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APPENDIX B 133 examination with that of clinical examination and mammography, in part due to the methodologic difficulties with properly designing such a study. Effectiveness of Early Detection The results of several large studies have convincingly demonstrated the effectiveness of clinical examination and mammographic screening for breast cancer in women aged 50 and older. The Health Insurance Plan of Greater New York (HIP) in 1963 began a randomized prospective study of clinical examination and mammography in 62,000 women.22 The follow-up of this group now exceeds 18 years. In women who were over age 50 at the time of entry into the study, mortality from breast cancer in the screened group was more than 50% lower than in the unscreened group at five years. This effect has gradually decreased to about 21% after 18 years. In the Swedish "two county study," a randomized controlled trial was begun in 1977 using single-view mammograms to screen about 78,000 women every 20 to 36 months.23 After six years of follow-up, the group of women who were over age 50 at the time of entry showed a significant decrease in breast cancer mortality. A recently reported randomized controlled trial in Malmo, Sweden, found that in 8.8 years of follow-up women aged 55 and older who received periodic mammographic screening had a significant reduction in mortality from breast cancer. 24 In the Netherlands, a screening program of single-view mammography every two years for women over age 35 was introduced in 1975.25 After seven years, this case-control study showed that mammography significantly reduced the risk of mortality from breast cancer in women 50 and over. A case-control study in Italy also reported a strong inverse relationship between mortality from breast cancer and mammographic screening in women aged 50 and older.26 More than 280,000 women in the United States were screened with a combination of clinical examination and mammography during the Breast Cancer Detection Demonstration Project.27 This demonstration project was not designed as a research study, however, and lacked a control group. Effectiveness was inferred by comparing the outcome among BCDDP participants with that observed in national cancer surveillance programs. These comparisons showed that BCDDP participants had higher survival rates than those of breast cancer cases in national sample groups.27 The finding of increased five-year survival was confirmed in a recent analysis of the BCDDP data, which also demonstrated that cumulative mortality from breast cancer was 80% of that expected of BCDDP participants without
APPENDIX B 134 diagnosed breast cancer at the start of the study.28 Due to the absence of internal controls in the original design of this study, however, it is unclear to what extent these differences were due to selection bias, lead-time bias, and other sources of bias.29 Although most authorities agree on the benefits of screening women aged 50 and over for breast cancer, there has been some uncertainty about the effectiveness of mammographic screening in women between the ages of 40 and 49.29,30,31 Mammography for women under 50 has not been shown to be effective in reducing breast cancer mortality in the Swedish "two county" trial23 or the Dutch study,25 although the follow-up period may not have been of sufficient duration to detect an effect on mortality. The Malmo, Sweden, trial also reported no benefit for women under age 55, but the mean follow-up period was less than 9 years; moreover, 24% of women in the control group are thought to have received mammography outside of the screening program and as many as 26% of women in the intervention program did not attend screening.24 Follow-up data from the HIP study suggest that women aged 40-49 who receive periodic mammography and clinical examination may experience a reduction of about 25% in breast cancer mortality, but the investigators and others have not found this difference to be statistically significant.22,32 Interpretations of statistical significance when analyzing these data are influenced by a number of factors, some of which include the definition of the 40-49 age group (i.e., age at entry into study vs. age at diagnosis), the length of follow-up, and the denominator chosen to calculate mortality (women entering the study vs. cases of breast cancer). The difference in mortality is statistically significant when cases of breast cancer are used as the denominator and age at entry defines the age group.33 Statistical significance may, however, be less a consideration than clinical significance. Although nearly 28,000 women aged 40-49 entered the HIP trial, after over 18 years there were only 16 fewer breast cancer deaths among screened women (61 deaths) than in the control group (77 deaths), a difference of about 12 in 10,000 women screened.33,34 There are few data regarding the optimal frequency of mammography or the age at which to discontinue screening in the asymptomatic elderly. Although an annual interval is widely recommended, a recent analysis of data from the Swedish "two county" study found little evidence that an annual interval conferred greater benefit than screening every two years.35 Although there are no reliable data on the optimal age to conclude mammographic screening, there are uncertainties regarding the effectiveness of screening beyond age 75 in asymptomatic women with consistently normal results on previous examinations. The incidence of