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RESEARCH:
Henrik Møller and Elizabeth Davies
Over-diagnosis in breast cancer screening
BMJ 2006; 332: 691-692 [Full text]

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How do we balance risk and benefit?: Neville W Goodman (24 March 2006)

Estimate of harm/benefit ratio of mammography screening was five times too optimistic: Peter C G�tzsche, Karsten Juhl J�rgensen (27 March 2006)

How do we balance risk and benefit? 24 March 2006

Neville W Goodman,
Consultant Anaesthetist
Southmead Hospital, Bristol, BS10 5NB
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Re: How do we balance risk and benefit?

The arguments and counter-arguments about screening for breast cancer have been difficult to follow. There have been many people, including some who have written letters published in this issue of the BMJ, arguing that women must be given the correct information. Up until now, that information has often involved arcane statistical arguments that few women will have been able to understand. In their commentary, M�ller and Davies state the problem simply (albeit, inevitably, simplistically) and clearly:
"In a population where the lifetime risk of breast cancer is 8% and the lifetime risk of dying from breast cancer from age 50 onwards is 2.5%, screening 250 women may prevent about one death from breast cancer. Screening would, however, also lead to the over-diagnosis of two cases."
So there it is: how do we decide whether the risk-benefit is "worth it"? I am not a woman, but do I want a 1 in 250 chance of being saved? Or a 2 in 250 chance of treatment that I don't need, of being told I am ill?
This is a cruel and excellent example of many decisions that we pretend that patients - or anybody - can make. They are intangibles. There is a new operation; it is better than the old one because the recovery is faster. But it has a higher risk of (rare) disaster. At what level of risk do we decide that the new operation is in all senses better? What of the patients badly harmed by the new operation? How do we balance 100 (or 200, or 300?) patients who used less morphine and were back at work within 2 weeks against 1 (or 2, or 3) patients permanently disabled?
One thing is certain: the risks must be fully stated, but that won't make life, or medicine, easier.
Competing interests: None declared

Estimate of harm/benefit ratio of mammography screening was five times too optimistic 27 March 2006

Peter C G�tzsche,
Director
Nordic Cochrane Centre, Rigshospitalet, DK-2100 Copenhagen �,
Karsten Juhl J�rgensen
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Re: Estimate of harm/benefit ratio of mammography screening was five times too optimistic

M�ller and Davies (M & D) draw attention to the importance of overdiagnosis in breast cancer screening [1], but misrepresent both benefits and harms. They extrapolate the effect seen in the screening trials to the remaining lifespan of the invited women and use lifetime- breast cancer mortality (after age 50) in their calculation of benefit [1]. However, an undiminished effect on mortality after screening has ceased is very unlikely. M & D also disregard that breast cancer mortality increases with age, and their estimate of overdiagnosis needs to be corrected for opportunistic screening in the control group [2].
Overdiagnosis is defined as cancers that would never have caused symptoms, nor been detected, in the absence of screening [3]. With reference to the updated Malm� trial [4], M & D suggest that the level of overdiagnosis is 10%. However, the serious flaws in this estimate, which has been diluted by 15 years without screening, need to be taken into account [2,5]. It is possible to infer the number of undetected cancers that exist at the end of the trial in the control group because they are subsequently diagnosed as �catch-up� cancers (calculated as the difference between number of cancers identified in the screened group and the control group during the next 15 years) [5]. Thus, it is possible to adjust for the lead-time bias caused by screening. Adding these cancers to the control group, the level of overdiagnosis when the trial ended becomes 18% [5]. However, it is also necessary to adjust for the finding that 24% of the women in the control group had undergone screening at least once during the trial [6]. In the screening trials from Stockholm, G�teborg and Two-County, the control group was invited to screening when the trials ended, and this had the effect that the number of cancers became very much the same as in the screened group (relative risks 0.98-0.99 [7-9]). Thus, a single screening led to a similar level of overdiagnosis as repeated screenings. This means that we can estimate the level of overdiagnosis, x, in the Malm� trial from:
(1+x)/(1+0.24x) = 1.18, which gives an overdiagnosis of 25%.
In the Malm� trial, as originally reported, there were 588 cancers in the screened group and 447 in the control group, i.e. a difference of 141 cancers, corresponding to a crude overdiagnosis of 32% [10]. The adjusted calculation gives 588 - 588/1.25 = 118 cases of overdiagnosis (25%). There were 3 fewer deaths from breast cancer in the screened group than in the control group [6]. Thus, after nine years of screening in the Malm� trial, 39 healthy women had been diagnosed and treated for breast cancer unnecessarily for every woman who had her life prolonged because of screening, i.e. a harm/benefit ratio of 39.
It is more informative, of course, to estimate the harm/benefit ratio from the results of all the screening trials. There are many problems with the quality of the other screening trials [10,11], and the often quoted estimate of a 30% reduction in breast cancer mortality is not tenable. In their review of the randomised trials, The US Preventive Services Task Force reported a breast cancer mortality reduction of 16% [11]. We used 15% as our estimate which gives 2000 as the number needed to screen to prolong one life [12]. By their inappropriate extrapolations, M & D estimated the number needed to screen at only 250, which is 4 times more optimistic than what has ever been reported in any screening trial [10,12] or screening program.
We believe that our estimate of 30% overdiagnosis is also reasonable [13], in particular considering that observational studies have reported higher estimates [12-14]. This gives a harm/benefit ratio of 10 after 10 years of screening [12], which is 5 times bigger than the harm/benefit ratio of 2 suggested by M & D.
Finally, M & D claim that when screening ceases, the breast cancer incidence rate returns to a lower than expected rate. The IARC report on screening noted that �No population into which breast screening has been introduced has yet been reported to show an unequivocal return of incidence rates to the baseline expected from pre-screening trends� [3]. Indeed, the incidence has remained elevated in Sweden in the older age groups, long after screening ceased [14], and persistent increases in the population have also been observed in other countries that have had screening for many years, e.g. in the USA and the UK [13,15].
We agree that overdiagnosis must be recognised and estimated. It is the most important harm of mammography screening and it is not clear whether the benefit outweighs the harms. It is indefensible that women are not being told that screening will turn many of them into cancer patients unnecessarily [12].
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2. G�tzsche PC. Overdiagnosis in the Malm� mammography screening trial was considerably underestimated. BMJ 2006;332:727.
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Competing interests: None declared