Trials
Randomized controlled trials (RCTs), with participation by nearly half a million women from four countries, examined the breast cancer mortality of women who were offered regular screening. One trial (the Canadian National Breast Screening Study [NBSS]-2) compared mammogram plus clinical breast examination (CBE) with CBE alone, but the other eight compared screening mammogram with or without CBE with a control consisting of usual care. The trials differed in design, recruitment of participants, interventions (both screening and treatment), management of the control group, compliance with assignment to screening and control groups, and analysis of outcomes. Some trials used individual randomization while others used cluster randomization in which cohorts were identified and then offered screening, and in one case, nonrandomized allocation by day-of-birth in any given month. Cluster randomization sometimes led to imbalances between the intervention and control groups. Age differences have been identified in several trials, although the differences were probably too small to have a major effect on the trial outcome. In the Edinburgh Trial, socioeconomic status differed markedly between the intervention and control groups. Since socioeconomic status is associated with the risk of breast cancer mortality, this difference makes it difficult, if not impossible, to interpret the trial results.
Since breast cancer mortality is the major outcome parameter for each of these trials, the methods used to determine cause of death is critically important. Efforts to reduce bias in the attribution of mortality cause have been made, including the use of a blinded monitoring committee (New York) and a linkage to independent data sources, such as national mortality registries (Swedish trials). Unfortunately, even these attempts may be unable to avoid prior knowledge of women's assignment to screening or control arms. Evidence of possible misclassification of breast cancer deaths in the Two-County trial that could bias results in favor of screening has been reviewed.
Differences exist in the methodology used to analyze the results of these trials. Four of the five Swedish trials were designed to include a single screening mammogram in the control group, timed to correspond with the end of the series of screening mammograms in the study group. The initial analysis of these trials used an "evaluation" analysis, tallying only the breast cancer deaths that occurred in women whose cancer was discovered at or before the last study mammogram. In some of the trials a delay occurred in the performance of the end-of-study mammogram, resulting in more time for control group women to develop or be diagnosed with breast cancer. Other trials used a "follow-up" analysis, which counts all deaths attributed to breast cancer, regardless of the time of diagnosis. This type of analysis was used in a meta-analysis of four of the five Swedish trials in response to previously expressed concerns about the effect of a delay in control group mammograms upon evaluation analyses.