UKCCCR multicentre randomised controlled trial of one and two view mammography in breast cancer screening

Introduction

It is unknown whether breast cancer screening should be performed with one or two x ray views of each breast. An oblique view is necessary, but the extra value of a craniocaudal view is uncertain.1 2 3 4 Two retrospective studies (examining films from women who had two views--one first, then both together)5 6 suggested 9% extra detection with two view mammography. Such studies could underestimate the advantage of the second view because readers were presented with a higher proportion of breast cancer cases than would be seen in ordinary screening and may have “played safe” by recommending higher recall rates than in normal screening practice. Similar prospective studies with a typical prevalence of breast cancer may not avoid the problem because the reader of the single view knows that no action will be taken until the second view has been examined. Some readers may disregard suspicious findings, underestimating one view detection. Others may recommend recalling more cases, knowing that the second film reading could correct the high recall rate.

To resolve the matter we, with the support of the United Kingdom Coordinating Committee on Cancer Research (UKCCCR) conducted a randomised trial allocating women to one view or two view mammography to determine (a) the additional breast cancer detection achievable with two views instead of one at the first screening examination, (b) the recall rates for the two policies, and (c) the economic implications of the two policies.

Patients and methods

A total of 40163 women were recruited between 1990 and 1994 from nine centres in England (West London 10610, Brighton 8048, Worthing 6564, North London 4260, Liverpool 3858, Reading 3141, Winchester 2388, Leeds 1060, and Southampton 234). Twenty one national breast screening programme film readers took part. All but two were radiologists. Women aged 50-64 were eligible for the trial at their first screening examination if they had not had breast surgery and could give consent. To be eligible for the trial, centres must have screened at least 5000 women as part of a general screening programme and identified at least four breast cancers for every 1000 women screened, with a recall rate of less than 10%, and have at least two film readers (X and Y).

In each centre women were randomised to one of three groups in the ratio 1:1:2 by means of a computerised random numbers generator. Group 1 had oblique view mammography alone, interpreted by film reader X; group 2 had two view mammography, interpreted by film reader Y; and group 3 had two view mammography, interpreted independently by X (reading the single view) and Y (reading both views). Women were entered into the trial before allocation was made and consent obtained from those allocated to two view mammography except in one centre, in which consent was given before randomisation. Readers reported results as positive (recall for assessment) or negative (no action to be taken). To avoid reader bias the two readers at each centre rotated, each reading the single views of women in groups 1 and 3 for one month (reader X), then switching to reading two views for the women in groups 2 and 3 (reader Y) for the next month.

The primary analysis of recall rates was between groups 1 and 2, and comparison of the rates of recommended recalls by readers X and Y in group 3 was a secondary analysis. The primary analysis of cancer detection was between the cancers detected by X and Y in group 3 (this maximised statistical power by removing between woman variation). Comparison of cancer detection in groups 1 and 2 was a secondary analysis.

Groups 1 and 2 were necessary to allow assessment of recall rates and avoid bias in the comparison of rates in group 3, in which the reader of the single view knew that another reader was examining two views. In the trial readers did not know to which group women were allocated, and one quarter of the women whose films were read by X would not receive a second view. Readers' performance was therefore likely to be typical of normal practice.

In group 3 a woman was recalled if either reader found a positive result. For the trial, if the one view reader recommended recall and the two view reader did not, the discordant interpretation was recorded as the study result. It was judged unnecessary and unethical to recall a woman for a second view when this had already been taken. The craniocaudal film was then shown to the single view reader, who gave a two view opinion. This second opinion was acted on, though the original recommendation was used in the statistical analysis. An “intention to treat” analysis was thereby preserved. The trial's design comparing the benefits and costs of two views with those of one view, followed by a second view when necessary, was preserved. The approach was therefore appropriate and ethical.

A random effects model7 was used in some analyses, when appropriate, to account for heterogeneity between study centres. Analyses in groups 1 and 2 were based on an intention to treat analysis. Comparisons in group 3 were restricted to 16677 women for whom both one view and two view opinions were available. This excluded 17% (3446/20123), almost all because the women declined two views or had large breasts, making two view mammography impracticable. In no case was exclusion linked to detection being better with one view or two. All P values were two tailed. The study was originally designed to recruit 100000 women with 50000 in group 3. This would yield 85% power of detecting an 8% difference in cancer detection at the 5% level of significance assuming a 5% random error in film reading. Funding was provided in two stages. Before claiming the second portion we found that the observed effect was greater than expected; a clear result had emerged and so the trial was stopped.

The costs of initial screening and of follow up diagnostic procedures were assessed separately for the one and two view procedures and the average cost estimated for each. The unit cost of film processing, clinical examination, cytology, biopsy, single view mammography, and the percentage of costs ascribed to overhead and capital expenditure were obtained from the Scottish Home and Health Department's 10 year study on economic costs of screening for breast cancer,8 updated to 1992-3 values. Extra initial screening costs incurred for the second view were estimated by using survey data from the 251 timings of radiographers' screening by one and two views, from the time taken to read 470 one and two view films by five radiologists, extra film and processing, and overhead and capital costs. A questionnaire concerning travel and time costs incurred at the recall appointment was completed by 338 women at nine screening centres to assess differences in personal costs. Follow up referral costs to the health service per woman screened were assessed by applying the unit cost of each procedure (including overhead and capital costs) to the proportion of screened women who received the procedure, and summing over all procedures for groups 1 (one view) and 2 (two views) separately.

Results

Discussion

Breast cancer screening by means of two view rather than one view mammography at the initial examination led to 24% more cancers being detected. If two view mammography detects all breast cancers this would mean that one view would detect only 81%. The recall rate was reduced by 15% with two view compared with one view mammography. The odds of a recalled woman having breast cancer were 1:10 with two view mammography and 1:14 with one view mammography (for groups 1 and 2 in table I). Two view mammography at the first screening examination is more effective than one view mammography.

The overall prevalence of detected cancer (6.6 cases per 1000 women screened) was similar to that in the British breast screening programme10 in 1993-4 (5.7 cases per 1000) among women aged 50-64 attending the first screening examination. The overall recall rate in the trial (7.6%) was somewhat higher than the corresponding rate in Britain (5.9%); this may be due, at least in part, to the double reading of films in many centres in the national programme. In the trial as a whole the proportion of tumours 1 cm or less in diameter was also similar (24%) to that in the national programme (23%). Our results therefore reflect typical screening practice.

The estimated long term implications of screening with two view mammography are summarised in table V. Three yearly one view mammography between the ages of 50 and 64 (five examinations) would be expected to reduce breast cancer mortality by 27% in screened women. This is derived from the 31% reduction in a meta-analysis of screening trials11--some using one view, some two and the 24% increase in detection in our trial (with the assumption that the 24% extra detection with two view mammography results in a 24% reduction in mortality). This is equivalent to 412 lives saved over 15 years per 100000 women screened with one view mammography and 99 extra lives saved per 100000 screened by two view mammography over all screening examinations. The average costs per life saved with one view and two views are similar (table V).

A recent review of breast cancer screening trials showed no significant difference in breast cancer mortality between trials using two view mammography and those using one view mammography in the age group 50-74 years,12 and the authors concluded that there was no advantage with two view mammography. However, the analysis was liable to between trial confounding. If centres using one view mammography (for example, the Swedish two counties study, which found a 28% reduction in breast cancer mortality) had, for reasons unrelated to the number of views taken, a better screening performance than centres using two views (for example, Malmo, which found a 14% reduction in breast cancer mortality) we should be liable to falsely conclude that two views were worse than one. Our results, though not based on mortality, compare the effects of one and two view mammography directly within the same programme in an unbiased way.

Routinely using two view mammography instead of one view increases overall costs by about 24%, but when the higher detection rate is taken into account such screening is as cost effective as one view mammography. Even if the lower limit of the 95% confidence interval on the estimated extra detection with two view mammography were used (16%) the increase in cost per case detected would still be small (6.8%).

The lifetime risk of breast cancer arising from the extra radiation with two view mammography compared with one view over five screening examinations is minimal (one to two cancers per 100000 women screened)13 and substantially less than the lives saved by the higher detection rate.

Our results are based on the first screening examination. The availability of a previous film for comparison at subsequent examinations is not a substitute for a second view. It is unlikely to increase detection materially, as all one of the 23 cancers missed with one view were interpreted as “normal appearance” without mention of a radiological abnormality. Hence it was rare to find a lesion that could be looked for in an earlier film to see if it had progressed. A previous film could, however, reduce the false positive rate, and hence the recall rate, by showing that a suspicious finding in a current film was present three years before, allowing it to be discounted as benign and avoiding an assessment. This effect could diminish the reduction in the recall rate resulting from the use of two concurrent views if the lesions thereby confirmed as benign tended to be those confirmed as benign in a previous view. Even at the extreme, if all benign lesions seen in a concurrent view were present in a previous film and the false positive rate reduced accordingly the extra cost per year of life saved with two view mammography would be only 2%.

Two view mammography improves the discrimination between women with and without cancer. Unless the presence of a previous film completely duplicates the extra information from a concurrent second view, which is implausible, there will continue to be a medical benefit in using two view mammography at subsequent screening examinations, though the size of the benefit is less certain. Even with a small benefit the cost per case detected, or the cost per year of life saved, would be similar to that with one view mammography at all screening examinations.

We conclude that (a) two view mammography increases the prevalence of cancers detected by about 24%, a difference that is likely to be similar at subsequent screening examinations; (b) two view mammography is expected to reduce breast cancer mortality by 34% in screened women compared with a reduction of 27% with one view; (c) two view mammography reduces the false positive rate, and therefore the recall rate, by about 15% at the first screening examination (it is also likely to be reduced at subsequent examinations, though the magnitude of this reduction remains uncertain); and (d) the cost per life saved with routine two view mammography will be similar to that with one view mammography. It is reasonable, therefore, that two view should replace one view mammography in breast cancer screening.

Trial collaborators who read the mammograms were Dr T Jeyakumar and Dr G Rubin (East Sussex Breast Screening Service, Brighton); Dr J A Clarke and Dr G Parkin (Leeds Breast Screening Service); Dr E White and Professor G H Whitehouse (Liverpool Breast Screening Unit); Dr T El-Sayed, Dr H Fadl, and Dr B E Nathan (North London Breast Screening Unit); dr M Busby, Dr R Cordingley, and Dr T Walker (Reading Screening Centre); Dr P Guyer and dr C M E Rubin (Southampton and Salisbury Breast Screening Unit); dr N Barrett, Dr H Fordle, and Dr S Guillani (West London Breast Screening Unit); Dr A Page and Dr M Sampson (Winchester Breast Screening Unit); and Dr A Hubbard and Dr L J Rockall (West Sussex Breast Screening Service, Worthing).