Trial to extend breast cancer screening won’t resume randomisation after pandemic
BMJ 2020; 370 doi: https://doi.org/10.1136/bmj.m3337 (Published 26 August 2020) Cite this as: BMJ 2020;370:m3337
All rapid responses
Rapid responses are electronic comments to the editor. They enable our users to debate issues raised in articles published on bmj.com. A rapid response is first posted online. If you need the URL (web address) of an individual response, simply click on the response headline and copy the URL from the browser window. A proportion of responses will, after editing, be published online and in the print journal as letters, which are indexed in PubMed. Rapid responses are not indexed in PubMed and they are not journal articles. The BMJ reserves the right to remove responses which are being wilfully misrepresented as published articles or when it is brought to our attention that a response spreads misinformation.
From March 2022, the word limit for rapid responses will be 600 words not including references and author details. We will no longer post responses that exceed this limit.
The word limit for letters selected from posted responses remains 300 words.
Dear Editor,
Thanks to Dr Goh, I take note that women in the control group of the Age trial were not informed they were part of a trial. However, it is difficult to imagine that none of them was aware that women of the same age as them had annual mammography from the age of 40 years, since around 50,000 women were in the intervention group, and this information could not be hidden.
Gunsoy et al. have reported a large percentage of drop-out in the intervention group (1), and it is reasonable to assume that having had ten years of apprehensiveness, sometimes with false alarms, did not encourage them to keep on being screened.
Therefore, I still think that the different attendance at screening at the age of 50 years explains the absence of excess cancers in the intervention group, which is an unusual feature of this particular trial.
Competing interests: No competing interests
Dear Editors
Dr Corcos suggested in his rapid response that "women who had participated in the Age trial (annual mammography screening from the age of 40 years) who were in the intervention group tended to abandon screening progressively, whereas women who knew they were in the control group were more likely to respond to invitation for screening at the age of 50 years." (Ref 1).
I would refer to this paragraph in the final report of the UK Age trial that states:
"Women in the intervention group were invited to participate by post. They received a trial information leaflet with their letter of invitation. Acceptance of the invitation to attend screening was taken to be informed consent to participate in the trial. The women in the uninvited control group were unaware of their inclusion in the trial, which was deemed acceptable because it was analogous to a geographically distinct population that are followed up to monitor cancer and mortality and receive no deviation from the usual care."
Hence the uninvited women cannot be aware of their participation in the UK Age Trial as a control group, and hence should not behave differently than any other women not involved in early breast cancer screening to "respond to invitation for screening at the age of 50 years" as Dr Corcos implies.
He may also be interested to know that the same researchers stated:
"There was no indication of an effect of the intervention on deaths from causes other than breast cancer, and no effect on all-cause mortality. The latter is to be expected, since the effect on all-cause mortality is overwhelmingly driven by causes of death on which the intervention has no effect. In this trial, breast cancer deaths from cancers diagnosed in the intervention phase comprised only 683 (7%) of all 10 439 deaths. It is also of interest that there was no evidence of an increase in deaths from causes other than breast cancer in women diagnosed with breast cancer in the intervention group." (Ref 2)
I agree with Dr Anthony Miller's comment (Ref 3) on their surprising conclusion:
"Results with respect to breast cancer incidence suggest at worst modest overdiagnosis in this age group, and that any overdiagnosed cancers would otherwise be diagnosed at NHSBSP screening from age 50 years onwards. Therefore, screening in the age group of 40–49 years does not appear to add to overdiagnosed cases from screening at age 50 years and older. There might have been some overdiagnosis in the intervention group and during the intervention period, which was balanced when the control group received screening in the NHSBSP. However, we cannot directly observe or estimate overdiagnosis in a trial in which the control group also receives screening, albeit later than the intervention group."
The researchers concluded:
"Our results suggest a reduction in breast cancer mortality with annual mammography in women aged 40–49 years within the first 10 years of follow-up, and no overdiagnosis in addition to that which arises from screening at age 50 years and older."
Dr Miller suggested that in view of this study with result of other research, "it could be argued that breast screening with mammography should not be initiated at any age, but rather women should be encouraged to practise breast awareness, with mammography used as a diagnostic test, while always remembering that in young women mammography can be negative even in the presence of physically detectable breast cancer." (Ref 3)
Which lead to the purpose of the AgeX trial which started some 11 years as (Nationwide Randomised Trial of Extending the NHS Breast Screening Age Range) before the final results of UK Age trial in 2020. AgeX was to assess reliably the risks and benefits of one extra screening invitation before age 50 and, separately, of one extra invitation after age 70, which is frankly surprising considering that UK Age Trial failed to show benefits in reducing breast cancer mortality at 10 years (Ref 4) or 17 years for that matter (Ref 5); how this one has passed any committee approval will need an appointment of a truly independent DMC "if we are to avoid harming the public, and avoid wastage" as Dr Thornton has advocated (Ref 6), particularly when millions of pounds of NHS programme and care via early breast cancer screening by mammography cannot show any difference in all cause mortality as UK Age Trial researchers had admitted
References:
1. https://www.bmj.com/content/370/bmj.m3337/rr
2. https://doi.org/10.1016/S1470-2045(20)30398-3
3. https://doi.org/10.1016/ S1470-2045(20)30428-9
4. http://dx.doi.org/10.1016/S0140-6736(06)69834-6
5. http://dx.doi.org/10.1016/S1470-2045(15)00128-X
6. https://www.bmj.com/content/370/bmj.m3337/rr-0
Competing interests: No competing interests
Dear Editor,
The AgeX trial is a supreme example for illustrating just why proper statistical planning and independent oversight are so crucially important if trial participants are to be properly informed and not duped, harmed and misled. Also, to ensure that NHS coffers (in this case) are not depleted unnecessarily and to ensure that trustworthy evidence is produced. This was highlighted in an exclusive News item, informing readers that the AgeX trial had definitely stopped randomisation in May 2020 after recruiting 4.4 million participants since it was started in 2009. [1] How can it be that the trial team can announce that `4.4 million will, with sufficiently long-term follow up suffice` when their intent had been to recruit `about 6 million women`? [2] Trials are costly, both economically (NHS funding – tax payers` money) and for participants. Why not 4.4 million at the planning stage if that would suffice, thus saving us all the costs that 1.6 million would accrue? Who undertook the power calculations? Even the huge number of 4.4 million indicates the magnitude of participants they would need to detect the effect of their intervention, which must therefore be very elusive.
Susan Bewley, the lead author of a paper questioning the costs of this trial [2], when calling for an independent enquiry, rightly described the trial as one `that rode roughshod over women`s rights`. This emphasises the need for early scrutiny and independent oversight of trials. Prompt appointment of a truly Independent Data Monitoring and Safety Committee (DMC) would ensure well conducted trials. Readers of trial reports need to know whether or not an independent DMC has been appointed, thus giving a greater degree of confidence in findings. The Damocles Study Group has recommended that information about DMC members should be named and their affiliations listed in the main report of trials. [4] https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(05)17965-3/fulltext A systematic Review of the reporting of DMCs in publications of randomised trials shows how unsatisfactorily this is done. [5] This is something that needs to be added to checklists for trial reporting and would go some way to achieving greater transparency and greater confidence in trials and their reports. The appointment of a truly independent DMC in the first place is clearly necessary if we are to avoid harming the public, and avoid wastage.
[1] Elizabeth Mahase. Trial to extend breast cancer screening won’t resume randomisation after pandemic. BMJ 2020; 370 doi: https://doi.org/10.1136/bmj.m3337 (Published 26 August 2020) BMJ 2020;370:m3337
[ 2] Completion of randomisation into the AgeX trial, with follow-up continuing throughout the 2020s. AgeX Trial. May 2020. http://www.agex.uk/File+download/34/AgeX+completion+of+randomisation.pdf.
[3] Bewley S, Blennerhassett M, Payne M. Cost of extending the NHS breast screening age range in England. BMJ2019;365:l1293. doi:10.1136/bmj.l1293 pmid:30971394
[4] Damocles Study Group*, a proposed charter for clinical trial data monitoring committees: helping them to do their job well. The Lancet. February 19th 2005. DOI: https://doi.org/10.1016/S0140-6736(05)17965-3
*AM Grant, DG Altman, AG Babiker, MK Campbell, et al.
[5] Jennifer S. Gewandter, Rachel A Kitt, Matthew R. Hunsinger, Joseph Poku, Jacqueline Lozano et al. Reporting of data monitoring boards in publications of randomised clinical trial is often deficient: ACTION systematic review. DOI: 10.1016/j.jclinepi.2016.12,018. 2017.
Competing interests: No competing interests
Dear Editor
Although there has been much criticism about the fact that women were not informed they were part of a trial, I believe that this will permit a better interpretation of the results. For instance, women who had participated in the Age trial (annual mammography screening from the age of 40 years) who were in the intervention group tended to abandon screening progressively, whereas women who knew they were in the control group were more likely to respond to invitation for screening at the age of 50 years.
The design of the AgeX trial should allow the observation of mammography-induced cancers (1) in the intervention group as an excess of cancers in women aged 55-60.
1) Corcos D & Bleyer A. N Engl J Med. 2020 Jan 2;382(1):96-98
Competing interests: No competing interests
Trial to extend breast cancer screening -factual inaccuracy
Dear Editor,
The article states that the Nationwide Randomised Trial of Extending the NHS Breast Screening Age Range was started by Public Health England in June 2009.
This is inaccurate because Public Health England became operational on 1 April 2013 as a result of the reorganisation of the National Health Service (NHS) in England outlined in the Health and Social Care Act 2012.
To attribute the extension of the NHS Breast Screening Age Range to Public Health England is factually incorrect.
Competing interests: No competing interests