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
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Jacob Levman (RR March 10, 2014) notes the hazard ratio for women age 40-49 in the mammography arm of the CNBSS was 1.47 and calls it a “remarkable imbalance”. In the 1985 report of the Two County study the relative risk of death for similar women is 1.26 (1).
Dr. Tabar’s RR of March 18 requires a brief response. Information from the media about a trial is not the equivalent of signed informed consent which was acquired from all CNBSS participants.
With respect to Dr Tabar’s complaint about our use of the term “county level”. The Two County study was as clearly county-based as the CNBSS was Canada-based. Blocks of the two counties were defined and divided into units, the units then being assigned to control or intervention status (1). The major issue is cluster rather than individually based randomization.
Dr. Tabar denigrates CNBSS mammographic quality choosing to ignore the fact that our Screen 1 detection rates exceeded those in his study (2). He also takes exception to the tumour size (28 mm) reported for his control group (3) He claims it was 22 mm and not 28. We cannot locate where details of this amended size were published.
Re death reviews, “A death was classified by members of the local project groups as being due to breast cancer only after a full review of the clinical and pathological records…” (1) There is no mention of the reviewers being blinded as to allocation. This is in contrast to the CNBSS procedure where an external review was conducted and the reviewers were blinded. This review was ongoing while the study was in progress.
As for reductions in advanced cancers, such reductions have not occurred in screened populations to an extent that balances the observed increased incidence of early cancers. Screening does not deliver what it promises to deliver.
References
1. Tabar L, Fagerberg CJG, Gad A et al. Reduction in mortality from breast cancer after mass screening with mammography. The Lancet 1985, 1, 829-832
2. Fletcher SW, Black W, Harris R, Rimer BK, Shapiro S. Screening for Breast Cancer. J Natl Cancer Inst. 1994 Apr 6;86(7):558-61.
3. Narod SA. On being the right size: a reappraisal of mammography trials in Canada and
Sweden. Lancet 1997;49:1869.
Competing interests: No competing interests
In his March 12th commentary, Jacob Levman discredits the Miller team study [1] with the argument that they had combined "tumours detected in the first round of screening with those detected at a later stage" which, purportedly, "biases the analysis against mammography."
Since the study compared a mammogram group to a group receiving routine care or a physical exam (i.e., other modalities of early detection), isn't this bias relatively irrelevant as it affects both groups (as depicted in the study's data analysis [1])?
Levman's disputation rests on the basic assumption that lethal breast cancers are consistently found by screening with mammography - specifically in the first round of its application.
About three weeks after the release of the study by Miller and colleagues, the publication of a European study on trends in breast cancer incidence distribution after the initiation of mammographic screening in Norway reported no noteworthy reduction in the incidence of advanced/lethal cancer in screened participants over an unscreened control group [2]. Prior research data had shown similar dismal findings [3,4], deflating fundamental premises behind mammography (and Levman's contention): that mammography finds cancers early, thus preventing their progression into advanced lethal types, and that it reliably detects lethal forms of breast cancer.
Despite the aforementioned citations [2-4], László Tabár in his response on March 17th, claims erroneously, referring to the Canadian trials of the Miller group (CNBSS) [1], that "[...] the CNBSS trials are the only ones which failed to reduce the rate of advanced breast cancers [...]."
Levman attempts to bolster the pro-mammography stance by reminding the reader "that every peer reviewed scientific study that has ever been retracted was first subjected to a review process that overlooked the study’s critical errors."
Actually, what the reader should always remember and keep foremost in mind is that the history of medicine, particularly organized medicine (including the science of mammography), is littered with instances where sound meaningful, albeit dissenting, scientific information, or the purveyors thereof, had been dismissed, ridiculed, removed, ignored, or oppressed mostly because it threatened orthodox scientific dogma, conventional medical assumptions, and powerful special interests [5-8].
Therefore, considering the arguably most predictable pattern of that (human) history, and in juxtaposition to Levman's last sentence, one can state with confidence that if "this study gets retracted it does not mean it was free from inappropriate or misguided peer review or that it was junk science."
References:
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 Feb 11;348:g366. doi: 10.1136/bmj.g366.
2. Lousdal ML, Kristiansen IS, Møller B, Støvring H, "Trends in breast cancer stage distribution before, during and after introduction of a screening programme in Norway", Eur J Public Health. 2014 Mar 4. [Epub ahead of print]
3. Autier P, Boniol M, Middleton R, Doré JF, Héry C, Zheng T, Gavin A, “Advanced breast cancer incidence following population-based mammographic screening”, Ann Oncol. 2011 Aug;22(8):1726-35.
4. Gøtzsche PC, Jørgensen KJ, Zahl PH, Mæhlen J, “Why mammography screening has not lived up to expectations from the randomised trials”, Cancer Causes Control. 2012 Jan;23(1):15-21.
5. Martin W, “Medical Heroes & Heretics”, Devin-Adair, 1977
6. Coulter HL, “Divided Legacy", Vol. 1-4, North Atlantic Books, 1982/1994
7. Carter JP, "Racketeering in Medicine: The Suppression of Alternatives", Hampton Roads Publishing Company 1992
8. Daniel Haley, "Politics in Healing: The Suppression and Manipulation of American Medicine", BioMed Publishing Group, 2000
Competing interests: Author of the (e)book "The Mammogram Myth"
In response to Dr Afsheen Zafar, I would like to clarify what screening brings to the table. In the Western world the incidence of invasive breast cancer is 90 per 100,000 females per year. The death rate is approximately 20% of this i.e. 18 per 100,000 females per year. If there was no screening and consequently no treatment for screened cases the death rate would rise to mirror the incidence rate as is seen in Pakistan or other non screened countries. Screening does 3 things. It picks up early cases, it directs them to treatment and it ensures they are closely monitored and re-screened and biopsied in an ongoing way. Thus the death rate is significantly reduced. The natural history of invasive breast cancer is to spread and cause death sooner or later. These 90 per 100,000 cases of breast cancer per year are invasive and why do they not progress to death? They don't because we can see from the death rates that it is less than 20% of the incidence rate. They don't because they are detected and treated and followed up closely.
In Pakistan or other countries where screening is not done at a population level the incidence rate and death rate are much closer to each other. The reason is because those with breast cancer mostly die from it. In the West they don't die else the incidence and death rates would be much closer to each other.
Incidence, prevalence, screening, treatment and death are on a continuum. The other parameter that is noteworthy is the relatively young age that breast cancer occurs in the West. The incidence graphs in USA and UK show a very large number of women in their 20's and 30's getting breast cancer. This is not a worldwide phenomenon. In the East breast cancer is mainly a disease of older women. The reason for the skewed age profile in the West is the triumvirate (or more correctly trium mulierate) of reduced birth rate, increased exogenous female hormone use, and increased breast cancer incidence.
Competing interests: No competing interests
Unacceptable mammographic image quality in the early 1980s in Canada must not influence our decision about early detection in 2014.
The attention given by the media to the “update” of the failed Canadian trials and their unjustified conclusion that early detection of breast cancer does not reduce mortality from the disease is surprising, especially after the publication of the Independent UK Panel on Breast Cancer Screening which concluded in a meta-analysis of 11 randomised trials, that “the relative risk of breast cancer mortality for women invited to screening compared with controls was 0•80 (95% CI 0•73–0•89), which is a relative risk reduction of 20%” (1). The two Canadian trials are the conspicuous outliers with no mortality decrease accomplished. Dr. Miller made no response to his co-worker Dr. Boyd’s prophetic statement, “…the results of these trials should not be used to change the prevailing scientific view of the potential benefits of screening with mammography”(2).
Professor Day and colleagues pointed out in 1989 in their landmark publication on monitoring breast cancer screening programs (3) that a reduction in breast cancer mortality can occur only after a significant decrease in advanced cancers. Since the CNBSS trials are the only ones which failed to reduce the rate of advanced breast cancers, the lesson to learn from this colossal failure is that they failed to find the potentially fatal cancers, no matter how many cancers were reported. Day and colleagues summarized in their Table III “a minimum set of measures that an information system should monitor to evaluate the effectiveness of the programme in reducing severity of and mortality from the disease. A favourable value for each of these measures is necessary, however, if an acceptable effect on breast cancer mortality is to be achieved. Poor performance indicates where remedial action is required”(3).
The authors of the CNBSS make numerous misleading and erroneous comments on the Two-County Swedish Trial which do not bring us any closer to finding out why the Canadian trials are unique among all the randomized controlled trials in their failure to reduce breast cancer mortality.
To inform the reader of the published facts concerning the Two-County Swedish Trial:
• This trial was designed and run by the Swedish National Board of Health and Welfare with Professor Gunnar Eklund as the Principal Investigator. It has never been my trial, contrary to Dr. Baines’ claim; Dr. Gunnar Fagerberg was the project leader for the E-county arm and I was the project leader for the W-county arm, as has been repeatedly mentioned in the publications from the trial.
• Drs. Miller and Baines are incorrect that there was no informed consent in the Two-County Swedish trial, since “the controls were only contacted after screening ceased in the active study population”. On the contrary, the National Board of Health and Welfare saw to it that the entire population of the two counties was extremely and repeatedly well informed by the media and by activities at all levels of the local governmental agencies. The execution of the randomization process was carried out by the local politicians according to the instructions and under the supervision of Professor Gunnar Eklund.
• It is embarrassing to read the authors’ statements that the randomisation in the Swedish Trial took place on the “county level” and that the tumor size in the control group was 28 mm when in reality it was 22 mm.
• Dr. Baines notes that the Canadian trials used two-view mammography at 12 month intervals whereas the Two-County trial used one-view mammography at 33 month intervals. This only emphasizes the remarkable difference in the performance of early detection between the two studies, since the Swedish trial reduced both the advanced cancer rate and mortality from breast cancer, while the Canadian trials failed on both counts.
• Dr. Baines correctly mentions that “an external audit of mammography based on stratified sampling” took place in the Canadian trials, but she does not acknowledge the impact of the unacceptable quality found by these external audits, my own included. It is an inescapable fact that poor quality mammography means poor quality detection of the potentially fatal cancers
• Dr. Baines comments that “Trial A [Canadian] has an external death review panel to determine cause of death in all cases of deaths in participants known to have breast cancer during the trial or suspected of having breast cancer after linkage with a national data base. Not so for Trial B” [Swedish]. This is patently untrue because so far there have been two external death review panels of the Swedish Two-County Trial, reviewing every breast cancer patient’s chart combined with the linkage to the National Death Registry (4,5). The individual patient charts of all breast cancer cases are still preserved in the county archives and the data are currently under a third external review directed by Professor Richard Peto at the University of Oxford, UK. On the other hand, Dr. Miller sent me an e-mail on Aug 28, 2012, in which he declared that “it was impossible to maintain all the paper records in storage, and it would be impossible to re-conduct a death review for the CNBSS”. Imagine my surprise at the publication of this “Twenty five year follow-up” without a new death review and long after the destruction of the original documents from the CNBSS trials.
In summary: women, the medical profession and public health decision makers should rest assured that the successful early detection of breast cancer and treatment in an early stage significantly improve the outcome and life quality of women afflicted by this disease. There is ample evidence that the modern therapeutic regimens are most effective against non-palpable, screen detected, early stage breast cancer. Instead of attempting to “prove” that early detection makes no difference to the outcome of breast cancer patients, our concerted efforts should use the evidence from well conducted randomized controlled trials (1) to provide even earlier diagnosis and better treatment to achieve further improvements in the outcome of breast cancer.
László Tabár, MD.
No conflict of interest declared
References
1. Marmot MG, Altman DG, Cameron DA, Dewar JA, Thompson SG, Wilcox M. The benefits and harms of breast cancer screening: an independent review. Br J Cancer. 2013 Jun 11;108(11):2205-40.
2. Boyd NF, Jong RA, Yaffe MJ, Tritchler D, Lockwood G, Zylak CJ. A critical appraisal of the Canadian National Breast Cancer Screening Study. Radiology. 1993 Dec;189(3):661-3.
3. Day NE, Williams DR, Khaw KT. Breast cancer screening programmes: the development of
a monitoring and evaluation system. Br J Cancer. 1989;59(6):954–8.
4. Nyström L, Rutqvist LE, Wall S, Lindgren A, Lindqvist M, Rydén S, Andersson I, Bjurstam N, Fagerberg G, Frisell J, et al. Breast cancer screening with mammography: overview of Swedish randomised trials. Lancet. 1993 Apr 17;341(8851):973-8. Erratum in: Lancet 1993 Nov 27;342(8883):1372.
5. Holmberg L, Duffy SW, Yen AM, Tabár L, Vitak B, Nyström L, Frisell J. Differences in endpoints between the Swedish W-E (two county) trial of mammographic screening and the Swedish overview: methodological consequences. J Med Screen. 2009;16(2):73-80. doi: 10.1258/jms.2009.008103.
Competing interests: No competing interests
This is in response to Eugene G Breen, who wrote that in countries where screening is not performed the incidence rate is similar to the mortality and thus it is an evidence that screening decreases mortality. He mentioned that performing screening will decrease it by 20%. He also mentioned Pakistan as an example.
Since I belong to Pakistan, I would like to add that the relationship between screening and mortality is not so simple where the treatment part is missing. Since you will only benefit by screening if all you screen are treated as well. The problem for patients in poor countries like Pakistan is that either they do not have access to proper treatment or they can't afford it. Compounding the problem are social taboos which do not let women seek treatment despite being diagnosed with the disease. Thus the mortality rate in these countries will not be reduced automatically by screening unless adequate treatment is ensured as well.
Competing interests: No competing interests
If existing data is consistent with conflicting interpretations, if it does not command consensus amongst reasonable disinterested qualified people, then the problem is not the quality of the analyses but the quality of the data.
Data that cannot clinch the matter is no basis for a screening programme.
It is uncontroversial that if a woman attends mammography screening, no conscientious practitioner can give her useful information about what her results mean.
Nobody can tell her that a negative mammogram means she doesn’t have cancer, still less that she won’t have it tomorrow.
If the mammogram shows something suspicious, diagnostic tests may yield a negative result. All anyone can say is that the bit that caused concern probably wasn’t cancerous, according to this competent pathologist, on balance. They can’t say she has no cancer, only that nothing else showed on the mammogram, and they can’t say that she won’t have cancer tomorrow.
Diagnostic tests may show cancer. Whether invasive or noninvasive, nobody can tell her that it will progress without treatment since some, but they don’t know how many, and they don’t know which, do not. They can tell her that estimates of numbers vary widely. So they don’t know if she has progressive cancer or not, and on this basis it’s time to decide about treatment.
She’ll want to know whether, if her cancer is progressive, earlier treatment will prolong her life. Nobody can tell her there is a good chance it will because nobody knows if there is any chance it will. Nobody can honestly say that anyone declining screening, or declining treatment at point of diagnosis after screening, will die sooner because they have not had earlier treatment.
They can tell her the wide range of estimates of the other treatment outcomes: life shortened, no difference to lifespan, unnecessarily treated. But they can’t say which will affect her. They can say how different the situation is now from when the poor to middling quality trials were carried out, making the estimates inapplicable to her present predicament. They can tell her about more recent research, but they’d have to say they can’t be more precise because the experts are still – er – debating – its implications and it would be misleading to give only one side of the debate.
She will wonder if anything she has heard constitutes information. For all she’s been through, she knows no more about her situation with regard to breast cancer than before she was screened. She could have read the tea leaves.
A person who declines screening is not risking death. Screening, if it worked, would offer a chance of longer life than fate decrees at a price, so declining it would be forgoing a chance of extra time and not paying the price, not risking earlier death. As things stand, being screened is risking grave harm for no known benefit. Declining it is opting out of Russian roulette.
No conscientious expert would deny these things.
Competing interests: Diagnosed through screening
A screening program monitors a population for disease over an extended period of time. The prevalent (first) round of screening contains many confounding variables and so relying on that first round of screening when evaluating a detection technology can be misleading. Tumours caught in the first round of screening that lead to patient death contribute to a degradation in the mortality associated with the screening technology being evaluated. When a lethal tumour has been caught in the first round of screening, the technology being relied upon (in this case mammography) did not have a chance of catching that malignancy during its treatable stage as it already reached a lethal stage of growth by the time the screening technology was applied to the patient. Thus combining tumours detected in the first round of screening with those detected at a later stage biases the analysis against mammography.
The confounding variables associated with the first round of screening are reason enough to focus one’s evaluation of a disease screening technology on subsequent screening rounds in order for the experiment to better reflect the reality of an on-going screening program. If a screening program detects many lethal tumours in its first round of screening it is justification for changing the parameters of the screening program so that it has a chance to catch those lethal tumours earlier on in their development (for example: by inviting patients to join screening at a younger age when their tumours would have, on average, been less developed or did not yet exist).
In a study such as this [1] where serious concerns have been raised regarding potential problems in patient randomisation [2, 3], relying on data from the first round of screening is liable to increase the inherent bias against screening described above. The results from the second round of screening onwards [1] indicate a mortality benefit from mammographic screening. Pooling the data from the first round of screening with subsequent rounds as has been relied upon in the author’s analyses biases the results against mammography, may have contributed to misleading the public and is based on the author’s assumptions, not facts.
Miller et al. consider the hazard ratio for death from breast cancer caught in the first round of screening (1.47) to be expected. There does appear to be considerable range in the literature that could influence expectation, however, it is entirely plausible that some of this hazard ratio’s large value was due to inappropriate randomisation. The authors have countered claims that their randomisation was inappropriate by citing the external review of their study which didn’t find any problems. It should be noted that every peer reviewed scientific study that has ever been retracted was first subjected to a review process that overlooked the study’s critical errors. That this study cleared an external review process does not mean it is free from inappropriate randomisation.
Jacob Levman, PhD
Institute of Biomedical Engineering
University of Oxford
[1] A B Miller, et al. Twenty five year follow-up for breast cancer incidence and mortality of the Canadian National Breast Screening Study: randomised screening trial, British Medical Journal, 2014;348:g366.
[2] D B Kopans, Re: Twenty five year follow-up for breast cancer incidence and mortality of the Canadian National Breast Screening Study: randomised screening trial, British Medical Journal, 2014;348:g366, Feb. 12th 2014.
[3] L K Tabar, Re: Twenty five year follow-up for breast cancer incidence and mortality of the Canadian National Breast Screening Study: randomised screening trial, British Medical Journal, 2014;348:g366, Feb. 18th 2014.
Competing interests: No competing interests
The terms `breast self-examination` (BSE) and `breast awareness` (BA) mean different things to different people: there is much confusion. [1] [2] Publication of the updated Canadian Study has raised many difficult issues, including the practice of physical breast examination. [3] Authors, in their rapid response 10th March 2014, in particular to Malgrem, provide some clarification about the ethics and practice of breast examination of various kinds at the time the study was launched.
‘Touching and finding’ can occur in different situations motivated by different attitudes of mind. ‘Chance detection’ can occur when women who are sensibly alert are showering, bathing or dressing; many cancers are found this way. ‘Deliberate detection’ can occur when women purposefully and routinely practise BSE or BA with the intention to check for abnormalities. This intervention is not without harms. [4]
But BSE continues in spite of evidence that it cannot now be recommended. A Cochrane Review concludes: `Data from two large trials do not suggest a beneficial effect of screening by breast self-examination but do suggest increased harm in terms of increased numbers of benign lesions identified and an increased number of biopsies performed. At present, screening by breast self-examination or physical examination cannot be recommended`. [4]
It is likely that women who are ‘sensibly alert’ to the possibility of finding an abnormality by chance will be less anxious than those who deliberately and routinely practice BSE or BA.
It is vital that clarification is provided so that women are not left without proper guidance. [5]
[1] Thornton H. Pillarisetti RR. ‘Breast awareness’ and ‘breast self-examination’ are not the same. What do these terms mean? Why are they confused? What can we do? Eur. J. Cancer 2008; 44:2118-2121
[2] McMenammin M, Barry H, Lennon AM, Purcell H, Baum M, Keegan D, McDermott E, O`Donoghue D, Daly L, Mucahy H. A survey of breast cancer awareness and knowledge in a Western population: lots of light but little illumination. Eur J Cancer. 2005 Feb;41(3):393-7.
[3] Miller AB, Wall C, Baines CJ, Sun P, To T, et al. Twenty five year follow-up for breast cancer incidence and mortality of the Canadian National Breast Screening Study: randomized screening trial. BMJ 2014;348:g366
[4] Kösters JP, Gøtzsche PC. Regular self-examination or clinical
examination for early detection of breast cancer. Cochrane
Database of Systematic Reviews 2003;(2). Art. No.: CD003373. doi:
10.1002/14651858. CD003373 (No change, Update, Issue 3, July
2008)
[5] Dillner L. Breast cancer: should I examine myself for lumps? | Women are often advised to check their breasts once a month. But there is strong evidence that self-examination doesn't work. The Guardian. 30th September 2012.
www.theguardian.com/lifeandstyle/2012/sep/30/breast-cancer-examine-mysel...
Competing interests: No competing interests
Jacob Levman (RR 10 March 2014) has misunderstood our data. He states: “The hazard ratio comparing breast cancer mortality from women in the mammography arm to women in the control arm during the first round of screening was reported as 1.47, implying that being assigned to the mammography arm was associated with substantially increased risk of dying of breast cancer (based on the results of the first round of screening only).” He has overlooked the fact that the prevalence screen has added to the mammography arm the cancers detected by mammography alone, half of which we have demonstrated are not over-diagnosed. Thus there will inevitably be more deaths from breast cancer in the mammography arm than the control arm in a sub-group analysis restricted to the prevalence screen. We also reported the hazard ratio for deaths from cancers diagnosed in years 2 to 5 was 0.90 (0.69 to 1.16; P=0.40), thus indicating that the apparently additional deaths from the prevalence screen were compensated by reduced deaths in subsequent screens, i.e. as we demonstrated in other analyses no overall breast cancer mortality reduction from mammography screening. We reported these results to emphasise the fact that the additional cancers, brought forward by the lead time from mammography, increases the period of life lived with cancer without benefit.
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
When I was being trained in medical statistics I was told that it is only valid to compare outcomes from the two complete arms of a randomised controlled trial (RCT). Otherwise any harmful treatments used differently in the two arms would confound the results and render the conclusions invalid.
So when I reviewed the seven RCTs evaluating mammography screening in 1996 I quickly concluded that screening had not been shown to be effective in reducing mortality among women randomised to be offered screening. I used the results to predict that harm from radiotherapy was a confounding factor.
These results confirmed the conclusion in my 1993 paper on the efficacy of cancer surgery that breast cancer, like other cancer, must be a systemic disease, with breast tumours being only symptoms. So earlier removal of tumours made possible by screening could not be expected to reduce breast cancer mortality.
A recent (2014) update of my 1993 paper 20 years later has only served to confirm this earlier conclusion. There are now results from trials evaluating screening for breast, bowel, lung, prostate and ovarian cancers. None of these has found any significant reduction in deaths from all causes among those offered screening.
In addition the two trials comparing radical prostatectomy with Watchful Waiting did not achieve any significant reduction in all-cause mortality among men randomised to be offered this operation.
It is not good enough for researchers to use the cop-out that none of the trials was powered to measure a reduction in all-cause mortality so we have to rely on deaths from breast cancer as the primary outcome.
In this sense most of the debate on the Canadian trial is of little value in determining the future of mammography screening. In my opinion the relevant issues are:
1. Did the Canadian trial show any significant reduction in deaths from all causes among women offered screening?
2. Did any of the other seven RCTs evaluating mammography screening find a significant reduction in deaths from all causes?
If the answer to both these questions is NO (which I understand it is), the third question to ask is:
3. Is it time to reopen the debate about whether or not breast cancer is a systemic disease?
References
Benjamin, DJ. The efficacy of surgical treatment of cancer. Medical Hypotheses 1993; 40 (2): 129-138.
Benjamin, DJ. The efficacy of surgical treatment of breast cancer. Medical Hypotheses 1996; 47 (5): 389-97
Benjamin DJ. The efficacy of surgical treatment of cancer – 20 years later. Med Hypotheses (April) 2014; 82 (4): 412–420. http://www.sciencedirect.com/science/article/pii/S0306987714000127
Competing interests: No competing interests