Debunking myths about screening: How to screen more judiciously

Guylène Thériault; Donna L. Reynolds; Roland Grad; James A. Dickinson; Harminder Singh; Olga Szafran; Viola Antao; Neil R. Bell

doi:10.46747/cfp.6911767

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RE: RE: A reply to Anna N. Wilkinson
Paula B Gordon

Published on: 01 May 2024
RE: A reply to Anna N. Wilkinson
From the Prevention in Practice article series writing group As above

Published on: 26 March 2024
Evidence based truths about the benefit of cancer screening
Anna N, Wilkinson

Published on: 20 February 2024

Published on: (1 May 2024)
Page navigation anchor for RE: RE: A reply to Anna N. Wilkinson
RE: RE: A reply to Anna N. Wilkinson
Paula B Gordon, Radiologist, University of British Columbia
1. On how earlier detection is needlessly identifying cancers which would not impact outcomes.

Dr. Grad is referring to the concept of overdiagnosis, the hypothetical occasion where a woman is diagnosed with cancer, is treated for it, but dies of another cause sooner than her breast cancer would have threatened her life. This can occur in several situations. For example:
The woman develops another more lethal cancer.
She dies sooner of another disease (heart disease, etc).
Or if the breast cancer is very low-grade/slow growing, it might never kill her before she dies of any other cause.

Because it cannot be known whether any given woman’s cancer will be “overdiagnosed,” all women with newly-diagnosed cancer are offered treatment. Overdiagnosis is only important if it leads to over-treatment, so the discussion about treatment should consider a woman’s general health, her life-expectancy, and her personal values/preferences.
Researchers studied overdiagnosis in seven European screening programs (Puliti). When they adjusted for breast cancer risk and lead time, they concluded that “the most plausible estimates of overdiagnosis range from 1% to 10%. Substantially higher estimates of overdiagnosis reported in the literature are due to the lack of adjustment for breast cancer risk and/or lead time.” Compare that estimate with the 48% overdiagnosis rate for women aged 40-49, 20 years post cessation of screening in the CNBSS trial (Baines), us...
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1. On how earlier detection is needlessly identifying cancers which would not impact outcomes.

Dr. Grad is referring to the concept of overdiagnosis, the hypothetical occasion where a woman is diagnosed with cancer, is treated for it, but dies of another cause sooner than her breast cancer would have threatened her life. This can occur in several situations. For example:
The woman develops another more lethal cancer.
She dies sooner of another disease (heart disease, etc).
Or if the breast cancer is very low-grade/slow growing, it might never kill her before she dies of any other cause.

Because it cannot be known whether any given woman’s cancer will be “overdiagnosed,” all women with newly-diagnosed cancer are offered treatment. Overdiagnosis is only important if it leads to over-treatment, so the discussion about treatment should consider a woman’s general health, her life-expectancy, and her personal values/preferences.
Researchers studied overdiagnosis in seven European screening programs (Puliti). When they adjusted for breast cancer risk and lead time, they concluded that “the most plausible estimates of overdiagnosis range from 1% to 10%. Substantially higher estimates of overdiagnosis reported in the literature are due to the lack of adjustment for breast cancer risk and/or lead time.” Compare that estimate with the 48% overdiagnosis rate for women aged 40-49, 20 years post cessation of screening in the CNBSS trial (Baines), used by the Task Force.
Moreover, overdiagnosis is vanishingly rare in younger/premenopausal women because their cancers grow and become lethal faster than cancers in older women, and they’re unlikely to have competing causes of death. Their rate would be in the lower end of the 1-10% cited above. Overdiagnosis is most relevant in elderly women. Women should be informed about overdiagnosis, but it should not be used as a reason to not screen women aged 40-49. And the trial that included the largest number of women in that age group, which also had the greatest incidence of overdiagnosis (Baines), has been discredited, and should be eliminated from consideration by the task force.(Yaffe, Seely, Seely)

2. On newer technology and health benefits for our patients

Dr. Grad was critical of Dr. Wilkinson for including therapy in the discussion of the benefits of early detection. But as he pointed out later on in the paragraph, the two are very much connected. It is unreasonable to make screening guidelines based on RCTs done not only with technology that is now obsolete, but performed when patients received therapies that were primitive, compared to what is available now.

Therapy is more effective when cancer is detected at earlier stages. Treatment of a cancer is based on its stage at the time of diagnosis, whether it is diagnosed by screening, or by the woman, finding a lump in her breast. The contribution of screening has been shown by studying women who died of breast cancer. By considering only the women who died of the disease, researchers eliminated lead time bias and overdiagnosis, because a cancer that kills a woman cannot have been overdiagnosed. They showed that women aged 40-69 who participate in screening are 60% less likely to die in the first 10 years after diagnosis, and 47% less likely to die in the 20 years after their diagnosis than women who have not attended screening (Tabar 2018).

Dr. Grad stated, “Interestingly, as cancer treatment improves, screening to achieve earlier detection becomes less important.” But as recently as August 2023, the Canadian Cancer Society reported that five-year survival is virtually 100% when cancers are detected at stage zero or one, and only 23% when they are detected at stage four (CCS).

Furthermore, his statement ignores the benefits of early detection that extend far beyond mortality reduction: Early detection offers better quality of life for women with cancer. Women who are diagnosed with early-stage cancer can be successfully treated with less aggressive surgeries (lumpectomy instead of mastectomy; sentinel node biopsy instead of axillary dissection), with a much lower risk of lymphedema, and they can potentially avoid chemotherapy. (Coldman, Ahn, Yaffe)

3.
Dr. Grad stressed the need for longer-term studies than 5-10-year survival, and made the point that “an overdiagnosed cancer does not kill.”

In a randomized trial in Sweden, women aged 40 to 74 who were invited to participate in screening showed a significant reduction in mortality of 27-31% at 29 years of follow-up (Tabar 2011).

This was also addressed by Dr. Tabar et al, (Tabar 2018) who showed that women aged 40-69 who participated in screening were 47% less likely to die within the 20 years following diagnosis, than women who don’t have screening.

1. Puliti D, Duffy SW, Miccinesi G, de Koning H, Lynge E, Zappa M, Paci E; EUROSCREEN Working Group. Overdiagnosis in mammographic screening for breast cancer in Europe: a literature review. J Med Screen. 2012;19 Suppl 1:42-56. doi: 10.1258/jms.2012.012082. PMID: 22972810.

2. Baines CJ, To T, Miller AB. Revised estimates of overdiagnosis from the Canadian National Breast Screening Study. Prev Med. 2016 Sep;90:66-71. doi: 10.1016/j.ypmed.2016.06.033. Epub 2016 Jun 29. PMID: 27374944.

3. Yaffe MJ, Seely JM, Gordon PB, Appavoo S, Kopans DB. The randomized trial of mammography screening that was not-A cautionary tale. J Med Screen. 2022 Mar;29(1):7-11. doi: 10.1177/09691413211059461. Epub 2021 Nov 23. PMID: 34812692; PMCID: PMC8892036.
https://pubmed.ncbi.nlm.nih.gov/34812692/

4. Seely JM et al. Errors in Conduct of the CNBSS Trials of Breast Cancer Screening Observed by Research Personnel, Journal of Breast Imaging, Volume 4, Issue 2, March/April 2022, Pages 135–143, https://doi.org/10.1093/jbi/wbac009
https://academic.oup.com/jbi/article/4/2/135/6555326

5. Seely JM et al. The Fundamental Flaws of the CNBSS Trials: A Scientific Review, Journal of Breast Imaging, Volume 4, Issue 2, March/April 2022, Pages 108–119, https://doi.org/10.1093/jbi/wbab099
https://academic.oup.com/jbi/article/4/2/108/6555324

6. Tabár L, Dean PB, Chen TH, Yen AM, Chen SL, Fann JC, Chiu SY, Ku MM, Wu WY, Hsu CY, Chen YC, Beckmann K, Smith RA, Duffy SW. The incidence of fatal breast cancer measures the increased effectiveness of therapy in women participating in mammography screening. Cancer. 2019 Feb 15;125(4):515-523. doi: 10.1002/cncr.31840. Epub 2018 Nov 8. PMID: 30411328; PMCID: PMC6588008. https://pubmed.ncbi.nlm.nih.gov/30411328/

7. https://cancer.ca/en/cancer-information/cancer-types/breast/prognosis-an...

8. Coldman AJ, Phillips N, Speers C. A retrospective study of the effect of participation in screening mammography on the use of chemotherapy and breast conserving surgery. Int J Cancer. 2007 May 15;120(10):2185-90. doi: 10.1002/ijc.22545. PMID: 17290404.

9. Ahn S, Wooster M, Valenti et al. Impact of Screening Mammography on Treatment in Women Diagnosed with Breast Cancer. Ann Surg Oncol 2018; 25:2979–2986.

10. Yaffe MJ, Jong RA, Pritchard KI. Breast Cancer Screening: Beyond Mortality. J Breast Imaging. 2019 Sep 4;1(3):161-165. doi: 10.1093/jbi/wbz038. PMID: 38424760.

11. Tabár L, Vitak B, Chen TH, Yen AM, Cohen A, Tot T, Chiu SY, Chen SL, Fann JC, Rosell J, Fohlin H, Smith RA, Duffy SW. Swedish two-county trial: impact of mammographic screening on breast cancer mortality during 3 decades. Radiology. 2011 Sep;260(3):658-63. doi: 10.1148/radiol.11110469. Epub 2011 Jun 28. PMID: 21712474.
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Competing Interests: None declared.
Published on: (26 March 2024)
Page navigation anchor for RE: A reply to Anna N. Wilkinson
RE: A reply to Anna N. Wilkinson
From the Prevention in Practice article series writing group As above, Family Physician, McGill University
In reflecting on the points raised by Dr Wilkinson, we would like to offer the following response.

1. On how earlier detection is needlessly identifying cancers which would not impact outcomes, Dr Wilkinson wrote: “Scientific data does not support the spontaneous regression of cancers: in a study of 479 untreated breast cancers followed over 10 years, zero cancers spontaneously regressed or disappeared.”

We are puzzled by this point, as spontaneous regression is tangential to our question: Does earlier detection of cancer result in better health outcomes? On this, the most important question, we provided three examples in cancer screening (i.e., melanoma, neuroblastoma and thyroid cancer). Scientists know that high quality evidence is required to be confident that earlier is better. To counter this point in our article, Dr Wilkinson referenced a single cohort study of the persistence of screen detected breast tumors (DCIS or invasive cancer).1 This reference was to an observational study that did not report health benefits that would truly matter to patients. As we write this letter, the benefit of detecting DCIS remains uncertain.

Bottom line? Earlier detection is essential for screening to be of benefit. Importantly,
early detection is often not beneficial.

2. On newer technology and health benefits for our patients, Dr Wilkinson wrote: “From 1975 to 2019, US breast cancer mortality decreased by 58%, attributable to both scree...
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In reflecting on the points raised by Dr Wilkinson, we would like to offer the following response.

1. On how earlier detection is needlessly identifying cancers which would not impact outcomes, Dr Wilkinson wrote: “Scientific data does not support the spontaneous regression of cancers: in a study of 479 untreated breast cancers followed over 10 years, zero cancers spontaneously regressed or disappeared.”

We are puzzled by this point, as spontaneous regression is tangential to our question: Does earlier detection of cancer result in better health outcomes? On this, the most important question, we provided three examples in cancer screening (i.e., melanoma, neuroblastoma and thyroid cancer). Scientists know that high quality evidence is required to be confident that earlier is better. To counter this point in our article, Dr Wilkinson referenced a single cohort study of the persistence of screen detected breast tumors (DCIS or invasive cancer).1 This reference was to an observational study that did not report health benefits that would truly matter to patients. As we write this letter, the benefit of detecting DCIS remains uncertain.

Bottom line? Earlier detection is essential for screening to be of benefit. Importantly,
early detection is often not beneficial.

2. On newer technology and health benefits for our patients, Dr Wilkinson wrote: “From 1975 to 2019, US breast cancer mortality decreased by 58%, attributable to both screening and treatment.”

To be clear, we referred to technology in our article in the context of imaging for cancer screening. However, Dr Wilkinson is touting the benefits of newer "cancer diagnostics and therapies”. Interestingly, as cancer treatment improves, screening to achieve earlier detection becomes less
important. In the context of screening, it is challenging to disentangle the fraction of cancer deaths prevented by improved treatment from that attributable to improved imaging. Research shows improvements in treatment were responsible for most of the observed reduction in breast cancer
mortality in the USA.2

3. On the point that “Cancers diagnosed through screening are earlier stage with better survival and decreased mortality, meaning that lives are saved,” 5-year survival statistics are presented as evidence.

An early article in ‘The Prevention in Practice’ series made the following key point: In screening for cancer, appropriate outcome measures for determining benefit include overall and disease-specific mortality; inappropriate measures include incidence (new cases) and 5- or 10-year survival. The use of a metric such as 5-year survival is highly inappropriate to judge the effect of screening because of the problems of lead time bias, length time bias and overdiagnosis of screen detected cancers. By definition, an overdiagnosed cancer does not kill. Overdiagnosis, lead time and length time bias lead to a mirage of benefit.

To contend that lives are saved at the population level is inaccurate as explained in our article. This important point received further support from a recent analysis of estimated lifetime gained by cancer screening tests.4

We would all hope to reduce premature mortality from cancer, or indeed any disease. Our patients need clinicians who relay accurate information they can understand in a calm, non emotional way. It is profoundly unjustified to suggest that members of the Canadian Task Force are anti-screening when we
write about the science and the need to balance potential harms against any benefits of cancer screening.

Our patients would be better served by collective effort to attack our lack of knowledge about screening, rather than continuing to attack the myths, or those who point to them. We suffer from many knowledge gaps with respect to the value of cancer screening interventions including that of newer screening tests. Randomized controlled trials are sorely needed to address these gaps.

From the Prevention in Practice article series writing group

1. Arleo EK, Monticciolo DL, Monsees B, McGinty G, Sickles EA. Persistent
Untreated Screening-Detected Breast Cancer: An Argument Against Delaying Screening or Increasing the Interval Between Screenings. J Am Coll Radiol. 2017;14(7):863-867.

2. Welch HG, Prorok PC, O'Malley AJ, Kramer BS. Breast-Cancer Tumor Size, Overdiagnosis, and Mammography Screening Effectiveness. The New England Journal of Medicine. 2016;375(15):1438-1447.

3. Bell NR, Grad R, Dickinson JA, et al. Better decision making in preventive health screening: Balancing benefits and harms. Can Fam Physician 2017;63(7):521-524.

4. Bretthauer M, Wieszczy P, Løberg M, et al. Estimated Lifetime Gained With Cancer Screening Tests: A Meta-Analysis of Randomized Clinical Trials. JAMA Internal Medicine. 2023.
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Competing Interests: This response was submitted by Roland Grad, former member and co-chair of the Canadian Task Force on Preventive Health Care.
Published on: (20 February 2024)
Page navigation anchor for Evidence based truths about the benefit of cancer screening
Evidence based truths about the benefit of cancer screening
Anna N, Wilkinson, Family Physician, GP Oncologist, The Ottawa Hospital
Dear Editor and Authors,

In my capacity as past Chair of the Cancer Care Member Interest Group and regular contributor to the Oncology Briefs series, I wish to express my profound concern that the Canadian Family Physician would publish an article with such blatant misinformation as was found in “Debunking the myths of screening”.(1) This article includes statements that are erroneous at best and dangerous at worst. For example:

A) It is a MYTH that earlier detection of cancer results in better outcomes.
In fact, earlier stage cancer is directly correlated with reduced mortality, increased survival and decreased morbidity of treatment, all of which are better outcomes than are seen in late stage cancer.(2) The authors suggest that earlier detection is needlessly identifying cancers which would not impact outcomes due to slow growth or regression. Scientific data does not support the spontaneous regression of cancers: in a study of 479 untreated breast cancers followed over 10 years, zero cancers spontaneously regressed or disappeared.(3)

B) It is a MYTH that newer technology produces more benefit.
Age standardized mortality rates have consistently declined in Canada since 1984 for breast, lung, prostate and colorectal cancers.(4) From 1975 to 2019, US breast cancer mortality decreased by 58%, attributable to both screening and treatment.(5) These large mortality reductions reflect the evolution of cancer diagnostics and therapies whi...
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Dear Editor and Authors,

In my capacity as past Chair of the Cancer Care Member Interest Group and regular contributor to the Oncology Briefs series, I wish to express my profound concern that the Canadian Family Physician would publish an article with such blatant misinformation as was found in “Debunking the myths of screening”.(1) This article includes statements that are erroneous at best and dangerous at worst. For example:

A) It is a MYTH that earlier detection of cancer results in better outcomes.
In fact, earlier stage cancer is directly correlated with reduced mortality, increased survival and decreased morbidity of treatment, all of which are better outcomes than are seen in late stage cancer.(2) The authors suggest that earlier detection is needlessly identifying cancers which would not impact outcomes due to slow growth or regression. Scientific data does not support the spontaneous regression of cancers: in a study of 479 untreated breast cancers followed over 10 years, zero cancers spontaneously regressed or disappeared.(3)

B) It is a MYTH that newer technology produces more benefit.
Age standardized mortality rates have consistently declined in Canada since 1984 for breast, lung, prostate and colorectal cancers.(4) From 1975 to 2019, US breast cancer mortality decreased by 58%, attributable to both screening and treatment.(5) These large mortality reductions reflect the evolution of cancer diagnostics and therapies which have revolutionized how we diagnose and treat cancers. To name just two examples, trastuzumab, a targeted agent, has reduced absolute 10-year mortality by 6.9% and all cause mortality by 6.5% in HER2+ breast cancers.(6) Adjuvant immunotherapy in unresectable stage III non small cell lung cancer patients has reduced the risk of death by 28% at 5 years compared with placebo.(7)

C) It is a MYTH that cancer screening saves lives.
The five-year survival for stage I breast cancer is 100%, for stage III is 74% and for stage IV 23%.(8) Lung, colon and cervical cancers have similar declines in survival with advancing stage. Cancers diagnosed through screening are earlier stage with better survival and decreased mortality, meaning that lives are saved.

Cancer screening is not for everyone, and patient preferences and co-morbidities must always be considered when engaging in shared decision making on this topic. I strongly believe that Canadian family physicians are educated enough and have enough common sense to inform their screening discussions judiciously so as to avoid overdiagnosis in patients with competing medical issues or advanced age. The statements made by the lead author and colleagues in this article risk misinforming a nation of family physicians about the pros and cons of screening. The publication of this misinformation is especially concerning given that author holds the influential, and theoretically, neutral position of co-chair of the Canadian Task Force on Preventive Health Care, the national body which determines screening guidelines for our country.

Sincerely,
Anna N. Wilkinson, MSc., MD, CCFP, FCFP
Associate Professor, University of Ottawa, Department of Family Medicine
Family Physician, The Ottawa Academic Family Health Team
GP Oncologist, The Ottawa Hospital Cancer Centre
Program Director, PGY-3 FP-Oncology
Regional Cancer Primary Care Lead, Champlain Region

(1)Thériault, G., Reynolds, D. L., Grad, R., Dickinson, J. A., Singh, H., Szafran, O., ... & Bell, N. R. (2023). Debunking myths about screening: How to screen more judiciously. Canadian Family Physician, 69(11), 767.
(2)Ellison, L. F., & Saint-Jacques, N. (2023, January 18). Five-year cancer survival by stage at diagnosis in Canada. Health Reports. https://www150.statcan.gc.ca/n1/pub/82-003-x/2023001/article/00001 eng.htm
(3)Arleo, E. K., Monticciolo, D. L., Monsees, B., McGinty, G., & Sickles, E. A. (2017). Persistent untreated screening-detected breast cancer: an argument against delaying screening or increasing the interval between screenings. Journal of the American College of Radiology, 14(7), 863-867.
(4)Brenner, D. R., Poirier, A., Woods, R. R., Ellison, L. F., Billette, J. M., Demers, A. A., ... & Holmes, E. (2022). Projected estimates of cancer in Canada in 2022. Cmaj, 194(17), E601-E607.
(5)Caswell-Jin, J. L., Sun, L. P., Munoz, D., Lu, Y., Li, Y., Huang, H., ... & Plevritis, S. K. (2024). Analysis of Breast Cancer Mortality in the US—1975 to 2019. JAMA, 331(3), 233-241.
(6)Bradley, R., Braybrooke, J., Gray, R., Hills, R., Liu, Z., Peto, R., ... & Swain, S. M. (2021). Trastuzumab for early-stage, HER2-positive breast cancer: a meta-analysis of 13 864 women in seven randomised trials. The Lancet Oncology, 22(8), 1139-1150.
(7)Spigel, D. R., Faivre-Finn, C., Gray, J. E., Vicente, D., Planchard, D., Paz-Ares, L., ... & Antonia, S. J. (2022). Five-year survival outcomes from the PACIFIC trial: durvalumab after chemoradiotherapy in stage III non–small-cell lung cancer. Journal of Clinical Oncology, 40(12), 1301.
(8)Canadian Cancer Society / Société canadienne du cancer. (2024b). Survival statistics for breast cancer. Canadian Cancer Society. https://cancer.ca/en/cancer-information/cancer-types/breast/prognosis-an...
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Competing Interests: Previous Chair of the Cancer Care Member Interest Group; Author/Contributor Oncology Briefs Series