EDITORIALS * EDITORIAUX

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Te Canadian Nati*onal Breast Screening Sudy: opportunity for a rethink Antoni S.H. Basinski, MD, PhD, CCFP

T he Canadian National Breast Screening Study (NBSS), reported in this issue (pages 1459 to 1488), is a remarkably important clinical trial. Assessment of this (or any) trial will ultimately rest on its credibility and the extent to which it provides evidence to strengthen or alter conclusions previously drawn. This study and its results will be applauded by some and criticized or dismissed by others. Yet, amid the controversy surrounding breast cancer screening, this study provides unique answers to important questions, offers valuable insights and affords the opportunity to re-evaluate approaches to screening for breast cancer. The NBSS is two clinical trials run in parallel, concerned with two populations and two bodies of evidence. For each population the study posed a distinct question and led to a clear conclusion. When the trial was designed, screening for breast cancer in women aged 40 to 49 years had not been shown to lead to any clear reduction in mortality rate.' In women aged 50 to 59 years there was some evidence of the benefit of mammography with or without physical examination versus usual care.2 In the intervening years, the evidence has been amplified by results from numerous trials, but the conclusions have remained largely the same.3 For women aged 40 to 49 years the NBSS was planned to determine the value of annual screening by any means over and above a single physical examination. That is,' the question was whether to screen at all. For women aged 50 to 59 years it was designed to determine the value of screening by annual mammography over and above regular physical examination. That is, the question was whether

to screen with mammography in addition to annual physical examination. All the women were to be taught breast self-examination. Overall, the study was meticulously well run. Many of the concerns about threats to internal or external validity raised with other trials4 do not apply to the NBSS. Internal validity was advanced by the quality control of radiology, physical examination and self-examination teaching. Randomization was on an individual basis and achieved comparable groups; subjects were followed up extensively; missing data, misallocations of participants and exclusions from analysis were minimal; the quality of the intervention, the follow-up and the database was reviewed in detail; and participation did not drop below 85% through year 5. No individual trial or meta-analysis has demonstrated reduced mortality rates due to screening for breast cancer. It might never be possible to show this, even if screening is beneficial in terms of breast cancer mortality, since only a minority of deaths are attributed to breast cancer. This places a greater burden on studies intending to demonstrate the benefit of a screening program: they must accurately ascertain cause of death. The procedures to verify cause of death in the NBSS were thorough and

apparently free of potential bias, thus further ensuring the internal validity of the study. The study has already been criticized on the basis of the quality of mammography and its credibility cast into doubt.56 Although it is troublesome that the quality was at first less than desirable,7 the extent to which poor or fair quality ratings affected the results of the trial is uncertain. Rather, estimates

From the Institute for Clinical Evaluative Sciences and the Department of Family and Community Medicine, University of Toronto, Toronto, Ont.

Reprint requests to: Dr. Antoni S.H. Basinski, Institutefor Clinical Evaluative Sciences, Sunnybrook Health Science Centre, A-443, 2075 Bayview Ave., North York, ONM4N 3M5 NOVEMBER 15, 1992

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of screening sensitivity and specificity8 and a review of cases to determine whether there were possible delays in diagnosis9 are more pertinent. Although agreement was relatively poor between the centre and reference radiologists in cases in which the women were not known to have cancer (they agreed on approximately half of each other's diagnoses of cancer),9 this might be expected given the high ratio of benign to malignant cases detected by mammography. Agreement in cases in which the women were known to have cancer was higher. For screen-detected cases the centre and reference radiologists agreed on 91% of each other's diagnoses of cancer.9 For these cases, since the centre and reference radiologists missed an equivalent number of cases that each other called positive, the number of "delayed cases" that might have been calculated for the reference radiologists had their diagnoses led to clinical decisions would not likely have been much lower. Since interobserver disagreement is inevitable, rating the centres by a single reference radiologist may be an excessively harsh way to view achievements. The ability of the centre radiologists to detect cancer was close to that of the reference radiologist. For cancer cases potentially detectable at the first screening, for example, the centre radiologists identified 207 of 238 (sensitivity 87%) and the reference radiologist 213 (sensitivity 89%).9 Although the overall sensitivity of the centre radiologists was estimated to be 75%, possibly in part because repeated misses of the same case were counted against them, the sensitivity of mammography in this study was higher than that achieved in other trials, whether those trials showed benefit or not.8 In the NBSS the number of cancers detected with the addition of mammography was substantially greater than the number detected without it. Many cancers were detected earlier than they would have been without mammography. However, the real benefits of early detection remain to be demonstrated.10 No higher mortality rate has emerged in the potentially delayed cases than in the screen-detected cases.9 Hence, although the quality of mammograms could be, and was, improved during the trial, no adverse effects (in terms of the primary study outcome) of delayed diagnosis are evident at this time. The technical quality of the mammograms should cause reflection about, not rejection of, the trial. Suboptimal quality may be expected to diminish the size of a potential effect but not abolish it. No large trial is without unanticipated shortcomings or faults. The NBSS investigators appropriately addressed internal quality control and took measures to improve quality when necessary. The greater detection rate of cancer in the NBSS 1432

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women aged 40 to 49 years who were screened annually was largely due to increased detection of in-situ and node-negative cancers as well as an increase in cancers with four or more positive nodes (half of these were detected at the first screening). Despite this, the rate of death from breast cancer was higher in the screened group. Although this ought to be investigated, the excess was not statistically significant, and unbounded attempts to explain it are not warranted. In addition, the total mortality rates in the screened and unscreened groups were virtually identical. In the group aged 50 to 59 years mammography tripled the number of biopsies done over 5 years and doubled the number of cancers detected. A large part of this increase is due to the detection, particularly at the first screening, of in-situ and node-negative cases of invasive cancer. The increase in the number of invasive cancers detected in women who underwent mammography between years 2 and 5 was relatively small and not statistically significant. After 7 years the overall mortality rate and the rate of death from breast cancer were indistinguishable between the two groups. For both age groups, although the combination of annual mammography and physical examination identifies more cancers than usual care (for women aged 40 to 49 years) or physical examination alone (for women aged 50 to 59 years), there are no compensatory decreases in the incidence of advanced cancer. Survival appears to be best in the subpopulation with cancer detected by mammography alone. However, survival curves calculated from the date of diagnosis are not the best method to assess the study's results because of lead time effects; that is, we do not know whether actual life is extended beyond the increase in life with identified disease. The initial results of the NBSS do not support regular screening for breast cancer with mammography at any age, but they do provide the opportunity for a rethinking of screening for breast cancer.10 Although these results may be early relative to the natural history of the disease - 7 years may not be a sufficient time for possible benefits of screening itself (for women aged 40 to 49 years) or annual mammography (for women aged 50 to 59 years) to emerge - they are not premature. The NBSS was planned to demonstrate benefit at 5 years. Trials with positive results have, for the most part, shown such results within 5 to 7 years,3 and trials with negative results have continued to show negative results throughout the follow-up.3 Exhortations to wait longer for potential benefit of a smaller magnitude to emerge over a longer term ring hollow,1' since no reduction, even nonsignificant, in the rate of death from breast cancer is evident. L.E lS NOVEMBRE 1992

Perhaps the most important consequence of the NBSS is that patients must now be offered clear choices and accurate information about both the risks and benefits of screening and of mammography. Previous policies for screening in women under the age of 50 were hampered by the lack of a definitive trial for this age group. All other trials demonstrated better results (whether statistically significant or not) for women 50 years and older than for women under 50 years and indeed a lack of benefit to those under the age of 50.3 Thus, policies promoting annual physical examination from age 40 onward,'2 although "conservative" compared with policies encouraging mammographic screening, were not based on high-quality evidence. The NBSS provides evidence that such policies were based on optimism. The decidedly "negative" results in the NBSS for women aged 40 to 49 years should, combined with the negative results for younger women in other screening trials, lay to rest all policies promulgating annual screening for breast cancer among low-risk women in this age group. Current European guidelines also suggest that asymptomatic women under the age of 50 who request mammographic screening be informed, on an individual basis, of its risks and benefits.'3 For this age group the lack of benefit in breast cancer mortality rate due to screening in general and to mammography in particular ought now to be clearly stated. The performance of annual physical examination must also now be addressed as having no basis. In addition, the increased rate of detection of breast cancer with screening must be balanced against the cascade of interventions that follow positive results and against the knowledge that, although there may be increased life with the disease, there is no clear survival benefit with screening. Clear choices may now be offered to women aged 50 years and older. Regular screening must still be promoted, since screening has been shown to lead to a reduced rate of death from breast cancer, and the NBSS has not changed that. However, "screening" previously meant mammography with or without physical examination. As a result of the NBSS annual physical examination alone may now be thought to offer an alternative to mammography (plus physical examination) to reap the benefits of a reduced rate of death from breast cancer. Some may argue for mammography on the basis of its increased rate of detection of breast cancer, if not on the basis of a reduction in the rate of death from breast cancer. For mammography, the salient question is Does the treatment of disease detected by mammography prolong life or does detection by mammography prolong the burden of living with the disease? That an increased rate of detection leads to an increased lifespan has not been shown. NOVEMBER 15,1992

The increased detection rate comes at a price. Large numbers of biopsies are required to diagnose a single cancer. In addition, given that the cumulative breast cancer detection rates for women aged 50 to 59 years were virtually parallel over the first 7 years after the initial screening it may be that a single mammogram, or having mammography every so many years, combined with regular physical examination, may be enough to uncover most of the additional cancers detected by annual mammography over and above physical examination. Suggesting breast self-examination alone as a substitute for physical examination as a means of screening cannot be justified. Although teaching self-examination to all subjects in the NBSS led to dramatic increases in rates of monthly self-examination'4 the effect of this on outcome is undetermined. The benefit of physical examination plus selfexamination versus self-examination alone will probably never be known conclusively,'4 but trials are under way in other countries to test this.3 However, expectations for self-examination have been diminished by the results of another trial.'5 Although hampered by low participation, this trial showed that women who were offered self-examination fared no better than a control group, whereas in districts where women were screened with physical examination annually plus mammography every 2 years there was a reduced rate of death from breast cancer 6 to 7 years after entry into the study.'5 A final caveat: screening of women at high risk for breast cancer was not the object of the NBSS; therefore, the conclusions drawn can be extended only to the general population, not to those at high risk. The NBSS has another message: what is done must be done well. Patients have the right to demand services of at least the same quality as was available in the trials upon which the proclaimed benefit is based. Whatever the problems of "poor" radiographic quality in the trial, overall the NBSS achieved many high standards of process of care. It demonstrated the "efficacy" of screening - what can be achieved under well-controlled and wellmanaged conditions. In practice myriad problems are currently encountered. Mammography services are variable,'6 and reports may be delayed, difficult to read'7 or not followed up in a timely fashion.'8 These factors and impediments to providing highquality physical examination, teaching self-examination, performing biopsies and treating invasive cancer will stifle the small gains of a screening program. Some of these difficulties could be averted by quality assurance procedures.'9 Standards for radiology now require dedicated equipment (with quality control), the reading by radiologists of a minimum of 480 mammograms per year, "concise and explicit" reCAN MED ASSOC J 1992; 147 (10)

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porting, the availability of a formal, written report within 24 hours and telephone follow-up in positive cases, the obtaining of treatment results for quality control, the identification of primary care physicians for patients who are self-referred and the retention of films for 5 to 7 years, by patients if necessary.'9 However impressive these standards are, taken individually they are inadequate. We need a systematic and seamless approach to quality of care that encompasses all aspects, from the decision to screen through to treatment for those with disease. This begins with providing accurate and unbiased information to patients and entails well-taught and wellpractised physical examination as well as radiographic quality assurance when mammography is used. Patients must be fully informed, and the review of diagnostic information, decisions about treatment and the provision of treatment must be timely and efficient. Organized programs delivering team-oriented care may be able to ensure systematic

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Conclusion

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As more sensitive and specific imaging techniques emerge and as treatment of early-detected disease improves, the possible benefits of mammog- 13. raphy may yet be realized. Evolving technology will inevitably fuel arguments for dismissing decade-old 14. evidence and induce hopes for the benefits of screening efforts based more on optimism in the future than on evidence from the past. The initial results of 15. the NBSS remind us that it is most prudent to temper optimism with caution. Rigorous testing often leads to sobering results, in this and other 16. arenas. 17.

References 1. Miller AB, Howe GR, Wall C: The National Study of Breast Cancer Screening: protocol for a Canadian randomized con-

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trolled trial of screening for breast cancer in women. Clin Invest Med 1981; 4: 227-258 Shapiro S, Venet W, Strax P et al: Ten- to fourteen-year effect of screening on breast cancer mortality. J Natl Cancer Inst 1982; 69: 349-355 Rutqvist LE, Miller AB, Andersson I et al: Reduced breastcancer mortality with mammography screening - an assessment of currently available data. Int J Cancer Suppl 1990; 5: 76-84 Skrabanek P: Shadows over screening mammography. Clin Radiol 1989; 40: 4-5 Kopans DB: The Canadian screening program: a different perspective. AJR 1990; 155: 748-749 Moskowitz M: Guidelines for screening for breast cancer. Is a revision in order? Radiol Clin North Am 1992; 30: 221-233 Baines CJ, Miller AB, Kopans DB et al: Canadian National Breast Screening Study: assessment of technical quality by external review. AJR 1990; 155: 743-747 Baines CJ, McFarlane DV, Miller AB: Sensitivity and specificity of first screen mammography in 15 NBSS centres. Can Assoc Radiol J 1988; 39: 273-276 Baines CJ: The role of the reference radiologist. Estimates of inter-observer agreement and potential delay in cancer detection in the National Breast Screening Study. Invest Radiol 1990; 25: 971-976 Roberts MM: Breast screening: Time for a rethink? BMJ 1989; 299: 1153-1155 Miller AB: Breast screening in women under 50 [C]. Lancet 1990; 338: 113 US Preventive Services Task Force: Guide to Clinical Preventive Services: an Assessment of the Effectiveness of 169 Interventions, Williams & Wilkins, Baltimore, 1989: 39-44 European Group for Breast Cancer Screening: Recommendations for breast cancer screening. Eur J Gynaecol Oncol 1990; 11:489-490 Baines CJ, Wall C, Risch HA et al: Changes in breast self-examination behavior in a cohort of 8214 women in the Canadian National Breast Screening Study. Cancer 1986; 57: 1209-1216 UK Trial of Early Detection of Breast Cancer Group. First results on mortality reduction in the UK trial of early detection of breast cancer. Lancet 1988; 2: 411-416 Ciccone G, Vineis P, Frigerio A et al: Inter-observer and intra-observer variability of mammogram interpretation: a field study. Eur J Cancer 1992; 28A: 1054-1058 Sierra AE, Bisesi MA, Rosenbaum TL et al: Readability of the radiologic report. Invest Radiol 1992; 27: 236-239 Robertson CL, Kopans DB: Communication problems after mammographic screening. Radiology 1989; 172: 443-444 Dodd GD: Quality assurance in mammography. Cancer 1989; 64 (suppl): 2707-2709

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The Canadian National Breast Screening Study: opportunity for a rethink.

EDITORIALS * EDITORIAUX ~ ~ CaainNtoa_ratSreigSuy The Te Canadian Nati*onal Breast Screening Sudy: opportunity for a rethink Antoni S.H. Basinski,...
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