Twenty five year follow-up for breast cancer incidence and mortality of the Canadian National Breast Screening Study: randomised screening trial
BMJ 2014; 348 doi: https://doi.org/10.1136/bmj.g366 (Published 11 February 2014) Cite this as: BMJ 2014;348:g366
All rapid responses
Rapid responses are electronic comments to the editor. They enable our users to debate issues raised in articles published on bmj.com. A rapid response is first posted online. If you need the URL (web address) of an individual response, simply click on the response headline and copy the URL from the browser window. A proportion of responses will, after editing, be published online and in the print journal as letters, which are indexed in PubMed. Rapid responses are not indexed in PubMed and they are not journal articles. The BMJ reserves the right to remove responses which are being wilfully misrepresented as published articles or when it is brought to our attention that a response spreads misinformation.
From March 2022, the word limit for rapid responses will be 600 words not including references and author details. We will no longer post responses that exceed this limit.
The word limit for letters selected from posted responses remains 300 words.
We have a major contradiction here.
The authors of the paper say "The examiners had no role in the randomisation that followed; this was performed by the study coordinators in each centre. Randomisation was individual and stratified by centre and five year age group. Irrespective of the findings on physical examination, women aged 40-49 were independently and blindly assigned randomly to receive mammography or no mammography."
In his response, Prof. Kopans says: "The study coordinators who were supposed to randomly assign the volunteers, probably with good, but misguided, intentions, could simply skip a line to be certain that the women with lumps and even advanced cancers got assigned to the screening arm to be sure they would get a mammogram. It is indisputable that this happened ..."
Only one of these statements can be correct. Which is it? Was allocation truly blind in this trial?
Competing interests: No competing interests
Having been one of the experts called on in 1990 to review the quality of their mammograms I can personally attest to the fact that the quality was poor (1). To save money they used second hand mammography machines. The images were compromised by scatter since they did not employ grids for much of the trial. They failed to fully position the breasts in the machines so that cancers were missed because the technologists were not taught proper positioning, and their radiologists had no specific training in mammographic interpretation.
The CNBSS's own reference physicist wrote:
"..in my work as reference physicist to the NBSS, [I] identified many concerns regarding the quality of mammography carried out in some of the NBSS screening centers. That quality [in the NBSS] was far below state of the art, even for that time (early 1980's). " (2)
In this latest paper (3) the authors gloss over the fact that only 32% of the cancers were detected by mammography alone. This extremely low number is consistent with the poor quality of the mammography. At least two thirds of the cancers should be detected by mammography alone (4). In their accompanying editorial (5) Kalager and Adami admit that " The lack of mortality benefit is also biologically plausible because the mean tumour size was 19 mm in the screening group and 21 mm in the control group....a 2 mm difference." Poor quality mammography does not find breast cancers at a smaller size and earlier stage and would not be expected to reduce deaths.
The documented poor quality of the NBSS mammography is sufficient to explain their results and all of the above disqualifies the CNBSS as a scientific study of mammography screening, but it was even worse than that. In order to be valid, randomized, controlled trials (RCT) require that assignment of the women to the screening group or the unscreened control group is totally random. A fundamental rule for an RCT is that nothing can be known about the participants until they have been randomly assigned so that there is no risk of compromising the random allocation. Furthermore, a system needs to be employed so that the assignment is truly random and cannot be compromised. The CNBSS violated these fundamental rules (6). Every woman first had a clinical breast examination by a trained nurse (or doctor) so that they knew the women who had breast lumps, many of which were cancers, and they knew the women who had large lymph nodes in their axillae indicating advanced cancer. Before assigning the women to be in the group offered screening or the control women they knew who had large incurable cancers. This was a major violation, but it went beyond that. Instead of a random system of assigning the women they used open lists. The study coordinators who were supposed to randomly assign the volunteers, probably with good, but misguided, intentions, could simply skip a line to be certain that the women with lumps and even advanced cancers got assigned to the screening arm to be sure they would get a mammogram. It is indisputable that this happened since there was a statistically significant excess of women with advanced breast cancers who were assigned to the screening arm compared to those assigned to the control arm (7). This guaranteed that there would be more early deaths among the screened women than the control women and this is what occurred in the NBSS. Shifting women from the control arm to the screening arm would increase the cancers in the screening arm and reduce the cancers in the control arm which would also account for what they claim is "overdiagnosis".
The analysis of the results from the CNBSS have been suspect from the beginning. The principle investigator ignored the allocation failure in his trial and blamed the early excess of cancer deaths among screened women on his, completely unsupportable, theory that cancer cells were being squeezed into the blood leading to early deaths. This had no scientific basis and was just another example of irresponsibility in the analysis of the data from this compromised trial and he finally retracted the nonsense after making front page headlines (6).
The compromise of the CNBSS trial is indisputable. The 5 year survival from breast cancer among women ages 40-49 in Canada in the 1980's was only 75%, yet the control women in the CNBSS, who were supposed to represent the Canadian population at the time, had a greater than 90% five year survival. This could only happen if cancers were shifted from the control arm to the screening arm. The CNBSS is an excellent example of how to corrupt a randomized, controlled trial. Coupling the fundamental compromise of the allocation process with the documented poor quality of the mammography should, long ago, have disqualified the CNBSS as a legitimate trial of screening mammography. Anyone who suggests that it was properly done and its results are valid and should be used to reduce access to screening either does not understand the fundamentals, or has other motives for using its corrupted results.
References:
1 Kopans DB. The Canadian Screening Program: A Different Perspective. AJR 1990;155:748-749.
2. Yaffe MJ. Correction: Canada Study. Letter to the Editor JNCI 1993;85:94
3. Miller AB, Wall C, Baines CJ, Sun P, To T, Narod SA. Twenty five year follow-up for breast cancer incidence and mortality of the Canadian National Breast Screening Study: randomised screening trial. BMJ 2014;348:g366 doi: 10.1136/bmj.g366
4. Mathis KL, Hoskin TL, Boughey JC, Crownhart BS, Brandt KR, Vachon CM, Grant
CS, Degnim AC. Palpable presentation of breast cancer persists in the era of
screening mammography. J Am Coll Surg. 2010 Mar;210(3):314-83. Kopans DB, Feig SA. The Canadian National Breast Screening Study: A Critical Review. AJR 1993;161:755-760.
5. Kalager M, Adami H. Bretthauer M. Too much mammography. Long term follow-up does not support screening women under 60. BMJ 2014;348:g1403 doi: 10.1136/bmj.g1403
6. Kopans DB, Feig SA. The Canadian National Breast Screening Study: A Critical Review. AJR 1993;161:755-760.
7. Tarone RE. The Excess of Patients with Advanced Breast Cancers in Young Women Screened with Mammography in the Canadian National Breast Screening Study. Cancer 1995;75:997-1003.
8. Merz B. Author of Canadian Breast Cancer Study retracts warnings. J Natl
Cancer Inst. 1992 Jun 3;84(11):832-4. PubMed PMID: 1593648.
Competing interests: No competing interests
Dear Editor,
In this 30-year old study, the authors report no mortality reduction when screening with mammography and 22% overdiagnosis (1). The sensitivity of the mammography technique has improved tremendously in the last three decades. Ten years ago we got digital mammography and recently we have got tomosynthesis (2). The detection rate at mammography in the Canadian study was about 3 per 1000 in the second and later screening rounds (3). In digital mammography, the corresponding detection rate is 6 per 1000 screened woman and in tomosynthesis, the detection rate is 8 per 1000 (2). It could even have been higher if the pathologists had time to perform more biopsies (personal communications). In tomosynthesis a large number of stellate lesions appear, many more than in traditional mammography, and they are probably representing a reservoir of overdiagnosed breast cancers. In the last 15 years, the rate of interval cancer has been constant and is at the same level as in Canada 30 years ago (4). Thus, the level of overdiagnosis is far much bigger today than in Canada 30 years ago.
1. Miller AB, Wall C, Baines CJ, Sun P, To T, Narod SA. Twenty five year follow-up for breast cancer incidence and mortality of the Canadian National Breast Screening Study: randomised screening trial. BMJ 2014;348:g366 doi: 10.1136/bmj.g366
2. Skaane P, Bandos AI, Gullien R, et al. Comparison of digital mammography alone and digital mammography plus tomosynthesis in a population-based screening program. Radiology 2013; 297: 47-56.
3. Miller AB, Baines CJ, To T, Wall C. Canadian National Breast Screening Study: 2. Breast cancer detection and death rates among women aged 50 to 59 years. CMAJ. 1992; 147(10): 1477-88.
4. Zahl P-H, Mæhlen J. Overdiagnostikk av brystkreft etter 14 år med screening. Tidsskr Nor Legeforen 2012; 132: 414-7.
Competing interests: No competing interests
Re: Twenty five year follow-up for breast cancer incidence and mortality of the Canadian National Breast Screening Study: randomised screening trial
Per-Henrick Zahl has, in his response to this article, comprehensively defined the concerns that surround screening mammography. He states that breast cancer screening using digital mammography has resulted in a doubling of breast cancer incidence in the second round screening, from 3/1,000 to 6/1,000. This increase has not been reflected in a reduction in the interval cancer rate, which has remained constant. These statistical observations clearly define the increased risk of breast cancer when digital mammography is used in screening, and correspond with the findings of Roman, Monsees and others (1,2,3)
The observation by Per-Henrick Zahl that tomosynthesis results in a further increase in the incidence of malignancy is equally disconcerting. The National Council for Radiation Protection has evaluated the medical radiation risk from CT scans. A similar risk assessment is now indicated for tomosynthesis.
The call by the Swiss Medical Board that "for all forms of mammography screening, a previous thorough medical evaluation and a comprehensible clarification with presentation of the desirable and undesirable are recommended" should be endorsed
References:
1. Roman R,Sala M., Salas D, Ascunce M,Zubiretta A,Castells X.Effects of protocol-related variables and women's characteristics on the cumulative false-positive risk in breast cancer screening.
Annals Oncol 23:1 104-111
2.Glynn CG,Farria DM,Monsees BS,Salcman JT,Wiele KN, Hidebolt CF Effects of transition to digital mammography on clinical outcomes. Radiol 2011 Sept(3)664 - 70;
3. Hambly N, McNicholas MM, Phelan N,Hargaden GC, O'Doherty A, Flanagan FI
Comparison of Digital Mammography and Screen-Film Mammography in Breast Cancer Screening:A review inn the Irish Breast Screening Program AJR Oct 2009 1012 - 1020
Competing interests: No competing interests