In the article below, University of Sydney Public Health Professor Alexandra Barratt explores the contention around the AgeX trial, the biggest randomised trial ever, which is considering how long should older women continue to be screened for breast cancer.

It is published as part of the TOO MUCH of a Good Thing series, which is investigating how to reduce overdiagnosis and overtreatment in Australia and globally, and is published as a collaboration between Wiser Healthcare and Croakey.

To follow the series, bookmark this link, and follow #WiserHealthcare on Twitter.

Alexandra Barratt writes:

As you read over the Queen’s Birthday Honours list this weekend, and perhaps admire the longest reigning British monarch ever, might you wonder whether Her Majesty has regular mammograms for breast screening?

If you did, the answer is ‘probably not’ as the Queen is aged over 90 years and the United Kingdom National Health Service breast screening program offers standard screening to women between the ages of 50 and 70 years.

But what if she were in her 70s or even her 80s? Should she still have a screen? If something was found, would she live long enough to see the benefit of early detection, or would she just experience the more immediate traumas of surgery, radiotherapy and hormone therapy?

This is the question which the AgeX trial, the biggest randomised trial the world has ever seen, is trying to answer: How long should older women keep going for breast screening?

Originally planned to offer just one more screen to English women over 70 years of age, AgeX is now inviting women for up to 3 more screenings through to age 79. That’s five years longer than the current Australian breast screening program which invites women from 50 to 74 years of age.

With a planned sample size of “at least 6,000,000” (yes you read that right, at least SIX MILLION women) this cluster randomised trial “will assess reliably the risks or benefits” of extending screening past 70 years of age. The trial was set up in 2009-2010 to inform screening policy because of uncertainty about the advantages and disadvantages of screening beyond 70 years, amid growing interest in screening longer as life expectancy increased for English women.

A gift to women?

The AgeX trial is a rare and laudable example of rigorous policy testing. It stands in stark contrast to the 2013 Australian extension of the upper age of breast screening from 69 years to 74 years without setting up any comparable study to assess the impact of the policy change. AgeX should be a gift to women the world over by providing much needed evidence about screening in the modern world.

But the AgeX trial has been repeatedly criticised over its design, cost, potential harm to participants, and, most vehemently, over its ethics.

One of the key grounds for concern is the harm that breast screening causes older women through overdiagnosis and overtreatment. Overdiagnosis happens when indolent (i.e. inactive) cancers are detected by screening, but they wouldn’t have caused any harm within the woman’s remaining lifetime had they been left undetected and untreated.

The UK’s own independent review in 2012 found the risk of overdiagnosis and overtreatment was the major downside of screening.

Older women are less able to tolerate surgery and other cancer treatments than younger women, so overdiagnosis and overtreatment have a greater impact on their quality of life. Their higher risk of having, and dying from, other conditions means they’re also more likely to be overdiagnosed in the first place, as well as being less likely to live long enough to benefit from early cancer detection.

A question of consent

Yet, despite older women’s greater risk of being harmed by screening and lower chance of benefiting from it, AgeX is including women (and their medical data) in the trial without their informed consent.

Instead, women in the control arm simply stop receiving invitations after their 71st birthday, while women randomised to the extended screening arm continue to be sent invitations for up to 3 more screens (brief information about the trial is mailed out along with these invitations, but there is no consent process).

So it’s likely that many women are unaware of the risk of overdiagnosis and overtreatment they’re taking by continuing to be screened, and also unaware that they’re participating in a giant experiment. Critics argue that isn’t good enough when the trial itself was designed precisely because the advantages and disadvantages of screening women past 70 years of age are uncertain. More detailed information and an explicit informed consent process is needed, they say.

Complaints are also directed at the analysis. Although the information for women reads “This trial will assess the risks of screening in particular, the chances of being diagnosed and treated for a non-life-threatening cancer”, overdiagnosis isn’t mentioned in the protocol and estimating overdiagnosis isn’t part of the analysis plan.

The primary outcome is breast cancer mortality. All-cause mortality – the outcome that’s crucial for being certain that harms don’t outweigh the benefits of screening – will be reported, but the investigators warn there probably won’t be sufficient statistical power to detect a significant effect as most deaths will be from causes other than breast cancer.

So it’s anything but clear how AgeX is going to measure reliably the risks of screening past 70 years of age.

While the cost of AgeX isn’t given in the protocol documents, funding is being allocated by the Department of Health for the additional screenings. The ever-increasing demand for screening is putting the UK breast screening workforce into crisis: “The number and complexity of breast imaging examinations is rising and services cannot cope” says the Royal College of Radiologists.

The additional screenings have flow-on effects too –  more women diagnosed with breast cancer means more surgeries, more radiotherapies and other cancer treatments. As well as extra costs, this has put extra load on surgical and oncology staff.

Coronavirus has changed all that, as breast screening – and AgeX – have been put on hold.  This could mean that the results of AgeX – which had already been pushed back from the mid to late 2020s – could be delayed further.

No wonder this trial keeps on whipping up a storm. And it doesn’t look like there will be evidence-based information to guide older women, and possibly Her Majesty, in deciding when to stop screening anytime soon.

Alexandra Barratt (MBBS, MPH, PhD) is a Professor of Public Health in the School of Public Health, University of Sydney. She has a background in epidemiological research spanning clinical epidemiology and public health epidemiology. She is recognised internationally for her research to quantify the benefits and harms (including overdiagnosis) of cancer screening, particularly breast cancer screening. She is a lead investigator on Wiser Healthcare, an NHMRC funded research collaboration to reduce overdiagnosis and overtreatment in healthcare. Overdiagnosis is one of the biggest drivers of iatrogenic harm, waste and opportunity cost in healthcare and is a serious challenge for citizens, patients and healthcare services around the world.

This article is part of an ongoing series that is published as a collaboration between Wiser Healthcare and Croakey.org.

The series investigates how to reduce overdiagnosis and overtreatment in Australia and globally. The articles are also available for republication by public interest organisations, upon request.

Bookmark this link and follow #WiserHealthcare on Twitter.