Karsten Juhl Jørgensen

BACKGROUND: A variety of estimates of the benefits and harms of mammographic screening for breast cancer have been published and national policies vary. OBJECTIVES: To assess the effect of screening for breast cancer with mammography on mortality and morbidity. SEARCH METHODS: We searched PubMed (22 November 2012) and the World Health Organization's International Clinical Trials Registry Platform (22 November 2012). SELECTION CRITERIA: Randomised trials comparing mammographic screening with no mammographic screening. DATA COLLECTION AND ANALYSIS: Two authors independently extracted data. Study authors were contacted for additional information. MAIN RESULTS: Eight eligible trials were identified. We excluded a trial because the randomisation had failed to produce comparable groups.The eligible trials included 600,000 women in the analyses in the age range 39 to 74 years. Three trials with adequate randomisation did not show a statistically significant reduction in breast cancer mortality at 13 years (relative risk (RR) 0.90, 95% confidence interval (CI) 0.79 to 1.02); four trials with suboptimal randomisation showed a significant reduction in breast cancer mortality with an RR of 0.75 (95% CI 0.67 to 0.83). The RR for all seven trials combined was 0.81 (95% CI 0.74 to 0.87). We found that breast cancer mortality was an unreliable outcome that was biased in favour of screening, mainly because of differential misclassification of cause of death. The trials with adequate randomisation did not find an effect of screening on total cancer mortality, including breast cancer, after 10 years (RR 1.02, 95% CI 0.95 to 1.10) or on all-cause mortality after 13 years (RR 0.99, 95% CI 0.95 to 1.03).Total numbers of lumpectomies and mastectomies were significantly larger in the screened groups (RR 1.31, 95% CI 1.22 to 1.42), as were number of mastectomies (RR 1.20, 95% CI 1.08 to 1.32). The use of radiotherapy was similarly increased whereas there was no difference in the use of chemotherapy (data available in only two trials). AUTHORS' CONCLUSIONS: If we assume that screening reduces breast cancer mortality by 15% and that overdiagnosis and overtreatment is at 30%, it means that for every 2000 women invited for screening throughout 10 years, one will avoid dying of breast cancer and 10 healthy women, who would not have been diagnosed if there had not been screening, will be treated unnecessarily. Furthermore, more than 200 women will experience important psychological distress including anxiety and uncertainty for years because of false positive findings. To help ensure that the women are fully informed before they decide whether or not to attend screening, we have written an evidence-based leaflet for lay people that is available in several languages on www.cochrane.dk. Because of substantial advances in treatment and greater breast cancer awareness since the trials were carried out, it is likely that the absolute effect of screening today is smaller than in the trials. Recent observational studies show more overdiagnosis than in the trials and very little or no reduction in the incidence of advanced cancers with screening.

OBJECTIVE: To estimate the extent of overdiagnosis (the detection of cancers that will not cause death or symptoms) in publicly organised screening programmes. DESIGN: Systematic review of published trends in incidence of breast cancer before and after the introduction of mammography screening. DATA SOURCES: PubMed (April 2007), reference lists, and authors. Review methods One author extracted data on incidence of breast cancer (including carcinoma in situ), population size, screening uptake, time periods, and age groups, which were checked independently by the other author. Linear regression was used to estimate trends in incidence before and after the introduction of screening and in older, previously screened women. Meta-analysis was used to estimate the extent of overdiagnosis. RESULTS: Incidence data covering at least seven years before screening and seven years after screening had been fully implemented, and including both screened and non-screened age groups, were available from the United Kingdom; Manitoba, Canada; New South Wales, Australia; Sweden; and parts of Norway. The implementation phase with its prevalence peak was excluded and adjustment made for changing background incidence and compensatory drops in incidence among older, previously screened women. Overdiagnosis was estimated at 52% (95% confidence interval 46% to 58%). Data from three countries showed a drop in incidence as the women exceeded the age limit for screening, but the reduction was small and the estimate of overdiagnosis was compensated for in this review. CONCLUSIONS: The increase in incidence of breast cancer was closely related to the introduction of screening and little of this increase was compensated for by a drop in incidence of breast cancer in previously screened women. One in three breast cancers detected in a population offered organised screening is overdiagnosed.

BACKGROUND: Randomized trials without reported adequate allocation concealment have been shown to overestimate the benefit of experimental interventions. We investigated the robustness of conclusions drawn from meta-analyses to exclusion of such trials. MATERIAL: Random sample of 38 reviews from The Cochrane Library 2003, issue 2 and 32 other reviews from PubMed accessed in 2002. Eligible reviews presented a binary effect estimate from a meta-analysis of randomized controlled trials as the first statistically significant result that supported a conclusion in favour of one of the interventions. METHODS: We assessed the methods sections of the trials in each included meta-analysis for adequacy of allocation concealment. We replicated each meta-analysis using the authors' methods but included only trials that had adequate allocation concealment. Conclusions were defined as not supported if our result was not statistically significant. RESULTS: Thirty-four of the 70 meta-analyses contained a mixture of trials with unclear or inadequate concealment as well as trials with adequate allocation concealment. Four meta-analyses only contained trials with adequate concealment, and 32, only trials with unclear or inadequate concealment. When only trials with adequate concealment were included, 48 of 70 conclusions (69%; 95% confidence interval: 56-79%) lost support. The loss of support mainly reflected loss of power (the total number of patients was reduced by 49%) but also a shift in the point estimate towards a less beneficial effect. CONCLUSION: Two-thirds of conclusions in favour of one of the interventions were no longer supported if only trials with adequate allocation concealment were included.

OBJECTIVES: To quantify the benefits and harms of general health checks in adults with an emphasis on patient-relevant outcomes such as morbidity and mortality rather than on surrogate outcomes. DESIGN: Cochrane systematic review and meta-analysis of randomised trials. For mortality, we analysed the results with random effects meta-analysis, and for other outcomes we did a qualitative synthesis as meta-analysis was not feasible. DATA SOURCES: Medline, EMBASE, Healthstar, Cochrane Library, Cochrane Central Register of Controlled Trials, CINAHL, EPOC register, ClinicalTrials.gov, and WHO ICTRP, supplemented by manual searches of reference lists of included studies, citation tracking (Web of Knowledge), and contacts with trialists. SELECTION CRITERIA: Randomised trials comparing health checks with no health checks in adult populations unselected for disease or risk factors. Health checks defined as screening general populations for more than one disease or risk factor in more than one organ system. We did not include geriatric trials. DATA EXTRACTION: Two observers independently assessed eligibility, extracted data, and assessed the risk of bias. We contacted authors for additional outcomes or trial details when necessary. RESULTS: We identified 16 trials, 14 of which had available outcome data (182,880 participants). Nine trials provided data on total mortality (11,940 deaths), and they gave a risk ratio of 0.99 (95% confidence interval 0.95 to 1.03). Eight trials provided data on cardiovascular mortality (4567 deaths), risk ratio 1.03 (0.91 to 1.17), and eight on cancer mortality (3663 deaths), risk ratio 1.01 (0.92 to 1.12). Subgroup and sensitivity analyses did not alter these findings. We did not find beneficial effects of general health checks on morbidity, hospitalisation, disability, worry, additional physician visits, or absence from work, but not all trials reported on these outcomes. One trial found that health checks led to a 20% increase in the total number of new diagnoses per participant over six years compared with the control group and an increased number of people with self reported chronic conditions, and one trial found an increased prevalence of hypertension and hypercholesterolaemia. Two out of four trials found an increased use of antihypertensives. Two out of four trials found small beneficial effects on self reported health, which could be due to bias. CONCLUSIONS: General health checks did not reduce morbidity or mortality, neither overall nor for cardiovascular or cancer causes, although they increased the number of new diagnoses. Important harmful outcomes were often not studied or reported. SYSTEMATIC REVIEW REGISTRATION: Cochrane Library, doi:10.1002/14651858.CD009009.