Information was available for 10 801 women in 17 trials (). Six trials were of radiotherapy after lumpectomy and included both low-risk and high-risk women (category A, 4398 women), four were of radiotherapy after sector resection or quadrantectomy (category B, 2399 women), and seven more recent trials were of radiotherapy after lumpectomy in low-risk women (category C, 4004 women). In most of the trials radiotherapy was to the conserved breast only (webappendix p 4
). Median follow-up was 9·5 years at risk per woman and 25% of women were followed up for more than a decade. 3143 (29%) had died by the final follow-up date of Sept 30, 2006.
Availability of data from randomised trials of radiotherapy after breast-conserving surgery for invasive cancer that began before the year 2000
The 10-year risk of any (locoregional or distant) first recurrence was 19·3% in women allocated to radiotherapy and 35·0% in women allocated to breast-conserving surgery only, corresponding to an absolute risk reduction of 15·7% (95% CI 13·7–17·7, 2p<0·00001; ). Nearly three-quarters of first recurrences in the no radiotherapy group were locoregional (25% locoregional first, 10% distant first), compared with fewer than half of those in the radiotherapy group (8% locoregional first, 12% distant first; webappendix p 9
). In addition to reducing recurrence substantially, radiotherapy also reduced breast cancer death by a moderate amount: the 15-year absolute risk reduction was 3·8% (95% CI 1·6–6·0, 2p=0·00005), suggesting on average about one breast cancer death avoided for every four recurrences avoided by radiotherapy.
Figure 1 Effect of radiotherapy (RT) after breast-conserving surgery (BCS) on 10-year risk of any (locoregional or distant) first recurrence and on 15-year risks of breast cancer death and death from any cause in 10 801 women (67% with pathologically node-negative (more ...)
Allocation to radiotherapy halved the average annual rate of any first recurrence (rate ratio [RR] 0·52, 95% CI 0·48–0·56, ). The proportional reduction was greatest in the first year (0·31, 0·26–0·37), but was still substantial during years 5–9 (0·59, 0·50–0·70; webappendix p 13
). Beyond year 10 there was no evidence of any further effect on the first recurrence rate, but information about recurrence in this period was incomplete so the number of events was small and the CI wide (). Radiotherapy reduced the annual breast cancer death rate by a sixth (RR 0·82, 0·75–0·90). The timing of breast cancer death differed from that of first recurrence, with few events during the first year (), and there were substantial numbers of breast cancer deaths after year 10.
Mortality without recurrence from non-breast-cancer causes was slightly higher in women allocated to radiotherapy than in women allocated to breast-conserving surgery only, but the excess was not significant (RR 1·09, 95% CI 0·97–1·22, 2p=0·14). If the mortality rate from non-breast-cancer causes in women allocated to radiotherapy had been identical to that in women allocated to breast-conserving surgery only, then the 15-year absolute risk reduction in all-cause mortality would have been 3·2%. In fact, the 15-year absolute risk reduction in all-cause mortality was 3·0% (95% CI 0·6–5·4, 2p=0·03; ).
Most women (n=7287) had pN0 disease. In this group, allocation to radiotherapy halved the average annual recurrence rate during the first decade (RR 0·46, 95% CI 0·41–0·51), reducing the 10-year risk of any first recurrence from 31·0% to 15·6%, an absolute reduction of 15.4% (95% CI 13·2–17·6, 2p<0.00001 ). For these women, radiotherapy reduced breast cancer death by about a sixth (RR 0·83, 95% CI 0·73–0·95), and reduced the 15-year risk of breast cancer death from 20·5% to 17·2%, an absolute reduction of 3·3% (95% CI 0·8–5·8, 2p=0.005; ).
Effect of radiotherapy (RT) after breast-conserving surgery (BCS) on 10-year risk of any (locoregional or distant) first recurrence and on 15-year risk of breast cancer death in women with pathologically verified nodal status
For the 1050 women with pN+ disease, allocation to radiotherapy reduced the 1-year recurrence risk from 26·0% to 5·1%, which is a five-fold reduction (RR 0·20, 95% CI 0·14–0·29). There was a moderate additional effect over the next few years but little further effect after year 5 (). When these very different proportional effects in different periods since treatment were combined, the mean annual recurrence rate during the whole of the first decade was halved in pN+ disease (RR 0·50, 95% CI 0·41–0·61). Although the proportional reductions in the mean annual recurrence rate were similar in pN0 and pN+ disease, the absolute 10-year recurrence reduction seemed to be somewhat larger in pN+ disease at 21·2% (95% CI 14·5–27·9, 2p<0·00001, 42·5% vs 63·7%). Radiotherapy also reduced breast cancer death in pN+ disease (RR 0·79, 95% CI 0·65–0·95, 2p=0·01), with a 15-year absolute reduction of 8·5% (95% CI 1·8–15·2; 42·8% vs 51·3%).
In both pN0 and pN+ disease, the first recurrence was locoregional for a higher proportion of women allocated to breast-conserving surgery only than of women allocated to breast-conserving surgery plus radiotherapy (webappendix p 10
Analyses of the effects of treatment in various subgroups of women with pN0 disease are much more likely to identify differences reliably if they are based on recurrence than on mortality, because the significance level of the effect of radiotherapy is much more extreme for recurrence than for mortality (2p<0·00001 for recurrence [χ21=209·0], 2p=0·005 for breast cancer death [χ21=7·8]).
In a series of analyses which focus first on proportional and then on absolute reductions in recurrence, women were subdivided into different groups to ascertain whether some groups benefit more than others from radiotherapy. In the first analysis, the proportional effect of radiotherapy on the rate of any first recurrence in pN0 disease during the first 10 years was estimated for each of several factors considered separately (). In most subgroups, radiotherapy roughly halved the annual recurrence rate (except that among women who had been given lumpectomy the proportional recurrence reduction was somewhat less extreme in ER-poor disease [2p=0·01, section (d) of ] and somewhat more extreme in the low-risk [category C] trials [2p=0·009, section (f) of ]).
Event rates for any (locoregional or distant) first recurrence (% per year) and recurrence rate ratios for various factors, considered separately, during years 0–9 in women with pathologically node-negative disease (n=7287)
Halving a big risk produces a bigger absolute benefit than halving a small risk. In women with pN0 disease, the annual recurrence rate without radiotherapy was strongly correlated with age (inversely), tumour grade, tumour size, ER status (especially when tamoxifen was used in ER-positive disease), and extent of surgery (inversely). The absolute recurrence reduction produced by radiotherapy also depended strongly on these factors (). In the second analysis, the way in which the absolute reduction in 10-year recurrence risk produced by radiotherapy depended on all the potential explanatory factors listed in considered together was modelled. The modelling was carried out by considering information both for women allocated to radiotherapy and for those allocated to no radiotherapy (webappendix pp 20–25
shows methodological details).
Effect of radiotherapy (RT) after breast-conserving surgery (BCS) on 10-year risk of any (locoregional or distant) first recurrence in women with pathologically node-negative disease (n=7287), subdivided by patient and trial characteristics
The absolute recurrence reduction produced by radiotherapy and the absolute recurrence risk remaining even with radiotherapy varied significantly with age, tumour grade, ER status, and tamoxifen use, even after adjustment for all other factors (). Tumour size was independently predictive of absolute recurrence risk although not of the absolute risk reduction.
When the original trials with lumpectomy (category A) and the later trials with lumpectomy in low-risk women (category C) were compared, there was a substantial difference in the absolute recurrence risk without radiotherapy and in the absolute reduction in this risk produced by radiotherapy, but these differences were largely accounted for by the other recorded factors (; webappendix pp 15–17, 19
Surgery that is more extensive than lumpectomy (as in the category B trials) reduced the absolute recurrence risk without radiotherapy and reduced the absolute reduction in this risk produced by radiotherapy. However, because the category B trials did not give tamoxifen, this effect of the extent of surgery on the absolute effect of radiotherapy was apparent only after adjustment for tamoxifen use (and the other recorded factors), but not before (; webappendix p 18
The characteristics that were independently predictive of the absolute risk of recurrence, or of the absolute risk reduction with radiotherapy, were included in a model to show how 10-year recurrence risks with and without radiotherapy depended in these trials on age, grade, ER status, tamoxifen (which was given much more often in the recent category C trials of low-risk patients than in the original category A trials), and extent of surgery. shows estimates based on this model. Within each section of the figure, younger women and those with high-grade tumours had substantially larger absolute recurrence risks without radiotherapy and substantially larger absolute risk reductions with radiotherapy than did older women and those with low-grade tumours (). Among women given lumpectomy but not radiotherapy, for a specific age and grade, the highest risks and largest absolute reductions with radiotherapy were for women with ER-positive disease not given tamoxifen; however, even with tamoxifen the additional effects of radiotherapy were substantial for women with high-grade tumours and younger women with intermediate-grade tumours ().
Figure 4 Absolute 10-year risks (%) of any (locoregional or distant) first recurrence with and without radiotherapy (RT) following breast-conserving surgery (BCS) in pathologically node-negative women by patient and trial characteristics, as estimated by regression (more ...)
Each woman with pN0 disease was assigned a predicted absolute reduction in 10-year recurrence risk from radiotherapy on the basis of her individual characteristics, the characteristics of the trial that she was in, and the model-based estimates in . The absolute reduction in 10-year recurrence risk was large (≥20%) for 1924 women (56% of women in trial category A, 16% of trial category B, and 9% of trial category C), intermediate (10–19%) for 3763 women (32%, 74%, and 53% of trial categories A, B, and C respectively), and lower (<10%) for 1600 women (12%, 10%, and 38% of trial categories A, B, and C respectively). For these three groups (pN0-lower, pN0-intermediate, and pN0-large), the observed 10-year recurrence risks with and without radiotherapy, calculated directly from data for individual women, were 26.0% versus 50.3% (absolute reduction of 24.3%, 95% CI 19.6–29.0), 12.4% versus 24.8% (absolute reduction of 12.4%, 9.7–15.1), and 12.0% versus 18.9% (absolute reduction of 6.9%, 2.2–11.6), respectively. The corresponding absolute reductions in 15-year risk of breast cancer death in the three groups were 7·8% (95% CI 3·1–12·5), 1·1% (–2·0 to 4·2), and 0·1% (–7·5 to 7·7), respectively (trend in absolute mortality reduction: 2p=0·03; , webappendix pp 35–37
). For all three groups, the first recurrence was locoregional for a much larger proportion of women allocated to breast-conserving surgery only than for those allocated to breast-conserving surgery plus radiotherapy (webappendix pp 38–39
). Because only 1050 women had pN+ disease in these trials, the relevance of prognostic factors and other characteristics could not be explored reliably in this group (webappendix pp 40–44
Absolute reduction in 15-year risk of breast cancer death with radiotherapy (RT) after breast-conserving surgery versus absolute reduction in 10-year risk of any (locoregional or distant) recurrence
On average, in all the women in these trials, about one breast cancer death was avoided by year 15 for every four recurrences avoided by year 10 (). For pN+ disease and for pN0 disease with large predicted absolute recurrence benefit the observed ratio was slightly larger, whereas for pN0 disease with intermediate or lower predicted absolute benefit it was somewhat smaller (). However, the departure from linearity was not statistically significant (2p=0·11).