DIABETES AND CANCER

By Dr. C. Bour, January 5, 2021

The link between diabetes and cancer in general and diabetes and breast cancer in particular is well known, as shown in a 2012 meta-analysis [1].

This meta-analysis revealed a significant increase in the risk of breast cancer in women with diabetes compared to non-diabetic women. However, the association between diabetes and breast cancer risk appeared to be limited to postmenopausal women. Type 1 diabetes and diabetes in premenopausal women were not associated with a significant increase in breast cancer risk.

People with type 2 diabetes have a higher risk of developing cancers of the breast, pancreas, liver, kidney, endometrium and colon. 
While patients with type 1 diabetes are more likely to develop cervical and stomach cancers.

Several studies have also shown that patients with diabetes and cancer have a poorer prognosis than those without diabetes. Diabetes and hyperglycemia are associated with higher infection rates, shorter remission periods and shorter median survival times, as well as higher mortality rates[2].

Several mechanisms might explain why type 2 diabetes could increase the risk of cancer are being implicated: hyperinsulinemia, hyperglycemia and inflammation. The increase in blood glucose levels is believed to have carcinogenic effects by causing DNA damage.

Particular case of breast cancer

The meta-analysis discussed at the beginning of this article was conducted using a random effects model to study the association between diabetes and breast cancer risk [3].

The risk of breast cancer in women with type 2 diabetes is increased by 27%, a figure that decreases to 16% after adjusting for BMI. Obesity is an aggravating factor as shown in other studies.  

No increase in risk has been observed in women in pre-menopausal age or with type 1 diabetes.

In addition to the over-risk of cancer in the diabetic patient, what about the management of the patient with both diabetes AND cancer? [4] [5]

The management of the diabetic patient requires treatment not only by hygienic and dietetic measures but also by a finely tuned medication protocol that may include insulin and one or more oral agents.

Chemotherapy and analgesics can affect glucose homeostasis[6] and insulin sensitivity; drug interactions can interfere with the patient's tolerance to diabetes drugs; decreased appetite, nausea, vomiting and weight loss resulting from both disease and cancer treatment can cause imbalances in blood glucose levels.

Chemotherapeutic agents

Several chemotherapies are known to cause or exacerbate these adverse conditions. For example, cisplatin is known to cause kidney failure, and anthracyclines can cause cardiotoxicity. Cisplatin, paclitaxel and vincristine may be neurotoxic. Unfortunately, many of these side effects may remain permanent.

For cancer treatment to be effective, at least 85% of the chemotherapy dose must usually be administered. Patients with diabetes should be carefully monitored before the start and during chemotherapy. Treatment decisions should be based on the patient's clinical picture, but always be aware that any change in dose, or alteration in the timing of administration, or substitution of another chemotherapeutic agent may compromise results by reducing the response rate to treatment.

Corticosteroids

They represent an important part of treatment in cancer pathologies and are widely used to improve nausea and vomiting associated with chemotherapy, as well as to suppress neurological symptoms when the cancer has metastasized to the spine or brain. And they cause significant hyperglycemia within hours after administration. 

The treatment of hyperglycemia resulting from glucocorticoids then depends on the type of diabetes, the severity of the hyperglycemia levels, the dose and the duration of therapy. Administering steroids in multiple doses throughout the day instead of a single bolus dose, or administering the entire daily dose of steroids intravenously over 24 hours, can help control hyperglycemia.

Patients with pre-existing diabetes can be maintained on oral hypoglycemic agents and closely monitored. However, these medications are generally unsuitable for managing hyperglycemia in this setting and insulin is used.

Patients using insulin prior to glucocorticoid therapy will typically require both basal and preprandial insulin. These patients may require two to three times their usual insulin dose. Insulin is the preferred drug for the management of steroid-induced or steroid-exacerbated hyperglycemia in patients with known diabetes.

Patients with type 1 diabetes will need to adjust their dose. Type 2 patients who are already taking oral agents at baseline will add insulin, but only during this period when their blood glucose levels are high.

Several studies of cancers as disparate as small cell lung cancer and breast cancer have found an association between poorly controlled hyperglycemia and poor outcomes in these patients with both diabetes and cancer. Hyperglycemia also increases the risk of infection.

In patients with active cancer, the management of hyperglycemia focuses on the prevention of long-term complications to avoid acute and sub-acute outcomes, such as dehydration due to polyuria, infection, catabolic weight loss, hyperosmolar non-ketotic states and diabetic ketoacidosis [7].

Analgesics

Analgesics can cause constipation that affects patients in two ways. It can make them want to not eat, but also, by slowing down intestinal motility, narcotics may delay the absorption of nutrients. This can lead to a mismatch between the administration of insulin and the absorption of glucose. The patient faces the risk of hypoglycemia.

Statins and chemotherapy [8]

Statins and chemotherapeutic agents are metabolized by the same enzymes in the liver. 

If the liver enzymes are all captured by statin therapy, this may result in less elimination of chemotherapy. Some research suggests that it also works the other way around. If you give a statin to a patient on chemo and then stop the statin, he or she will eliminate the chemotherapy drug much more quickly. 

In general, therefore, there is a reluctance to start statin therapy in someone just starting chemotherapy because of possible hepatotoxicity," says Lavis [9] . If patients are already on statins, it is important to be aware of their effects and monitor them carefully. 

It is appropriate to target therapeutic interventions according to the patient's prognosis. If the prognosis is poor, we should be less demanding about the goals and not overburden the patient's treatment based on excessive expectations.

Prognosis and comfort

Prognosis, longevity and quality of life are important considerations in setting blood glucose targets. A pragmatic approach to the management of hyperglycemia in these patients is necessary.

The interest of a very strict glycemic control is to try to prevent complications in 10, 15, 20 years. 

But in a person with a poor prognosis or a life expectancy of only a few years, one must be more concerned about comfort and quality of life in the remaining years.

The goal would then be to avoid the effects of acute hyperglycemia, such as dehydration and ketoacidosis.

Conclusion

There is strong epidemiological evidence that diabetic diseases are associated with an accumulated risk of several cancers. There is also growing evidence that the degree of hyperglycemia and the treatment modalities for hyperglycemia influence cancer risk. 

The risk of breast cancer in women with type 2 diabetes is increased and obesity is an aggravating factor. On the other hand, there is no over-risk observed in women in pre-menopausal age or with type 1 diabetes.

The management of blood glucose levels in patients with diabetes and cancer can pose a significant clinical challenge. As there is no clear evidence that tight glucose control improves cancer outcomes, hyperglycemia must be managed pragmatically to ensure that the patient remains asymptomatic and at low risk of acute decompensation. 

Proactive management of glucocorticoid-induced hyperglycemia can help reduce large fluctuations in glucose levels. 

Read also :

https://www.healthline.com/diabetesmine/living-with-cancer-and-diabetes#1

References

[1] Diabetes and breast cancer risk: a meta-analysis  British Journal of Cancer (2012) 107, 1608–1617 https://pubmed.ncbi.nlm.nih.gov/22996614/

P Boyle M Boniol A Koechlin .....and P Autier1/Prevention Research Institute, 95 cours Lafayette, 69006 Lyon, France

[2] Clinical Challenges in Caring for Patients With Diabetes and Cancer
Helen M. Psarakis, RN, APRN-Diabetes Spectrum Volume 19, Number 3, 2006

https://spectrum.diabetesjournals.org/content/19/3/157

[3] https://pubmed.ncbi.nlm.nih.gov/22996614/

[4] https://endocrinenews.endocrine.org/july-2014-double-jeopardy/

[5] Clinical Challenges in Caring for Patients With Diabetes and Cancer-Helen M. Psarakis, RN, APRN-Diabetes Spectrum Volume 19, Number 3, 2006

https://spectrum.diabetesjournals.org/content/19/3/157

[6]  Phenomenon by which a key factor is regulated to persist around a beneficial value for the body.

[7] https://www.cancernetwork.com/view/diabetes-management-cancer-patients

[8] https://endocrinenews.endocrine.org/july-2014-double-jeopardy/

[9] Victor Lavis, MD, professeur au Département de néoplasie endocrinienne et des troubles hormonaux à l'Université du Texas MD Anderson Cancer Center à Houston.( https://endocrinenews.endocrine.org/july-2014-double-jeopardy/)

 

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PRESS RELEASE, English version of Cancer Rose web site.

2021, January 7

After several months of dedicated work, time and energy, we are pleased to announce the launch of English version of Cancer Rose web site.

Cancer Rose is a Non-Profit Organization under French law made up of independent Medical Doctors, a Doctor in Toxicology and a patient representative, with the goal of providing fair, transparent and objective information for French women on mass screening for breast cancer, based on scientific evidence.

We participated in the French Citizen and Scientific Consultation on Breast Cancer Screening organized by French Minister of Health in 2015, following the controversy on this topic in France.

We founded Cancer Rose organization and created the website in 2016.

At the international level, we exchange and share information on medical issues including over-diagnosis and the resulting over-treatment, with members of different organizations such as HealthWatch Charity in the UK,  the Institute of Scientific Freedom in Denmark, Choosing Wisely health organization in Canada, Wiser Healthcare Group of collaborating researchers in Australia, as well as American patient advocate Donna Pinto, member of the Steering Committee of the International “Precision” Project.

Our aim with this English version is to inform international visitors about our activities, to create connections and share our views on mass breast cancer screening controversy with women and professionals around the world.

We will update our content with new information, posts, announcements, events.

We hope you can find this website useful and easy to navigate.

Please follow us on Twitter and Facebook for news.

If you have any questions, suggestions, feedback or comments, please contact us.

Members of Cancer Rose have no sponsorships, honoraria, monetary support or conflict of interest from any commercial sources. They dedicate their time to this activity on a voluntary basis. The funds necessary for the functioning of this website and production of information materials (educational films, brochures, posters) are generated by individual donations and members contributions.

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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.

Cancer diagnosis: the bone of death or symbolic effectiveness

Annette LEXA, PhD Toxicology (Eurotox)

Expert Regulatory Toxicologist-Environmental Health Risk Assessor

22 February 2016

In today's health care system, a cancer diagnosis can be the most traumatic announcement that a patient will ever experience. And for some people, the announcement will be even more deadly than the cancer itself or its treatment. This is what a cohort study published in 2012 in the New England Journal of Medicine has masterfully demonstrated. The follow-up of this historical cohort of 6 million Swedes between 1991 and 2006, examined the link between cancer diagnosis and the immediate risk of suicide or death from a cardiovascular accident. In the first week after the announcement, the relative risk of committing suicide was 12.6 and the relative risk of dying from a cardiac accident was 5.6 compared to the control group without a cancer diagnosis. This indisputable result is observed equally in men and women.

According to the authors, a negative attitude from the healthcare professional, his or her beliefs around a diagnosis, will cause a deep distress to the patient, especially for cancers with a poor prognosis, leading to death within a week of diagnosis.

The major public health campaigns, the health system and the health professionals themselves, who are part of this dreaded particular colloquium, should be better consider this syndrome in their decision-making process based on the benefit-risk analysis, this potentially fatal psycho-physiological stress induced by the diagnosis itself.

Marcel Mauss and the death bone 

This study, which followed the standards of Evidence Based Medicine, confirms what ethnologists such as Claude Levy-Strauss in 1946 or Marcel Mauss in 1926 had already studied in the 20th century. This fatal syndrome is better known as "bone-pointing syndrome". This ancestral practice has been described among the first peoples of Australia, New Zealand and Polynesia. It consists in condemning a person to die after pointing towards to him a few meters away, a thin bone (often a kangaroo or emu femur of about 45 cm). This ritual is still at use today in Australia where health professionals are trained to face these fearsome situations, where the strength of beliefs prevails to the point of making the victim die from panic fear that disrupts the instinct of conservation, life itself. It is not a death of starvation where the individual would have let himself die of hunger and thirst, no, it is a panic fear that leads to a very rapid death that is not a deliberate choice of the individual or a death due to pre-existing psychological disorders, which the researchers verified in the Swedish study.

Marcel Mauss (1872-1950) wrote the following in 1926: "The Australians consider to be natural only those deaths that we call violent . (...) All the other deaths have a magical or religious origin (...). Mr. Mac Alpine employed a young Kurnai in 1856-57. This young boy was very healthy. One day, he fell ill. He explained that he had done what he shouldn't have done. He had stolen a female opossum before having permission to eat it. The old men had found out about it. He knew that he would not grow any more. He went to bed, practically under the effect of this belief; he never stood up again and died within three weeks. 

(…) Two recent observers, one of whom is a doctor, tell how people die from the death bone among the Wonkanguru: they are very scared. If this bone is found, the bewitched one gets better; if not, he gets worse. European medicine does not inspire confidence. It can do nothing (...) "

Mauss quotes Sir Barry Tuke, a physician who attests to having known "a healthy individual with a Herculean constitution". He died of this "melancholy" in less than three days. Another, "in excellent appearance, and certainly without any lesions of the thoracic viscera, was grieved by life: he said he was going to die and died in 10 days". In most of the cases studied by the doctor, the period was two or three days.

Marcel Mauss reminds us that sociology, like psychology, is only part of biology. Ideas that haunt the social body (death by cancer) have an immense capacity for development and persistence in individual consciousness. It is at the level of biology, of the psychophysiology of the individual that the collective suggestion crystallizes; the consciousness is entirely invaded by ideas and feelings that associate cancer and inevitable death and that are entirely of collective origin. Individuals die "by enchantment". Our human societies are animal societies, highly evolved indeed, but animal societies above all. And man is only a symbolic social mammal for whom language and symbols are powers that sustain his impulse of life and death.

Claude Lévy-Strauss and symbolic effectiveness

Claude Levy Strauss (1908-2009) later formulated the concept of symbolic effectiveness, based on the work of the American physiologist Waler Bradford Cannon (1871-1935). Cannon theorized the famous principle of the fight-or-flight response. In the face of a threat, if fighting or fleeing is no longer possible, physiological stress puts the organism in danger (illness, death). "An individual conscious of being the object of an evil spell is intimately persuaded, by the most solemn traditions of his group, that he is condemned: parents and friends share this certainty. From then on, the community retracts: one moves away from the cursed one, one behaves towards him as if he were not only already dead, but a source of danger for all those around him...".

Of course, there has to be a belief in "magic". This symbolic power implies a macabre ballet of three: the sorcerer, the victim and the group, all must share the same belief, the same trust and the same requirement. The fundamental problem is the relationship of a certain type of individual that we might qualify as easily influenced by certain requirements and beliefs of the group (cancer is an inexorably deadly and horrible disease that threatens and terrorizes us all).

Announcement consultation or "the pink bone".

The passive patient-victim and the active doctor-shaman then engage in this macabre dance orchestrated by the health care system around the panic fear of cancer: the doctor must at all costs fight this modern-day plague that threatens the entire community. His feverishness in making appointments for further tests and treatments reinforces the idea of imminent death. Some patients are convinced that they are already, in a way, banished from the world of the living. Society as a whole is threatened by cancer (how else to explain this collective obsession to "fight against cancer"?) and each new diagnosis is threatened with expulsion from the social body (work, family, insurance, bank...). Her stress is such that some of them can lose control of their lives, all choice. Their metabolic, psychophysiological and even vital functions are in danger. The victim succumbs without having been able to fight or flee: they die of a heart attack if their constitution allows it, otherwise they commit suicide under the effect of the dramatic collapse of their neurotransmitter balance.

The obsession with breast cancer screening, with its lot of over-diagnoses, stems from this hysterized macabre dance, linking women, doctors and the social body: terrified at the idea of being socially banished, how many pre-cancerous or cancerous women have already been victims of this disastrous fate by the collapse of their vital defenses? Nobody knows it and nobody wants to know it, the important thing is to fight cancer at all costs, isn't it? Without going as far as to the death, the announcement of the presence of a cancerous tumor can trigger in some women the collapse of their psycho-neuro-immunological defenses, making even more difficult the medical fight to be carried out during heavy treatments sometimes engaged in excess (surgery, radio- and chemotherapy) and accepted because they seem to be the price to pay to continue to keep its place among the living.

The society tries to exonerate itself and save face by multiplying "empathic" campaigns aiming to give "tips and tricks" on how to "live well with cancer while remaining feminine and keeping one's morale, energy and smile", but some victims, once they have received the ACR4 mark, are not as fortunate as others to have a mind of steel when faced with the symbolic effectiveness of the pink bone.

Bibliography

Cannon W.C., Voodoo death, American anthropologist, 1942, 44(2), 169-181.

Gaudard P.Y.,  Suggestion of the idea of death in Marcel Mauss, acute fatal catatonia, phobia and symbolic modalities, Journal français de psychiatrie, 2010/4 (n°39)

Marcel Mauss, Definition of the collective suggestion of the idea of death. In Sociology and Anthropology, 313-320

Suicide and Cardiovascular Death after a Cancer Diagnosis, Fang Fang et al, N Engl J Med 2012;366:1310-8.

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.

Cost of extending the NHS breast screening age range in England

10 April 2019

https://www.bmj.com/content/365/bmj.l1293.full

https://www.healthwatch-uk.org/projects/breast-cancer-screening-age-extension/122-age-extension-trial-of-mammography-screening-part-5-april-2019.html

Susan Bewley emeritus professor of obstetrics and women’s health, Mitzi Blennerhassett medical writer , Mandy Payne freelance editor  [i]

Context and concerns

AgeX is the acronym for the UK government inspired and funded, cluster randomised controlled trial of extending the NHS breast cancer screening age range in England. The trial aims to assess the risks and benefits of extending mammography screening for breast cancer outside the current 50-70 year age range by offering one extra mammogram to women between the ages of 47 and 49 and up to three to those over 70. Announced as “likely to be the largest randomised controlled trial ever undertaken in the world,”during 2010-16 AgeX randomised three million women into the extended age groups and screened one million. Concerns have been raised by Susan Bewley of the Health Watch observer group over the adequacy of the benefit-risk information provided to the women included in the study. According to Health Watch observers, there is a risk of harm through overtreatment by surgery and other risks to participants. Women learn of their inclusion in research through a letter with a screening appointment that has already been scheduled. There is a possible surgical over-treatment risk for women aged 47-49 years, and the authors question whether continued breast cancer screening is still appropriate, as the accumulation of evidence challenges its assumed benefits.

Breast screening policy and controversy in the UK

Mammography screening aims to find breast cancer before a lump is palpable, giving the opportunity to start treatment earlier. The current UK screening programme, started in 1988, offers triennial mammography to all women aged 50-70. Of the 2.85 million women invited in 2015-16, 75% attended. In common with programmes worldwide, the screening age range was defined based on evidence of when mammography is most effective at detecting tumours in the breast.

The programme has been estimated to prevent 1300 deaths from breast cancer each year. But evidence suggests improvements in breast cancer survival rate since the introduction of mass screening probably result from concurrent improvements in the adjuvant hormonal and chemotherapy used to treat breast cancer.

There is also evidence that screening does not reduce number of tumours reaching late stage and that it results in substantial overdiagnosis, with consequent radiotherapy, lumpectomies, and mastectomies.

Age extension trial in the UK (XAge Trial)

In 2007 the Labour government’s cancer reform strategy recognised late diagnosis as a factor contributing to poor cancer survival rates in the UK. The government’s proposals included extending the age range for breast cancer screening. By 2012, it promised, women would receive nine screens between the ages of 47 and 73, with a guaranteed first mammogram before age 50. Limited capacity forced a decision to phase in the proposed extension. According to the organisers, randomising would, “provide a unique opportunity to obtain unbiased evidence on the net effects of the new policy,” although the extension would “proceed regardless of whether the study goes ahead or not” . The Nationwide Randomised Trial of Extending the NHS Breast Screening Age Range was started by Public Health England [ii]  in June 2009 with an original expected participation of 1.1 million women over 13 years. The cluster design randomises batches of 1000 screening invitations normally sent to women aged 50-70 to be extended to comprise those aged either 47-70 or 50-73. Half of all women aged 47-49 and half of all women aged 71-73 are invited to screening, while all women aged 50-70 are invited to screening as usual. The trial compares breast cancer incidence and mortality between screened and unscreened participants in the studied population. In 2016, the Age Extension trial was renamed as AgeX. The recruitment target was raised to “at least six million.”

Shaky foundation

It is laudable to test government policy before it is rolled out. But the design of this trial does not meet standards for generating evidence that would be robust enough to inform future policy. It is good practice for scientific experiments to be preceded by a systematic review of the evidence to avoid wasteful research and repeating unnecessary harms.

Emerging concerns about the lack of efficacy and potential harms of screening were mentioned briefly as “so-called overdiagnosis” in AgeX’s seven page original trial protocol.The trial’s sponsor (University of Oxford), when asked whether the protocol had been subjected to independent scientific peer review, told authors only that it had been reviewed by the Department of Health advisory committee on breast cancer screening.

Results

AgeX’s primary outcome measure is death from breast cancer. Total cancer deaths are not recorded, and overall mortality was added in 2016 as a subsidiary outcome but will not be included in the primary analysis. Measuring breast cancer mortality alone excludes deaths resulting from side effects of treatment or cancers caused by mammography. This is relevant as suitably randomised trials of breast cancer screening find no effect on total cancer mortality.

Potential for bias

Estimates of breast cancer mortality in screening are particularly vulnerable to bias because large numbers need to be screened to see the small effect and there is a long lead time for outcomes to become evident. Bias in suboptimally randomised trials of breast cancer screening may have resulted in benefit being overestimated.

During the past decade, AgeX increased its planned duration and sample size, study outcomes were changed, and a proposal for statistical analysis was retrospectively appended.These factors, coupled with the protocol’s stated plan to continue the trial beyond a “fixed, predetermined sample size” until “clear answers emerge” all increase the likelihood of a biased assessment. (Editor’s note : Protocols are normally never changed afterwards).

Lack of explicit, fully informed consent

According to good clinical practice, trial participants must be told that they are in a trial and given details of all known benefits and harms in language they can understand.

When the age extension trial was first conceived, screening was already known to be associated with harms, but these were not believed to outweigh the benefits of early detection. Harms range from false positive results with associated psychological distress to overdiagnosis—with abnormalities that would not have harmed the woman in her lifetime being found, leading to potentially dangerous, painful, and disfiguring treatment.

Early AgeX trial documentation refers to “so-called overdiagnosis”. But the team’s assumption that overdiagnosis was unimportant was challenged in 2012 when the Independent UK Panel on Breast Cancer Screening, chaired by Michael Marmot [iii],, published a detailed review of the evidence. The report recognised and quantified overdiagnosis—for every breast cancer death averted, three “cancers” that would never have troubled women during their lifetimes would be found and treated.

The physical and psychological harms resulting from such treatment are substantial. Yet in 2016, when AgeX’s recruitment target was raised to six million, this increase—with corresponding potential for harm—was not referred to or justified in an accompanying application for ethics approval.

With Marmot’s publication, the confirmation that predicted benefits were accompanied by appreciable and quantifiable risks to participants should have triggered a reflective review of the research question and study design.

Crucially, this should have included whether participants should now be given full risk-benefit information and the opportunity for explicit, fully informed consent.

In AgeX, an early decision had been taken to forgo such consent. The original protocol said, “100% coverage is essential for the scientific validity of the study, and excluding participants for whom we cannot get consent could seriously bias the results ... consent is implied for those who attend for screening.”

Women in the invited clusters learn of their inclusion through a letter with a prebooked screening appointment, general mammography advisory notes with the sign-off, “Remember ... screening saves lives,” a brief leaflet describing the trial (but not the potential risks of participation), and the standard pink breast cancer screening booklet  written for women aged 50-70.  The trial participation leaflet was expanded in 2014 from one to four pages but description of risks is limited to »being asked to return for more tests.

Trial participants’ understanding that they are voluntary participants in research rather than routine NHS screening, and at risk of unnecessary surgery and other harms, is never explicitly checked.

Cluster randomised trials can be run without seeking individual participants’ explicit, fully informed consent. As participants are randomised in large groups to invitation batches for a local breast screening unit, obtaining prior consent from individuals in the cluster is normally unfeasible. International guidance on the conduct of such cluster randomised trials states that the requirement for consent may be waived when the study intervention(s) poses no more than minimal risk.

Authors believe that the level of risk to participants in AgeX necessitates a trial design that enables fully informed consent.

The public overestimates the benefits and has a poor sense of the harms of screening tests in genera so researchers have a responsibility to dispel misconceptions. Physicians themselves often do not fully understand the benefit:harm ratios and consequently are poorly equipped to counsel their patients.

Well designed decision aids could support doctors and their patients, but AgeX does not refer to any. Members of HealthWatch formulated a complaint to AgeX’s principal investigator about the paucity of participant information, which  was rebutted by saying the approach had been approved by ethics committee. A similar complaint to the ethics committee was in turn responded to by deferring to the principal investigator’s assurances.

Effects of extending age range

Information about the balance of risks and harms may be particularly relevant for women over 70. The risk of developing breast cancer increases with age. In 2014 a prospective nationwide population based study of breast cancer screening in women aged 69-75 in the Netherlands reported a steep rise in the numbers of “early” cancers in the screened group, without significantly reducing numbers of advanced cancer cases. Effectively, screening was leading to many more older women “living with cancer,” with little effect on actual deaths from breast cancer. [iv]

Although such observational evidence may not be as powerful as that from a randomised trial, a study of this size should have flashed a warning light. Instead, in 2016 AgeX was amended to further extend the programme for older women, who would now be invited triennially at ages 71-76, or 71-79 subject to funding. Older women are less able to tolerate surgery than younger women because of increased likelihood of comorbidities, so overdiagnosis and overtreatment have a greater effect on their quality of life and physical function. This information should be made available to women considering screening.

We cannot yet know the full effects—good and bad—of extending the age range for breast cancer screening, but a study from Devon, southwest England, sheds light on one aspect: the numbers of extra surgical procedures in the younger women screened.

In Devon, all women aged 47-49 are invited to screening because Inhealth, the region’s breast cancer screening provider, is not permitted to take part in clinical trials. The results from the first year show that 4250 (76%) of the 5624 invited women in this age group were screened, resulting in 125 surgical outpatient consultations and 53 operations. This gives an indication of the short term extra surgical workload from screening women under 50, although as the study authors point out, estimating the longer term surgical and financial effect is more complex.

Women participating in the AgeX trial must be given the opportunity to balance the possibility of lesions being detected earlier (with more opportunity for breast conserving surgery) against real risks of harm. Extrapolating the Devon figures to all women in England screened before age 50 over the duration of AgeX, we estimate that several thousand women would need surgery. Given what we know about overdiagnosis in breast cancer screening from sources such as the Independent UK Panel on Breast Cancer screening , we know that a substantial proportion of this surgery will be unnecessary. The full financial and human costs of AgeX will also include extra general practitioner visits and physical and psychological harms from diagnoses of cancer that otherwise would not have caused problems during the women’s lifetime. The trauma of living with cancer can be lifelong, including lasting effects of surgery or other treatments, fear of recurrence, and loss of self esteem and body confidence. Research shows that when women are fully informed of the risks and benefits of regular screening, fewer opt to be screened.

Despite pressures on NHS budgets, AgeX increases the workload for the already stretched NHS breast screening programme by 14%. The resultingextra treatment also creates a considerable burden on the NHS.

Author’s conclusion

The balance of benefits and harms from breast cancer screening remains contested. Three years after AgeX began, an architect of the NHS breast cancer screening programmes (Pr Michaël Baum) argued that deaths after treatment of screen diagnosed breast cancer may exceed those from breast cancer in an unscreened population (https://www.bmj.com/content/346/bmj.f385).

In 2014, the Swiss medical board advised its government to stop recommending mammography screening.

 In 2016 an open letter from French scientists [v] who had conducted a consultation into France’s breast cancer screening for their ministry for health called for a halt to breast cancer screening for low risk women under 50, and an end or thorough review of the programme for women over 50.

People must be given sufficient information to decide whether they wish to participate in research, particularly when the risks are unclear. We recommend the National Screening Committee uses high quality fact boxes and icon arrays20 to support patient consent in AgeX and all screening programmes. We call on the investigators and verifiers of any data resulting from AgeX to use all-cause death as the primary outcome. An independent inquiry into the scientific quality, governance arrangements, and ethical issues arising from the trial would inform future high standards for the design and conduct of government run trials.

On the Health Watch website

Observers, including Susan Bewley, say :

Thousands of unnecessary mastectomies could be the result of encouraging women to participate in the government's AgeX study. 

The study, announced as "the largest randomized controlled trial in history," has already invited more than a million women to undergo breast cancer mammography screening without first making sure they are aware that the test could do them as much harm as good.

https://www.healthwatch-uk.org/news.html

Comment by Cancer Rose:

Even if the design of trials is based on randomized groups, women should be informed through flyers, posters, press, radio, television, social networks, etc. In this era of communication, there is no reason why women's right of access to information should be limited by so-called scientific necessities. Indeed, a lack of transparency and information given to the public is quite often linked to bad science.

The same could be said of the MyPeBS trial [vi]: the problems are similar, in the low-risk screening group, mammograms will start at age 40, instead of age 45 or 50 in the usual screening group. Women at moderate risk will have more mammograms than women in the usual screening group. Some women over 50 will have fewer mammograms and some will have more.

Financial costs will be increased and, more importantly, there is an increased risk of over-detection for women. For which scientific result? We already know the result. The design of this non-inferiority trial, with a 25% threshold, means that if the new screening results in 25% more advanced breast cancers, the new screening will nevertheless be considered "not inferior" to the usual screening. Even if the new screening has no effect at all on the incidence of advanced breast cancer and mortality, it will be considered equivalent to the usual screening.

Is it a simple coincidence that in MyPeBS, as in AgeX, information to participants is minimal? In the MyPEBS leaflet given to women, over-diagnosis is greatly minimized and over-treatment, a tangible consequence for women, is not mentioned at all.

Bad information given to patients is also, in the Mypebs trial, related to bad science.

OUR RAPID RESPONSE BMJ

"Rapid response" published in the BMJ

To download below, BMJ2019-364-I1293

References

[i] https://www.healthwatch-uk.org/


[ii]  an executive agency of the U.K. Department of Health and Social Affairs, resulting from the reorganization of the National Health Service (NHS) in England, assuming the role of a health protection agency

[iii] Independent UK Panel on Breast Cancer Screening. The benefits and harms of breast cancer screening: an independent review. Lancet 2012;380:1778-86. 10.1016/S0140-6736(12)61611-0 23117178

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3693450/

[iv] https://www.bmj.com/content/349/bmj.g5410

See also our article : https://www.cancer-rose.fr/la-campagne-pour-le-depistage-de-la-femme-agee-par-le-college-national-des-gynecologues-et-obstetriciens-de-france-cngof/

[v] Organized screening of breast cancers by mammography: to evolve. Letter to the Minister of Health. Prescrire 2016 Oct 14.

http://www.prescrire.org/fr/3/31/52235/0/NewsDetails.aspx

[vi] http://mypebs.cancer-rose.fr/

The issues of My PEBS, for our english speaking readers

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.

Manipulation of information provided to women on breast cancer cancer screening by mammography is a topic of interest for research studies

Marc Gourmelon, MD

Cécile Bour, MD

September 2, 2020

At the beginning of July 2020, a research article detailing how to successfully manipulate women in order to increase their participation in breast cancer screening programs by mammography,  was published under the title: 

The Good Outcome of Bad News.
A Field Experiment on Formatting Breast Cancer Screening Invitation Letters [1]. 

This article is published  by Italian authors in a journal which defines itself as follows: 

“The American Journal of Health Economics (AJHE) provides a forum for the in-depth analysis of health care markets and individual health behaviors. The articles appearing in AJHE are authored by scholars from universities, private research organizations, government, and industry. Subjects of interest include competition among private insurers, hospitals, and physicians; impacts of public insurance programs; pharmaceutical innovation and regulation; medical device supply; the rise of obesity and its consequences; the influence and growth of aging populations; and much more. The journal is published for the American Society of Health Economists (ASHEcon), which is a professional, non-profit organization dedicated to promoting excellence in health economics research in the United States. All ASHEcon members receive the journal as part of membership.”[2]

This article is not a scientific medical analysis about the relevance of screening by mammography  for women, but a health economics study, from the point of view of health economics carried out by economists. Screening is an integral part of the "health care market" and women behavior is evaluated, based on the manipulation of the information provided to them.

“We show that giving enhanced loss-framed information about the risks of not having a mammography increases the take-up. This manipulation is most effective among sub-groups with lower baseline take-ups, thereby reducing inequalities in screening.”

OBJECTIVE AND STUDY METHODOLOGY

The goal of this study is to evaluate the impact of the interplay between the "frame” of the invitation letter and the "level" of the information disclosed in it, on the rate of participation in the national breast cancer screening program.

There are four "manipulations" being evaluated, depending on the frame and the level of information. The frame of information refers in this case on how to deliver an information in the form of "gains" from being screened, or rather in the form of a grid of "losses" from not being screened.

The level refers to the quality and completeness of the information.

-The "benefit" of the screening procedure is valued by a high quality information 

-The "benefit" of the screening procedure is valued by a basic information

-The emphasis is placed  on the "loss" of not being screened by using a high quality of information

-The emphasis is placed on the "loss" of not being screened by using basic information.

“To the best of our knowledge, this is the first experimental study assessing how the interplay between the frame of the invitation letter and the information disclosed in it influences the take-up rates for a national breast cancer screening program” explained the authors.

MAIN RESULT

“Results show that the take-up rate in the group that received the letter combining the loss frame with enhanced information on the negative consequences of not taking the mammography is about 2.5 percentage points higher than in the baseline group.”

 According to the authors, “this is a sizeable effect”.

The authors congratulate themselves on these findings showing that that this manipulation “helps to decrease inequalities in screening”,   as it allows for a greater manipulative impact for subjects that, according to them, are “with low average education, with no recent screening experience, and for whom the available observable characteristics would lead us to predict a low likelihood of screening in the absence of any manipulation”.

IDENTIFIED ISSUES

A- THE ETHICAL ISSUE

 It seems to us the major one.

First of all, the aim to increase womens participation, at all costs, is clearly stated. Thus, these researchers claim that « the use of letters sent to women at their houses and the invitation for a free and pre-booked mammography increase take-up rates for breast cancer screening »

« In this respect, the present study aims ...at providing insights on how to design effective invitation letters to promote cancer screening activities. »

The intentions are clearly stated. The authors are well aware that providing the most complete information to women incited to be screened, will reduce their participation in screening:

« Previous studies have analyzed the impact of providing a rich amount of detailed medical information concerning the disease (for instance, as in Bourmaud et al. 2016 and Wardle et al. 2016, by including a booklet in the envelope of the invitation letter) on the take-up rate and generally found negative or zero effect ».

They hypothesize that  « ...invitation letters containing a loss-framed message (meaning « loss »to the woman or even risk if she declines to participate in screening, editor’s note) with enhanced information about the consequences of not taking part in the program are more effective at increasing take-up rates than letters with a gain-framed content or with a restricted informational content ».

Thus, this is about pure and simple manipulation, perfectly claimed since the term itself is used several times in the text, and the authors justify this manipulation as necessary for  « limiting women’s cognitive overload »

We wonder about the authors representation of women.

Cognitive overload is defined as follows: "Cognitive overload corresponds to a mental state in which an individual is engaged in the accomplishment of a task that is extremely demanding for him: he does not have sufficient cognitive resources for the easy implementation of this task. » [3]

If we understand correctly the authors, women would not have the mental state necessary to understand the comprehensive information on breast cancer screening. Isn't this a sexist and paternalistic attitude?

In any case, this runs contrary to the "shared medical decision"  that many medical actors claim.…

B- VALUATION OF THE SCREENING AND NEGATION OF ITS RISKS

Right from the introduction, despite the scientific uncertainty about the interest of screening, which has risen since the 2000s, the doubt about the relevance of breast cancer screening by mammography is swept away.

« Mammography screening programs at population-level are a key component of breast cancer control in many countries. The continuous implementation of these policies over the last decades mirrors the current consensus on the effectiveness of mammography screening. »

The authors are, however, forced to admit that there is « uncertainty about the magnitude of the effects of screening on mortality (see e.g. Welch et al. 2016) and the growing evidence on overdiagnosis » by citing a 2012 study and hurrying to downplay the level of overdiagnosis, which is the major adverse effect.

« However, to the best of our knowledge, the estimated extent of overdiagnosis in Italy is low, as it ranges between 1 and 4.6 percent (see the review by Puliti et al. 2012). These data lead us to consider the phenomenon as negligible for our population of interest ».

The authors deliberately disregard the numerous and more recent studies [4] which no longer demonstrate effectiveness of screening in reducing mortality in women, in reducing the rate of the most severe cancers, or to alleviating the treatment inflicted to them.

In addition to the lack of benefit, multiple adverse effects of screening, such as false alarms leading to over-medicalization of women and over-diagnosis, currently estimated at between 30% and 50% and indicating that one out of three cancers detected or even one out of two cancers detected is an unnecessary detection,  should not be ignored[5][6].

In this respect, here is a link to a recent additional study that we already discussed: this research (a review of cross-sectional studies) showed that mammographic screening did not reduce the stage of cancer, nor did it enable cancers to downgrade from the elevated stage to the early stage cancers. The results strongly suggest that it is the adjuvant therapy and not mammographic screening associated with the decrease in specific breast cancer mortality reported since the initiation of these therapies (1990s).

C –CYNISM AND CONFISCATED INFORMATION


Consequently, under no circumstances should women be properly informed or should the risks of participating in the screening be addressed, as the authors have demonstrated. Otherwise, this would decrease the participation in screening, as these Italian authors have well understood,  on the basis of a French study.

« Bourmaud et al. (2016) assessed the effect of providing a 12-page information leaflet on the take-up rate for breast cancer screening of a randomly selected sample of French women. They found a significant negative effect on the take-up rate. »
Later in the text, the authors intentionally skip over the details on disclosed information: « our baseline invitation letter contains no information on the consequences of screening ». And they add: « We show that a negatively-framed message, which adds “cheap” information in the form of brief and general statements about the consequences of screening to the original invitation letter, is able to enhance take-ups ».

In their conclusion, the Italian authors reach what seems to us to be the very height of cynicism by stating: « In addition, the effect of our proposed manipulation is stronger for subjects identified by the literature as being at higher risk of non-participation, such as those living farther away from the screening sites, the low educated and those with no recent screening experience. »

As a result, the less educated women are, the more effective it is to hide and manipulate information for them.

THE FRENCH PARALLEL

A– INVOLVEMENT OF MEDICAL DOCTORS

The potential influential role of the medical profession is not forgotten: « endorsement of the screening program by general practitioners on the invitation letter increased the overall take-up rate, while a letter of reminder was especially effective at increasing the take-up rate of subjects residing in socio-economically deprived areas »

The promoters of screening in France are also well aware of this, having included the "screening mammography" item in the performance-based remuneration of general practitioners [8].

B – THE LACK OF INFORMATION PROVIDED BY OFFICIAL BODIES

The authors of this Italian study state that « the use of letters sent to women at their houses and the invitation for a free and pre-booked mammography increase take-up rates for breast cancer screening »

It should be noted that this is exactly what is being done in France with the organized breast cancer screening program. The citizens' consultation clearly defined the unacceptable gaps in the information provided to women, and in France we are not outdone to regard patients as unworthy to receive quality medical information due to them[9]. In addition, we examined the lack of this information in the material provided by the INCa[10][11].

IN CONCLUSION

-Denial of the risks of mammography screening for breast cancer.

-Assertion against a large majority of clinical research on the effectiveness of screening.

-The manipulation of the letter of invitation to the screening.

-Sexism and paternalism.

This economic study published in July 2020 by Italian authors, with references to other similar studies, including French ones, leaves us with a deeply bitter taste,  on ethics, on the women representation in academic community or on the promotors behavior  of breast cancer screening through mammography.

It should be noted that the majority of those involved in screening justify the assumed manipulation of women for the sole purpose of raising their involvement in the public health system, which has not only failed to prove effective but is also harmful to women's health.

Références


[1]                              https://www.journals.uchicago.edu/doi/10.1086/708930

[2]                          https://www.journals.uchicago.edu/journals/ajhe/about

[3]                              https://www.universalis.fr/encyclopedie/surcharge-cognitive/

[4]                              https://cancer-rose.fr/category/etudes/

[5]                                 https://cancer-rose.fr/2019/09/06/le-depistage-mammographique-un-enjeu-majeur-en-medecine/

[6]                                 https://cancer-rose.fr/2020/01/28/30-000-cancers-surdiagnostiques-par-an-dans-une-etude-australienne-un-enjeu-de-sante-publique/

[7]                              https://www.oncotarget.com/article/7332/text/

[8]                               https://cancer-rose.fr/2020/04/20/la-nouvelle-rosp-quel-changement-pour-le-medecin-concernant-le-depistage-du-cancer-du-sein/

[9]                                 https://cancer-rose.fr/2016/12/15/nouvelles-du-front-premiere-manche/

[10]                               https://cancer-rose.fr/2017/09/17/analyse-critique-du-nouveau-livret-dinformation-de-linca/

[11]                               https://cancer-rose.fr/2018/02/11/2175-2/

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.

LETTER of 4 Collectives on the subject of MyPEBS study

What is the MyPEBS study?

https://cancer-rose.fr/my-pebs/wp-content/uploads/2019/12/MyPEBS-Protocol-.V1.2-du-27.07.18-.pdf


MyPeBS is a clinical trial which compares the incidence of advanced breast cancers in a group of women subjected to breast cancer risk-based screening tests and in a control group undergoing current standard planned screening tests.Stratified screening on risk factors is an interesting project in itself, and carrying out a clinical study can only be favorable in order to confirm whether it is or not.


This study, however, would have to be carried out with appropriate methodology, which appears not to be the case of MyPeBS.


1st point: the choice of using standard screening as a control arm is contestable.

Three options can be considered for future screening programs: changing to stratified screening tests, continuing current standard screening tests, or discontinuing all screening tests. Comparing the stratified screening arm to a current standard control arm could hopefully provide the answer to the question: is stratified screening more efficient or less efficient than standard screening? The answer to this question would only enable to make a choice between changing to a risk based strategy and continuing with the standard screening strategy. It will not provide any additional information to enable to make a choice between screening; stratified or standard, and no screening.
It is all the more regrettable that planned screening does not seem as adequate in 2018 as when it became the standard strategy. In terms of benefits, the 20% relevant mortality risk reduction is based on old studies and has not been found in recent studies. In terms of risks, overdiagnosis has possibly been underestimated, as recent studies have evaluated it nearer to 40% than to 10% as initially forecast. It should not be forgotten that overdiagnosis = unnecessary treatment, side effects - sometimes serious- with no benefits in return.
MyPeBS therefore represents a missed opportunity: the opportunity to provide the answer, with current data, to the question: should planned screening tests be discontinued, be continued or be changed to risk-based? To achieve this, including 3 arms in the study: one risk-based screening arm, one standard screening arm, and one with no screening would have been sufficient.
Of course this would mean accepting to reconsider the importance of screening if the study did not demonstrate superiority of screening compared to no screening. The sponsors of MyPeBS do not appear to be ready to call into the possible question.


2nd point: a lax approach as to non-inferiority.


The main objective of MyPeBS is to demonstrate non-inferiority of risk-based screening, as compared to standard screening. Contrary to what one might believe, A non-inferior to B does not mean that A is at least as performant as B. A non-inferior to B, means in effect that A can be inferior to B but that this inferiority does not exceed a certain threshold.`
In the case of MyPeBS, this threshold of non-inferiority is set, arbitrarily, to -25%. In other words, it is easy to think that at the end of the study, risk-based screening is certainly less performant than standard screening with, for example, performance loss somewhere between -5 and -20%; however, as the performance loss does not reach -25%, non-inferiority is confirmed, when in fact at best, the loss is of -5%, and at worst, this performance loss could reach -20%. Supposing your employer were to inform you that your salary scale was going to be revised downwards or upwards. Would you be truly reassured if your boss specified that in any case, if your salary were to decrease, this decrease would not be inferior to -25% ?And would you consider that a decrease of -25% of your income is insignificant? Well, this is exactly what MyPeBS puts forward. Simply replace “employer” by “study protocol” and “salary” by “screening efficiency”.


3rd point: deceitful information.

In the information leaflet, large-scale studies which showed that screening had reduced the mortality rate of breast cancer by around 20% are mentioned in the part of the text “Advantages and disadvantages of standard breast cancer screening”. Indication that those studies are old and probably obsolete or that a significant decrease of mortality by screening has not been found in recent studies [1,2] has been carefully omitted.
Concerning overdiagnosis, the leaflet merely mentions 10%, failing to specify that the frequency of overdiagnosis is not well known, with rates of up to 50% in some studies [3,4]. Furthermore, there is no mention of overtreatment that occurs with overdiagnosis. Nevertheless, they are indeed unnecessary treatments, with multiple side effects, which represent the major risks of screening tests.
Present scientific uncertainties make the presentation of benefits and harms of screening difficult. However, no information should be withheld, or for the purpose of clarity, should only convenient statistics be presented and others overlooked.
Studying the interest of stratified screening on risk factors might seem useful, but not haphazardly and certainly not with the main intention of promoting mammography screening one way or the other. This intention is clearly mentioned in Dr Balleyguer’s statement, page 14 in the press folder MyPeBS, 28 September 2018: "MyPeBS will probably encourage more women to enter national screening programs. Today, barely one out of two are taking part” [5 ].

READ MORE :
https://cancer-rose.fr/my-pebs/2019/08/02/mypebs-clinical-trial-failed-before-starting-2/

In response to these concerns

In response to these concerns, 4 European collectives, militating for independence in health, published an open letter, here is the English version:
https://cancer-rose.fr/my-pebs/wp-content/uploads/2020/02/LETTRE-COMMUNE-ANGLAIS.pdf

This letter was picked up by the press and mentioned in an article of the BMJ.

Press feedbacks


Article JIM
Article Quotidien du Médecin du 12 mars 2020 (french)
Article BMJ


Extract from article BMJ


The groups criticise the trial for assuming that breast screening is beneficial and for failing to compare stratified screening with a “no screening” group.
“MyPeBS represents a missed opportunity to provide the answer, with current data, to the question: should planned screening tests be continued, be changed to risk based screening, or stopped?” they wrote.
They also raise concerns about the trial’s “lax approach to non-inferiority” and point out that the two groups will be statistically compared with a threshold of “non-inferiority” arbitrarily set at 25%.
They go on to explain, “This comparison is obscure and conceals disconcerting information. According to the sponsors of MyPeBS, in the standard screening group, 480 new cases of severe tumours per 100 000 women are expected to be diagnosed. If the same rate does not exceed 600 per 100 000 women in the new personalised risk based group, both groups
will be declared equivalent. This means that if the rate of serious cancers is increased by less than 25% (for example 18% or 24%), then the study will be considered a success and the researchers conclude that the new screening methods are ‘as efficient’ as the former ones. In other words, +25% of serious cancers equals zero.”
Karsten Juhl Jørgensen, acting director of the Nordic Cochrane Centre and an author of the Cochrane review on breast screening, said that screening trial data were old, women below the screening age had experienced far greater reductions in breast cancer mortality than those invited, and new treatments have a far more important role than screening.
Jørgensen told The BMJ, “We desperately need a new trial of screening that can inform us about its role today. Whether personal screening strategies can optimise benefits and reduce harms is an important and relevant question. But screening trials need to be done extremely well to be informative, part of which means not relying on surrogate outcomes such as stage at detection, which we know can be misleading. The design of the new trial seems to raise more ethical questions than it answers.”

Ref.

  1. Autier P., Boniol M., Koechlin A., Pizot C, Boniol M. (2017), Effectiveness of and overdiagnosis from mammography screening in the Netherlands: population based study. BMJ 2017;359:j5224 (https://www.bmj.com/content/359/bmj.j5224)
  2. Møller M.H., Lousdal M.L., Kristiansen I.S., Støvring H. (2018), Effect of organized mammography screening on breast cancer mortality: A population-based cohort study in Norway. Int J Cancer. (https://europepmc.org/article/med/30144028
  3. Junod B., Zahl P.-H., Kaplan R.M., Olsen J., Greenland S. (2011), An investigation of the apparent breast cancer epidemic in France: screening and incidence trends in birth cohorts. BMC Cancer. 2011 Sep 21,11(1):401.(https://bmccancer.biomedcentral.com/articles/10.1186/1471-2407-11-401)
  4. Welch H.G., M.P.H., Prorok P.C., O’Malley A.J., Kramer B.S. (2016), Breast-Cancer Tumor Size, Overdiagnosis, and Mammography Screening Effectiveness. N Engl J Med 2016; 375:1438-1447. (https://www.nejm.org/doi/full/10.1056/NEJMoa1600249)
  5. http://www.unicancer.fr/sites/default/files/MyPeBS-DP.pdf

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 largest clinical trial in Great Britain on breast cancer screening was halted

https://www.bmj.com/content/370/bmj.m3337.full

Summary by C. Bour, MD

27 August 2020

A major UK breast cancer screening trial called AgeX [1], was halted, more exactly inclusion and randomization of new participants will not resume.
Age X is the acronym of the trial founded by British Gouvernment: it is a controlled randomized trial set up to expand the age bracket determined by NHS (National Health Service) for the breast cancer screening in UK.

The trial investigates the incidence and mortality from breast cancer in different groups and aims to evaluate the risks and benefits of expanding mammography screening for breast cancer beyond the current age range of 50 to 70 years by providing an additional mammogram to women aged 47 to 49 and up to 73 years of age. Announced as "probably the largest randomized controlled randomized trial ever performed in the world," AgeX has randomized 4.4 million women to date in the expanded age groups.
Normally, the goal was to recruit a total of 6 million women in the trial in order to ensure statistical significance and draw conclusions.

This trial had generated a strong scientific controversy on both methodological and ethical arguments when it was set up in 2009, as the women included in the trial were unaware that they were part of it.

The contesting was brilliantly led by the HealthWatch UK site under the chairmanship of Professor Susan Bewley, but also by medical author Mitzi Blennerhassett and independent scientific editor Mandy Payne.[2] [3]

Here we have summarized the entire issue [4], the authors pointing first and foremost to the omission of the informed consent of participating women.

They also denounced the fact that screening does not demonstrate sufficient evidence of effectiveness, but instead, it can be harmful for women who are not fully aware of all these risks, and that the number of mastectomies could increase with the inclusion of more women, which were also uninformed.

Finally, to make sure of the informed consent of women in the AgeX trial as well as in all screening programs, Susan Bewley, Mandy Payne and Mitzi Blennerhassett requested the National Screening Committee to use high-quality text boxes and charts with visual pictograms.
They asked investigators and auditors of all data resulted from AgeX trial, to use the rate of death for “all-cause” as main result. Then finally, they called for an independent investigation of the scientific quality, governance mechanisms and ethical issues arising from this trial in order to identify future high quality standards for the design and execution of future government-sponsored trials.

Discontinuation of the trial

The trial was halted alongside other screening services to allow the NHS to cope with covid-19 [5].
The researchers have announced that randomization will not resume.
However, they said that follow-up by electronic linkage to routine government records will continue “throughout the 2020s and beyond.”
The AgeX website [1] now says, “Following the suspension of routine breast screening throughout the UK in March 2020 due to COVID, and the substantial and prolonged overload on breast screening services to be expected when screening restarts, the AgeX investigators decided in May 2020 that further randomisation into AgeX should cease permanently.”
The trial’s team said : “Although the intent had been to continue until about 6 million had been recruited, 4.4 million will, with sufficiently long-term follow-up, suffice”

The contesting continues, an inquiry is requested

Commenting on the trial, M.Blennerhassett said, “Having sat on a local research ethics committee, I was shocked that this trial had been approved. When I raised concerns my questions were not answered. I was simply referred to the NHS Breast Screening Programme website which, at that time, had no information regarding the trial.”
Susan Bewley told The BMJ, “Although covid will be credited with ending AgeX, this trial would not have stopped prematurely with no fanfare were it actually answering a necessary research question that had been through proper channels of peer review and funding.
“This largest randomised controlled trial in history has been criticised for having no statistical plan or oversight at onset, and repeatedly changing protocol, numbers, and endpoints. Four million women have already taken part in this unethical human experiment, without having had their understanding checked and giving their explicit informed consent.”
Susan Bewley has called for an independent inquiry “to learn the lessons of this government funded research, sponsored by the University of Oxford, and approved by the Human Research Authority that rode roughshod over women’s rights for a decade … We need to ask the question: who approved this, and how much did it cost?”

Références

[1] http://www.agex.uk/
[2] https://www.healthwatch-uk.org/projects/breast-cancer-screening-age-extension/122-age-extension-trial-of-mammography-screening-part-5-april-2019.html
[3] Bewley S, Blennerhassett M, Payne M. Cost of extending the NHS breast screening age range in England. BMJ 2019;365:l1293. doi: 10.1136/bmj.l1293 pmid: 30971394
[4] https://cancer-rose.fr/2019/04/10/3924-2/
[5] National Health Service

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.

Absence of benefit from mammograms in women aged 40-50 years confirmed by final results of UK Age Trial

Cancer Rose, 16 August 2020


In August 2020, the final results of the UK Age Trial [I] were published.

For women aged 40-49 years


Between 1990 and 1997, this British trial included approximately 161,000 women aged 39 to 41.Women were randomly selected and an annual mammography up to the age of 48 was proposed for about one in three (53,883 women), while the remainder had no screening. All the women then joined the standard British screening program, which includes a mammogram between the ages of 50 and 69 every three years. The main aim of the trial was to determine whether screening could reduce mortality from breast cancer before the first mammogram of standard screening program, which starts after the age of 50.

Prior to these results, no evidence of a benefit


After 10 years, the UK Age Trial results showed a statistically significant decrease in the number of breast cancer deaths before routine screening program. The authors announced a 25% decrease in relative value, but this actually corresponds to a gain of only 4 deaths from breast cancer per 10,000 women screened and followed for 10 years. Furthermore, the results did not demonstrate a decrease in total mortality (or all-cause mortality).*
There was no statistically significant decrease in deaths from cancer when the results of all nine studies that included women aged 40-49 (not just the UK Age Trial) were considered.

*Only the total mortality includes all elements of patient management, hence also the effects of treatment, overdiagnosis and overtreatment.
This makes more sense because any cancer detected will be treated, the treatments themselves sometimes causing deaths, which will be counted in the «all cause mortality» , thereby better reflecting the screening reality.

After these results, even less evidence of a benefit

After 23 years, the UK Age Trial results no longer indicate a significant decrease in the number of breast cancer deaths in women screened between the ages of 40 and 49.
The authors of the trial write: «Overall, there was no significant reduction in breast cancer mortality in the intervention group compared with the control group» (p4 penultimate paragraph (ref1 PDF)).

Prior to these final results, analyses that considered the results of all trials already concluded that there was no measurable benefit. Or, at the time, the UK Age was one of those trials that supported screening program.
With these results, we can be even more affirmative in saying that attempting to screen for breast cancer before the age of 50 does not have any tangible benefit.

When should we expect a re-assessment of these results?

Another trial is underway to evaluate the possible benefit of expanding screening to women before age 50 and after age 69: the Age X Trial. Its results are not expected before 2026.

Controversy in Great Britain

The publication of these results caused a great deal of controversy in Great Britain. Not because they were challenged or questioned, because the trial is of a good methodological level.
But because the authors [iii], no doubt disappointed with the results, tried to hide their negative character by insisting on the results obtained at the end of a 10-year follow-up and not at the end of the 23-year follow-up.
Some popular media journalists were thus prompted to write that the results were in favor of the effectiveness of the screening, hence the controversy [iv].

Read more about:

The international reactions to attempts to cover up screening failure in a publication

REFERENCES

[i] Duffy SW et coll. "Effects of mammogrpahic screening from age 40 years on breast cancer mortality (UK Age trial) : final results of a randomised, controlled trial" The Lancet Oncology online. 12 août 2020. Website www.thelancet.com/oncology. Doi : 10.1016/S1470-2045(20)30398-3
Document PDF of the study


[ii] Nelson HD et coll. "Screening for Breast Cancer: A Systematic Review to Update the 2009 U.S. Preventive Services Task Force" Recommendation. Evidence Synthesis No. 124. AHRQ Publication No. 14-05201-EF-1. Rockville, MD: Agency for Healthcare Research and Quality; 2016.
See particularly table 28 page 128.


[iii] Who are the authors of this study?
They are Duffy’s team and his staff from Queen Mary University in London.
Dr.Duffy is already well known in the world of screening, as he is one of the oldest pioneers in the promotion of screening and has published several studies seeking to quantify overdiagnosis, most often at its lowest range, according to him from 1 to 10%. (Overdiagnosis in mammographic screening for breast cancer in Europe: a literature review. Puliti D, Duffy SW, Miccinesi G, by Koning H, Lynge E, Zappa M and the EUROSCREEN Working Group. J Med Screen 2012;19 Suppl1:42-56.)

This was a review of studies, and this work had been highly controversial as a source of multiple rather crude biases. In their analysis the authors, Duffy and Puliti, had deliberately excluded many reference studies, Zahl’s in 2008 and Junod’s in 2011( Junod B, Zahl P-H, Kaplan Rm, Olsen J, Greenland S. An investigation of the apparent breast cancer epidemic in France: screening and incidence trends in birth cohorts. BmC Cancer. 2011 Sep 21;11(1):401.)

The Prescrire Review in 2006, after a careful analysis, as well as the exhaustive analysis made by Professor Autier, and many others even more recent, currently conclude that the rate of overdiagnosis may be between 30 and 50%.
Revue Prescrire :
*Dépistage des cancers du sein par mammographie Deuxième partie Comparaisons non randomisées : résultats voisins de ceux des essais randomisés. Rev Prescrire. 2014 Nov;34(373):842–6.
*Dépistage des cancers du sein par mammographie Première partie Essais randomisés : diminution de la mortalité par cancer du sein d’ampleur incertaine, au mieux modeste. Rev Prescrire. 2014 Nov;34(373):837–41.
*Dépistage des cancers du sein par mammographies Troisième partie Diagnostics par excès : e et indésirable insidieux du dépistage. Rev Prescrire. 35(376):111–8.


[iv]
How screening promoters try to justify the alleged success:
In the screening group, after 10 years, for every 10,000 women in the screening group, there were 14 deaths from breast cancer, while for every 10,000 women in the control group, there were 20 deaths.This relatively small benefit (including adverse effects of screening) was statistically significant. It is this difference that the authors rely on to argue that there could be a benefit, which they proclaim as “25%” (20-14 / 20 = 25%).

However, at the end of the follow-up, after 23 years, for 10,000 women in the screening group, there were 39 deaths from breast cancer, while for 10,000 women in the control group, there were 44. This time the difference is not statistically significant. And in relative terms it is 44 – 39 / 44 = 11%.
Above all, the important thing to remember: no significant difference in all-cause mortality was found between the two groups, neither after 10 years, nor at the end of the follow-up, after 23 years
At the end of the trial, there were 650 deaths per 10,000 women in the screening group and 648 deaths per 10,000 women in the control group.

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An unexpected side effect of the covid epidemic-19

The following is the view of two researchers regarding the long-term contribution of suspending cancer screening, to the advancement of cancer knowledge.


Gilbert Welch (Centre for Surgery and Public Health at Brigham and Women's Hospital and author of "Less Medicine, More Health")
And Vinay Prasad (oncologist, Associate Professor of Medicine in Oregon Health and Science University et auteur de "Malignant: How Bad Policy and Bad Medicine Harm People With Cancer")
https://edition.cnn.com/2020/05/27/opinions/unexpected-side-effect-less-medical-care-covid-19-welch-prasad/index.html


Synthesis by Cécile Bour, MD, 28/05/2020


We had already recently reported the views of Judith Garber, a political and health policy scientist at the Lown Institute, and also whose of Susan Bewley, Professor Emeritus of Obstetrics and Women's Health at King's College London and President of HealthWatch.

According to the authors, due to the fact that medical care services were overwhelmed by the epidemic, some patients certainly suffered harm on their health.
For others, though, the two authors suggest that the delay may have been beneficial.
In addition to the effect of the decrease in surgical interventions, emergency room admissions, requests for additional biological and radiological examinations, and the increase in telemedicine, the two researchers review the impact of suspending cancer screening.
Previous research on the global effects of physician strikes has suggested a decrease in mortality concomitant with reduced medical consumption. It therefore seems relevant to carefully study mortality trends in 2020 and to disentangle Covid-related deaths from other causes of death. It would be just as important to look at inequalities according to socio-economic background: the interruption of medical care may reduce mortality among the over-medicated wealthy, but the opposite phenomenon is feared among the poorest.

The screening area

Suspending cancer screening is one of the areas to be studied according to Welsch and Prasad. For them, there is no doubt that the decline in mammography will lead to a decrease in the number of breast cancers diagnosed. But is this a bad or a good thing?
This is a good opportunity to study what will happen in American cancer statistics when screening resumes, in the opinion of these authors.
They expect one of two observations:

  • Breast cancer rates might "catch up" with the delay in diagnosis, meaning the deficit in cancer diagnoses during the pandemic would be matched for by a surplus of cancers in subsequent years. In other words, any cancers not detected in patients during the pandemic would eventually be found afterwards.
  • The alternative would be that breast cancer diagnoses would never catch up…
    Why ?
    Years ago, researchers observed this phenomenon in Norway. Welsch and Prasad refer here to the famous Oslo Institute study of 2008: in a group, women aged 50-64 years had three mammograms in six years, and at the end of six years it turned out that they had more invasive breast cancers detected than women in the comparison group, who had only one mammogram after six years. If all breast cancers were expected to become symptomatic, there would have been as many in both groups. There is no reason why there should be fewer in the group that was not regularly screened, except that breast tumors that never expressed themselves and even regressed spontaneously were detected in excess in the group that had more frequently mammography. This study was at the origin of the demonstration and quantification of overdiagnosis. (See our brochure).

A mammographic procedure done later and less frequently therefore leads to fewer breast cancer diagnoses. It could be argued that this deficit eventually manifests itself in undetected tumors appearing within a longer time frame, around 5, 10 or 25 years. However, this is not the case; this deficit is never caught up even after 25 years of follow-up, as Miller's study shows.
The results of the 2008 Oslo study suggest that some small cancers regress on their own. Question: could this be happening now during the Covid-19 pandemic? And could it be highlighted?

In the article the authors also look at the decline in heart attacks and strokes observed during this period. These diseases were either under-diagnosed or there were actually fewer of them?
Who benefited from this period of less medicalization, and who lost?

Conclusion of the authors

We won't find the benefits unless we look for them, say Prasad and Welsch. We need physician-researchers who are willing to ask hard questions about the services they provide - questions that may threaten their own professional/financial interests.

Covid-19 provides a once in a lifetime opportunity to study what happens when the well-oiled machine of medical care downshifts from high to low volume in order to focus on acutely ill patients. It will be comfortable for physician researchers to study what was lost. It will be courageous for them to study what was gained.

Our opinion

Here, the two researchers present and highlight the question of overdiagnosis and discuss its causes (spontaneous regression of a slow-growing/null tumor), rather than trying to quantify it.
Indeed, the period of suspending screening is likely to be too short for examining its impact reliably. For that it would require that the interruption last two or three years or more (as in the Oslo study comparison group, where the time period for mammography non-examination in the comparison group was 6 years), and that this interruption concerns people who would have been eligible within that time period, according to the initial schedule, as well as that there be no attempt to catch up with the delay.
In our situation, only a few months of over-diagnosed cancers will disappear.
Already in our country the INCa has been rushing, although the epidemic is not yet totally behind us, to send a note to the ARSs (Regional Health Agency) asking to set up a timetable to catch up with the screenings not carried out! (Page 2)
"A plan to catch up on screening not carried out will be established by each CRCDC (regional coordination centers for cancer screening), depending on the estimated number of screenings not carried out and on the epidemiological situation in the territories, its own resources and the methods for resuming activity".
It should be noted that there is an obsessively technocratic concern about the activity indicators of the screening centers, there is no question of reflecting on the possibility of a study based on the data collected during the suspension of screening period, no, it is a question of catching up on indicators that would have lagged behind schedule for the last three months.
A Danish physician colleague confirms that in Denmark, as well, the reactivation has also taken place, and it is not lagging behind….


Another reflection is that if we will find only a slight reduction in incidence due to the short duration of suspending cancer screening, it will be very difficult to detect reliably the eventual compensatory increase mentioned by the authors, or on the contrary the absence of a compensatory increase, not to mention the fact that tumors that disappear by themselves (the over-diagnosed) need nevertheless at least several months, if not years, to disappear.

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.