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.
Paul A Lindholm still doesn’t get it.
He claims that mammography diagnosed early smaller cancers who therefore survived longer .. but where’s the evidence ? Diagnosis of harmless lesions, and gaining lead-time on harmful lesions would equally account for such a claim.
A woman's chance of dying was NOT affected by mammography ! Just look at the bald facts: -
“During the five year screening period, 666 invasive breast cancers were diagnosed in the mammography arm (n=44 925 participants) and 524 in the controls (n=44 910), and of these, 180 women in the mammography arm and 171 women in the control arm died of breast cancer during the 25 year follow-up period. The overall hazard ratio for death from breast cancer diagnosed during the screening period associated with mammography was 1.05 (95% confidence interval 0.85 to 1.30). The findings for women aged 40-49 and 50-59 were almost identical. During the entire study period, 3250 women in the mammography arm and 3133 in the control arm had a diagnosis of breast cancer, and 500 and 505, respectively, died of breast cancer. Thus the cumulative mortality from breast cancer was similar between women in the mammography arm and in the control arm (hazard ratio 0.99, 95% confidence interval 0.88 to 1.12).”
Competing interests: No competing interests
I don't get it. The only patients diagnosed in the study by screening had a 7.8% better 25 year breast cancer specific survival.
Mammograms diagnose earlier smaller cancers and prevent many deaths. This study supports that. What do the 6000+ patients diagnosed after the brief screening period have to do with the study results? How unconscionable to have discontinued screening. Why not one year of screening and 25 years of follow up without screening? How would you expect to see a difference in outcomes?
Competing interests: No competing interests
When a study demonstrates a reduction of breast cancer mortality of approximately 10% (as in the CNBSS trial’s non prevalence screening rounds) or approximately 20% (as in the UK Age Trial and Malmo I) but does not reach statistical significance, the study had insufficient statistical power on which to base the statistical significance test as a 10% to 20% reduction effect is large enough to be statistically significant provided an adequate number of samples are collected. In such a situation, more samples were needed to further confirm the mortality reduction demonstrated from the few samples available and to allow the analysis of this mortality reduction effect to reach statistical significance provided that the additional samples follow the same trend of reduced breast cancer mortality. A lack of statistical significance is not the same as an insignificant effect. It is dangerous to ignore the fact that the UK Age Trial reported “Mortality reduction adjusted for non-compliance in women actually screened was estimated as 24%” [1]. It is dangerous to ignore the fact that the Malmo I trial reported that “women in the study group aged greater than or equal to 55 had a 20% reduction in mortality from breast cancer” and that “Cancers classed as stages II-IV comprised 33% (190/579) of cancers in the study group and 52% (231/443) in the control group” [2]. When you have clearly positive results demonstrating benefits from mammographic screening it is particularly dangerous to base one’s conclusions on the flawed statistical significance test.
Hopefully women will ignore Mr. Hefti’s opinions as I fear they may very well lead to preventable breast cancer deaths. I will not be investing any additional time and effort debating opinions supported by arguments based on no relevant research training such as: citing papers that don’t support the statements presented, producing quotations not included in the studies cited, ignoring or not comprehending the limitations of statistical significance testing while erroneously suggesting I would heavily focus on statistically significant findings supportive of my arguments (I think statistical significance should be ignored as much as possible) and so on. I would caution any woman from making a decision about breast cancer screening based on his opinions.
Mr. Hefti’s contribution to this debate has a negative impact on the legitimate concerns of those scientists keen to identify the actual shortcomings of mammographic breast cancer screening by contributing to the perception that those critical of mammographic screening are biased and must resort to weak and misleading tactics. I am keen to fully comprehend all of the shortcomings of mammographic breast cancer screening and much of my research interests are focused on overcoming those limitations. Although criticizing mammographic screening is helpful to me as motivation for my existing research interests and all my presentations on breast cancer screening include criticisms of mammography, it is also clearly important to accurately assess the mortality benefits of mammographic breast cancer screening, whatever they may be.
Jacob Levman, PhD
Centre of Excellence in Personalized Healthcare
Institute of Biomedical Engineering
University of Oxford
References:
[1] Moss SM, Cuckle H, Evans A, Johns L, Waller M, Bobrow L; Trial Management Group, "Effect of mammographic screening from age 40 years on breast cancer mortality at 10 years' follow-up: a randomised controlled trial", Lancet. 2006 Dec 9;368(9552):2053-60.
[2] Andersson I, Aspegren K, Janzon L, Landberg T, Lindholm K, Linell F, Ljungberg O, Ranstam J, Sigfússon B, "Mammographic screening and mortality from breast cancer: the Malmö mammographic screening trial", BMJ. 1988 Oct 15;297(6654):943-8.
Competing interests: No competing interests
I have serious concerns about the quality of mammography in this study. As seen in Table 2, there was no relevant difference in mean tumor size (1.9 cm vs. 2.1 cm) and lymph node status (59.2% vs. 57.8% lymph node negative) between the mammography and control arms of this study. This indicates insufficient mammography technique and/or interpretation.
For comparison, recently published nationwide figures for the German mammography screening program show quite different figures: median tumor size decreased from 2.1 cm prior to screening to 1.4 cm with screening, while the fraction of lymph node negative cases increased from 57% to 78%.
Interestingly, Miller et al. did in fact find a significant breast-cancer specific mortality reduction in patients with non-palpable tumors, which are more similar to cases found in current quality-controlled screening programs. It is surprising that they did not comment on this.
For me, the most important question regarding this article is: how did it pass the peer review process at the BMJ?
Competing interests: Affiliation with both a university hospital and a breast screening unit.
PART 2:
Levman keeps dismissing population-based studies, as they are, allegedly, inferior (or "misleading") to the findings of randomized controlled trials. Yet, the Cochrane group reported that out of the eight large prospective randomized mammogram trials half of them are seriously flawed, while only three trials are adequately randomized none of which showing a statistically significant breast cancer mortality benefit [13]. If you take the commonly unacknowledged flaws in the pro-mammogram studies into consideration you'll end up with very little, if any, robust evidence, as far as randomized controlled trials concern, in favor of a mammography benefit [9,13].
Levman explained that randomized controlled trials are "the strongest source" of scientific evidence [1]. A much more important and fundamental principle affects any methodological source of evidence, beyond the strength of source of evidence. That is, a good "tool", such as a randomized controlled trial, is only of meaningful service and reliance if it is utilized properly.
For instance, the HIP trial was shown to be severely flawed and biased [13]. The Swedish Two-County trial has also many serious flaws: the assessment of cause of death by the trial authors was not blinded [23], another investigation of the data of one of the counties found only a 10% decrease in mortality (compared to 24% as claimed by Tabar, et al.) [24], and a number of breast cancers and deaths were not accounted for [25]. Evidently, "confounding factors", leading to misleading unreliable conclusions, are quite abound in large pro-mammogram randomized trials [13].
Highly touted by the leadership of the mammography community, these two aforecited large randomized trials were very influential in the induction of organized screening programs around the world. Where were the pro-mammogram voices who are swift and eager to "find fault" in anti-mammogram research but remained silent and inert about these seriously flawed randomized trials? Why, instead, do they keep citing them as relevant pro-mammography evidence? If a good tool had been used improperly, is the result of its use still relevant simply because the tool has the name "randomized controlled trial" stamped on it?
Levman's prime reliance on the value of randomized controlled trials would suggest he would heavily focus on statistically significant findings thereof, as it is the principal overriding factor of the method to form strong conclusions from. But oddly, in his response [1], after commenting on a subunit of data of the current Miller et al. study [16] regarding the prevalence screening issue, showing no statistical significance, Levman also goes on to cite "the UK Age trial" [11] in which no statistical significance was reached in terms of breast cancer mortality reduction as if these data were embodied with great scientific relevance. Does Levman inadvertently assign an undeserved status of specious significance to statistically insignificant pro-mammogram findings within fundamentally anti-mammogram randomized controlled trials? Is the resort to potential random findings of failed randomized controlled mammogram trials superior to findings of rigorous population-based studies?
Contrary to Levman's statement "the alternative population based studies that do not control the mammographic screening status of each subject are a much less reliable source on which to base conclusions", Gøtzsche explained why the old randomized mammogram trials are inadequate and unreliable to reveal the effect of screening and why, therefore, population-based studies become most relevant to present times [9].
Ask yourself, should you ignore or casually dismiss a plethora of relevant population-based studies from many nations, such as Norway, the US, the UK, the Netherlands, Australia, Italy, Sweden, Switzerland, Belgium, Denmark, that show either no noteworthy reduction in breast cancer mortality from systematic screening with mammography or no significant change in incidence of invasive advanced breast cancers after 10-15+ years of widespread screening in favor of a few large prospective randomized controlled trials some of which are seriously flawed and the most reliable of the bunch found no statistically significant decrease in mortality from breast cancer?
To get a clear(er) picture of a situation, arguably, the overall evidence needs to be taken into consideration, rather than relying on a very small set of large randomized controlled trials, very few of which are scientifically reliable. And, if one recognizes and acknowledges the significant impact of vested interests in a lot of pro-mammogram research [9,26], the medical industry's unscientific notions on the progression of breast cancer, the neglect or dismissal of the data on total mortality, collateral damages, and the vast extent of overdiagnosis in the evaluation of the benefit of mammography, if one does not neglect to earnestly consider the various research data from numerous meaningful population studies on the lack of a notable benefit on mortality and the incidence of advanced malignant breast cancer, or the data from many nations showing that breast cancer mortality had declined years prior to the general introduction of organized mammographic screening programs or that the reduction in breast cancer mortality in non-screened ages declined much more than in screen ages [27], the overall evidence for the pro-screening value of mammography resembles much more a piece of Swiss cheese rather than a block of solid concrete.
One can hope that the public recognizes the importance and necessity to scrutinize mammography on many of these, oftentimes disregarded albeit pertinent, issues to gain a more complete and more realistic view of the status of this procedure.
References
1. Levman J, "Re: Accusations of Bias Versus Actual Bias Regarding Mammography", British Medical Journal, 348:g366, 7-April-2014.
2. Hefti R, "Accusations of Bias Versus Actual Bias Regarding Mammography", British Medical Journal, 348:g366, March 31, 2014.
3. Gøtzsche PC, "Relation between breast cancer mortality and screening effectiveness: systematic review of the mammography trials", Dan Med Bull. 2011 Mar;58(3):A4246.
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. Bleyer A, Welch HG, "Effect of three decades of screening mammography on breast-cancer incidence", N Engl J Med. 2012 Nov 22;367(21):1998-2005. doi: 10.1056/NEJMoa1206809.
6. Gøtzsche PC, Olsen O, “Is screening for breast cancer with mammography justifiable”, Lancet. 2000 Jan 8;355(9198):129-34.
7. Gøtzsche PC, “Commentary: Medicalisation of risk factors”, BMJ. 2002 April 13; 324(7342): 886–891.
8. Gøtzsche PC, “Time to stop mammography screening”, CMAJ. 2011 Nov 22;183(17):1957-8.
9. Gøtzsche PC, "Benefit and harms of mammography screening, and invitations to screening, Written statement for the UK hearing on mammography screening, 8 March 2012", 2012 Feb 27. http://www.cochrane.dk/screening/Statement for UK Panel.pdf.
10. Gøtzsche PC, “Mammography Screening: Truth, Lies and Controversy”, 2012
11. Moss SM, Cuckle H, Evans A, Johns L, Waller M, Bobrow L; Trial Management Group, "Effect of mammographic screening from age 40 years on breast cancer mortality at 10 years' follow-up: a randomised controlled trial", Lancet. 2006 Dec 9;368(9552):2053-60.
12. Andersson I, Aspegren K, Janzon L, Landberg T, Lindholm K, Linell F, Ljungberg O, Ranstam J, Sigfússon B, "Mammographic screening and mortality from breast cancer: the Malmö mammographic screening trial", BMJ. 1988 Oct 15;297(6654):943-8.
13. Gøtzsche PC, Nielsen M, "Screening for breast cancer with mammography", Cochrane Database Syst Rev. 2009 Oct 7;(4):CD001877. doi: 10.1002/14651858.CD001877.pub3.
14. Gøtzsche PC, Jørgensen KJ, "Screening for breast cancer with mammography", Cochrane Database Syst Rev. 2013 Jun 4;6:CD001877. doi: 10.1002/14651858.CD001877.pub5.
15. Brodersen J, Jørgensen KJ, Gøtzsche PC, “The benefits and harms of screening for cancer with a focus on breast screening.”, Pol Arch Med Wewn. 2010 Mar;120(3):89-94.
16. 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.
17. Lynge E, "Mammography screening for breast cancer in Copenhagen April 1991-March 1997. Mammography Screening Evaluation Group", APMIS Suppl. 1998;83:1-44.
18. Welch HG, “Should I Be Tested for Cancer?: Maybe Not and Here's Why”, 2006
19. Zahl PH, Maehlen J, Welch HG, “The Natural History of Invasive Breast Cancers Detected by Screening Mammography”, Arch Intern Med., Vol. 168, No. 21, Pg. 2311-2316, 2008
20. Baum M, "Harms from breast cancer screening outweigh benefits if death caused by treatment is included", BMJ. 2013 Jan 23;346:f385. doi: 10.1136/bmj.f385.
21. Early Breast Cancer Trialists' Collaborative Group, “Favourable and unfavourable effects on long-term survival of radiotherapy for early breast cancer: an overview of the randomised trials”, Lancet. 2000 May 20;355(9217):1757-70.
22. Early Breast Cancer Trialists' Collaborative Group, “Radiotherapy for early breast cancer”, Cochrane Database Syst Rev. 2002;(2):CD003647.
23. Gøtzsche PC, Nielsen M, "Screening for breast cancer with mammography", Cochrane Database Syst Rev. 2006 Oct 18;(4):CD001877.
24. Nyström L, Andersson I, Bjurstam N, Frisell J, Nordenskjöld B, Rutqvist LE, “Long-term effects of mammography screening: updated overview of the Swedish randomised trials”, Lancet. 2002 Mar 16;359(9310):909-19.
25. Zahl PH, Gøtzsche PC, Andersen JM, Mæhlen J., “Results of the Two-County trial of mammography screening are not compatible with contemporaneous official Swedish breast cancer statistics.”, Dan Med Bull. 2006 Nov;53(4):438-40.
26. Jørgensen KJ, Klahn A, Gøtzsche PC, “Are benefits and harms in mammography screening given equal attention in scientific articles? A cross-sectional study”, BMC Med. 2007 May 30;5:12.
27. Autier P, Boniol M, Gavin A, Vatten LJ, “Breast cancer mortality in neighbouring European countries with different levels of screening but similar access to treatment: trend analysis of WHO mortality database”, BMJ. 2011 Jul 28;343:d4411. doi: 10.1136/bmj.d4411.
Competing interests: Author of the (e)book "The Mammogram Myth" (2013)
PART 1:
This commentary addresses several points Jacob Levman had brought forward on April 7th [1] pertaining to my previous letter [2].
For example, Levman paints a mistaken and inexcusably misleading picture of Peter C. Gotzsche's stance on mammography, specifically in relation to mortality. Levman writes [1] "Gøtzsche concedes that mortality benefits are obtainable from mammographic screening", citing these two papers: [3,4]. In the first citation [3], Gøtzsche stated that the reductions in breast cancer mortality found in some studies were due to pro-screening biases or flaws in study designs and that in their absence "screening appeared ineffective".
In the second citation [4], Gøtzsche and collaborators wrote, "The observed decline in breast cancer mortality in many countries seems to be caused by improved adjuvant therapy and breast cancer awareness, not screening." - a conclusion corroborated by other investigators [5]. This Gøtzsche et al. paper is also the study Levman is referring to when he falsely accuses me of having stated a contradiction when Levman said this study "indicates that “the trials suggest only a 12% reduction in breast cancer mortality” in contradiction to Mr. Hefti’s statement of no mortality effect." I've never said "no mortality effect", I essentially echoed what Gøtzsche and colleagues had found (no relevant mortality benefit from screening, or: yes a mortality benefit but not from screening - see their aforementioned quote), that there was no statistically significant reduction in breast cancer mortality from longterm screening [2].
Anyone who carefully reviews Gøtzsche's overall mammography work, which considers both randomized controlled studies, rigorous observational studies, and other related research, will find statements that for over a decade have quite consistently and very clearly pointed in only one direction, such as “Screening for breast cancer with mammography is unjustified.” [6], "no reliable evidence shows that breast screening saves lives" [7], "Screening seems ineffective [...]" [8] and, "It is time to stop screening. This is my scientific conclusion [...]" [9] or, if still in doubt, read his book [10].
It is also strongly misleading for Levman to claim that "Two of Gøtzsche’s three adequate trials reported a mortality benefit from mammographic breast cancer screening (the UK Age trial and Malmo I) [...]" [1] when the UK Age trial [11] showed no statistically significant reduction in mortality from breast cancer and the Malmo I [12] trial found "no overall effect on the mortality from breast cancer" and concluded that "The results of our study cannot be used to advocate introduction of mammographic screening in all ages in an urban population" [13,14].
Levman pointed out that I rely heavily on Gøtzsche's work [1]. Yes, admittedly, I do rely heavily on Gøtzsche's and his allied Cochrane collaboration's work. Presumably anyone else would too if they were to recognize that their mammogram research is among the least biased, most transparent, and most substantial works available to the public (Gøtzsche's been one of the most prolific mammogram scientists ever), rather unlike many of the pro-mammogram investigations that are shrouded in secrecy about their raw data, encrusted with complicated statistical models, or heavily afflicted by conflict-of-interests. Historically, secrecy, complexity, and vested interests mean one thing: control of a specific ideology by a certain group of people, whether political or medical.
Because the mortality rates of breast cancer are low without screening, few women will benefit from screening [15]. In juxtaposition, regarding the alleged "significance" of lethal cancers found in the prevalence screening over breast examination in the Miller team trial [16], the prevalence of breast cancer in women of screening age is under 1% [17] and over 99% of screening participants will be healthy, both before and after screening, making this a very small absolute gain. And if you add my point from my previous letter [2] and the fact that some screen-detected invasive ("lethal") breast cancers can grow so slow they'd be cases of overdiagnosis or end in spontaneous remission [9,18,19], the "relative significance" becomes even more an "absolute insignificance" (and some participants may get needlessly harmed).
Levman claim (regarding the detection of late-stage cancer in the prevalence screening) that "Mortality will not improve from the detection of disease that has already reached a lethal stage of development" [1] has to be understood and viewed from his belief in the doctrinaire but erroneous "standard model of malignant tumour progression" [1] which assumes breast cancers grow linearly and progressively from a benign, non-lethal, early-stage to an invasive, advanced, lethal, malignant stage. Yet there is substantial scientific data showing that even advanced, malignant, "lethal" cancers can spontaneously regress or grow exceedingly slow as to constitute cases of overdiagnosis [9,18,19]. In fact, mortality could actually increase in mammography-detected advanced lethal cancers because an overdiagnosed and overtreated patient with a so-called "lethal" cancer, for instance, only receives harm, possibly leading to the premature demise of the patient from the aggressive interventions.
Levman remarked that the Bleyer & Welch study [5] assumed "that every in situ cancer detected by mammography is a case of overdiagnosis" - an assumption he calls "absurd" [1]. First off, Bleyer & Welch did only include ductal carcinoma in situ (DCIS) cancers while lobular carcinoma in situ cancers were excluded from their study [5]. Secondly, how much less "absurd" is their assumption really when over 50% of carcinoma in situ (CIS) cancers represent cases of overdiagnosis [10] and that "practically all women diagnosed with CIS are treated as if the condition would progress to invasive cancer, which leads to considerable overtreatment" [15]? Levman's "absurdity" clause on the extent of in situ overdiagnosis unintentionally but misleadingly deflects from an extremely disconcerting reality.
Levman's casual dismissal [1] of "Baum's work" [20] is also erroneously leading the reader into thinking the issue of harm from radiation therapy is of no or inconsequential relevance. This significant source of injury had long been reported by various investigations [21,22], but typically has been disregarded by pro-mammogram supporters in their estimates of benefits of mammography, thus "radiation treatments" had not been systematically replaced by "alternative therapies". Early-stage breast cancers still get commonly treated by radiation therapy [9]. Thus, contrary to Levman's accusation, I'm not "tarnishing mammography with the deficiencies of different technology", instead he is "tarnishing" the real facts of the matter. Furthermore, other "alternative therapies", such as chemotherapy, also increase the risk of death in overdiagnosed individuals [9].
(continues with PART 2)
References (see PART 2)
Competing interests: Author of the (e)book "The Mammogram Myth" (2013)
Mr. Hefti has challenged my previous letters [1], my rebuttal follows. He begins with the issue I have raised that lethal tumours caught in the first round of screening degrade mortality results unfairly between the two arms of the trial: “If … this prevalence bias were significantly relevant … and if mammography were so much more effective in detecting the lethal advanced breast cancers … you'd expect to find a large highly significant reduction in breast cancer mortality after excluding the data of the first round of screening”. Mr. Hefti is mistaken, if a given screening technology is very good at catching lethal stage cancers it will not necessarily be good at reducing the mortality of the disease it is detecting. Mortality will not improve from the detection of disease that has already reached a lethal stage of development. Mr. Hefti continues: “the Miller group study reports no statistically significant decrease in the mortality rate after omitting the data of the prevalent screening”. Miller’s reported hazard ratio for death from breast cancer in subsequent screening rounds is 0.9 which indicates a mortality benefit from mammographic screening. That their results are not statistically significant is not surprising given the limited number of samples, as previously discussed [2]. A lack of statistical significance is not the same as an insignificant effect.
Mr. Hefti writes: “other studies (including trials without the confounding factor of a mixed experimental group) found no significant reduction in lethal late-stage breast-cancer incidence” citing [3-5]. Citation [3] refers to a textbook on radiation oncology, focused on the therapeutic applications of radiation and is not an appropriate reference towards discrediting mammography. Mr. Hefti’s following citations [4, 5] are population based studies that do not control the mammographic status of the subjects. It is misleading to cite these three references [3-5] at the end of a statement that implies they avoid the confounding factor of having mixed experimental groups, they most certainly do not.
Mr. Hefti writes in reference to the Marmot review [6]: “the panel combined the more reliable and the less reliable mammogram studies to estimate the effect on breast cancer mortality” and continues with “Isn't this the same type of confounding factor, "mixing" diverging entities together and deriving conclusions from it, Levman had dismissed my Lousdal et al. citation? Wouldn't it then also call for Levman's dismissal (instead of his advocation) of the review panel's investigation based on the same methodological argumentation?” The answer is no, this is not the same type of confounding factor that contributed to dismissing the Lousdal study [7]. The Lousdal study’s experimental group was not purely patients who received mammography. The randomized controlled trials from Marmot’s review [6] all had experimental groups controlled to only include subjects receiving mammography. The Marmot review’s combination of multiple randomized controlled trials is not needed to assess the effect of breast cancer screening as the review included the results of each trial individually, indicating cancer screening mortality benefits from almost every trial, with this Canadian trial being the exception.
Mr. Hefti continues: “Many of the large prominent pro-mammography trials have severe methodological limitations and flaws” citing [8, 9]. He continues: “other independent mammogram scientists, evaluating several randomized studies that compared screened versus non-screened groups, reported that the most adequate, well-designed of those studies denoted no "statistically significant reduction in breast cancer mortality"” citing [9-12]. These main criticisms have been raised by Gøtzsche whose own competing reviews published with the Nordic Cochrane Database [9, 12] combine three randomized controlled trials he assessed as having adequate randomization. Two of Gøtzsche’s three adequate trials reported a mortality benefit from mammographic breast cancer screening (the UK Age trial and Malmo I), the remaining trial was the Canadian study we are presently discussing. Gøtzsche’s combination of these three trials is misleading given that the Canadian trial compares mammography to breast examination while the other two trials compare mammography to nothing. Thus their combination is inappropriate towards the independent assessment of the mortality benefits of mammography. Citation [10] indicates that “the trials suggest only a 12% reduction in breast cancer mortality” in contradiction to Mr. Hefti’s statement of no mortality effect. Hefti’s citation [11] is another population based analysis that does not control the subject’s mammography status and was not a randomized trial contrary to Mr. Hefti’s statement.
Mr. Hefti writes: “Aggressive lethal breast cancers tend to grow fast and frequently at a size too small for mammography to timely detect in the preclinical stages” and cites two academic papers in support [4, 11]. These papers are discussion pieces that are far less reliable than a randomized controlled trial. Mr. Hefti continues: “Levman mentions an independent review … as proof that mammographic screening evokes a significant mortality benefit”. There appears to be a misunderstanding here as to what constitutes scientific proof. Randomized controlled trials are considered the gold standard evaluation method. While I certainly believe they are the strongest source available on which to base our conclusions, by no means do I consider their results proof. However, the alternative population based studies that do not control the mammographic screening status of each subject are a much less reliable source on which to base conclusions.
Mr. Hefti writes: “another investigator … remarked that the mammographic benefit is outstripped by harm if the data on "death caused by treatment is included" ” citing [13]. This article [13] is based on an overestimate of the rate of mammographic overdiagnosis provided by Bleyer [14], which is based on the absurd assumption that every in situ cancer detected by mammography is a case of overdiagnosis. While it is inevitable that some in situ cancers need not be treated, assuming that they are all indolent ignores the standard model of malignant tumour progression whereby invasive life-threatening tumours are expected to develop through an in situ stage. Baum’s work [13] is self-described as a crude estimate and its criticism of mammographic screening is based on the shortcomings of subsequent radiation treatments which could be replaced with alternative therapies, thus the author is tarnishing mammography with the deficiencies of different technology.
Mr. Hefti writes: “Levman discredits one of my citations (while overlooking the others)”. I will endeavour to be more thorough given the journal’s space allotment rules. Autier’s study [15] suffers from the same type of problem as the Lousdal study [7] that I have previously discussed [16] in that the mammographic status of the subjects was not controlled, which is not a reliable type of experiment to rely on. The remaining citation [10] was addressed above. Mr. Hefti writes: “Furthermore, an analysis of the population-based mortality data pertaining to national breast screening programs found no effect from mammographic screening”. The study cited [17] suffers from the same class of shortcoming as the Lousdal study [7], whereby the mammographic status of the patients wasn’t controlled.
Hefti has written that I am “silent about the fact that the Miller study included and calibrated for a vast multitude of confounding factors or variables”. Miller at al. [18] and many studies attempt to control for confounding factors without providing a complete set of details regarding the exact adjustments that have been employed in their calculations. On this point I am sympathetic to the authors [18] as journal publication rules regularly exclude the possibility of providing every relevant detail due to limited publication space. Given the complexity of modern research, it is a challenge to present one’s work thoroughly while simultaneously balancing clarity and abiding by the journal’s publication space requirements. A large amount of relevant calculations are typically not provided in studies such as this, preventing informed commentary on much of the methods employed. Thus, this task is typically left to the publishing journal’s peer reviewers.
Hefti has written: “As Miller had pointed out, Levman, oddly, had also ignored crucial confounding factors, such as lead and length biases”. I merely don’t think it is safe to ignore the study’s survival data which indicates benefits from mammographic screening, especially in favour of mortality data that penalizes mammography for having been presented with so many detectable lethal stage tumours in the first round of screening.
Mr. Hefti writes: “a review of several randomized mammogram trials also found no screening effect from high sensitivity of tumor detection and breast cancer mortality” citing [8]. The following passage [8] conflicts with Mr. Hefti’s assessment of the article: “Comprehensive systematic reviews have suggested that mammography screening reduces breast cancer mortality by 15-16%” [8] citing [9].
In summary, Mr. Hefti’s arguments rely heavily on population based research that doesn’t control the mammographic screening status of each patient. Mr. Hefti’s arguments also rely heavily on the work of Gøtzsche. However, Gøtzsche concedes that mortality benefits are obtainable from mammographic screening [8, 10] and of the three randomized controlled trials he has deemed acceptable in his reviews on the subject [9, 12], two reported mortality benefits from mammography. Combining this Canadian trial’s negative results with the remaining two that he deemed acceptable was misleading due to differences between the trials. Pooling these three randomized controlled trials is not appropriate towards the independent assessment of the mortality benefits of mammographic screening. Furthermore, whether randomization was implemented appropriately in this Canadian trial remains an open question with poignant criticisms raised by Dr. Kopans at Harvard University who was involved early on in the trial’s review process [19]. It is not safe to conclude no mortality benefits are obtainable from mammographic breast cancer screening based on the results of this study [18] or any review that includes it in a pooled analysis [9, 12].
Jacob Levman, PhD
Institute of Biomedical Engineering
University of Oxford
References
[1] Hefti, Accusations of Bias Versus Actual Bias Regarding Mammography, British Medical Journal, 348:g366, March 31, 2014.
[2] Levman, Subject randomisation and mortality in mammographic breast cancer screening, British Medical Journal, 348:g366, March 10, 2014.
[3] Perez et al., Principles and Practice of Radiation Oncology, 4th Edition, 2003.
[4] Esserman et al., Rethinking screening for breast cancer and prostate cancer, Journal of the American Medical Association, 2009;302(15):1685-92.
[5] Kalager et al., Overdiagnosis of invasive breast cancer due to mammography screening: results from the Norwegian screening program, Annals of Internal Medicine, 2012;156(7):491-9.
[6] Marmot, et al, The benefits and harms of breast cancer screening: an independent review, British Journal of Cancer, 2013;108:2205-2240.
[7] Lousdal et al., Trends in breast cancer stage distribution before, during and after introduction of a screening programme in Norway, European Journal of Public Health, Published online ahead of print edition, March 4th, 2014, doi:10.1093/eurpub/cku015.
[8] Gøtzsche, Relation between breast cancer mortality and screening effectiveness: systematic review of the mammography trials, Dan Med Bul, 2011;58(3):A4246.
[9] Gøtzsche, Nielsen, Screening for breast cancer with mammography, Cochrane Database Syst Rev. 2009, Issue 4.
[10] Gøtzsche et al., Why mammography screening has not lived up to expectations from the randomised trials, Cancer Causes Control, 2012;23(1):15-21.
[11] Jørgensen et al., Is mammographic screening justifiable considering its substantial overdiagnosis rate and minor effect on mortality, Radiology, 2011;260(3):621-7.
[12] Gøtzsche, Jørgensen, Screening for breast cancer with mammography, Cochrane Database Syst Rev. 2013, Issue 6.
[13] Baum, Harms from breast cancer screening outweigh benefits if death caused by treatment is included, British Medical Journal, 2013;346:f385.
[14] Bleyer, Welch, Effect of three decades of mammography on breast-cancer incidence, New England Journal of Medicine, 2012;131:949-55.
[15] Autier et al, Advanced breast cancer incidence following population-based mammographic screening, Annals of Oncology, 2011;22(8):1726-35.
[16] Levman, Hazard ratios and bias against mammography, British Medical Journal, 2014;348:g366, March 25, 2014.
[17] Mukhtar et al., Breast cancer mortality trends in England and the assessment of the effectiveness of mammography screening: population-based study, J R Soc Med. 2013 Jun;106(6):234-42.
[18] 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.
[19] 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, February 12, 2014.
Competing interests: No competing interests
In regard to Jacob Levman's commentary from 25-March-2014 [1].
Levman argued that because mammography has a "substantially differing sensitivity to the detection of breast cancer", compared to breast examination, leading to an "increased tumour yield in the mammography group", the bias from the prevalence (first round) screening is relevant [1]. Levman's basic assumption is that among the "increased tumour yield in the mammography group" is a significant higher number of lethal advanced late-stage breast cancers versus in the breast examination arm at the prevalent screening.
Higher tumor sensitivity via mammography detection, over breast examination, isn't the same as actually and reliably spotting (more) lethal breast cancers, rather the technology is capable of detecting a higher total number of abnormal tissue growths (i.e., "increased tumour yield in the mammography group"). Mammography, specifically the latest technology of it, detects a large percentage of cancers of low malignant potential or indolent "cancers" (e.g., cases of overdiagnosis), accounting for its capability to catch more "cancers" over breast examination.
Because mammography commonly misses many lethal advanced cancers of smaller size, and even above 20mm [2], those it does detect at the prevalence screening, representative of late-stage tumors, are thus also going to be relativity larger, increasingly diminishing and closing the gap, difference, or bias, of those lethal late-stage cancers capable of detection by breast examination.
If, as Levman insists, this prevalence bias were significantly relevant, compared to breast examination, and if mammography were so much more effective in detecting the lethal advanced breast cancers, due to higher sensitivity, you'd expect to find a large highly significant reduction in breast cancer mortality after excluding the data of the first round of screening and particularly after many rounds of screening spanning over a long period of time. Instead, the Miller group study reports no statistically significant decrease in the mortality rate after omitting the data of the prevalent screening [3]. A review of several randomized mammogram trials also found no screening effect from high sensitivity of tumor detection and breast cancer mortality [4].
Conceivably to further bolster his point on the prevalence bias, Levman discredits one of my citations [5] (while overlooking the others) from a prior BMJ comment of mine [6] on research showing no (significant) reduction in the incidence of lethal advanced breast cancer from the use of mammographic screening because the experimental group was "mixed" with screened and unscreened women, incurring "confounding factors" [1].
However, it should be noted that, apart from those studies I've already mentioned, other studies (including trials without the confounding factor of a mixed experimental group) found no significant reduction in lethal late-stage breast-cancer incidence despite several years of good participation in mammographic screening [7-9].
In addition, strong research data supports the notion that screening with mammography systematically fails to detect lethal cancers at an early treatable phase, strengthening and corroborating the findings of a lack of consistent reduction in incidence of lethal late-stage cancers. Aggressive lethal breast cancers tend to grow fast and frequently at a size too small for mammography to timely detect in the preclinical stages [2,8,10].
Presumably to strengthen his pro-mammography position, Levman mentions an independent review [11] of several randomized trials examining the breast screening situation, comprising "studies that carefully compare women who receive mammographic breast cancer screening with those that do not have regularly", as proof that mammographic screening evokes a significant mortality benefit. Yet, another investigator, referring to the aforementioned review, remarked that the mammographic benefit is outstripped by harm if the data on "death caused by treatment is included" [12], an obviously important set of data because the detection of breast cancer by screening typically results in the commencement of treatment. Furthermore, the review panel ignored critical issues in their evaluation described and submitted to them by the Nordic Cochrane Centre [13]. For instance, the panel combined the more reliable and the less reliable mammogram studies to estimate the effect on breast cancer mortality [13].
Isn't this the same type of confounding factor, "mixing" diverging entities together and deriving conclusions from it, Levman had dismissed my Lousdal et al. citation for [1]? Wouldn't it then also call for Levman's dismissal (instead of his advocation) of the review panel's investigation based on the same methodological argumentation? Is the reader supposed to selectively discharge one set of faulty research while paying heed to another faulty investigation?
Furthermore, an analysis of the population-based mortality data pertaining to national breast screening programs found no effect from mammographic screening [14]. Other independent mammogram scientists, evaluating several randomized studies that compared screened versus non-screened groups, reported that the most adequate, well-designed of those studies denoted no "statistically significant reduction in breast cancer mortality" after more than a decade of screening [2,15-17].
Many of the large prominent pro-mammography trials have severe methodological limitations and flaws [4,15], albeit this is rarely mentioned by supporters of the procedure, instead they have a tendency to refer to these trials as reliable well-conducted studies.
For example, Levman swiftly points out a "confounding factor" in the Lousdal et al. study [5] but he (and other mammogram supporters) are silent about the fact that the Miller study included and calibrated for a vast multitude of confounding factors or variables while in the most prominent, large pro-mammogram screening trials (e.g., HIP, Swedish Two County, Edinburgh, etc.) few variables were taken into consideration. Yet, they loudly and ad nauseam knock at the alleged flawed randomization process of the Miller team trial. As Miller had pointed out [18], Levman, oddly, had also ignored crucial confounding factors, such as lead and length biases, in one of his prior BMJ responses [19], criticizing the Miller team study.
Confounding factors, or bias, operate at many different levels, including on the perception and presentation of data. Is the omission or disregard of relevant scientific details and data, or the selective portrayal of evidence, a potentially highly significant "confounding factor" for an individual not to see the actual picture on mammography, and, by extension, for whomever is exposed to such a biased presentation of the facts about the screening procedure?
References
1. Levman J, "Hazard ratios and bias against mammography", British Medical Journal, 2014;348:g366, March 25, 2014
2. Jørgensen KJ, Keen JD, Gøtzsche PC, “Is mammographic screening justifiable considering its substantial overdiagnosis rate and minor effect on mortality”, Radiology. 2011 Sep;260(3):621-7.
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 Feb 11;348:g366. doi: 10.1136/bmj.g366.
4. Gøtzsche PC, "Relation between breast cancer mortality and screening effectiveness: systematic review of the mammography trials", Dan Med Bull. 2011 Mar;58(3):A4246.
5. 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]
6. Hefti R, "Re: Twenty five year follow-up for breast cancer incidence and mortality of the Canadian National Breast Screening Study: randomized screening trial", British Medical Journal, 2014;348:g366, March 18, 2014
7. Perez CA, Brady, LW, Halperin EC, Schmidt-Ullrich RK (Editors), “Principles and Practice of Radiation Oncology”, 4th Edition, 2003
8. Esserman L, Shieh Y, Thompson I, "Rethinking screening for breast cancer and prostate cancer", JAMA. 2009 Oct 21;302(15):1685-92. doi: 10.1001/jama.2009.1498.
9. Kalager M, Adami HO, Bretthauer M, Tamimi RM, "Overdiagnosis of invasive breast cancer due to mammography screening: results from the Norwegian screening program", Ann Intern Med. 2012 Apr 3;156(7):491-9. doi: 10.7326/0003-4819-156-7-201204030-00005.
10. Welch HG, “Should I Be Tested for Cancer?: Maybe Not and Here's Why”, 2006
11. 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. doi: 10.1038/bjc.2013.177. Epub 2013 Jun 6.
12. Baum M, "Harms from breast cancer screening outweigh benefits if death caused by treatment is included", BMJ. 2013 Jan 23;346:f385. doi: 10.1136/bmj.f385.
13. Gotzsche PC, "The Nordic Cochrane Centre's comments on “Independent UK Panel on Breast Cancer Screening. The benefits and harms of breast cancer screening: an independent review", Lancet 2012 Oct 30. (See http://www.cochrane.dk/screening/comments-on-UK-panel.htm )
14. Mukhtar TK, Yeates DR, Goldacre MJ, "Breast cancer mortality trends in England and the assessment of the effectiveness of mammography screening: population-based study", J R Soc Med. 2013 Jun;106(6):234-42. doi: 10.1177/0141076813486779.
15. Gøtzsche PC, Nielsen M, "Screening for breast cancer with mammography", Cochrane Database Syst Rev. 2009 Oct 7;(4):CD001877. doi: 10.1002/14651858.CD001877.pub3.
16. 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.
17. Gøtzsche PC, Jørgensen KJ, "Screening for breast cancer with mammography", Cochrane Database Syst Rev. 2013 Jun 4;6:CD001877. doi: 10.1002/14651858.CD001877.pub5.
18. Miller AB, "Re: Twenty five year follow-up for breast cancer incidence and mortality of the Canadian National Breast Screening Study: randomized screening trial", British Medical Journal, 2014;348:g366, February 17, 2014
19. Levman J, "Re: Twenty five year follow-up for breast cancer incidence and mortality of the Canadian National Breast Screening Study: randomized screening trial", British Medical Journal, 2014;348:g366, February 14, 2014
Competing interests: Author of the (e)book "The Mammogram Myth" (2013)
Miller has argued that their hazard ratio comparing death by breast cancer (1.47) between their mammography group and their control group from the first round of screening is expected and Miller cites the Swedish two county trial’s hazard ratio of 1.26 as evidence that their hazard ratio is not abnormally imbalanced against mammographic screening [1]. It should be noted that the 1.26 hazard ratio from the Swedish trial was based on comparing mammography to a control group receiving no additional care, whereas Miller’s hazard ratio of 1.47 is based on comparing mammography to a control group receiving breast examinations. Since breast examinations provide benefit by identifying some malignant tumours, we should expect the CNBSS trial [2] to achieve a lower hazard ratio than the Swedish two county trial’s 1.26, however it is noticeably larger. The risk of death from breast cancer does indeed appear to be inflated for women in the first round of screening in the mammography group of the CNBSS trial [2] and inappropriate randomization is a plausible explanation as identified by Dr. Kopans at Harvard [3].
I have previously mentioned the additional issue that lethal advanced stage tumours caught in the first round of screening contribute to degrading the mortality results of any screening technology being evaluated as the technology was not given the opportunity to detect those tumours at a treatable stage. Rolf Hefti has asked “isn’t this bias relatively irrelevant as it affects both groups”? [4] The answer is no, this bias is not irrelevant because the two techniques being compared (mammography and breast examination) have substantially differing sensitivity to the detection of breast cancer. Miller’s study demonstrated increased tumour yield in the mammography group. The bias from including lethal tumours detected in the first round of screening preferentially degrades the results of any technique that is more sensitive to detecting those lethal tumours, in this case mammography. Mammography was in fact catching more cancers and for every additional lethal cancer mammography catches in the first round of screening, its mortality results degrade. This bias does of course exist in the control group as well (when breast examination catches a lethal tumour in the first round of screening), however, whichever technique detects the most lethal tumours in the first round of screening is negatively affected by this bias the most. Since mammography substantially increases tumour yield in the first round of this trial, this bias is not irrelevant as it preferentially degrades the mammography mortality results. This bias can be avoided in both groups by simply comparing their mortality results from subsequent rounds of screening only. If we look exclusively at the tumours detected after the first round of screening (from both mammography and breast examination) then the results of this study demonstrate a mortality benefit from mammography (hazard ratio 0.9), though admittedly it is smaller than the mortality benefits reported in most major randomized controlled trials. Potential reasons for the underperformance of this trial have been presented previously [3, 5].
Rolf Hefti [4] has also cited a recent publication from Norway [6] and indicated that it supports his anti-mammographic screening position. It should be noted that the Norwegian trial cited [6] is population based and did not include a careful assessment whereby all the women in the experimental group received mammography. The experimental group was mixed including both women who receive mammographic screening and those who do not. Basing conclusions as to the effectiveness of a disease screening technology on a study such as this is fraught with peril, as confounding factors are impossible to disassociate from the analysis. It should also be noted that their control group was young women, whereas their experimental group was substantially older. Given that it is known that older women are more likely to develop breast cancer, this comparison was inappropriate. Studies that carefully compare women who receive mammographic breast cancer screening with those that do not have regularly demonstrated a mortality benefit from the use of mammography, which is well summarized in the Marmot review [7].
Jacob Levman, PhD
Institute of Biomedical Engineering
University of Oxford
[1] Miller, Baines, Re: Twenty five year follow-up for breast cancer incidence and mortality of the Canadian National Breast Screening Study: randomized screening trial, British Medical Journal, 2014;348:g366, March 19, 2014.
[2] Miller et al., Twenty five year follow-up for breast cancer incidence and mortality of the Canadian National Breast Screening Study: randomized screening trial, British Medical Journal, 2014;348:g366.
[3] Kopans, Re: Twenty five year follow-up for breast cancer incidence and mortality of the Canadian National Breast Screening Study: randomized screening trial, British Medical Journal, 2014;348:g366, February 12, 2014.
[4] Hefti, Re: Twenty five year follow-up for breast cancer incidence and mortality of the Canadian National Breast Screening Study: randomized screening trial, British Medical Journal, 2014;348:g366, March 18, 2014.
[5] Tabar, Re: Twenty five year follow-up for breast cancer incidence and mortality of the Canadian National Breast Screening Study: randomized screening trial, British Medical Journal, 2014;348:g366, February 18, 2014.
[6] Lousdal et al., Trends in breast cancer stage distribution before, during and after introduction of a screening programme in Norway, European Journal of Public Health, published online ahead of print edition, March 4, 2014.
[7] Marmot et al., The benefits and harms of breast cancer screening: an independent review, British Journal of Cancer, 2013 108:2205-2240.
Competing interests: No competing interests
Early detection illusions
Dear Editors,
Overzealous frequent aggressive multimodal device scanning of women's breasts in order to detect minuscule tumours, arbitrarily claiming early findings and consequent early surgery/radiotherapy/chemotherapy increases patient survival, is wrong.
Recent evidence reveals that even invasive breast cancers of 1cm size eventually demonstrate equal survival rates with smaller cancers, at 100% in 15 years, irrespective of the number of positive lymph nodes.
Additionally, even tumours larger than 2 cm demonstrated 96% survival rates, irrespective of the number of positive lymph nodes. [1]
Aggressive and frequent radiological methods for detecting minuscule breast tumours are therefore useless, and could increase false positives.
Creating artificial demand of a useless product or service for profit, is unethical.
Reference
[1] BMJ 2015;351:h4901
http://www.bmj.com/content/351/bmj.h4901
Competing interests: No competing interests