Lowering the age for starting screening, but at what cost?

May 15, 2023, by Cancer Rose

As reported by the Globe and Mail and numerous other North American media outlets in early May 2023, a proposed update to the guidelines of the USPSTF, the U.S. Preventive Services Task Force, would recommend that women at average risk for breast cancer receive screening mammograms every two years beginning at age 40.
The news has caused quite a stir because it lowers screening recommendations by 10 years from the previous screening guidelines, which called for breast cancer screening at age 50 only due to increased risks for younger populations and too little benefit.

This is a significant change.

According to USPSTF Past President Dr. Carol Mangione, "things have changed": breast cancer rates in young women have increased, advances in digital mammography have improved their detection accuracy, and better treatments result in improved survival.

At this point, we already note two statements that should raise the question of the relevance of screening:
- If the number of cancers in young women is increasing, isn't it time to investigate the causes and identify the elements that contribute to this "rejuvenation" of breast cancers?
- It is the advancement of treatment improvements that have raised breast cancer survival, and the impact of screening in this improvement of survival is now becoming increasingly doubtful, which is further inflated by the over-diagnosis that screening causes. Why advocate it then?
Explanation here: https://cancer-rose.fr/en/2021/03/26/what-is-survival/

Not surprisingly, "The American Cancer Society (ACS) applauds the return of the USPSTF recommendations to begin screening at age 40" in a press release. Companies providing imaging services to women, such as Hologic and iCAD, saw their stock prices skyrocket due to the announcement, as volumes of screening mammograms will significantly increase.

And by the way, why not recommend that women be screened by mammography starting at age 40 AND annually, and even throughout their lives without the recommended stop at age 74, so no upper limit?
This is a step blithely taken by the American Cancer Society "because age should not be a determining factor for stopping screening, but rather general health ..." as stated by Stamatia V. Destounis, MD, chair of the ACR (American College of Radiology) Breast Commission and a member of the North American Society of Radiology Public Information Advisors Network.
(For Ms. Destounis's conflicts of interest with imaging industrialist iCAD, see here: https://www.rsna.org/-/media/Files/RSNA/Annual%20meeting/2022-AMPPC-Planners-Disclosure).

JUSTIFICATION AND CONSEQUENCES OF THIS CHANGE

Judith Garber, a science journalist and policy analyst at the Lown Institute, in one article, and John Horgan, also a science writer, in another article, both try to analyze the reasons given by the American agency, which are essentially twofold:
-increase in breast cancers in younger women, and
-an increase in the most aggressive cancers in black women.

Judith Garber correctly notes that "the change in USPSTF guidelines came as a surprise to many health experts, as there have been no new clinical trials on breast cancer screening that would warrant adjusting the guidelines."

A-screening could shorten more lives than it "saves."

"The task force," Horgan explains, "justifies its decision by citing the recent increase in breast cancer among women in their 40s and the higher-than-average mortality rates among black women.
This makes no sense because mammograms do not help women live longer - according to the task force itself! Mammography has been shown to shorten more lives than it saves," according to this review* cited by Horgan, published in 2021.
In any case, both Garber and Horgan explain that even adjusting the predictive models to account for higher cancer rates in young women, the benefit-risk balance is still not much different from the previous USPSTF findings in 2016, with the harms still outweighing the expected benefit.
* "Examining the trend in all-cause mortality reveals that the trade-off between the harms and benefits of mammography has shifted toward the harms over time."

"Change always happens over time as the evidence evolves," says Ruth Etzioni, a biostatistician working at the Fred Hutchinson Cancer Center in the STAT media.
"At the same time, there has to be a compelling reason, and in the literature here, I don't see a compelling reason yet. When I looked at the 2016 modeling studies, the benefit-risk analysis was very similar."

B-The excess of aggressive cancers in black women

"The USPSTF also wanted to emphasize that black women are diagnosed with breast cancer at a more advanced stage and face a higher breast cancer mortality rate than other racial groups," J.Garber resumes; "therefore, an earlier screening start date for these patients could save lives and reduce racial disparities in breast cancer outcomes. However, although the USPSTF has used new models exploring the benefits and risks of screening for black women, it has refrained from recommending earlier screening for black women in particular."
For Ms. Garber:
-lowering the age will not solve the problem of access to care for certain populations.
- lowering the screening age is not enough to reduce racial disparities. Disparities in breast cancer mortality in the U.S. are often the result of structural, social, and economic disparities, with less opportunity for access to care for black populations.

C-benefit on mortality, but what is the trade-off?

The U.S. agency claims that the benefits of mammography, which ideally detects cancer at an early stage when it is easier to treat, outweigh the harms (i.e., false positives and over-diagnosis). But these alleged benefits of screening, which are highly hypothetical and increasingly questioned, only appear in studies that measure breast cancer mortality, and they do not consider the harms associated with overdiagnosis. They do not consider radiation-induced secondary cancers following radiotherapy (secondary bronchial cancers, leukemia), heart disease, which is significantly increased in cancer survivors, suicides, anxiety-depression syndromes, etc.

"For these reasons," Horgan writes, "researchers are increasingly focusing on 'all-cause mortality,' i.e., death from any cause, as a measure of the effectiveness of screening. Death is a strict criterion, leaving no subjective room for maneuvering. Various studies have shown that mammography does not prolong life when all-cause mortality is measured. For this reason, some experts advocate abandoning mammography screening."

J.Horgan cites Amanda Kowalski, a healthcare economist, who presents this data in "Mammograms and Mortality: How Has the Evidence Evolved?" published in the Journal of Economic Perspectives in 2021.
"Over 20 years, women who were screened died at a significantly higher rate than women in the control group," she says. Kowalski notes that screened women had an elevated risk of dying from lung and esophageal cancer; she cites evidence that radiation therapy for breast cancer increases patients' risk of fatal lung and esophageal cancer."
Here's J.Horgan's caveat: "Mammograms may benefit women with above-average breast cancer risk, such as those whose family members have succumbed to the disease. But Professor Kowalski's findings have a devastating consequence: screening healthy, asymptomatic women ends up killing more women than it saves."
This corroborates M. Baum's findings in a 2013 BMJ publication that the harms of breast cancer screening outweigh its benefits if deaths from treatment are considered.

SCENARIOS

The USPSTF's modeling report for its new recommendations presents many scenarios that estimate the rates at which breast cancer screening would result in certain benefits and harms at different ages of onset, duration, and to varying screening rates.

But in every case, a person with no particular excess risk who gets screened is more likely to be treated for cancer that would never have hurt her than to avoid dying from breast cancer. She is more than twice as likely to die of breast cancer anyway, says J.Garber, than to have aggressive cancer detected and successfully treated. And screened women are far more likely to undergo a biopsy unnecessarily or receive a false-positive result than to avoid dying from breast cancer.

It's all about the trade-offs: increasing screening, starting it earlier, and continuing it later, may prevent deaths, but at the cost of how many false positives, over-diagnosis, and over-treatment, which in turn compromise health and survival?
What are the compromises we accept? Is every individual willing to accept the same trade-off as their neighbor?
A decision made in the interest of population health may not be acceptable to every individual. What price is each woman willing to pay for a death from breast cancer to be prevented, knowing that at the same time, other women (including herself) may experience the detection of cancer that would not have been fatal, exposing her to overtreatment, to possible secondary cancer due to radiation therapy for cancer that could have been ignored?

With the lowering of the screening start age from 50 to 40, the USPSTF is effectively saying that to avoid one additional breast cancer death per 1,000 women screened, women must accept an additional 519 false positives, 62 more unnecessary biopsies and two additional cases of overdiagnosis" compared to the false positives, unnecessary biopsies, and overdiagnoses that already exist for screening starting at age 50.

This is exactly what lowering the screening start age by a decade means.

CONCLUSION, a step backward

According to Horgan, these changes in the USPSTF recommendations are not justified. For him, "the lure of profit cannot be dismissed. Breast cancer management is a vast, profitable business, fueled by women's fear of the disease." This cancer business is what he explains at length in this article.

The modeling used to concretely assess what screening will produce "still does not take into account the long-term negative implications of cancer screening (e.g., overdiagnosis) or the fact that tumors sometimes grow in unexpected ways, or the fact that tumors sometimes grow and regress at different rates," as V. Prasad, an American professor of oncology and hematology, explains in his 2021 video.

Other reactions note the very lucrative nature of this new recommendation: https://radiologybusiness.com/topics/medical-imaging/womens-imaging/uspstf-recommends-women-begin-breast-cancer-screening-40-boosting-stocks-mammo-related-firms
The Radiology business says, "The U.S. Preventive Services Task Force released new recommendations on breast cancer screening Tuesday, now urging all women to be screened every two years starting at age 40.
The draft guidelines mark a change from previous USPSTF standards, which called for screening starting at age 50. Women's imaging vendors such as Hologic and iCAD saw their stock prices soar Tuesday morning following the news, as screening volumes are expected to increase.
The influential USPSTF had previously encouraged women to "make an individual decision" about when to begin screening before age 50, but is now reversing course and aligning with guidelines set forth by medical societies."

This move, which you can bet will be adopted in other Western countries, can be viewed as a real step backward at a time when modern medicine is more about measured, weighted thought in collaboration with the patient, and when the question of de-escalation of harmful routine procedures was beginning to be asked.

Without any evidence, women's information is being put at risk once more, with the message that more screening equals saving lives.

At the same time, the Council of Europe calls for caution.
Even the American Cancer Institute encourages guideline developers (study financed by the NCI) to do more research before updating their guidelines for revision to ensure that the best possible data on the adverse effects of screening are used to make their recommendations.

We are a long way from that...

Cancer Rose est un collectif de professionnels de la santé, rassemblés en association. Cancer Rose fonctionne sans publicité, sans conflit d’intérêt, sans subvention. Merci de soutenir notre action sur HelloAsso.


Cancer Rose is a French non-profit organization of health care professionals. Cancer Rose performs its activity without advertising, conflict of interest, subsidies. Thank you to support our activity on HelloAsso.

Breast density notifications: implications and overuse

Translation by Cancer Rose, an article published by Judith Garber, a political scientist at the Lown Institute, a nonpartisan think tank for a more just and equitable health care system.

March 18, 2023

LOW-VALUE CARE

New FDA guidance on breast density notifications and the implications of overuse - BY Judith Garber | March 10, 2023

Background

The radiological criterion of "breast density," the predominance of fibroglandular tissue over fatty tissue in the female breast, is now considered to be a risk factor for breast cancer on its own, despite the lack of evidence-based studies.

Breast density is generally high in young, non-menopausal women (but may persist after menopause), in thinner women with low body fat, and in women undergoing menopausal hormone replacement therapy.

A law passed in 2019 by the U.S. Congress required the U.S. Food and Drug Administration (FDA), as part of the regulatory process, to ensure that all mammography reports and summaries provided to patients include information on women's breast density. This authority, which oversees the regulation of mammography facilities and quality standards, has previously required the reporting of breast density in radiologists' reports.

It's done. The FDA recently updated its guidelines to require mammography facilities to inform patients of their breast density.

Why is this an emerging concern for European women populations as well?

Because with the advent of so-called predictive software, the radiological criterion of breast density is being incorporated as a risk factor in its own right in studies such as the European MyPEBS for individualized screening, whereas published studies (see article) show that the increase in breast cancer risk associated with breast density is modest and that for women diagnosed with breast cancer, increased breast density was not associated with an increased risk of poor prognosis cancer or death from breast cancer.

The FDA's decision is supposed, according to Volpara, a company that markets automatic breast density measurement software, to serve as an example "to the rest of the world." (See the very last chapter of this article, "Cancer Rose comments")

The USPSTF (independent task force reviewing U.S. preventive services), already in 2016, raised several points of concern about this legislation requiring women to be notified of their breast density information.
- Significant variability and limited reproducibility in the determination of dense breasts. This variability exists whether one radiologist or different radiologists read it. The exam for a given patient may have different classifications and lead to misunderstandings leading to a reduction in a woman's confidence in screening in general and confusion about her breast cancer risk.
- Uncertainty about steps taken by women notified of significant breast density to reduce their risk of dying from breast cancer. This is the request for additional tests for which no evidence supports the indication. There is no evidence that adding imaging other than mammography for women with dense breasts will reduce cancer mortality; these additions increase false positives, unnecessary biopsies, and overdiagnosis. The recall rate (for false positives) is significantly increased by the addition of ultrasound (by 14%) and by the addition of MRI (from 9 to 23%) with low PPVs[16] and an obvious additional cost. The authors remind us that MRI, often considered harmless, would be susceptible to a (low) excess risk of nephrogenic systemic fibrosis and uncertain risks of gadolinium deposition in the brain when the examinations are repeated.
Tomosynthesis (TS) is mentioned as an additional technique used. Still, the authors point out that longer-term studies are needed to determine whether the routine use of TS in women with dense breasts improves breast cancer outcomes (mortality, decrease in the rate of serious cancers).
- Difficulty communicating information about breast density to patients. Experts consider this communication complex and dependent on the population's literacy level. Study results show poor understanding, confusion, and misinformation among patients when information about breast density is given.

Article of Judith Garber

-Follow link for the complete article-

The US Food and Drug Administration (FDA) recently updated their mammography guidelines to require mammography facilities to notify patients about their breast density. This change, which goes into effect September 2024, is a final version of a rule proposed in 2019 (see our previous coverage on this topic). 

The FDA guidelines contain suggested language for notifications about breast density: 
“Breast tissue can be either dense or not dense. Dense tissue makes it harder to find breast cancer on a mammogram and also raises the risk of developing breast cancer. Your breast
tissue is dense. In some people with dense tissue, other imaging tests in addition to a mammogram may help find cancers. Talk to your healthcare provider about breast density, risks for breast cancer, and your individual situation.”

There are a lot of issues here.....

Comments Cancer Rose

Conflicts of interest of Dense Breast Info members can be seen here in the list by following this link: https://www.rsna.org/-/media/Files/RSNA/Annual%20meeting/2022-AMPPC-Planners-Disclosure

RSNA: Radiological Society of North America, it is a non-profit organization and an international society of radiologists, medical physicists and other medical imaging professionals

Among the "educational supports" we find the Volpara Society. Volpara is a publicly traded New Zealand company (Volpara Solutions Ltd.) that markets software to generate standardized breast density measurements automatically.

Volpara's Investor Statement on 30 Sep 2022 reads:
https://wcsecure.weblink.com.au/pdf/VHT/02601721.pdf

“Volpara is delivering strong growth in line with its upgraded guidance of between NZ$33.5M and NZ$34.5M. We continue our strategy of balancing purpose with profitable growth leveraging focus: our most profitable products, most lucrative markets, and providing the best value for "elephants," or large enterprise accounts. We await the release of the FDA’s breast density legislation, expected between now and early 2023, as per the latest FDA release, which can be found here.

"Waiting for the Mandate on Breast Density by FDA

- late 2022/early 2023

- Validates the importance of breast density

- Set an example for the rest of the world

- Federal decision = everyone should be informed

- Breast density is considered in risk assessment"

For example, a radiologist extremely well known in the Canadian media, Dr Paula Gordon, who advocates for early breast cancer screening and challenges the CanTaskForce** recommendations for caution, is a shareholder of Volpara company. We can thus read her regular statements in the Canadian press, describing the

Canadian group CanTaskForce as "killers of women":

1- https://theprovince.com/opinion/op-ed/dr-paula-gordon-new-breast-cancer-screening-guidelines-are-going-to-kill-many-women
"Dr Paula Gordon: New breast cancer screening guidelines will kill many women"

2-https://medicinematters.ca/breast-cancer-screening-mammogram-policies-are-based-on-flawed-research-dr-paula-gordon/
"Policies on breast cancer screening mammograms are based on flawed research / Dr Paula Gordon

3-https://globalnews.ca/news/8239335/breast-cancer-screening-canada-report/
"Outdated" breast cancer screening guidelines are failing Canadian women."

** The Canadian Task Force on Preventive Health Care was established by the Public Health Agency of Canada (PHAC) to develop clinical practice guidelines that support primary care providers in delivering preventive health care.

Cancer Rose est un collectif de professionnels de la santé, rassemblés en association. Cancer Rose fonctionne sans publicité, sans conflit d’intérêt, sans subvention. Merci de soutenir notre action sur HelloAsso.


Cancer Rose is a French non-profit organization of health care professionals. Cancer Rose performs its activity without advertising, conflict of interest, subsidies. Thank you to support our activity on HelloAsso.

Interval cancers, incidentalomas, the losers of screening

Cancer Rose summary, February 20, 2023

A-the interval cancers

https://www.academicradiology.org/article/S1076-6332(23)00020-X/fulltext

A retrospective cohort study* published in February 2023 in "Academic Radiology" compares the characteristics of interval breast cancers, the so-called false negatives, i.e., cancers that were not detected at mammography and occur between two screening mammograms, with breast cancers detected at screening mammography.

What is interval cancer, why is it very frustrating for women participating in screening, and what are the study's findings on their characteristics?

* A type of investigation that consists of examining, based on data present in medical files or in data registers, a defined population (the cohort) and comparing a criterion or an event (here the characteristics of breast cancer) observed with one or several other groups of individuals defined according to criteria (age, living conditions, etc.)

False-negative

illustration from C. Bour's book "mammo ou pas mammo?" Souccar edition

There can be two different scenarios:

1° cancer already exists and is really "missed"-

The mammographic examination is not infallible. Dense breasts are difficult to explore, and the glandular tissue is very present, resulting in a kind of opacity on mammography that prevents cancer detection. Some cancers are said to be "infiltrating" and blend in with the breast tissue. Others are atypical in shape, and still, others are completely hidden: they are not visible; the woman feels a lump one day, but the cancer is still not identifiable on mammography.

2° interval cancer

Interval cancer is cancer that was not present at the time of the mammographic examination or was only present in the form of cells. But its aggressiveness and growth are such that it develops very quickly, in a few days, weeks or months, thus in the theoretical interval between two screening mammograms, hence its name.

This situation is very frustrating for the patient, who has been told that screening is protective and saving and feels that she has "done everything right" but is not well rewarded for her diligence.

A false negative !

"Meh, small benign warts!" illustration from the book by C.Bour "Mammo ou pas mammo ?", edition T.Souccar

Results of the study

The major conclusions drawn by the authors are that interval cancers, in comparison with those detected by mammography, are, on average :

- More frequent in women with dense breasts (almost three times more)
For the authors, breast density remained significantly associated with the development of interval cancer.
When stratified by age, breast density was only significant for women over 50. This may be because dense breast tissue is more common in younger women, being present in more than 50% of women under 50 but only in less than 30% of women over 70.

- It is more advanced and has worse biological characteristics than cancers detected by mammography. In other words, screening detects mostly low-stage cancers and carcinomas in situ, many of which contribute to the pool of overdiagnosis.
Compared with screen-detected cancers, interval cancers were more often invasive than ductal carcinoma in situ (88% versus 75%, p = 0.007).
In addition, 43% (41/96) of interval cancers were primary tumours of stage 2 or higher, compared with only 12% (139/1136) of screen-detected breast cancers (p < 0.001).
Interval cancers were most often diagnosed because of symptoms and abnormalities in the breast.

- Women with a family history of breast cancer, especially first-degree (mother, sister, daughter), compared with women diagnosed with screen-detected cancer. However, family history was insignificant in multivariate analysis (a statistical method used when multiple factors potentially influence an outcome).

Conclusion of the authors

The aggressive phenotype of interval cancers may explain why they were not visible at the initial screening examination but were detectable less than a year later. These cancers are likely to be fast-growing, either new or too small to be visible at screening. The authors note that this was explicitly studied by Gilliland et al.

Furthermore, in subset analysis, interval cancers diagnosed at high-risk screening MRI were more likely to be ductal carcinoma in situ and stage 0 or 1 primary tumours, compared with symptomatic interval cancers...

For the authors, this would confirm the usefulness of screening MRI for high-risk women with high breast density, as MRI helped identify some interval cancers at an earlier stage than interval cancers identified by patients due to a symptom in the breast.

(However, it may be objected that the discovery of an earlier stage cancer in high-risk women does not tell us whether it is an interval cancer that was actually detected earlier and will thus be prevented from progressing or whether it is an intrinsically favourable cancer that would not have progressed or would have progressed little. To learn more about the problem of additional MRIs (overdiagnosis, cascades of examinations, false positives), read : https://cancer-rose.fr/en/2021/01/26/additional-mri-screening-for-women-with-extremely-dense-breast-tissue/

Cancer Rose Commentary

We repost the commentary from the excellent blog of our fellow Dr Agibus -

In his Dragiwebdo post #386, chapter 5, Dr Agibus summarizes the study's conclusion very well by recalling the so-called "barnyard" pattern, barnyard analogy breast cancer screening -

Below is what he writes:

"One paper explores mammography and interval cancers. The authors compared cancers diagnosed on screening mammograms with those diagnosed while a previous screening mammogram had been performed. They found that interval cancers were of higher stage and poorer prognosis (triple negative, adenopathy) than cancers discovered during screening. This study confirms (or at least appears to support) that screening mammography detects cancers that are not very aggressive (rabbits and turtles, sometimes too turtles, in fact). In contrast, aggressive cancers (birds) slip through the cracks and are detected on symptoms, even in the case of regular mammograms. For reminder :

Click on the image

In other words, aggressive cancers are intrinsically aggressive, so they are not anticipated. Those detected by repeated mammography correspond to less severe and curable cancers, with a sufficiently long residence time in the breast so that screening can detect them, but of which a large part contributes to over-diagnosis (especially the carcinoma in situ). For explanation, read: https://cancer-rose.fr/en/2020/12/17/are-small-breast-cancers-good-because-they-are-small-or-small-because-they-are-good/

B-the incidentalomas

https://www.birpublications.org/doi/10.1259/bjr.20211352

Here the authors warn of unnecessary findings in routine examinations, leading to so-called "cascades of examinations".

One of the paradoxes of modern medical imaging, they say, is that the source of our greatest achievement - the ability to image the human body in ever greater detail - is also the source of one of our most significant challenges.

The success of medical imaging as a diagnostic tool has led to a dramatic increase in its use. Technological advances make it possible to acquire images at higher resolution and in more significant numbers than ever before. This has led to an increase in the detection of findings that do not appear to be related to the primary purpose of the examination and have been referred to as "incidental," This is especially true of CT and MRI scans. Many of these are harmless, but some have significant consequences for the patient's health.

Radiologists, authors say, need to become familiar with the most common incidental findings to assess their significance in each case best and to be able to recommend appropriate further investigations, when justified, because these incidental findings have implications for the patient and the service as a whole and must be thought through carefully.

Incidental findings are defined as all findings that are not directly related to the main purpose for which the imaging examination was performed, for example, the discovery of an adrenal nodule without any complaint from the patient during a CT scan or ultrasound for abdominal pain, a common and not always very specific symptom. Or the discovery of a renal nodule during a CT scan for pulmonary disease.

The development and potential widespread introduction into clinical practice of blood tests for circulating tumour DNA may add another layer of complexity.
Read here : https://cancer-rose.fr/en/2022/09/16/liquid-biopsies-the-grail/

This increased rate of detection brings with it a number of problems. The authors explain:

“Sometimes the images themselves may include features which allow us to be reasonably confident that a particular finding is either important or not - site, size, morphology, attenuation or signal characteristics may all be helpful. In many other cases there will be doubt and a decision must be made about how best to manage this uncertainty.

If it is decided that a particular lesion cannot be dismissed as irrelevant, further imaging or other more invasive tests may be recommended. The impact on the patient can range from anxiety and minor inconvenience to real harm in the event of a complication from an invasive procedure such as biopsy or endoscopy.

Much has been written about the concept of overdiagnosis – the detection and subsequent treatment of disease which if left alone would not cause problems in the patient’s lifetime. Although the term is most commonly used in relation to screening programmes, it applies equally to IFs found in symptomatic patients.”

The person lives with and will die with their cancer, not because of it.
Illustration from C.Bour's book "mammo ou pas mammo?", T.Souccar edition

The story of early diagnosis is seductive, but the term cancer - as it is currently used - covers many different diseases, including some indolent lesions that traditional therapeutic strategies would overtreat. (Editor's note: one reference cited is for low-grade DCIS). It is hoped that developments in artificial intelligence will help us in the future to better stratify these patients into different management strategies, some of which may involve observation rather than intervention.

For now, there is still a significant risk that the detection and reporting of an IF will result in over treatment. Aside from the impact on the individual patient, there are significant implications for radiology services, particularly in a constrained tax-funded system...
The direct cost of follow-up investigations is one consideration but an even greater risk is the potential that an increase in the number of studies performed to follow-up incidental findings will inevitably make services harder to access for other patients, some of whom may have greater need."

The conclusion:

" Firstly we must accept that given the uncertainties inherent in radiology practice and the limitations of the tests we use, we will not always get it right.
Next we should put ourselves in a position to make the best possible assessment as to the likely relevance of each finding. We should acquaint ourselves with the appearances of the common IF in each organ as described in the articles which follow, together with the features which in each case give the best possible steer as to their likely importance.
Finally we must recognise that choosing to mention any particular finding in a radiology report is not a neutral act – it carries consequences for the patient, for the service and for other patients. For the patient, we are potentially committing them to further tests, some of which may cause concern or even real harm. For the service we are imposing a burden…”

Our conclusion

We all have a duty and responsibility to make medical decisions about the examinations we order and perform for the patient's benefit. Not only prescribers but also radiologists must ask themselves about the scope of what they are looking for and then, for radiologists, what they are describing. How much weight and importance should be given to what they find?
Simply listing images and leaving it up to the treating physician to decide what to do with them puts the responsibility for the outcome on the prescriber alone.

Patients, too, need to be adequately informed of what systematic, routine examinations, or examinations, as we sometimes read on prescriptions, of "reassurance" may involve for their health.

Screening examinations are not infallible or harmless. They are not unstoppable shields against diseases. They can "miss" genuine lesions. They can make the patient discover unnecessary things and fall into a disease they would never have known without them.

Incidental Findings and Low-Value Care

Invited Clinical Perspective Matthew S Davenport MD-2023 Jan 11.
Departments of Radiology and Urology, Michigan Medicine, Ann Arbor MI 48108
doi: 10.2214/AJR.22.28926. Epub ahead of print. PMID: 36629303.

https://www.ajronline.org/doi/abs/10.2214/AJR.22.28926

Highlight:

Detection of incidental findings in a low-risk population generally results in low-value and potentially harmful care, including paradoxically for many cancers

Summary

Incidental findings are analogous to the results of screening tests when screening is applied to unselected, low-risk patients. They generally result in low-value and potentially harmful care. Patients with incidental findings but low risk for disease are likely to experience length bias, lead-time bias, overdiagnosis, and overtreatment that create an illusion of benefit while conferring harm. This includes incidental detection of many types of cancers that, although malignant, would have been unlikely to affect a patient’s health had the cancer not been detected. Detection of some incidental findings can create high-value care, but most do not, and differentiation is often unclear at the time of identification. Higher patient- and disease-related risk increase the likelihood an incidental finding is important. Clinical guidelines for incidental findings should more deeply integrate patient risk factors and disease aggressiveness to inform management. However, lack of outcome and cost-effectiveness data lead to reflexive management strategies that create low-value, expensive, potentially harmful care.
Radiology needs outcome and cost-effectiveness data to inform its management recommendations for incidental findings.

So, What Should We Do?

It is increasingly recognized that incidental findings are incompletely understood, expensive, and surprisingly harmful. Rather than a benefit of imaging, they are usually a harm. They are not sought, the odds of them being important is low, and they create tremendous uncertainty and low-value care. The pragmatic challenge is what to do about it in the near- and medium-term.
Some have wondered if certain incidental findings should not be reported at all. The medicolegal environment complicates matters. Some incidental findings are cancer. Sophisticated understanding of the biases which predict low-value care—that early detection of some cancers can produce a paradoxically worse outcome than had those cancers never been detected at all—is not a reasonable thing to expect of patients or the legal system in 2022; it is difficult for medical practitioners to understand. But we shouldn’t simply maintain the status quo. Here are several recommendations.

First, we should heed the call to action raised by some asking us to be more aware of the harms of overdiagnosis and overtreatment cascading from the detection of incidental findings. Incidental findings are a complication of diagnostic imaging—inadvertent harm despite positive intent—like bleeding following an image-guided biopsy. The specific harms of incidental finding management are opaquer than bleeding and harder to understand. But this simply means we (radiologists) should take a more active role in studying and managing them. It is our complication and our challenge to solve.

Second, we should advocate for incidental findings guidelines, especially our own but others as well, to explicitly incorporate and recommend appropriate studies to confirm they are working as intended. Working as intended means “producing high-value care”.
We should expect incidental findings guidelines to emphasize the creation of high-value care rather than an exclusive or overweighted focus on maximizing diagnostic sensitivity. This is not a radiology-only dilemma. Incidental findings guidelines exist in many medical and surgical specialties, and we should work collaboratively with them to promote a high-value approach.

Third, we should advocate for funding organizations to prioritize the study of incidental finding management. We have a compelling argument. Incidental findings are ubiquitous and an enormous burden on the health care system. Randomized trials could be conducted in which deferral of aggressive diagnosis and management is a treatment arm. The emergence of active surveillance as a valid strategy for many cancer types is a precedent we can follow, apply, and expand upon here.

Fourth, we should avoid being alarmist in our reporting. Yes, at present, we should follow the guidelines we support until stronger evidence arises, but we also should recognize that most incidental findings are not harmful if left alone in low-risk patients. Low prevalence of disease and the biases inherent to screening help explain why this is so. When in doubt about the significance of an incidental finding, and the guidelines are unclear or give leeway, err on the side of minimizing it.

Fifth, because the clinical importance of an incidental finding is highly dependent on patient risk, we should pursue information technology solutions, in collaboration with referring providers, to make relevant risk factors more visible to radiologists (e.g., hypertension uncontrolled on multiple medications [adrenal nodule], unreported head and neck cancer [liver lesion]). In current state, radiologists often rely on a brief historical snippet focused on the chief concern to interpret an examination. Incidental findings are definitionally unrelated to the chief concern and therefore not always informed by it.

Sixth, in our reporting, we should attempt to balance diagnostic sensitivity with other competing risks.
We should understand the cascading harm that can result from management of an incidental finding and allow that potential for harm to influence our recommendations. We are still largely ignorant about which incidental findings are important and how best to manage (or ignore) them. In the years between now and a clear solution, we should do our best to minimize collateral harm to the patients we are trying to help.

Cancer Rose est un collectif de professionnels de la santé, rassemblés en association. Cancer Rose fonctionne sans publicité, sans conflit d’intérêt, sans subvention. Merci de soutenir notre action sur HelloAsso.


Cancer Rose is a French non-profit organization of health care professionals. Cancer Rose performs its activity without advertising, conflict of interest, subsidies. Thank you to support our activity on HelloAsso.

A letter from Ameli (French Health Insurance)

27 October 2022, by Cancer Rose
Updated December 2022

Dear Sir or Madam,

Your attending physician plays a central role in prevention actions. Depending on your situation, he can inform you and answer your questions about organized screening for breast, cervical and colorectal cancer, which can save lives. The earlier these cancers are detected, the better the prognosis.
To help your doctor in his mission of providing health advice to his patients, the Health Insurance will provide him with the list of his patients concerned by these screenings and who have not completed them (1).
Under the provisions relating to personal data protection, you have until December 1, inclusive, to oppose this transmission via the following link: https://www.demarches-simplifiees.fr/commencer/declarer-mon-opposition.
If you make your objection after December 1st, your request will not be considered for the first available list but will be considered for future lists.
Your situation could mean that some of these organized screenings do not apply to you; in this case, please disregard this message.

Please be assured of our attention and availability,
Your Health Insurance Correspondent

This is the letter that everyone has received from their Health Insurance.

Remember that during the citizens' consultation, the Health Insurance Institution's simplistic communication was criticized; read pages 95 and 96 of the citizen consultation on breast cancer screening report.
It cannot be stated that communication is more advanced in 2022, leaving any opportunity for reflection or doubt.

In this email, it is claimed that these screenings save lives. However, there is no scientific evidence, no study given, no justification, and no single reference. The message notifies you that your attending physician will be informed of the screenings you have not yet completed...
Ideally, one would hope that this approach would encourage discussion with the family physician about the relevance of screening, leading to a consultation that would result in a shared decision and information that would allow an informed choice. But what about in real life? One of our readers correctly asks if this will not instead allow putting a little more pressure on patients to participate in screenings that are losing momentum rather than an informed decision consultation if the health insurance institution itself starts with the presumption that screenings save lives, which is far from reality. There is little communication about the scientific challenges still rising regarding the true relevance of screening and its harms. [1] [2] [3] [4] [5].

The user who receives this email must activate the rejection; hence, if he does not click on the link allowing him to oppose, his acceptance is activated by default.

This initiative appears to be a part of the larger European plan to increase European population participation in various screenings, despite many scientists' requests for better information on the benefit-risk balance of these health programmes.
The target is for 90% of EU citizens to participate in colorectal, breast, prostate, and cervical cancer screenings by 2025.

The new French 10-year plan states (https://www.e-cancer.fr/Institut-national-du-cancer/Strategie-de-lutte-contre-les-cancers-en-France/La-strategie-decennale-de-lutte-contre-les-cancers-2021-2030):

“Improving access to screening will be strengthened.”

"It will be a matter of better understanding the determinants of reluctance to screening and simplifying access to screening (direct order, diversified health professionals, mobile teams in particular). Approaches will be developed that offer screening after a preventive intervention or unscheduled care.

For example, partnerships with food aid organizations will be considered to carry out awareness-raising efforts, particularly among the most disadvantaged. First, contact information tools for health, medical, and social workers will be provided, and mobile applications with information and reminders will be developed. To encourage people to participate in screening, material incentives will be tested. Finally, screening age limits will be reconsidered. "

The financial incentives specified in the text allow for the recruitment of the most economically disadvantaged people, again disregarding any medical knowledge, as was denounced in an article in the BMJ, whose one of its authors is a French citizen[6]. For these more vulnerable persons, the consequences of abusive screening can be dramatic, resulting in impoverishment, loss of income, and difficulty getting jobs.
The problem of these underprivileged people is much more the access to care than finding unnecessary cancers that would never have harmed them. It is also a problem of good medical information and fight against risk factors to which they are more exposed.

But sometimes, too much is the enemy of the good. With the other screenings of the European plan that are going to be added with new invitations, reminder letters, mobile applications, and increased medical consultations, the effect obtained could be the opposite: a weariness of the population, already more and more distrustful of medical injunctions, and who will turn away, as it is already the case, from traditional medicine that is more and more coercive and harassing.

Enough is enough.

Update December 2022

https://www.ameli.fr/medecin/actualites/depistages-organises-des-cancers-envoi-aux-medecins-traitants-de-listes-de-patients-eligibles

The summum is reached in a communication dated November 23, 2022, in which doctors are explicitly asked to incite their patients to undergo screening.

In addition to the ROSP system (remuneration based on public health objectives, which is already highly questionable and contested), the Assurance Maladie (French National Insurance) wishes to strengthen the role of primary care physicians in inciting screening by using lists of patients who are eligible but have not participated in screening.

"The effectiveness of these screenings has been demonstrated because the earlier cancers are detected, the better the prognosis: they save lives," they write in their letter.

This is inaccurate, incomplete, and unethical in its deliberate silencing of the harms and risks of screenings, for which the citizen consultation requested clear information for women. The EU Council has recently reaffirmed and reiterated this demand for transparent information.

The Health Insurance views the doctor as a simple inciting player for patients who are listed and are not compliant with the screening; the comprehensible information requested by the citizens, which is the primary responsibility of the attending physician, is thus buried, and informed consent is a utopia....

Communication text :

Organized cancer screenings: lists of eligible patients sent to attending physicians

November 23, 2022

At the beginning of December, the Assurance Maladie (French National Health Insurance) will mail to attending physicians a list of their patients who have not had cancer screening (cervical cancer, breast cancer, and colorectal cancer) within the recommended intervals.

Based on the double observation that France lags behind its European neighbors in terms of participation rates in organized screenings and that these have stagnated since 2018, Assurance Maladie wishes to strengthen the role of attending physicians in inciting screenings by providing them with a list of their eligible patients.

These screenings have demonstrated effectiveness because the earlier cancers are detected, the better the prognosis: they save lives.

The crucial role of general practitioners in screening participation has been demonstrated both in France and abroad. Because of their privileged relationship with their patients, doctors can incite them to undergo these screenings and answer their questions during a consultation.

To facilitate the execution of this public health mission, the list made available to attending physicians includes their patients who have not participated in the screenings for which they are eligible, according to the recommended intervals, whether within the framework of organized screenings or an individual approach.

These are:

- women aged 25 to 65 for organized cervical cancer screening ;
- women aged 50 to 74 for organized breast cancer screening;
- women and men aged 50 to 74 for organized colorectal cancer screening.

Please note: despite all the attention paid by Assurance Maladie to the targeting of the insured persons on this list, it is possible that some of them are not concerned (specific follow-up, recent screening, etc.). Some patients may have expressed opposition to being included on these lists.

References

[1] https://cancer-rose.fr/en/2022/09/13/the-risks-of-screening-an-elephant-in-the-room/

[2] https://cancer-rose.fr/en/2021/02/11/parallel-to-breast-screening-prostate-screening-overdiagnosis-as-well/

[3] https://www.nejm.org/doi/full/10.1056/NEJMoa2208375

[4] https://cancer-rose.fr/en/2021/02/01/overdiagnosis-of-thyroid-cancer-another-womans-concern/

[5] https://cancer-rose.fr/en/2021/02/24/being-a-woman-and-smoking-x-rays-in-perspective/

[6] https://www.bmj.com/content/376/bmj-2021-065726

Cancer Rose est un collectif de professionnels de la santé, rassemblés en association. Cancer Rose fonctionne sans publicité, sans conflit d’intérêt, sans subvention. Merci de soutenir notre action sur HelloAsso.


Cancer Rose is a French non-profit organization of health care professionals. Cancer Rose performs its activity without advertising, conflict of interest, subsidies. Thank you to support our activity on HelloAsso.

Screening: it is urgent to improve the information for women

DECEMBER 14, 2022, BY CANCER ROSE

Recently, we relayed the EU Council's new screening guidelines, which we found to be rather prudent and thoughtful.
The text of the EU Council can be found here.

In broad terms, the Council emphasizes the need for additional information on the effectiveness, cost-effectiveness, and feasibility of certain screening strategies in the real life, especially for new screenings such as prostate, lung, and stomach cancer.
Member States are invited to evaluate the introduction of cancer screenings based on conclusive scientific evidence, taking into account the balance between the benefits and risks of the screenings, about which the public should be informed.

Publication in the Official Journal

The text has been published in the Official Journal. The following paragraphs seem to be of capital importance because they reflect the 2016 French citizens' consultation demands.

(8) “Screening is the process of testing for diseases in people in whom no symptoms have been detected. In addition to its beneficial effect on disease-specific mortality and on incidence of invasive cancers, the screening process also has inherent limitations, which can have negative effects for the screened population. These include false positive results, which can cause anxiety and may require additional testing that may pose potential risks, false negative results, which provide false reassurance leading to delays in diagnosis, overdiagnosis (i.e. detection of cancer not expected to cause symptoms during the patient’s lifetime) and subsequent overtreatment. Healthcare providers should be aware of all the potential benefits and risks of screening for a given type of cancer before embarking on new organised cancer screening programmes. Furthermore, these benefits and risks need to be presented in an understandable way that allows individual citizens to give informed consent to participate in the screening programmes.”

(24) It is an ethical, legal and social prerequisite that cancer screening should only be offered to fully informed people with no symptoms, if the benefits and risks of participating in the screening programme are well-known and the benefits outweigh the risks, and if the cost-effectiveness of the screening is acceptable. This assessment should be an inherent part of the implementation at national level.

The Council also recommends, in the same text, that Member States :

(4) “ensure that benefits and risks, including potential overdiagnosis and overtreatment, are presented to the people participating in the screening in an understandable way, potentially including on a health professional-to-participant basis, allowing individuals to express informed consent when deciding to participate in the screening programmes, and that the principles of health literacy and informed decision-making to increase participation and equity are taken into account;.”

Improving women's access to information: an absolute necessity


We emphasized the insufficient information in the INCa booklet sent to women, which, although some changes over the previous one, still lacks a visual pictogram allowing a simple understanding of the benefit/risk balance and does not mention screening risks but instead uses the term "limits" along with explanations to minimize them.

Download / Télécharger


This publication is not in accordance with EU Council recommendations.
It is sent to the woman only once when she reaches the age of 50, after which she will only receive a leaflet at each subsequent screening, that fails to mention any of the risks of screening and refers to a website that is similarly susceptible to criticism. Over the course of a woman's lifetime, it is evident that the message that will remain in her memory will be the "embellished" leaflet, that omits the risks completely.

Leaflet - Breast Cancer Screening. Practical guide

This leaflet, whose content is largely based on that of the booklet, will be sent to women aged 50 and over when they renew their invitation to participate in the DOCS. It can also be distributed at information meetings.

In the EU Council's document, the different risks of screening, such as false alarms and overdiagnosis, are well defined (in part 8). In contrast, in the INCa leaflet, the definitions of these concepts are sometimes imprecise, often minimized, the definition of overdiagnosis is incomplete, and overtreatment is not explained (see our analysis).
In the booklet, there is no mention at all of overdiagnosis.
It is therefore urgent, based on the EU requirement regarding the presentation of screening risks to targeted populations, to improve the information provided to women invited to screening beyond the age of 50, from the age of 52 onwards, while also respecting the requirements for good literacy and without obscuring the concepts of false alarm and overdiagnosis, the two major risks of breast cancer screening.
In addition, 5-year survival is highlighted as a "benefit" in both the booklet and the leaflet, despite the fact that it is not a measure of screening effectiveness.
In the recommendation of the Council, it is stated:
(6) The main indicator of the effectiveness of screening is a reduction in disease-specific mortality or in incidence of invasive cancers.

In addition, the presentation of benefits and risks does not conform to EU Council recommendations for comprehension. The reduction in breast cancer mortality is given as a relative percentage reduction (15-21%), whereas the percentage of overdiagnosis is described as an absolute percentage (10-20%), making comparison impossible. This flaw already exists in the 2017 publication.
A 20% reduction in cancer mortality does not correspond to 20 fewer cancer deaths per 100 women screened.

This is an indication a relative risk only. 20% fewer deaths does not imply that 20 fewer women out of 100 will die of breast cancer if screened. The 20% reduction in mortality is simply a relative risk reduction between the two groups of women being studied.
In fact, according to a projection produced by the Cochrane Collective based on numerous studies, out of 2,000 women screened over a 10-year period, four die of breast cancer, whereas out of the same number of women who were not screened, five die of breast cancer. The shift from five to four represents a 20% reduction in mortality, but in absolute terms, just one woman's death will be prevented (absolute risk of 0.1% or 0.05%).
The range of 10-20% provided for the rate of overdiagnosis represents the lowest estimate. Other research indicate substantially higher overdiagnosis rates. Overdiagnosis is largely overlooked in the leaflet, and there is a striking omission of risk information that is easily understood.

Read more:

What could be improved?

It is time for the health authorities to finally respond rigorously to the Council's recommendations published in the Official Journal and to respect the French population by complying with these recommendations.
These recommendations state that "the benefits and risks must be presented in an understandable way to allow citizens to give their informed consent to participate in screening programs."

To do this, a modern and validated strategy employs decision support tools, such as the one developed by the Harding Center for Literacy, which describes how harms might be presented visually.
https://www.hardingcenter.de/en/transfer-and-impact/fact-boxes/early-detection-of-cancer/early-detection-of-breast-cancer-by-mammography-screening

The methodology is perfectly described here:
https://www.hardingcenter.de/de/transfer-und-nutzen/faktenboxen,
with the reference: https://www.hardingcenter.de/sites/default/files/2021-06/Methods_paper_Harding_Center_EN_20210616_final.pdf
8) Page 13, “Handling numbers and presentation of risks. The benefits and harms of medical intervention are balanced in fact boxes. By specifying the references and using the past tense, it is clear that these are study results, and thus no individual prediction is possible. The reference in numbers is always the same for the intervention and control groups. The event frequencies are communicated in absolute numbers. Relative risks are not reported. Which reference value is chosen (100, 1,000, or even 10,000) depends on the study data. It has to be ensured that the indication of integers is possible and that existing statistically significant differences become clear. The absolute change in risk is shown in the short summary of the fact box and the accompanying text. Mismatched framing (the presentation of advantages and disadvantages in different formats) is not used. ”

Another illustration is available in the WHO guide, on pages 37/38
https://apps.who.int/iris/handle/10665/330829
“Both laypeople and clinicians tend to overestimate the benefits of screening and underestimate the harm of screening (36). Training personnel on communicating risk and tools such as infographics, videos and decision aids can be used to facilitate understanding and promote informed consent and evidence-informed practice (Fig. 15).”
See the infographic on page 38
We propose on our side a short illustrated tool, "Cancer Rose", based on French data, which you can consult here: https://cancer-rose.fr/en/breast-cancer-decision-aid/

To conclude

The Council of the EU has issued recommendations, particularly on public information and the presentation of information that meets citizens' demands.

- The WHO calls for the respect of the Wilson and Junger principles (read here, middle of the article);

- the French citizen and scientific consultation asks for an improvement of the information with an honest and neutral presentation of the data,

- the EU Council strongly recommends an understandable presentation of the risks of screening, so what is the additional step that our French health authorities need to take in order to honestly and sincerely explain the benefits and risks to women allowing them to make a real informed choice?

We must stop hiding the risks of screening, to which women are shamefully subjected. Instead, we should inform them that screening might expose them to inconveniences and risks, including overdiagnosis, which can unnecessarily lead to a disease they would never have known without it.

Yes, it's really time....

Cancer Rose est un collectif de professionnels de la santé, rassemblés en association. Cancer Rose fonctionne sans publicité, sans conflit d’intérêt, sans subvention. Merci de soutenir notre action sur HelloAsso.


Cancer Rose is a French non-profit organization of health care professionals. Cancer Rose performs its activity without advertising, conflict of interest, subsidies. Thank you to support our activity on HelloAsso.

Caution of the Council of European Union regarding screenings extension

By Cancer Rose, December 11, 2022

In September 2022, the European Commission issued recommendations for a new approach to screening.
We wrote about it here: https://cancer-rose.fr/en/2022/09/24/a-new-eu-approach-to-cancer-screening/

The European Commission proposed an extension and/or a reintroduction of some screenings and an implementation of new ones, some of which do not exist ( gastric cancer screening)...
The objective is that by 2025, 90% of the EU population should be screened for breast, prostate, cervical and colorectal cancer.
Lung and gastric cancer screenings would be added, although no conclusive study exists for the latter.
We are relieved that the Council of the European Union has not followed these recommendations and has been cautious. In this month of December is published the adopted text which we will analyze.

Comparison of press releases
Comparison of the recommendations between the initial proposal and the adoption of the final recommendations by the member states
Summary of breast cancer screening recommendations
Recap of the lung cancer screening controversy
Reminder of the prostate cancer screening controversy
Conclusion
Reactions
Reaction of WONCA

Comparison of press releases

Below is a comparison between the original draft from September 2022 and the one issued in December 2022, which presents the adopted final recommendations.

Download/Télécharger

Differences between the proposal and the adopted text are highlighted :

- For cervical and colorectal cancer, more moderate terms are used on the use of tests, described as a "preferred" tool for cervical cancer screening or as a "preferred screening" regarding immunochemical tests for colorectal cancer screening.

- For the three new screening tests (lung, gastric, prostate cancers), the Council invites to carry out research beforehand to study the feasibility and effectiveness of these tests and therefore refrains from introducing them as initially recommended.

- For breast cancer, the recommendation remains between 50 and 69, and screening is only suggested between 45-74 (not "recommended" as initially intended by the EC).
It should be noted that screening at 45-50 years was already initially only "suggested."

Comparison of the recommendations between the initial proposal and the adoption of the final recommendations by the member states

Caution: link modification for the new proposal for a Council Recommendation (CR) on Strengthening prevention through early detection: A new approach on cancer screening replacing CR 2003/878/EC https://health.ec.europa.eu/publications/proposal-council-recommendation-cr-strengthening-prevention-through-early-detection-new-approach_en

Download/Télécharger

Here are the main improvements in the final text and the precautions retained by the decision-makers:

  • The Junger and Wilson* principles are recalled, which should be applied as well as other criteria set out by the WHO to assess the feasibility of screening before its implementation
  • The risks of overdiagnosis (with a clear definition) and overtreatment were added, as well as the need for information.
  • Technical support for informed decision-making is mentioned
  • The notion of "screening effectiveness" is finally defined by mentioning that the decrease in specific mortality and the decrease in the incidence of invasive cancers defines it.
  • It is recalled that for lung and prostate screening, the evidence is limited
  • It is emphasized that aspects of the health system's capacity to support screening and the resources required must be considered.
  • "Screening should be offered when there is evidence that screening improves specific mortality" is replaced by "screening should be offered when the benefits and risks are well known, and benefits outweigh the risks."
  • Regarding cost-effectiveness, this should be considered at the national level
  • It is recalled that screening tests (for the 3 current screenings (cervical, colo-rectal and breast cancers) and for 3 new screenings (lung, gastric and prostate cancers) to be studied) should be offered only if it is proven that the Junger and Wilson criteria outlined by the WHO are met and that information on benefits and risks is reliable.
  • Emphasis is placed on considering national capacities and priorities when implementing new screening programs.
  • The objective of 90% of the European population to be offered all 3 screenings (breast, colorectal, and cervical) by 2025 is removed from the text (probably unrealistic).
  • In informing the population, the benefits and risks, including overdiagnosis and overtreatment, must be presented, potentially through an exchange between the patient and the health professional, for an informed decision made by the patient.
  • For new screening tests, the implementation should be considered only after randomized trials with scientific evidence of effectiveness.
  • It is also necessary to work and cooperate on predictive tests and algorithms to reduce overdiagnosis and overtreatment.
  • The need to have scientific evidence (evidence-based) is recalled, and the term "risks" is added next to "benefits" in the evaluation of screening programs,
  • Technical support with information activities, where relevant, for the general public and stakeholders about the benefits and the risks of participation in the screening programmes, taking into account the principles of health literacy and informed decision-making, could be provided.

*Junger and Wilson's principles for implementing screening:

What are the criteria used by the WHO to determine the appropriateness of screening?

The 10 criteria used by the WHO are:

- The disease studied must present a major public health problem
- The natural history of the disease must be known
- A diagnostic technique must be able to visualize the early stage of the disease
- The results of the treatment at an early stage of the disease must be superior to those obtained at an advanced stage
- Sensitivity and specificity of the screening test should be optimal
- The screening test must be acceptable to the population
- The means for diagnosis and treatment of abnormalities found in screening must be acceptable.
- The screening test should be repeatable at regular intervals if necessary
- The physical and psychological harm caused by screening should be lower than the expected benefit
- The economic cost of a screening program should be outweighed by the expected benefits

Summary of breast cancer screening recommendations

- 1) Current European guidelines for 45-50 and 70-74-year-olds

The current guidelines, published on the European website, do not recommend screening for women aged 45-50 and 70-74 but only "suggest" it.

https://healthcare-quality.jrc.ec.europa.eu/european-breast-cancer-guidelines/screening-ages-and-frequencies/women-45-49

https://healthcare-quality.jrc.ec.europa.eu/ecibc/european-breast-cancer-guidelines/screening-ages-and-frequencies#recs-group-70-74

These guidelines, which date from 2019, are published in the journal :https://www.acpjournals.org/doi/10.7326/m19-2125

The supplement provides the table with the current recommendations that "suggest" but do not recommend screening between the ages of 45-50 and 70-74.

https://www.acpjournals.org/doi/suppl/10.7326/M19-2125/suppl_file/M19-2125_Supplement.pdf

- 2) European Commission proposal to extend screening to the age range 50-69 to 45-74

In September 2022, the European Commission attempted an extension of the cut-off points with a proposal to change the guidelines

PROPOSAL:

Text, page 1: https://health.ec.europa.eu/publications/proposal-council-recommendation-cr-strengthening-prevention-through-early-detection-new-approach_en

“Extending breast cancer screening from women aged 50 to 69 to include women between 45 and 74 years of age and to consider specific diagnostic measures for women with particularly dense breasts;"

Annex page 1

https://health.ec.europa.eu/publications/annex-proposal-council-recommendation-cr-strengthening-prevention-through-early-detection-new_en

« Breast cancer: 
Breast cancer: Breast cancer screening for women starting aged 45 to 74 with digital mammography or digital breast tomosynthesis 1 , and for women with particularly dense breasts consider magnetic resonance imaging (MRI), where medically appropriate."

- 3) EU Council counter-proposal: no change to current guidelines, no extension to include 45-74 year olds, screening not recommended but only suggested for ages 45-50 and 70-74

In response to this proposal, the Council of the European Union, in the text published on 9 December 2022, did not adopt this extension.
The guidelines for the 45-50 and 70-74 age groups have remained the same (identical to the current guidelines)

Annex, page 21

https://data.consilium.europa.eu/doc/document/ST-14770-2022-INIT/en/pdf

“Breast cancer:
Considering the evidence presented in the European guidelines 9, breast cancer screening for women aged 50 to 69 with mammography is recommended. A lower age limit of 45 years and an upper age limit of 74 years is suggested. The use of either digital breast tomosynthesis or digital mammography is suggested. The use of magnetic resonance imaging (MRI) should be considered when medically appropriate."

Recap of the lung cancer screening controversy

We have reported on the lung cancer screening controversy and subsequent reactions and publications here, updated to March 2022: https://cancer-rose.fr/en/2021/02/24/being-a-woman-and-smoking-x-rays-in-perspective/

Reminder of the prostate cancer screening controversy

Here's a reminder about prostate cancer screening and why the French National Authority for Health does not recommend it:
https://cancer-rose.fr/en/2021/02/11/parallel-to-breast-screening-prostate-screening-overdiagnosis-as-well/

https://www.has-sante.fr/jcms/c_1238318/fr/cancer-de-la-prostate-identification-des-facteurs-de-risque-et-pertinence-d-un-depistage-par-dosage-de-l-antigene-specifique-de-la-prostate-psa-de-populations-d-hommes-a-haut-risque

"To date, there is no robust demonstration of the benefit of prostate cancer screening by prostate-specific antigen (PSA) testing in the general population, either in terms of reduced mortality or improved quality of life. Thus, no prostate cancer screening program is recommended in the general population, in France, in the United States, New Zealand, or the United Kingdom."

Conclusion

The Council stresses the need for further evidence on the effectiveness, cost-effectiveness, and feasibility of specific screening strategies in real-life settings.
Member States are invited to consider the implementation of the mentioned cancer screenings based on conclusive scientific evidence while evaluating and deciding at the national or regional level based on the burden of disease and available healthcare resources, the balance of benefits and harms, and the cost-effectiveness of cancer screening, as well as the experience from scientific trials and pilot projects

For breast cancer: a low limit of 45 years and a high limit of 74 years are suggested (not recommended as in the original proposal).(The inclusion of MRI for women with dense breasts is highly debated; see https://cancer-rose.fr/2022/04/26/grosse-deconvenue-pour-lirm-mammaire/)

The Council adopts a moderate position for the new screenings (prostate, lung, gastric cancers), inviting further research to assess the feasibility and including the notion of effectiveness.
For lung cancer, the program should also include primary (tobacco control) and secondary prevention strategies.
For gastric cancer, the proposal for immediate implementation is deleted, and feasibility tests are requested.

Reactions

The reaction of the European Commissioner who initiated the project of new recommendations:

Today’s adoption by the Council of new EU recommendations for cancer screening is a milestone for cancer care both at national and European level. 20 years have passed since the current recommendations were adopted and medicine has made incredible advances. It is high time that new, up-to-date, screening recommendations are rolled out across the EU and that the unacceptable disparities in access are addressed. Whilst I would have liked to see an even more ambitious approach, today represents a watershed moment for citizens in the EU and a key achievement for Europe’s Beating Cancer Plan.
Stella Kyriakides, Commissioners for Health and Food Safety - 09/12/2022

The protest letter of the European Cancer Organisation (gathering urologists, radiologists, gastro, oncologists, ...) 

https://www.europeancancer.org/screening

" Late interventions to insert excessive caution and reduced ambition

...However, following a closed meeting of Member State representatives on Monday 24 October we understand that significant rewriting of the Commission’s proposal has taken place to:

  • Undermine and contradict advice provided by the EU’s Group of Chief Scientific Advisors, particularly with regards to the addition of new cancer screening programmes and areas for update in respect to tumour types presently covered in the 2003 EU Council Recommendations;
  • Delete from the text the Beating Cancer Plan targets on screening uptake;
  • Insert whole new sections stating every potential and historic cited risk of cancer screening;
  • Impose specific criteria each EU member state should use in making decisions on cancer screening,
  • Insert exaggerated emphasis on national prerogatives for countries to exempt themselves of the recommendations;
  • Dilution of advice on meeting the psychological needs of those diagnosed with cancer as a result of screening; and,
  • Weakening of sections relating to the need for fit for purpose systems for recording and publishing information on screening performance. "

Members - European Cancer Organisation

Reaction of WONCA

EUROPREV Statement about European Commission announcement of a new EU approach on cancer detection

https://europrev.eu/2022/11/27/statement-about-a-new-eu-approach-on-cancer-detection/

November, 27, 2022

EUROPREV – the European Network for Prevention and Health Promotion in Family Medicine and General Practice

EUROPREV is one of the five network of WONCA Europe

WONCA Europe
The European Regional Branch, WONCA Europe, is the academic and scientific society for general practice/family medicine in Europe, that  represents 47 member organisations and more than 90,000 family doctors in Europe. 

WONCA World 
WONCA is an acronym comprising the first five initials of the World Organization of National Colleges, Academies and Academic Associations of General Practitioners/Family Physicians. The short name is the World Organization of Family Doctors. WONCA was established by 18 members in 1972. It currently consists of 122 member organisations in 102 countries, with a total of 500,000 family doctors. WONCA represents and acts as an advocate for its constituent members at an international level, where it interacts with world bodies such as the World Health Organization. It is comprised of seven regions: Africa, North America, Asia Pacific, Europe, South Asia, Iberoamericana-CIMF and WONCA East Mediterranean Region.

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In cancer screening, often less is MORE 

To the European Commission – Health and Food Safety
To Directorate-General Health & Food Safety
To European Union Health Authorities
To European Family Medicine and Public Health professionals

 Last September 20th, the European Commission announced: “A new EU approach on cancer detection – screening more and screening better”.(1)
Among others, the new recommendations include: 
– The extension of the target group for breast cancer screening to include women between 45 and 74 years of age (as compared to the current age bracket of 50 to 69);
– Lung cancer testing for current heavy and ex-smokers aged 50-75.
– Prostate cancer testing in men up to 70 on the basis of prostate specific antigen testing, and magnetic resonance imaging (MRI) scanning as follow-up.

Considering the best available scientific evidence, we call your attention to the following facts:

Breast cancer screening

– For every 2000 women screened with annual mammography for ten years, one death of breast cancer will be prevented. But, at the same time, 200 women will suffer the long-lasting consequences of having a false positive result, and ten women will be overdiagnosed and overtreated including all the harms from being labelled as a cancer patient to side-effects and late effects of cancer treatment. Therefore, the balance between benefits and harms is unclear, and every woman should be given this information.(2)

– The extension of the target group will relatively increase the harm and diminish the benefits associated with this screening. Increased harm: younger women have denser breast tissue, and this increases the rate of false positives and elderly women have a higher competing risk of dying from other reasons than breast cancer and thereby the risk of overdiagnosis will increase. Diminished benefits: the incidence of breast cancer is much lower among women aged 45-49 and thereby the reduction in mortality is in absolute numbers much smaller and in elderly women the expected benefit from a mortality reduction is much less likely due to their shorter expected lifespan.

Prostate cancer screening

– If best available evidence is used from two independent institutes: the Cochrane Collaboration and the USPSTF, then there is robust evidence of no mortality reduction from PSA screening. If cherry picking the evidence, than in best case scenario is has been shown that for every 1000 men screened with PSA, two avoid death from prostate cancer. But, at the same time, 155 men will experience a false alarm. Usually, this is associated with unnecessary tissue removal. And 51 men will be overdiagnosed and unnecessarily treated, with significant deterioration of the quality of life (urinary incontinence, erectile dysfunction).(3)

– The potential harm associated with this screen is of great concern, and this is why, until now, no population-based prostate cancer screening programs have been implemented in Europe.  

Lung, gastric and other cancer screenings

– The available evidence about the benefits and harms of this screening is still scarce. There are also concerns about false positives and overdiagnosis with these screening programs. No population-based cancer screening program should be implemented without adequately designed randomized controlled trials in European populations assessing the balance of benefits and harms related to each screening.(4)

The myth of early diagnosis

According to the European Commission, these new recommendations aim “to increase the number of screenings, covering more target groups and more cancers“. 

Although well intended, this will, in practice, translate into more healthy people unnecessarily transformed into patients – overdiagnosis. 

In addition, and again although well intended, this will, in practice, translate into more suffering, cancer, and costs to health systems that are already overloaded and with scarce resources.

Finally, and again, although well intended, in a perspective of the climate crisis, carbon emissions of such low-value care interventions, as the suggested screening programs, are not sustainable. Moreover, these programs will increase social inequity in health and promote the inverse care law.

The EU Commission’s proposal is based on a medical myth. According to the EU Commission statement, “The sooner cancer is detected, it can make a real difference by increasing treatment options and saving lives”. In screening, this is a myth. We now have data from population-based screening programs showing that the critical factor in reducing mortality of cancer is not related to early diagnosis but to good access to healthcare and new cancer treatments.(5–7)

In cancer, very often, early diagnosis means only more burden of disease, with more suffering. 

OUR RECOMMENDATION 

The current EU Commission proposal needs to be revised.

If we really want to improve the way cancer is handled in Europe, then the focus should be:

– Primary prevention: on a population level improve diet, increase physical activity, diminish smoking and lower the consumption of alcohol. Structural societal interventions has with robust evidence of high quality been shown to be effective, while primary preventive intervention on an individual level has been shown to have no – or only short-term effect.

– Good access to Primary Healthcare Care. Every European citizen should have the right to have their Family Doctor, and this means having the right to be cared for by doctors with a specialty in Family Medicine in a trustful relationship with continuity and where the general practitioner is trained in evidence-based medicine. 

– Tertiary prevention: when diagnosed with cancer, good and quick access to specialized oncological centres (or other relevant specialists) is key to improving the outcome. This also includes good access to novel evidence-based cancer therapies.

-Quaternary prevention: new screening programs should only be implemented when the benefits outweigh the harms.

References

1. European Health Union: cancer screening [Internet]. European Commission - European Commission. [cited 2022 Nov 8]. Available from: https://ec.europa.eu/commission/presscorner/detail/en/ip_22_5562
2. Gøtzsche PC, Jørgensen KJ. Screening for breast cancer with mammography. Cochrane Database Syst Rev. 2013 Jun 4;(6):CD001877.
3. Harding Center for Risk Literacy. Early detection of prostate cancer with PSA testing [Internet]. Available from: https://www.hardingcenter.de/en/transfer-and-impact/fact-boxes/early-detection-of- cancer/early-detection-of-prostate-cancer-with-psa-testing
4. Heleno B, Thomsen MF, Rodrigues DS, Jorgensen KJ, Brodersen J. Quantification of harms in cancer screening trials: literature review. BMJ. 2013 Sep 16;347(sep16 1):f5334–f5334.
5. 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.
6. 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.
7. 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.

 

Cancer Rose est un collectif de professionnels de la santé, rassemblés en association. Cancer Rose fonctionne sans publicité, sans conflit d’intérêt, sans subvention. Merci de soutenir notre action sur HelloAsso.


Cancer Rose is a French non-profit organization of health care professionals. Cancer Rose performs its activity without advertising, conflict of interest, subsidies. Thank you to support our activity on HelloAsso.

The short news of October 2022

Synthesis Dr C.Bour, October 20, 2022

1°-We start with an article in Medscape, written by Ryan Syrek,

editorial director of Medscape US, on sexual dysfunction and poor self-image in women treated for breast cancer, often with hormone therapy.

This is an almost taboo subject and is obviously under-addressed. The author's concern is the hype surrounding certain therapies with dubious or non-existent benefits. He also points to overtreatment in women with CCIS (carcinoma in situ) who "are generally uninformed about their diagnosis and make uninformed treatment decisions."

The insufficient information of healthy women (in relation to screening) as well as of affected women (on their therapeutic possibilities), can be once again to be deplored.

But what are the obstacles to informing women properly; laziness? Lack of time? Or is it also a persistent patriarchal consideration that women are insufficiently armed to understand or decide, and that they must be spared any cognitive overload? Is this a caricature? Not at all, the art of manipulating women has even given rise to a real study: https://cancer-rose.fr/en/2020/12/17/manipulation-of-information/

We would also like to add that information should already be focused on the risks of screening in general, and in particular on over-diagnosis, which is largely fuelled by the discovery of many "in situ" carcinomas (see FAQ article), the vast majority of which do not affect women, but which are unfortunately mostly detected by repeated mammograms.

2°-In the BMJ, the authors ask the question about doctors' knowledge of overdiagnosis, which should be a prerequisite for explaining it to patients.... A study is in progress, presented here: https://bmjopen.bmj.com/content/12/10/e054267.info

Piessens V, Heytens S, Van Den Bruel A, et al : "Do doctors and other healthcare professionals know overdiagnosis in screening and how are they dealing with it? A protocol for a mixed methods systematic review"  BMJ Open 2022;12:e054267. doi:10.1136/bmjopen-2021-054267

Introduction Overdiagnosis is the diagnosis of a disease that would never have caused any symptom or problem. It is a harmful side effect of screening and may lead to unnecessary treatment, costs and emotional drawbacks. Doctors and other healthcare professionals (HCPs) have the opportunity to mitigate these consequences, not only by informing their patients or the public but also by adjusting screening methods or even by refraining from screening. However, it is unclear to what extent HCPs are fully aware of overdiagnosis and whether it affects their screening decisions. With this systematic review, we aim to synthesise all available research about what HCPs know and think about overdiagnosis, how it affects their position on screening policy and whether they think patients and the public should be informed about it.

Methods and analysis We will systematically search several databases (MEDLINE, Embase, Web of Science, Scopus, CINAHL and PsycArticles) for studies that directly examine HCPs' knowledge and subjective perceptions of overdiagnosis due to health screening, both qualitatively and quantitatively. We will optimise our search by scanning reference and citation lists, contacting experts in the field and hand searching abstracts from the annual conference on 'Preventing Overdiagnosis'.

After selection and quality appraisal, we will analyse qualitative and quantitative findings separately in a segregated design for mixed-method reviews. The data will be examined and presented descriptively. If the retrieved studies allow it, we will review them from a constructivist perspective through a critical interpretive synthesis.

3°-In the Annals of Internal Medicine is presented an initiative that our French National Cancer Institute could learn from. https://www.acpjournals.org/doi/10.7326/M22-1139

For the authors, Aruna Kamineni, V. Paul Doria-Rose, Jessica Chubak, et al, cancer screening should be recommended only when the balance of benefits and risks is favorable. The review presented here evaluates how US cancer screening guidelines report risks.

Objective: To describe current reporting practices and identify opportunities for improvement.
Design: Guideline review.
Setting:United States, study funded by the American Cancer Institute.
Patients: Patients eligible for breast, cervical, colorectal, lung, or prostate cancer screening according to US guidelines.
Results: Harms reporting was inconsistent across organ types and at each step of the cancer screening process. Guidelines did not report all harms for any specific organ type or for any category of harm across organ types. The most complete harms reporting was for prostate cancer screening guidelines and the least complete for colorectal cancer screening guidelines. Conceptualization of harms and use of quantitative evidence also differed by organ type.

Conclusion:
The review identified opportunities for improving conceptualization, assessment, and reporting of screening process–related harms in guidelines. Future work should consider nuances associated with each organ-specific process to screen for cancer, including which harms are most salient and where evidence gaps exist, and explicitly explore how to optimally weigh available evidence in determining net screening benefit. Improved harms reporting could aid informed decision making, ultimately improving cancer screening delivery.

4°-Finally, two more publications:

A "letter to the editor" by Rani Marx (Medical Decision MakingVolume 42, Issue 8, November 2022, Pages 1041-1044)and a recent editorial, by Marilyn M. Schapira, Professor of Medicine in Pennsylvania and Katharine A. Rendle, Assistant Professor of Family Medicine and Community Health at the Perelman School of Medicine (Pennsylvania), both advocating for awareness of the need for de-escalation of screening and the need for change for the benefit of women.

In her letter "Overscreening for Women's Cancer: Time for Change," Dr. Marx, an epidemiologist and patient, relates:
"Unnecessary and potentially dangerous cancer screening for women is a burden on health care and likely harms patients." The author decries "abundant testing, despite little evidence of improved population health or reduced mortality..."
Furthermore, she shares her own experience in 2020.

In her commentary "Overscreening for Women's Cancer: Time for Change," Dr. Rani Marx addresses the complex issue of informed, value-based decision-making in women's health. Drawing on her experience in health services research and epidemiology, as well as her own experience as a 'patient', Dr. Marx describes her frustrating attempts over a lifetime of screening to engage clinicians in considering the importance of risk on benefit-risk balance. She exposes the trade-offs involved in making decisions about cancer screening tests.
When asked, Dr. Marx explains, many patients and clinicians accept and recognize the need to de-escalate care when supported by scientific evidence, and to engage in an informed, shared decision-making process.

The editorial by Schapira and Rendle, on the other hand, advocates for the challenge of de-escalation: a multi-level change is needed to improve clinical practice. These improvements should focus on guidelines, efforts to achieve consensus on those guidelines, and shared decision-making processes between a woman and her clinician, leading to individualized screening decisions that reflect the woman's values and preferences.

This is in fact what the citizens' consultation demanded, but the road is long, and shared decision making appears to be a mirage when we see the INCa's television spots encouraging women to undergo screening, or the institute's information documents, which are still insufficiently balanced and scarcely descriptive of the risks of screening.

Cancer Rose est un collectif de professionnels de la santé, rassemblés en association. Cancer Rose fonctionne sans publicité, sans conflit d’intérêt, sans subvention. Merci de soutenir notre action sur HelloAsso.


Cancer Rose is a French non-profit organization of health care professionals. Cancer Rose performs its activity without advertising, conflict of interest, subsidies. Thank you to support our activity on HelloAsso.

The new INCa 2022 booklet on breast cancer screening

October the 20th

In 2017, we conducted a critical review of the French National Cancer Institute (INCa) information booklet for women on breast cancer screening, being sent with their first invitation.

At the time, the score for the quality of the information was not outstanding. A new 2022 edition for women is now accessible online. We will examine and compare the changes made between the two editions.

Sophie, our patient referent, compared the two booklets to assess how the INCa's communication was progressing. Below is a summary of the analysis she conducted.

The negative points 

1) This booklet is only sent once, at the age of 50, for the first screening, and then at each of the subsequent screenings, a different document (a short leaflet) is provided: the leaflet does not mention any of the harms of screening. Instead, it indicates a link to a website for more information. It is obvious that, over time, the message that will remain in the minds of women will be the one in the leaflet, with none of the harms presented, which will be completely forgotten.

2) Among the benefits, a special emphasis is placed on 5-year survival, which is not an indicator for screening effectiveness.

3) The mortality reduction is presented as a relative percentage reduction (15-21%), meanwhile the overdiagnosis is presented as an absolute percentage (10-20%), which are not comparable. This flaw exists in the 2017 booklet as well.

ATTENTION: A 20% decrease in cancer mortality does not mean that 20 fewer women screened out of 100 will die of cancer. This is just an indication of relative risk. The authors disregard the request of women citizens to no longer be misled by numbers that do not mean what they appear to suggest. The 20% fewer deaths does not mean that 20 fewer women out of 100 will die of breast cancer if they are screened. The 20% reduction in deaths is only a relative risk reduction between two compared groups of women.

In fact, according to a projection made by the Cochrane Collaboration based on several studies, for every 2,000 women screened over a period of 10 years, 4 will die of breast cancer; for a group of women not screened over the same period of time, 5 will die of breast cancer; the reduction from 5 to 4 mathematically represents a 20% reduction in mortality, but in absolute terms, only one woman's death will be prevented.

Actually, this corresponds to an absolute risk reduction of 0.05% (1 woman in 2000) to 0.1% (1 woman in 1000) at the end of 10 to 25 years of screening, depending on the estimates used (American, US TaskForce, Prescrire journal). (5)

Concerning the rate of overdiagnosis, the 10 to 20% indicated corresponds to the lowest evaluation, other studies suggest much higher rates of overdiagnosis.

4) The NIH (National Cancer Institute) website is cited in the booklet's references to support the survival statistics put forward in the booklet. But it omits the page of the same institute that indicates that survival is not a good indicator of the effectiveness of screening, and it also omits the page where the rate of overdiagnosis is given as 20 to 50%. Indicating a rate at its low range is an option in a document, but the high range must also be honestly given.

What does the NIH say specifically regarding these two parameters ?

On overdiagnosis rates https://www.cancer.gov/types/breast/hp/breast-screening-pdq#_13_toc
Magnitude of Effect: Between 20% and 50% of screen-detected cancers represent overdiagnosis based on patient age, life expectancy, and tumor type (ductal carcinoma in situ and/or invasive).[11,12] These estimates are based on two imperfect analytic methods:[11,13]
Long-term follow-up of RCTs of screening.
The calculation of excess incidence in large screening programs.[11,12]
Study Design: RCTs, descriptive, population-based comparisons, autopsy series, and series of mammary reduction specimens.

On survival and screening effectiveness https://www.cancer.gov/about-cancer/screening/research/what-screening-statistics-mean

Much of the confusion surrounding the benefits of screening comes from interpreting the statistics that are often used to describe the results of screening studies. An improvement in survival—how long a person lives after a cancer diagnosis—among people who have undergone a cancer screening test is often taken to imply that the test saves lives.

But survival cannot be used accurately for this purpose because of several sources of bias.

5) The “choice of screening” is no longer mentioned in the booklet title, and the last chapter on screening options (to accept or do not accept) has been removed and replaced with testimonials on the benefits (a reassuring example of a screening that "saved" a woman's life, another of a woman who, not having been screened, might have received a more aggressive treatment)

This option of choice was included at the end of the 2017 booklet:

6) There is still no visual pictogram (as requested by women citizens), that illustrates in absolute numbers the benefits and the harms, to have a global vision and to allow the women to make their choice.

7) The harms of screening continue to be named "limitations" (page 13 of the booklet), whereas the term in English is "harms".

"Limitations" rather implies the inability to detect correctly.

8) Messages from personalities (president of INCa), authorities (recommendation in Europe), appeals to fear (if you don't get screened...), are used as influence techniques.

The positive points.

1) A specific page that groups screening harms (also present in 2017, but not grouped together and without a clear title for each harm).

2) Better organization of information on prevention (risk and protective factors, table on cancer statistics related to each risk factor, page 9)

3) Easier to read, a more visual document

4) The addition of the midwife (alternative to the general practitioner or gynecologist) in the follow-up clinical examinations and to answer questions on screening.

Comparison of the texts of the two booklets in the table

Download / Télécharger

In conclusion

This booklet, ideally corrected to address the persistent deficiencies that Sophie identified for us, may be sent with each screening invitation, not just at age 50.

In the leaflet for successive screenings (beyond the age of 50), the harms of screening and recommendations on prevention have been omitted, resulting in abbreviated and insufficient information.

Women must now be completely and appropriately informed, as requested during the citizen consultation, and that for the rest of their lives of “screened women”.

Those women who had their initial screening before 2022 will never receive this information.

This can be implemented without too much difficulty by simply replacing the leaflet planned for the next invitations by this booklet, duly completed and corrected for its weaknesses.

Cancer Rose est un collectif de professionnels de la santé, rassemblés en association. Cancer Rose fonctionne sans publicité, sans conflit d’intérêt, sans subvention. Merci de soutenir notre action sur HelloAsso.


Cancer Rose is a French non-profit organization of health care professionals. Cancer Rose performs its activity without advertising, conflict of interest, subsidies. Thank you to support our activity on HelloAsso.

A new EU approach to cancer screening

September 22, 2022 - Abstract Dr. C.Bour

https://ec.europa.eu/commission/presscorner/detail/fr/QANDA_22_5584

Within the framework of the European program of the fight against cancer and cancer screening, which will be included in a large European plan, the European Commission proposes an extension and/or a restart of certain screenings and an implementation of new ones.
The objective is that by 2025, 90% of the EU population will be screened for breast, prostate, cervical and colorectal cancer. Lung and stomach cancer screenings are also included, although no conclusive studies exist for the latter.

Regarding funding: “Europe's Beating Cancer Plan is supported using the whole range of Commission funding instruments, with a total of €4 billion being earmarked for actions addressing cancer. This includes around € 38.5 million committed from the EU4Health programme for screening-related projects and € 60 million under the Horizon Europe. The Commission will propose additional funding for cancer screening under the 2023 EU4Health programme.”

A blatant disregard for acquired knowledge and established recommendations

1° breast cancer

The Commission wishes to extend breast cancer screening to younger women, including women starting at 45 years of age.

However, a British trial, the UK Age Trial, delivered its results in 2021. After 23 years, the results of the UK Age Trial no longer showed a significant decrease in the number of deaths from breast cancer in women screened between the ages of 40 and 49. The authors of the trial concluded: "Overall, there was no significant reduction in breast cancer mortality in the intervention group compared with the control group.”
The results also showed no reduction in total mortality (or all-cause mortality).
The justification for this extending screening to a younger age is as brief as it is unscientific:
https://healthcare-quality.jrc.ec.europa.eu/european-breast-cancer-guidelines/screening-ages-and-frequencies/women-45-49#rec-question

“The GDG (development group of these guidelines)  agreed this recommendation by consensus with no need for voting.”
“The decision on this recommendation takes into account the balance between desirable and undesirable effects that probably favours organised mammography screening for women aged 45 to 49 in the context of moderate certainty of the evidence.”

Yet the downloadable 2016 PDF detailed the doubts that exist for this screening: "Mammography, compared with no screening, did not significantly reduce the risk of breast cancer mortality..... in women invited to screening during 16.4 years of follow-up."...
"Mammography, compared with no screening, reduced the risk of stage IIA or higher breast cancer (46 fewer cases of breast cancer per 100,000 women ...but did not reduce the risk of all-cause mortality."
(Recall that overall mortality includes all elements of healthcare, so also the effects of treatment, overdiagnosis, and overtreatment. This figure is more meaningful because any cancer detected will be treated; the treatments themselves sometimes cause deaths, which will be included and encompassed in the 'all-cause mortality,' thus better reflecting the reality of screening).

"Adverse events:
Women aged 40-74 randomized to 'invitation to screening' were more likely to undergo mastectomy....
Overdiagnosis is estimated to be 12.4% (moderate quality evidence) from a population perspective and 22.7% from the perspective of a woman invited to screening (moderate quality evidence).
The number of false positives will depend on age at the first screening. Estimated cumulative risk of false-positive screening: The rate of women aged 50 to 69 years who underwent 10 biennial screenings was 19.7%. However, higher false-positive rates were observed among women younger than 50 years than among women aged 50 to 69 years.
In addition, 2.2% of women had a needle biopsy after the initial screening mammogram.
False-positive mammograms are also associated with greater anxiety and distress about breast cancer as well as negative psychological consequences that can last up to three years (low quality evidence). ..."

2.Prostate cancer

The Commission proposes introducing a prostate-specific antigen (PSA) test - similar to a blood test - in men up to age 70, combined with additional magnetic resonance imaging (MRI) as a follow-up test.

Yet, prostate cancer screening has been long debated and is not longer recommended by the HAS since 2013- https://www.has-sante.fr/jcms/c_1623737/fr/detection-precoce-du-cancer-de-la-prostate
"the HAS recalls that the implementation of a screening program for prostate cancer using total serum PSA measurement is not recommended, either in the general population or in men at high risk."

The lack of benefit in mortality reduction and significant overdiagnosis motivated this decision. More explanation here:
https://cancer-rose.fr/en/2021/02/11/parallel-to-breast-screening-prostate-screening-overdiagnosis-as-well/

Conclusion

The extension of screening to the younger age group is a step forward from 2019, when, regarding the 45-49 age group, the GDR (expert panel proposing the recommendations) suggested at that time a triennial or biennial mammographic screening in the context of an organized screening program, mentioning a low level of certainty.

In the meantime, the MyPEBS study has been set up to test the possibility of more targeted screening since it must be admitted that the current screening does not work as expected: "After analysis of all the components, the final objective of Mypebs is to provide the best recommendations for the best breast cancer screening strategy in Europe.
The MyPEBS promoters' argument also states: "A major challenge is to make women more informed and more active in their screening decisions, as clearly recognized by several international studies. Indeed, a major concern of national screening programs in all participating countries is to promote informed choices about decisions to participate in screening and subsequent treatment options. Informed choices require that good quality, relevant information be provided to women so that they can make decisions consistent with their values."

So it appears that the EU sees no contradiction in funding a €12M study to achieve more precise, risk-based screening and, on the other hand, expanding the age ranges for screening without evidence, even before MyPEBS has delivered its results...
Or else there is no contradiction, and the MyPEBS study is meant to achieve this, to finally impose screening to all women, with an extension of the age to younger age groups as early as 40 years old as we already figured...?

Read: https://cancer-rose.fr/my-pebs/2019/06/13/argument-english/

These new EU recommendations just jump to the front.
This current 2021 EU report states that for the 45-49 age range, "full details, including downloadable supporting documents for health professionals, will be available soon."

We hope these will be real scientific justifications and that the promise made to citizens after the French citizen consultation to provide support tools for an informed decision, including the decision not to be screened, will not be forgotten.

Cancer Rose est un collectif de professionnels de la santé, rassemblés en association. Cancer Rose fonctionne sans publicité, sans conflit d’intérêt, sans subvention. Merci de soutenir notre action sur HelloAsso.


Cancer Rose is a French non-profit organization of health care professionals. Cancer Rose performs its activity without advertising, conflict of interest, subsidies. Thank you to support our activity on HelloAsso.

Liquid biopsies, the Grail?

Synthesis Dr. C.Bour, September 15, 2022

Main article

Article by Brenna Miller

The Damocles syndrome

Preamble

Early cancer detection is and remains a Grail for which we have absolute faith in technology. Despite all the failures of screening (melanoma, thyroid, prostate, breast) to overcome cancer and its, unfortunately, most serious forms[1], we nevertheless remain convinced that if we detected all cancerous cells, we could "beat" the disease.
Studies show that the small gains in mortality in cancerology are not due to detection but almost essential to progress in treating advanced forms. Breast cancer is an example.

The media is often the spokesperson for "spectacular discoveries," and we have already reported on the problem of the media coverage of scientific innovations, such as screening and blood tests (liquid biopsies) for early detection of cancer, which was the subject of a study published in JAMA in 2021.

With the multiplication of screenings, most of them failing to decrease overall mortality and reduce the most advanced forms of cancers, our societies have ended up with two kinds of diseases.
On the one hand, diseases that are experienced by the patient, with specific symptoms and identified by the clinician, and on the other hand, conditions that are not experienced but detected by screening and defined as diseases. In the latter case, it is complicated to determine what a patient is. A person in whom the pathologist has found a cancerous cell under his microscope?  A person with a cancerous cell cluster in an organ that will never affect it? A person with a polyp that might have become cancerous one day?

The paradox is that with mass screening and no particular selection, more and more people are declared "sick" without being so, and above all, "cured" before ever being clinically ill. Thanks to the biomedical miracle, they are even treated and then cured of a disease they would never have known. If this is not progress... The problem is that, on the one hand, the treatments themselves can make people sick. On the other hand, the knowledge of their "cancer" exposes people to a suicide rate five times higher, with a maximum observed just after the diagnosis's announcement, whether it is a detected lesion or a "real" clinical cancer. The announcement multiplies by 12 the risk of death by cardiovascular accident.

We (re)-talk about liquid biopsies

An article in La Croix (French newspaper) announces, as did other media recently (Futura Science, Tops Santé, etc.), a blood test consisting of detecting tumor DNA circulating in the blood and thus making it possible to detect 50 types of cancers.

But, as explained above, early detection of cancers does not mean an automatic cure and does not protect against false positives or unnecessary detections.

This is the concern expressed by Gilbert Welsch and Barnett Kramer in an article published in the journal STAT.
Welsch, a general internist and senior researcher at the Center for Surgery and Public Health at Brigham and Women's Hospital in Boston, details this notion in the article dedicated to liquid biopsies, with a critical analysis that you can find here in STAT+
Barnett Kramer is an oncologist, member of the Lisa Schwartz Foundation for Truth in Medicine, and former director of the Division of Cancer Prevention at the National Cancer Institute.

What are liquid biopsies?

A liquid biopsy allows the detection of circulating tumor cells dislodged from a primary tumor or even from metastases and carried in the vascular system, as well as the circulating DNA of these circulating tumor cells. The hope is to be able to detect cancer before its expression.

It was back in 2015 in the United States when members of Congress introduced a bill requiring US Medicare to cover a costly cancer screening test offered to the entire population, but for which so far, there is no scientific evidence that the procedure saves lives.
The American Cancer Society, an American nonprofit organization founded in 1913 to fight cancer and firmly in favor of screening, approved the project, arguing that this expensive and unproven test would solve health disparities.

The two American authors then asked two fundamental questions:
Do liquid biopsies work as advertised?
If liquid biopsies are effective, are they effective enough to be worthwhile?
Finally, a third question emerges: What about the reduction in disparities that the American Cancer Society claims?

Do liquid biopsies work as advertised?

It is claimed, say the authors, like a mantra, regularly repeated in a loop by opinion leaders and media who do not care about the controversy, that 90% of cancers detected very early are cured. This is not, nevertheless, proof that screening saves lives...

What does the notion of 5-year survival mean?

The "90% survival at five years" for cancers is true, but only for cancers with a very good prognosis and those that should never have been discovered and would never have made anyone sick. For cancer that would never have killed its host, it is quite normal that the host is alive after 5 years. It is also true that cancers with a good prognosis have a better survival rate than those with a poor prognosis and metastatic disease. Still, the real question is: is screening capable of discovering these latter cancers in due time, the ones we should be catching because they kill? And this is where the problem lies (see ref 1)...

First, say Welsch and Kramer", early detection of some cancers may not be possible. Despite four decades of mammography screening, for example, the incidence of metastatic breast cancer remains virtually unchanged. Very aggressive cancers have often spread by the time they become detectable." Indeed, aggressive, metastatic cancers do not arise from smaller or lower-grade cancers; they are lesions that are aggressive from the start and have such a molecular component that they have already metastasized in the body; even when they can be detected, they are large at the time of diagnosis because they are very fast. Lanning's study explains the mechanics of cancer very well.

"Second, although earlier detection of some potentially aggressive cancers is possible, early treatment may not change the time of death. Survival statistics hide this possibility."
This is called lead time, which is explained in detail here.
Detection advances the "birth date" of cancer and thus benefits survival statistics but has no impact on people's longevity. It is an optical illusion.

And third, survival statistics are inflated by overdiagnosis, i.e., the unnecessary detection of lesions that would never have killed.
According to Prof. Welsch, "High survival statistics may indicate a problem. For example, the 90% 5-year survival for early-stage cancers includes many cancers detected by blood tests, such as prostate cancer and PSA testing, or by imaging, such as breast cancer and mammography, that were not intended to progress to late-stage cancer or cause death. Overdiagnosis - common in breast, prostate, thyroid, and melanoma skin cancers - significantly inflates survival rates. Higher survival due to overdiagnosis is not a benefit, but harm, with more people, diagnosed and treated for "cancers" that were never going to cause problems."

If liquid biopsies are effective, are they effective enough to make them worthwhile?

We quote below what the two scientists write:

"Even if medical intervention is effective, it is essential to evaluate its side effects. Aspirin, for example, is effective in preventing heart attacks and strokes but not enough in the general population to justify the associated harms, such as brain and intestinal bleeding.
Liquid biopsies will have unintended disadvantages: more tests, more treatments, and the psychological and physical problems that come with them. Some people will be told they have a "cancer signal" - triggering fear and more tests - only to learn later that it was a false alarm. Others will be overdiagnosed and treated for cancers that otherwise would never have worried them. Some will be affected by the treatment; some may even die.
Still, others will have significant cancers discovered earlier than they would have without the liquid biopsy but will not live longer. They will be subjected to the toxicity of cancer therapies earlier, at a time when they would otherwise have no symptoms. These side effects exist in all cancer screening programs. But multicancer liquid biopsy screening has one of its own: While it may be evident that a person has cancer, it is not always clear where that cancer is. Imagine being told you have cancer, but no one knows what type it is.
No one knows how common these side effects are because these tests have not been rigorously studied. But a bad test is as bad as a wrong drug. That's another reason why a randomized trial is needed - not just to determine if liquid biopsies provide benefits but also to determine how often they cause harm.
One thing we know about liquid biopsy screening is that it will be costly."

One test, the Galleri test, for example, costs $949. If it's recommended every year for people 50 and older, Welsch calculates, with 100 million Americans in that age range, that would be about $100 billion a year, he says.
Moreover, additional examinations and other tests will be required to search for and confirm cancer that the liquid biopsy suggests, and the number of medical consultations will be multiplied.

Because if there are wandering tumor cells, cancer must still be found.

Reduction of disparities?

Here again, the two researchers are very doubtful...

"Those who want to address the significant drivers of health disparities should be less concerned with the Medicare population and more concerned with people under age 65, especially where the disparities really start: among young adults and children. And they should be less concerned with medical interventions such as cancer screening and more concerned with the real determinants of health, such as diet, housing, and income security.
Increased mammograms and colonoscopies have not solved the health effects of poverty, and liquid biopsies won't solve them."

In another article published in the Boston Globe, Welsch cites the example of the Galleri test, which has avoided the FDA approval process (the U.S. Food and Drug Administration, which verifies and approves the marketing of drugs) through a waiver. Galleri is sold directly to consumers for $949 per person.
"The company that sells Galleri," says Welsch, "recommends that people take the test once a year. Let's do the math. Given that there are about 60 million Medicare beneficiaries, that would be about $60 billion a year. That would represent a 7% increase in total Medicare spending ¬- to be passed on to taxpayers and/or Medicare beneficiaries in the form of higher premiums.
All this for one test. And no one knows if that test helps people live longer or better."

What should be done?

For G.Welsch, there is only one way to test liquid biopsies on their effectiveness in detecting cancers early: to conduct a randomized trial in which participants are divided into two groups. One group is screened regularly; the other is not. The participants are then followed for about ten years, counting the number of deaths in each group. Randomized controlled trials are the "gold standard" of scientific studies and are a proven method. England's National Health Service (NHS) is currently recruiting 140,000 people for such a trial. The most relevant outcome to measure would be the number of deaths in each group.

The US National Cancer Institute is planning a randomized trial of liquid biopsy screening. Ironically, says G. Welsch in the Boston Globe, the adoption of Medicare coverage for these tests would hamper this trial "because of a dynamic we've already seen. In the 1990s, many doctors and patients believed that a transplant of one's bone marrow was an effective treatment for metastatic breast cancer. The press focused on young women who were dying of aggressive cancer without access to this "life-saving" procedure ...... The presumption of benefit was so strong that researchers had difficulty finding volunteers to participate in studies to determine whether the procedure worked. Everyone already assumed it did. But it didn't.
.... "randomized trials finally showed that bone marrow transplants didn't help women live longer. And they certainly didn't live better. Tens of thousands of women underwent an arduous procedure, often complicated by anemia, infection, and diarrhea. And some died as a result."

So don't put the cart before the horse; it's urgent...wait, the researcher implores Congress at the end of the article to let the American National Cancer Institute and the US Preventive Services Task Force do their work. (USPSTF: group mandated to review the evidence and make recommendations on prevention devices).

Article by Brenna Miller, Lown Institute

Finally, you can find here the summary of the facts, written by Brenna Miller, a health communication specialist at the Lown Institute. She holds a master's degree in public health from Tufts University School of Medicine.

The Lown Institute is "a nonpartisan think tank that advocates bold ideas for a fair and caring health care system."

The author refers to Theranos, an American health technology company that supposedly developed the first liquid biopsy tests without independent evaluations or scientific publications and whose executives were finally indicted in 2018 for massive fraud.

The Damocles Syndrome
Blood Tests That Detect Cancers Create Risks for Those Who Use Them

The New York Times, By Gina Kolata on June 10, 2022

Testimonials

The article features testimonials highlighting the benefits of these tests for patients, but also the risks they pose, especially if, as is currently the case, companies don't wait for a green light from legislators, shortcut approvals and sell the tests directly to consumers.

"Jim Ford considers himself a lucky man: An experimental blood test found his pancreatic cancer when it was at an early stage. It is among the deadliest of all common cancers and is too often found too late. After scans, a biopsy and surgery, then chemotherapy and radiation, Mr. Ford, 77, who lives in Sacramento, has no detectable cancer.
“As my doctor said, I hit the lottery,” he said."

The Damocles syndrome

But there are other testimonials and less enthusiastic comments on the tests:

“When Susan Iorio Bell, 73, a nurse who lives in Forty Fort, Pa., saw an ad on Facebook recruiting women her age for a study of a cancer blood test, she immediately signed up. It fit with her advocacy for preventive medicine and her belief in clinical trials.
The study was of a test, now owned by Exact Sciences, that involved women who are patients with Geisinger, a large health care network. The test looks for proteins and DNA shed by tumors. Ms. Bell’s result was troubling: Alpha-fetoprotein turned up in her blood, which can signal liver or ovarian cancer. She was worried — her father had had colon cancer and her mother had breast cancer. Ms. Bell had seen what happened when patients get a dire prognosis. “All of a sudden, your life can be changed overnight,” she said. But a PET scan and abdominal M.R.I. failed to find a tumor. Is the test result a false positive, or does she have a tumor too small to be seen? For now, it is impossible to know. All Ms. Bell can do is have regular cancer screenings and monitoring of her liver function. “I just go day by day,” she said. “I am a faith-based person and believe God has a plan for me. Good or bad, it’s his will.”
Some cancer experts say Ms. Bell’s experience exemplifies a concern with the blood tests. The situation may involve only a small percentage of people because most who are tested will be told their test did not find cancer.
Among those whose tests detect cancer, scans or biopsies can often locate it. But Dr. Susan Domchek, a breast cancer researcher at the University of Pennsylvania, warned that when large numbers of people get tested, false positives become “a real problem,” adding, “we need to know what to do with those results and what they mean.”

Dr. Daniel Hayes, a breast cancer researcher at the University of Michigan, refers to the situation as a Damocles syndrome: “You’ve got this thing hanging over your head, but you don’t know what to do about it.”

Donald Berry, a statistician at MD Anderson Cancer Center in Houston, shares his experience and doubts. When GRAIL was first formed, its leaders invited him, to be on its scientific advisory board.
“They said they needed a skeptic,” Dr. Berry said. “I told them I was a skeptic and I was quite negative. I told them there was this real hurdle — they will have to run very large clinical trials and the endpoint must be survival. They have to show that detecting cancer early is more than just detecting cancer early. It has to mean something.”
A few years later, the company restructured its scientific advisory board to include many new experts, and Dr. Berry is no longer a member. He is not sure why.
“Being generous, I’d say they no longer needed my expertise,” Dr. Berry said. “Being realistic, they got tired of hearing my complaints that finding cancer early was not enough.”

Reasons for reluctance

Difficult questions from Donald Berry concern overdiagnosis: "finding small tumors that would never have been noticed and may not have caused any harm. Some cancers simply fail to grow or are destroyed by the body’s immune system.
But without knowing if the cancer is dangerous, it will be treated as though it is, subjecting people to therapies that are often difficult or debilitating and may be unnecessary. Dr. Kramer said this also happens with standard screening tests, which can result in the removal of thyroid glands, breasts or prostates for small tumors that are actually harmless."

Another issue is the efficiency of detection for these tests, especially in the most aggressive cancers, according to Dr. Kramer, an oncologist, member of the Lisa Schwartz Foundation for Truth in Medicine, and former director of the Division of Cancer Prevention at the U.S. National Cancer Institute.
“We will dip more and more deeply into the iceberg of disease,” Dr. Kramer said, finding “lesions that look like a cancer to the pathologist but may not have the same natural history at all.” It may not even be possible to find the most aggressive cancers early enough for a cure, Dr. Kramer added. The tumors that shed the most DNA and proteins into the blood are the largest tumors.”

The article concludes with the opinion of the aforementioned statistician Dr. Berry:
“Dr. Berry, though, is not assuaged and fears that the public’s faith in early detection which, he says, “is like a religion,” will rule the day, even without good evidence.“Everybody loves early detection, but it comes with harms,” Dr. Berry said. “The harms, we know,” he added. “The benefits are very uncertain.”

“But a definitive study to determine whether the tests prevent cancer deaths would have to involve more than a million healthy adults randomly assigned to have an annual blood test for cancer or not” explains the article. “Results would take a decade or longer”.

Will the public, the media, the companies marketing the tests have the patience to wait?

Références

[1] Non reduction of metastatic cancers since screening for breast and prostate cancer, studies:

Autier P, Boniol M, Koechlin A, Pizot C, Boniol M. Effective- ness of and overdiagnosis from mammography screening in the Netherlands: population based study. BMJ 2017;359:j5224.

Autier P, Boniol M, Middleton R, Dore JF, Hery C, Zheng T, et al. Advanced breast cancer incidence following population- based mammographic screening. Ann Oncol 2011;22(8): 1726e35.

Bleyer A, Welch HG. Effect of three decades of screening mammography on breast-cancer incidence. N Engl J Med 2012; 367(21):1998e2005.

De Glas NA, de Craen AJ, Bastiaannet E, Op ’t Land EG, Kiderlen M, van de Water W, et al. Effect of implementation of the mass breast cancer screening programme in older women in The Netherlands: population based study. Bmj 2014;349:g5410.

Autier P, Boniol M. The incidence of advanced breast cancer in the West Midlands, United Kingdom. Eur J Cancer Prev 2012; 21(3):217e21.

Nederend J, Duijm LE, Voogd AC, Groenewoud JH, Jansen FH, Louwman MW. Trends in incidence and detection of advanced breast cancer at biennial screening mammography in The Netherlands: a population based study. Breast Cancer Res 2012;14(1):R10.

Lousdal ML, Kristiansen IS, Moller B, Stovring H. Trends in breast cancer stage distribution before, during and after intro- duction of a screening programme in Norway. Eur J Public Health 2014;24(6):1017e22.

Johnson RH, Chien FL, Bleyer A. Incidence of breast cancer with distant Involvement among women in the United States, 1976 to 2009. JAm Med Assoc 2013;309(8):800e5.

Esserman L, Shieh Y, Thompson I. Rethinking screening for breast cancer and prostate cancer. Jama 2009;302(15):1685e92. [53] Jorgensen K, Gøtzsche PC, Kalager M, Zahl P. Breast cancer screening in Denmark: a cohort study of tumor size and over-diagnosis. Ann Intern Med 2017 Mar 7;166(5):313e23.

Welch HG, Gorski DH, Albertsen PC. Trends in metastatic breast and prostate cancer dlessons in cancer dynamics. N. Engl JMed 2015;373(18):1685e7.

Di Meglio A, Freedman RA, Lin NU, Barry WT, Metzger-Filho O, Keating NL, et al. Time trends in incidence rates and survival of newly diagnosed stage IV breast cancer by tumor histology: a population-based analysis. Breast Cancer Res Treat 2016;157(3):587e96.

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