OBJECTIVE: To determine whether the previously observed 25% reduction in breast cancer mortality in Copenhagen following the introduction of mammography screening was indeed due to screening, by using an additional screening region and five years additional follow-up. DESIGN: We used Poisson regression analyses adjusted for changes in age distribution to compare the annual percentage change in breast cancer mortality in areas where screening was used with the change in areas where it was not used during 10 years before screening was introduced and for 10 years after screening was in practice (starting five years after introduction of screening). SETTING: Copenhagen, where mammography screening started in 1991, and Funen county, where screening was introduced in 1993. The rest of Denmark (about 80% of the population) served as an unscreened control group. PARTICIPANTS: All Danish women recorded in the Cause of Death Register and Statistics Denmark for 1971-2006. MAIN OUTCOME MEASURE: Annual percentage change in breast cancer mortality in regions offering mammography screening and those not offering screening. RESULTS: In women who could benefit from screening (ages 55-74 years), we found a mortality decline of 1% per year in the screening areas (relative risk (RR) 0.99, 95% confidence interval (CI) 0.96 to 1.01) during the 10 year period when screening could have had an effect (1997-2006). In women of the same age in the non-screening areas, there was a decline of 2% in mortality per year (RR 0.98, 95% CI 0.97 to 0.99) in the same 10 year period. In women who were too young to benefit from screening (ages 35-55 years), breast cancer mortality during 1997-2006 declined 5% per year (RR 0.95, CI 0.92 to 0.98) in the screened areas and 6% per year (RR 0.94, CI 0.92 to 0.95) in the non-screened areas. For the older age groups (75-84 years), there was little change in breast cancer mortality over time in both screened and non-screened areas. Trends were less clear during the 10 year period before screening was introduced, with a possible increase in mortality in women aged less than 75 years in the non-screened regions. CONCLUSIONS: We were unable to find an effect of the Danish screening programme on breast cancer mortality. The reductions in breast cancer mortality we observed in screening regions were similar or less than those in non-screened areas and in age groups too young to benefit from screening, and are more likely explained by changes in risk factors and improved treatment than by screening mammography.
Effective breast cancer screening should detect early-stage cancer and prevent advanced disease.
To assess the association between screening and the size of detected tumors and to estimate overdiagnosis (detection of tumors that would not become clinically relevant).
Denmark from 1980 to 2010.
Women aged 35 to 84 years.
Screening programs offering biennial mammography for women aged 50 to 69 years beginning in different regions at different times.
Trends in the incidence of advanced (>20 mm) and nonadvanced (=20 mm) breast cancer tumors in screened and nonscreened women were measured. Two approaches were used to estimate the amount of overdiagnosis: comparing the incidence of advanced and nonadvanced tumors among women aged 50 to 84 years in screening and nonscreening areas; and comparing the incidence for nonadvanced tumors among women aged 35 to 49, 50 to 69, and 70 to 84 years in screening and nonscreening areas.
Screening was not associated with lower incidence of advanced tumors. The incidence of nonadvanced tumors increased in the screening versus prescreening periods (incidence rate ratio, 1.49 [95% CI, 1.43 to 1.54]). The first estimation approach found that 271 invasive breast cancer tumors and 179 ductal carcinoma in situ (DCIS) lesions were overdiagnosed in 2010 (overdiagnosis rate of 24.4% [including DCIS] and 14.7% [excluding DCIS]). The second approach, which accounted for regional differences in women younger than the screening age, found that 711 invasive tumors and 180 cases of DCIS were overdiagnosed in 2010 (overdiagnosis rate of 48.3% [including DCIS] and 38.6% [excluding DCIS]).
Regional differences complicate interpretation.
Breast cancer screening was not associated with a reduction in the incidence of advanced cancer. It is likely that 1 in every 3 invasive tumors and cases of DCIS diagnosed in women offered screening represent overdiagnosis (incidence increase of 48.3%).
To determine the effect of mammography screening on surgical treatment for breast cancer.
Comparative analysis of data from Norwegian cancer registry.
Mammography screening, Norway (screening of women aged 50-69 was introduced sequentially from 1996 to 2004).
35,408 women aged 40-79 with invasive breast cancer or ductal carcinoma in situ treated surgically from 1993 to 2008.
Rates of breast surgery (mastectomy plus breast conserving treatment) and rates of mastectomy for three age groups of women: 40-49, 50-69, and 70-79. Changes in rates from pre-screening period (1993-5) to introduction of screening phase (1996-2004) and then to screening period (2005-8) are presented as hazard ratios in invited and non-invited women.
The annual rate for breast surgery from the pre-screening period (1993-5) to screening period (2005-8) in Norway increased by 70% (hazard ratio 1.70, 95% confidence interval 1.62 to 1.78), from 180 to 305 per 100,000 women in the invited age group (50-69 years). In the younger, non-invited age group (40-49 years), however, the increase was only 8% (1.08, 1.00 to 1.16), from 133 to 144 per 100,000 women per year, whereas in the older, non-invited age group (70-79 years) the rate decreased by 8% (0.92, 0.86 to 1.00), from 227 to 214 per 100,000 women per year. The rates for mastectomy decreased similarly from the pre-screening period to screening period in invited and non-invited women. From the pre-screening period to the introduction phase of screening (1996-2004), however, the annual mastectomy rate in women aged 50-69 invited to screening increased by 9% (1.09, 1.03 to 1.14), from 156 to 167 per 100,000 women, and in the younger non-invited women declined by 17% (0.83, 0.78 to 0.90), from 109 to 91 per 100,000 women. In consequence, the mastectomy rate was 31% (1.31, 1.20 to 1.43) higher in the invited than in the non-invited younger age group.
Mammography screening in Norway was associated with a noticeable increase in rates for breast cancer surgery in women aged 50-69 (the age group invited to screening) and also an increase in mastectomy rates. Although over-diagnosis is likely to have caused the initial increase in mastectomy rates and the overall increase in surgery rates in the age group screened, the more recent decline in mastectomy rates has affected all age groups and is likely to have resulted from changes in surgical policy.
Cites: Breast Cancer Res. 2009;11 Suppl 3:S1920030870
We have previously described how a series of trials sponsored by Pfizer of its antifungal drug, fluconazole, in cancer patients with neutropenia handicapped the control drug, amphotericin B, by flaws in design and analysis. We describe similar problems in two pivotal trials of Pfizer's new antifungal agent, voriconazole, published in a prestigious journal. In a non-inferiority trial, voriconazole was significantly inferior to liposomal amphothericin B, but the authors concluded that voriconazole was a suitable alternative. The second trial used amphothericin B deoxycholate as comparator, but handicapped the drug by not requiring pre-medication to reduce infusion-related toxicity or substitution with electrolytes and fluid to reduce nephrotoxicity, although the planned duration of treatment was 84 days. Voriconazole was given for 77 days on average, but the comparator for only 10 days, which precludes a meaningful comparison.In a random sample of 50 references to these trials, we found that the unwarranted conclusions were mostly uncritically propagated. It was particularly surprising that relevant criticism raised by the FDA related to the first trial was only quoted once, and that none of the articles noted the obvious flaws in the design of the second trial.We suggest that editors ensure that the abstract reflects fairly on the remainder of the paper, and that journals do not impose any time limit for accepting letters that point out serious weaknesses in a study that have not been noted before.