By Frances Rylands-Monk, AuntMinnieEurope.com staff writer

September 16, 2014 -- A U.K. clinical trial examining whether mammography screening should be offered to a broader range of women must be halted due to ethical and medical concerns, according to a letter published in BMJ by a group of longtime opponents to breast screening. But not everyone agrees, and the controversy looks set to continue.

In a strongly worded letter published on 16 September (BMJ), a group led by Dr. Susan Bewley raised concerns about the U.K. age-extension trial, which is examining whether the age range for screening should be extended to both younger and older women. They challenge the design of the trial as well as the qualifications of its chief investigator, calling the study an "out of control trial with ineffective oversight."

But this isn't the first time that the age-extension trial has been targeted by the group, which includes some of breast screening's most vociferous opponents, such as Dr. Peter Goetzsche, director of the Nordic Cochrane Center in Copenhagen. Several of the signatories to the letter have gone on record previously as stating that breast screening should be stopped for women of all ages.

The age-extension trial

In its National Health Service (NHS) Breast Screening Programme, the U.K. historically offered breast screening every three years to women 50 to 70 years old, but in 2012 this was extended to women 47 to 73 years old. At the same time, U.K. authorities noted they believed there was little evidence on the benefit of offering screening to women in the younger and lower age ranges.

Dr. Susan Bewley
There is no overall mortality benefit from breast screening at any age if you look at the Nordic Cochrane review, stated Dr. Susan Bewley.

Therefore, the NHS commissioned a study that would randomize the phase-in of the age extension, and collect data on breast cancer incidence and mortality for the following 10 years. Recruitment of women would continue through 2016, with follow-up continuing through the 2020s.

The age-extension trial has become a front on the ongoing war over breast cancer screening, however, with mammography opponents challenging the study design in several previous BMJ publications. This week's letter continues this angle of attack, claiming that women are not being informed about the potential harms of overdiagnosis, or the detection of early slow-growing cancer that would not grow into life-threatening or clinical disease. The authors also raise the question of whether women are even aware they are in a randomized clinical trial.

"Our concerns relate to the science and ethics of this trial. Women should always be told the full facts -- here they are unwittingly participating in a research trial without fully realizing that the harm/benefit ratio is uncertain," Bewley said. "There is no overall mortality benefit from breast screening at any age if you look at the Nordic Cochrane review -- only a reduction in breast cancer mortality."

The Swiss example

The BMJ letter is being published concurrently with the Preventing Overdiagnosis conference, being held 15-17 September in Oxford, U.K. The speaking roster for the meeting includes a number of skeptics of aggressive medicine, as well as a keynote session chaired by Dr. Fiona Godlee, editor in chief of BMJ.

Speaking to AuntMinnieEurope.com from the conference, Dr. Michael Baum, emeritus professor of surgery and medical humanities at University College London, pointed to the Swiss Medical Board's recent -- and controversial -- recommendation to stop screening in the country. Like Bewley, Baum has previously expressed his opinion that mammography screening should be shut down.

"Launching an extended-age screening project now when there are so many uncertainties about screening women between 50 to 65 years, is insane. Secondly, the rollout of the National Health Service's program provides an excuse for the trial, but this predetermines the outcome which we won't know until 2022!" he noted. "Third, there is no hint in the leaflets provided to screening patients that they are in a controlled trial, which is unethical as they haven't had the opportunity for proper informed consent."

Baum set up the U.K.'s first breast screening program in 1987 and resigned 10 years later when he expressed concern that the new data emerging suggested benefits were exaggerated and harms ignored. He now believes the money spent on breast screening would be better used in preventing and treating cardiovascular disease -- which is five to seven times more likely to kill women older than 65 than breast cancer.

"In younger patients, screening throws us more false alarms and the potential harm increases. In older patients with comorbidities, life expectancy is being ignored," he said.

Baum's sentiment was echoed by Goetzsche, one of the co-authors of the BMJ letter and also the lead author or co-author on a number of other papers claiming that breast screening both fails to save lives and is actively harmful to women due to overdiagnosis and false positives.

"The psychological harm due to the many false-positive findings is, for example, very substantial and long-lasting; even three years later, women may still be suffering from it. The only interesting question that remains in relation to mammography screening is: Which country will be the first to stop it?" Goetzsche noted in an email to AuntMinnieEurope.com. "My own view is that screening should be stopped in all ages, as any utility analyses that take all the benefits and harms into account will invariably come out negative, as also shown by the independent Swiss Medical Board recently."

Personal attack?

The BMJ letter is likely to anger many mammography proponents, and some thought leaders have been openly skeptical of Bewley's criticisms about the U.K. age-extension trial.

"I find the communication less than persuasive, in particular the personal attack on the chief investigator," said Dr. Stephen Duffy, professor of cancer screening at the Wolfson Institute of Preventive Medicine at Queen Mary University of London. "Whether a study should proceed depends on the research question, quality of design, and the conduct of the study, not on whom the chief investigator is."

Stephen Duffy
The authors' concern about overdiagnosis is misplaced, according to Dr. Stephen Duffy.

Duffy believes concern about overdiagnosis is misplaced, because studies that adequately account for lead time and underlying incidence trends find overdiagnosis to be a minor phenomenon. Also, he disagrees with the emphasis on all-cause mortality as an outcome, which is an inaccurate and inefficient surrogate for breast cancer mortality, the most important endpoint of breast cancer screening.

The letter by Bewley and colleagues does not provide persuasive reasons to support their opinion that the proposed trial is poor science or should be halted, pointed out Sir Nicholas Wald, professor of preventive medicine at the Wolfson Institute of Preventive Medicine, Barts and the London School of Medicine and Dentistry, and Queen Mary University of London.

Overdiagnosis is an issue with all cancer screening programs, and is one of the reasons that the value of screening for specific cancers needs to be assessed in randomized trials, he pointed out.

"It is scientific uncertainty that underpins the ethical position. If the value of screening is clearly favorable or unfavorable, a study to investigate this would be unnecessary and hence unethical. If the value is uncertain it is necessary and ethical to conduct a randomized trial to reduce the uncertainty," Wald said. "If trials show that screening reduces deaths from breast cancer, a separate analysis is needed on possible harms and costs. But if screening saves lives, it is probably a price worth paying."

Need for new evidence

Calling an ongoing trial "unethical" and calling for it to be stopped are strong words, according to Dr. Gabor Forrai, vice president and president-elect of the European Society of Breast Imaging (EUSOBI) based in Budapest.

Dr. Gabor Forrai
New evidence is likely to be of value to everybody in the field, said Dr. Gabor Forrai.

"It means that the continuation of the study would bring definitely more harm than possible advantages," Forrai said. "I don't see the dangerous new harms this study may produce. On the contrary, it may bring new evidence to the field."

According to U.K. data, it is a statistical fact that 33% of new breast cancer cases arise after 69 years of age, and 20% before 50 years of age. Therefore, it is of utmost importance to investigate the screening possibilities and results in these specific age groups, which cover altogether 53% of the new breast cancers, he commented.

Forrai also pointed to the age limits of 47 and 73 as nothing extraordinary: numerous European countries have limits lower than 47 and/or higher than 73 in their standard screening protocol.

"Is it realistic that experienced and developed countries such as Sweden, the Netherlands, Austria, France, and Hungary haven't ever included any statistician during the design of their screening programs and that they based them on 'unethical' grounds?" he said. "While the methods and details of any study may be calmly and scientifically questioned, to use this strong public wording will encourage women -- of any age -- to refrain from screening. This may cause real, evidence-based harm to them as their breast cancers would remain undiscovered."

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Last Updated bc 9/17/2014 1:27:42 PM

12 comments so far ...
9/16/2014 4:12:25 PM
Jerry Kolb
As the screening wars continue in this new phase, may I suggest that the term "over diagnosis" is both over used and inaccurate.  Breast imagers diagnose cancer only from histology that is the product of a pathologist's analysis of tissue taken from the patient's breast, and surgeons operate based on that histology.  I suspect that the term over diagnosis is used to indicate that some breast cancers may not proceed to mortality in all instances, although I have never heard anyone indicate a reliable method for identifying specific individual tumors that will not kill the patient.
 
The over use of the term over diagnosis leads only  to confusion.  If those who wish to make the case that mammography is over utilized are interested in clarifying their arguments and engaging in honest scientific debate, they must begin to describe their arguments more succinctly, omitting the term over diagnosis from the discussion.  It may make headlines, but it only confuses the women that I believe we all want to help.
 

9/16/2014 5:32:21 PM
Ken Mask, MD
The use of modern technology requires that we aggressively screen. The clinical trails and ongoing debate fuels ignorant lay population delay of office visits, and testing and adds to confusion. One patient. One life.

9/17/2014 4:16:21 AM
msparks
As a radiologist working in the UK Breast screening programme I agree with your comments regarding "over diagnosis".  We do not overdiagnose breast cancer - the pathological diagnosis is not in doubt. 
 
We, I think, have successfully managed to get this point across and the media no longer bandy this term with such abandon as has happened in recent years.
 
What we are being criticised for is "over treating".  Over treating conditions such as low grade DCIS that are unlikely to cause long term physical harm or affect life span.  Overtreatment that induces anxiety and other morbidities associated with that treatment process. 
 
Many of us are acutely aware of this problem but unless we continue with research we will not get to the answer.  Stopping screening now will not help.  Modifying screening to a more targetted, individualised, client centred approach will only come about with more data.

9/17/2014 2:35:29 PM
John Keen, MD
Dr. Kolb:
How can there be an honest scientific debate when you propose to censor the term that describes the major harm from screening mammography?
As per the article, even Dr. Duffy the screening advocate acknowledges the harm of overdiagnosis.  His estimates are low since he uses inflated estimates of lead time, 3-5 years instead of 1-2, since his lead time estimates include overdiagnosed cases.
The major problem is not that mammography is overutilized, although 8 billion dollars a year at least (in the US) has alternative and likely more effective uses-like treating women with heart disease as Dr. Baum mentions.  The major problem is that women are not being told the truth about the harms, especially by radiologists with financial conflicts of interest.  Urologists don't seem to have a problem acknowledging overdiagnosis, it is time radiologists, especially those with academic credentials, acknowledge this harm. 
John D. Keen, MD

9/17/2014 7:57:44 PM
DKopans
It is surprising to see that the UK is still wrestling with the question of the age at which screening for breast cancer should begin.  The randomized, controlled trials proved that screening significantly reduces deaths from breast cancer beginning at the age of 40.  Even the US Preventive Services Task Force (USPSTF), and the Cancer Intervention and Surveillance Network (CISNET) models that they relied on, clearly show that the most lives are saved by screening women annually beginning at the age of 40 (1).  Numerous observational studies have confirmed that when screening is introduced into the population the death rate from breast cancer falls for women in their forties (2,3,4,5,6).  Dr. Keen's fanciful belief that mammography finds invasive cancers that, if left alone would, regress or disappear is based on scientifically unsupportable claims such as those published by Bleyer and Welch in their New England Journal article (7), that should  have never passed peer review.  Bleyer has admitted  that their analysis was based on "best guesses".  When actual data are used, there is no evidence of overdiagnosis of invasive cancers (8) (Ductal Carcinoma in Situ is a legitimate are of disagreement).   Bleyer and Welch claimed that, in 2008 alone, there were 70,000 cancers in the U.S. that, if left alone, would regress or disappear.  Yet neither Bleyer nor Welch, nor anyone else has ever seen an invasive breast cancer regress or disappear on its own - 70,000 each year and not a single credible report?  The accusation is made that radiologists refuse to acknowledge massive overdiagnosis.  Dr. Keen's argues as if he has vast experience.   I would challenge him to show a single credible case of an invasive breast cancer disappearing on its own.   It is astonishing that this type of, scientifically unsupportable  misinformation has been promulgated through credible journals.
The promulgation of misinformation is endangering women.  The death rate from breast cancer in the United States, unchanged in 40 years, began to suddenly decline in 1990 soon after a sudden increase in cancer detection rates indicated the start of screening in the U.S.in the mid 1980's.  As more and more women have participated in screening the death rate  has continued to decline.  Those who claim that therapy is the reason for the decline need to show direct data that proves that therapy is the reason for this decline in deaths.  The fact is that there are no direct data.  Randomized, controlled trials of therapy show that therapy has improved, but there is no direct measure of its effect when introduced into the general population.  Why did the death rate for males with breast cancer, with access to all the modern therapies, increase in 1990 and stay elevated while the death rate for women fell?   In 2005 the death rate for men returned to 1990 levels and has remained there despite modern therapy while the death rate for women continued to decline. The difference ?  Men are not screened and present with later stage disease.   I know of no expert in oncology who supports curtailing screening, because they know that therapy is most effective when breast cancers are treated earlier.  Of course as a breast cancer expert ??? Dr. keen may have had a different experience.
I would challenge anyone who claims that the age of 50 is a legitimate threshold for screening.  There is no biological or scientific support for using this age as anything but arbitrary.  None of the parameters of screening changes abruptly at the age of 50 or any other age (9).  Data manipulation such as grouping and averaging results for women ages 30-49 (no one was suggesting screening women in their 30's) and comparing them dichotomously to women grouped and averaged for ages 50 and over has been used to mislead and create a biologically ridiculous idea that screening suddenly begins to save lives at the age of 50 (10).  It is time for the medical journals that have been promulgating their biases in an effort to curtail screening, to stop publishing material that is scientific nonsense.   It is time for thoughtful physicians to review the details of the scientifically unsupportable analyses that have made it past poor peer review. 
Of course women should be informed of the fact that 10% will be recalled from screening, but most of these will be resolved by a few extra mammograms or an ultrasound.  Approximately 1-2% of women will be advised to have an imaging guided needle biopsy under local anesthesia with 20-40% yielding cancer.  When surgeons biopsied clinically evident cancers before imaging was available the yield of cancer was even lower at 15% (11).  I do not recall Dr. Keen or Dr. Baum mentioning these facts.  It is remarkable that paternalistic opponents of screening think that women would prefer to die from breast cancer in order to be spared some inconvenience and anxiety.  Rather than reducing access to screening, how about providing women with facts (not fantasy) and allowing each to make her own decision as to what she wishes to do.
Mammography screening is not the ultimate answer to breast cancer, but it is having a major effect, and until there is a universal cure, or a safe way to prevent breast cancer (none is on the horizon) women should have access to annual screening beginning at the age of 40. 
 
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