Re: Twenty five year follow-up for breast cancer incidence and mortality of the Canadian National Breast Screening Study: randomised screening trial
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)
Rapid Response:
Re: Twenty five year follow-up for breast cancer incidence and mortality of the Canadian National Breast Screening Study: randomised screening trial
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)