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1 Articles and tamoxifen in women with completely excised ductal carcinoma in situ of the breast in the UK, Australia, and New Zealand: randomised controlled trial UK Coordinating Committee on Cancer Research (UKCCCR) Ductal Carcinoma in situ (DCIS) Working Party* on behalf of DCIS trialists in the UK, Australia, and New Zealand Summary Background As a consequence of mammographic breast screening programmes, ductal carcinoma in situ is diagnosed with increasing frequency. Mastectomy for localised ductal carcinoma in situ is thought to be an overtreatment by many physicians, but there is much controversy as to whether complete local excision alone is sufficient. We aimed to assess the effectiveness of adjuvant radiotherapy and tamoxifen. Methods We used a 2 2 factorial design in a randomised controlled trial. Between May, 199, and August, 1998, 171 patients recruited from screening programmes were randomised to both treatments in combination or singly, or to none, or to either one (eg, radiotherapy) with an elective decision to give or to withhold the other (ie, in this case tamoxifen). Patients had complete surgical excision of the lesion confirmed by specimen radiography and histology. Patients have been followed up at least once a year. Median follow-up was 52 6 (range ) months. Our primary endpoint was the incidence of ipsilateral invasive disease. Findings Ipsilateral invasive disease was not reduced by tamoxifen but recurrence of overall ductal carcinoma in situ was decreased (hazard ratio 68 [ 49 96]; p= 3). reduced the incidence of ipsilateral invasive disease ( 45 [ 24 85]; p= 1) and ipsilateral ductal carcinoma in situ ( 36 [ 19 66]; p= 4), but there was no effect on the occurrence of contralateral disease. There was no evidence of interaction between radiotherapy and tamoxifen. Interpretation can be recommended for patients with ductal carcinoma in situ treated by complete local excision; however, there is little evidence for the use of tamoxifen in these women. Lancet 23; 362: *Members listed at the end of report Correspondence to: Mrs Joan Houghton, Clinical Trials Group, Department of Surgery, Royal Free and University College Medical School, Charles Bell House, London W1W 7EJ, UK ( j.houghton@ctg.ucl.ac.uk) Introduction Before the National Health Service (NHS) breast screening programme was introduced in the UK in 1988, only a very small proportion of newly diagnosed breast cancers were ductal carcinoma in situ. However, the frequency of diagnosis of this type of disease was expected to increase as a result of the screening programme, 1 and randomised trials were needed to define the best management of small impalpable screen-detected ductal carcinoma in-situ lesions. Before screening programmes, this form of breast cancer was often treated by mastectomy; although effective, this approach is probably an over-treatment for many lesions detected by screening. At that time, results of several randomised trials had shown that breast conservation for invasive cancer was a safe alternative to mastectomy, 2 5 but there was little evidence to recommend this treatment in women with ductal carcinoma in situ. Since ipsilateral breast irradiation is useful in the management of invasive disease treated by complete local excision, we chose to assess this approach in the ductal carcinoma in situ trial. When our trial begain, two other trials of radiotherapy after breast-conserving surgery for women with ductal carcinoma in situ (NSABP B-17 and EORTC 1853) were recruiting patients, but results were not available. We chose also to assess adjuvant tamoxifen in the study because of evidence that this treatment can reduce rates of ipsilateral and contralateral breast cancer in women who had breast-conserving surgery for invasive disease. 6,7 After our trial began, one other study (NSABP B-24) started to investigate the role of tamoxifen in ductal carcinoma in situ after complete local incision and radiotherapy. 8 In our 2 2 factorial trial, we aimed to compare the efficacy of complete local excision alone with excision followed by radiotherapy to the residual ipsilateral breast, or excision followed by tamoxifen for 5 years, or both, in reducing the incidence of subsequent ipsilateral invasive breast carcinoma in patients with ductal carcinoma in situ. Our second objective was to determine the incidence of subsequent ductal carcinoma in situ in the ipsilateral and contralateral breasts of patients treated by complete local excision alone with complete local excision followed by radiotherapy or tamoxifen. Methods Patients We included patients who had unilateral or bilateral ductal carcinoma in situ detected in a breast screening programme, and who were deemed suitable for breast conservation. All UK centres in the national screening THE LANCET Vol 362 July 12,

2 programme were invited to participate. The Australian- New Zealand Breast Cancer Trials Group (ANZBCTG) joined the trial in September, Patients with symptoms who had the ductal carcinoma in situ confirmed in the same way as in screening clinics were also eligible for inclusion. In October, 1993, inclusion criteria were amended to allow patients with microinvasion (ie, <1 mm in diameter) provided the lesion had been completely excised, as defined by free margins. We excluded patients with lobular carcinoma in situ or atypical ductal hyperplasia in the absence of ductal carcinoma in situ, those in whom pathological margins of disease were uncertain, and people with Paget s disease of the nipple. Furthermore, patients who had a reduced life expectancy because of previous or concomitant invasive malignant disease or because of a non-malignant condition were excluded, as were individuals who were unsuitable for any of the treatment options. We gave information leaflets to patients that described the disease, treatment choices, and trial design. Patients gave either written or verbal consent, which was witnessed by a third party. Ethics approval was obtained from local ethics committees at participating hospitals. Procedures A patient s eligibility was determined by their treating surgeon, who completed an eligibility checklist after obtaining consent and receiving a written pathology report. Because clear margins are a key factor in low recurrence rates, we stipulated complete excision of the carcinoma, defined by radiology of the surgical specimen and free margins on histological examination. If ductal carcinoma in situ extended to the margin of the specimen, re-excision was done to establish clear margins. Pathological examination was done to identify the type of ductal carcinoma in situ, to show disease extent, to determine its correlation with mammographic findings and the excision margins, and to confirm the absence of invasion. We did not stipulate a specific technique for margin assessment, although use of surface marking, such as India ink staining, was advised. We recorded the size of lesions and if re-excision was done, an estimate of the maximum diameter of the total lesion was recorded. Slides, blocks, and copies of pathology reports were kept locally to allow subsequent central review. This review is in progress and results will be published separately. Randomisation was independent for each of the two treatments (radiotherapy and tamoxifen), stratified by screening assessment centre, and blocked in groups of four. Trial offices prepared their own schedules using a common algorithm, and these schedules were available only to trial staff who were trained in the procedure. Trial design We used a 2 2 factorial design. Surgeons in discussion with each patient decided whether to enter her into the four-way or one of two separate two-way s. Treatment allocations in accordance with the two-way (excision versus excision and radiotherapy, or excision versus excision plus tamoxifen) were used for patients for whom treatments were not equally suitable or if the patient expressed a preference. Within the two, two-way s, surgeons in discussion with their patient could choose before whether the alternative treatment ie, tamoxifen or radiotherapy should be given in addition to their randomly allocated treatment. Thus, we had two groups control and treated for each main comparison of effects ie, tamoxifen versus control and radiotherapy versus control. In both treated and control groups, the alternate treatment was decided either electively or by. The term control does not necessarily mean untreated. It includes those who were randomised not to have the treatment under evaluation, but who might have had or not had the alternate treatment assigned to them, either by random allocation or by choice. Treatments Patients who had radiotherapy were given supervoltage treatment with tangential fields, that included the whole breast and axillary tail, but with minimum inclusion of the lung. We suggested a dose of 5 Gy in 25 fractions over 5 weeks (tumour dose fractionation [TDF]=82) prescribed at the isocentre or at the point of intersection of the two tangential fields. We did not recommend boost treatment at the excision site. was prescribed at a dose of 2 mg daily for 5 years. Follow-up and data collection The frequency of clinical review was in accordance with local practice, but we stipulated that every clinician should keep to a constant follow-up protocol for all patients in the trial. Yearly bilateral mammography was recommended for the first 7 years and every 2 years thereafter. Dates of histologically confirmed local relapse (ductal carcinoma in situ or invasive cancer), diagnosis of any new non-breast malignant disease, and death whether due to breast cancer or not were noted. Patients in the UK who were lost to follow-up were registered with the Office for National Statistics so that we would be notified of the date, place, and cause of death. Statistical analysis We assumed a local incidence rate of 1% for invasive cancer at 5 years after complete local excision without adjuvant treatment. 5 patients were needed in each of the two groups (control and treated) for each main effects comparison (tamoxifen vs control and radiotherapy vs control) to have 8% power to detect a 5% reduction in recurrence from either treatment ie, a reduction from 1% to 5%. Thus, 1 patients were needed if clinicians randomly allocated patients to all four arms of the trial. However, because many clinicians favoured the two-way, we needed to recruit more than 1 patients overall. To assess effects in the two main treatment comparisons, we confined analysis to those who were allocated to each main treatment comparison. Hence, for the tamoxifen comparison, we analysed results from those patients who were randomly allocated to receive tamoxifen or not to receive tamoxifen. Patients who chose whether they had tamoxifen or not were excluded from analysis of this treatment effect. In the same way, patients who chose whether they received or did not receive radiotherapy were excluded from the main radiotherapy comparison. Thus treatment comparisons were not confounded by the alternate treatment. All analyses were stratified in accordance with whether the alternate treatment had been given or not, and whether this was by choice or because of random treatment allocation. All patients, apart from those incorrectly deemed eligible, have been included in the appropriate analyses as per an intention-to-treat approach. In addition to the primary and secondary endpoints, we assessed the effects of tamoxifen or radiotherapy on the 96 THE LANCET Vol 362 July 12, 23

3 242 randomised to radiotherapy and tamoxifen (T, R) 912 chose to enter randomised to tamoxifen only (T,C R ) 22 randomised to radiotherapy only (C T, R) 226 randomised to no adjuvant treatment (C T, C R ) 1694 entered in study 782 chose to one of the treatments (2-way ) 664 made choice about radiotherapy, and assigned to tamoxifen 118 made a choice about tamoxifen and assigned to radiotherapy 63 elected not to have radiotherapy 61 elected to have radiotherapy 29 elected not to receive tamoxifen 89 elected to have tamoxifen 35 randomised to no tamoxifen (C T, ) 298 randomised to tamoxifen (T, ) 31 randomised to no tamoxifen (C T, ) 3 randomised to tamoxifen (T, ) 13 randomised to no radiotherapy (, C R ) 16 randomised to radiotherapy (, R) 45 randomised to no radiotherapy (, C R ) 44 randomised to radiotherapy (, R) Figure 1: Design of UK DCIS Trial and patient entry Codes indicate the treatment comparison to which that group contributed. T=included in treatment group for tamoxifen comparison. C T =control group for tamoxifen. R=included in treatment group for radiotherapy comparison. C R =control group for radiotherapy. Dotted lines indicate that allocations were by choice: solid lines indicate a random allocation. frequency of new breast events (both DCIS or invasive), ipsilateral events (both DCIS or invasive), contralateral events, and contralateral invasive events. We used the lifetable method to analyse events and compared differences using the stratified logrank test. We compared subgroup analysis hazard ratios by dividing the difference in hazard ratios between the two subgroups by the square root of the sum of the variances, and referring this to a standard normal distribution. All p values are twosided. Role of the funding source The trial was developed by a subcommittee of the UKCCCR (now the National Cancer Research Institute [NCRI]). The trial was done through three trial offices (Cancer Research UK and University College Cancer Trials Office, London; the Scottish Cancer therapy Network, Edinburgh; and the ANZ Cancer Trials Office in, Newcastle, New South Wales, Australia). The Trials Committee of the UKCCCR appointed the working party and the independent data monitoring committee, and the writing group of the working party interpreted the data. Results Between May, 199, and August, 1998, 171 patients were entered in the trial (CRC Breast Cancer Trials Group [879], Scottish Cancer Trials Breast Group [635], and Australian-New Zealand Breast Cancer Trials Group [187]). We excluded seven patients from analysis after because of protocol violations (two had previous malignant disease; four had mastectomy before ; and one had invasive cancer) patients were included in the analysis (figure 1). Unless we had evidence to the contrary, we assumed that patients were free of disease on April 1, 2. At that time, 126 patients (7%) had not been followed-up in the preceding 12 months. 6 patients (4%) had follow-up information missing for more than 24 months. Median follow-up was 52 6 months (range ). 59 patients (3%) had micro-invasive disease, with about the same number in each treatment group. The rate of recurrence in this small subgroup did not differ from that in the overall group. 13 patients (8%) were on hormone replacement therapy at the time of. Because neither factor was confounding, all patients were included THE LANCET Vol 362 July 12,

4 No adjuvant treatment alone alone and tamoxifen Total (n=1694) (n=544) (n=567) (n=267) (n=316) Breast events Ductal carcinoma in situ 76 (14%) 57 (1%) 1 (4%) 7 (2%) 15 (9%) Invasive carcinoma 39 (7%) 43 (8%) 12 (4%) 14 (4%) 18 (6%) Unknown 4 (<1%) 1 (<1%) 5 (<1%) Total 119 (22%) 11 (18%) 22 (8%) 21 (6%) 263 (16%) Woman-years of follow-up Event rate per 1 woman-years All cause deaths (deaths 1 (4) 13 (1) 7 (2) 15 (7) 45 (23) attributable to breast cancer) Data for descriptive purposes only. For comparison of treatment effects, factorial analysis as shown in tables 2 and 3 should be used. Table 1: New breast disease events and deaths by treatment received in analyses. Although the trial was designed for women whose disease was detected through the national screening programme (for those age 5 years or older), 161 (1%) patients were younger than 5 years at (figure 2). Figure 1 shows the number of patients randomised to each treatment group.thus, data for 13 patients were used in comparisons for radiotherapy (58 patients in the control group and 522 in the treated group) and for the tamoxifen analyses there were 782 controls and 794 in the treated group. New breast events 263 women (16%) developed new breast disease during the follow-up period (table 1). Of these, 15 (9%) were recurrent ductal carcinoma in situ and 18 (6%) were invasive cancer; disease type is yet to be confirmed for five patients. Of the 263 events, 223 were in the ipsilateral breast and 35 in the contralateral breast; data are missing for five patients. Table 1 shows the type of new events (ductal carcinoma in situ or invasive cancer) by treatment allocation. The event rate per 1 woman-years was highest in the group who received no adjuvant treatment (4 77), and second highest in the group who received tamoxifen only (3 86). Women in the two groups who received radiotherapy had the lowest event rates. comparison 1576 patients were randomly allocated to groups for the tamoxifen comparison. Of the 794 patients randomised to receive tamoxifen, 86 (11%) stopped taking the drug before 5 years or, for those who had not reached the 5-year point, took it for less than the time they had been on trial. However, of these, 56 had taken at least 2 years of Number of women % 2 6% 6 2% 29% 25 2% 26 4% Age at (years) 7 1% 2 8% Figure 2: Distribution of randomised patients by age at treatment. Of 251 new breast events noted in these patients, 114 arose in the 794 patients who were randomly allocated to receive tamoxifen and 137 in the 782 not given tamoxifen (table 2). did not significantly reduce the overall event rate, nor the rate of invasive events (figure 3). However, it did reduce the overall rate of ductal carcinoma in situ (figure 3). This drop was mostly related to a reduction in ipsilateral ductal carcinoma in situ of 26%. Although we noted fewer contralateral events in patients who had tamoxifen, the total number of events was too small to allow a meaningful comparison. comparison 13 patients were included in the analysis of the effect of radiotherapy. 12 of these patients had new breast events 58 ductal carcinoma in situ, 6 invasive cancer. Data are missing for two patients. Of the 12 new breast events, 38 (7%) were in the 522 patients who were randomly allocated radiotherapy and 82 (16%) in the 58 who did not have this treatment. Thus, the event rate was lower in patients who received radiotherapy than in those who did not (p< 1, table 3). was associated with a reduction in absolute risk of 8 9% for all ipsilateral events, (13 7% in the control group; 4 8% in the irradiated group). Ipsilateral invasive events were reduced by 55% an absolute risk reduction of 2 8% (from 5 3% in the control group to 2 5% in the radiotherapy group) and ipsilateral ductal carcinoma in situ by 64% (figure 4). The rate of contralateral events was not affected by radiotherapy. New non-breast primary cancers 33 (2%) of patients have developed a new non-breast cancer eight have gynaecological tumours (two Randomised Randomised Hazard ratio (95% CI) p to tamoxifen to no (n=794) tamoxifen (n=782) Ipsilateral Invasive 45 (6%) 35 (4%) 1 31 ( ) 23 DCIS 57 (7%) 77 (1%) 74 ( ) 8 DCIS or 12 (13%) 114 (15%) 9 ( ) 42 invasive* Contralateral Invasive 1 (1%) 15 (2%) 66 ( ) 3 Invasive or 11 (1%) 21 (3%) 52 ( ) 7 DCIS* Total invasive 55 (7%) 5 (6%) 1 11 ( ) 59 Total DCIS 58 (7%) 84 (11%) 68 ( 49 96) 3 Total invasive 114 (14%) 137 (18%) 83 ( ) 13 or DCIS DCIS=ductal carcinoma in situ.*for four patients, laterality or invasive status of the tumour were not known. Table 2: New breast events in patients in the tamoxifen comparison 98 THE LANCET Vol 362 July 12, 23

5 endometrial, four ovarian, and two unspecified). Of these, one with an ovarian tumour did not receive adjuvant therapy, three received only tamoxifen, and four had radiotherapy and tamoxifen. Cumulative frequency All breast events Invasive recurrence Ductal carcinoma in situ recurrence 5 1 Years since HR= 83 ( ) p= 13 HR=1 11 ( ) p= 59 HR= 68 ( 49 96) p= Figure 3: Kaplan-Meier curves for cumulative incidence of all breast events, invasive recurrence, and recurrence of ductal carcinoma in situ in patients in the tamoxifen comparison Randomised Randomised Hazard ratio p to to no radiotherapy radiotherapy (95% CI) (n=522) (n=58) Ipsilateral Invasive 15 (3%) 3 (6%) 45 ( 24 85) 1 DCIS 14 (3%) 38 (7%) 36 ( 19 66) 4 Invasive 29 (6%) 69 (14%) 38 ( 25 59) < 1 or DCIS Contralateral Invasive 9 (2%) 6 (1%) 1 5 ( ) 44 Invasive or 9 (2%) 11 (2%) 82 ( ) 65 DCIS* Total invasive 24 (5%) 36 (7%) 62 ( ) 7 Total DCIS 14 (3%) 44 (9%) 31 ( 17 56) < 1 Total invasive 38 (7%) 82 (16%) 43 ( 29 63) < 1 or DCIS* DCIS=ductal carcinoma in situ. *For five patients the laterality of the tumour was unknown, and for two the invasive status was unknown. Table 3: New breast events in patients in the radiotherapy comparison Deaths and their causes 45 patients died during follow-up (table 1). For 23 patients, cause of death was breast cancer or breast cancer was present at death. Of the remaining 22, nine were attributed to cancers other than breast, four to cardiac failure, two to vascular events, and two to other causes. Data were missing for five patients. There are too few deaths for a meaningful analysis of cause of death by treatment. Subgroup analyses To assess whether there were interactions between the effects of radiotherapy and tamoxifen on clinical outcome, we did stratified analyses. Since only about a third of patients in the tamoxifen comparison also received radiotherapy (523), the number of events in these subgroups is small and the 95% CI around the hazard ratios (HR) are wider than for patients who did not receive radiotherapy (153, table 4). The effect of tamoxifen was not altered by radiotherapy with respect to the occurrence of new events. The only significant reduction associated with tamoxifen in the absence of Randomised Randomised Hazard ratio (95% CI) p to tamoxifen to no (n=794) tamoxifen (n=782) Patients not receiving radiotherapy (153) Ipsilateral 37 (5%) 29 (4%) 1 32 ( ) 26 invasive Ipsilateral 5 (6%) 68 (9%) 73 ( ) 1 DCIS Total invasive 42 (5%) 39 (5%) 1 11 ( ) 64 Total DCIS 51 (6%) 75 (1%) 68 ( 47 97) 3 Total invasive 94 (12%) 117 (15%) 8 ( ) 11 or DCIS Patients receiving radiotherapy (523) Ipsilateral 8 (1%) 6 (1%) 1 25 ( ) 68 invasive Ipsilateral 7 (1%) 9 (1%) 75 ( ) 57 DCIS Total invasive 13 (2%) 11 (1%) 1 11 ( ) 8 Total DCIS 7 (1%) 9 (1%) 75 ( ) 57 Total invasive 2 (3%) 2 (3%) 95 ( ) 88 or DCIS DCIS=ductal carcinoma in situ. Table 4: Events in patients randomised to tamoxifen stratified by whether or not they had radiotherapy THE LANCET Vol 362 July 12,

6 radiotherapy was in the rate of ductal carcinoma in situ. For patients who also received radiotherapy, reduction in these events was not significant (table 4). Cumulative frequency All ipsilateral recurrence HR= 38 ( 25 59) p< 1 Ipsilateral invasive recurrence HR= 45 ( 24 85) p= 1 HR= 36 ( 19 66) p< Ipsilateral ductal carcinoma in situ recurrence Years since Figure 4: Kaplan-Meier curves for cumulative incidence of all ipsilateral breast events, invasive cancer, and recurrence of ductal carcinoma in situ allocated to the radiotherapy comparison 475 patients in the radiotherapy comparison did not have tamoxifen and 555 received radiotherapy and tamoxifen. There was no difference between these groups with respect to endpoints related to the occurrence of new events ie, there was no evidence of any treatment interaction (data not shown). As expected, radiotherapy had no effect on the rate of new contralateral events. To compare our results with those from the NSABP B-24 trial, 12 we assessed the effect of radiotherapy and tamoxifen, stratified by age ( 5 years vs >5 years). Table 5 shows the result of the tamoxifen comparison stratified by age at. The numbers of total and ipsilateral events are shown, and the comparable ipsilateral result from the B-24 trial given in parentheses below each set. Investigators in the B-24 trial did not report contralateral events. Only 16 (9 5%) patients in our trial were younger than 5 years at. Of these, 146 were randomised to the tamoxifen comparison, and 11 to radiotherapy or no radiotherapy. There was an association between age and the reduction of risk achieved by radiotherapy, but the number of events in this subgroup of patients is small (table 5). Discussion We report the first analysis of the 1694 eligible patients in the UK/ANZ Trial. Ipsilateral invasive disease was not reduced by tamoxifen. However, radiotherapy was associated with a reduced incidence of ipsilateral ductal carcinoma in situ, but there was no effect on contralateral incidence. 13 patients were randomly allocated to the radiotherapy comparison, which is about the same number of patients investigated in each of the previously reported trials of radiation after breast conserving surgery for ductal carcinoma in situ NSABP B-17 and EORTC ,1 The rate of recruitment into the radiotherapy was substantially slower than that in the tamoxifen, the result of physicians opinions and beliefs in the UK at the time the trial began. Paradoxically, this bias was not because clinicians were electing to give radiotherapy, but rather because they deemed radiotherapy unnecessary if excision of the lesion was complete. Early results from NSABP B-17 had little effect on this belief. At the launch of our trial, data from the NSABP B-17 trial or the EORTC trial were not available. Our findings from the radiotherapy comparison confirm those of the two previous trials, 9,1 in which reductions of about 6% in ipsilateral recurrent ductal carcinoma in situ (64%) and ipsilateral invasive cancer (55%) event rates were reported. At 5 years follow-up, this represents an absolute reduction in the risk of ipsilateral disease of 8 9% for all ipsilateral disease and 2 8% for ipsilateral invasive disease. The reductions in relative risk are similar to those reported from NSABP B-17 in which ipsilateral noninvasive disease was reduced by 47% and invasive disease by 71% and are greater than those reported in the EORTC trial (35% for DCIS and 4% for invasive disease). By contrast with NSABP B-17 and EORTC, our results show a greater risk reduction for ductal carcinoma in situ than for invasive disease. This discrepancy might have important repercussions for future management. The main objective of adjuvant treatments is to reduce the chance of invasive relapse. The drop in occurrence of invasive disease after radiotherapy is much less in our trial than in the NSABP B-17. This difference might be the result of the type of patients entered; the UK trial had older patients than did NSABP B-17, and most of these patients had disease detected through a screening programme. 1 THE LANCET Vol 362 July 12, 23

7 Randomised to tamoxifen Randomised to no tamoxifen Hazard ratio (95% CI) p 5 years DCIS or invasive events Total 14 (18%) 18 (26%) 62 ( ).19 Ipsilateral invasive or DCIS 1 (13%) 15 (22%) 52 ( ) 12 B-24 ipsilateral invasive or DCIS 32 (11%) 48 (16%) ( 62) ( )* ( 9)* >5 years DCIS or invasive events Total 1 (14%) 119 (17%) 85 ( ) 24 Ipsilateral invasive or DCIS 92 (13%) 99 (14%) 95 ( ) 72 B-24 ipsilateral invasive or DCIS 31 (5%) 39 (7%) ( 78) ( )* ( 36)* DCIS=ductal carcinoma in situ. *95% CI and p values for the B-24 trial are our calculations based on binomial approximations. Table 5: Effect of tamoxifen in patients by age at : a comparison with results from the NSABP B-24 trial Of note is that the absolute recurrence rate was lower in this trial than in either of the other two ductal carcinoma in-situ trials. At 5 years, the NSABP B-17 reported 1% and 21% recurrence rate in the radiotherapy and control groups, respectively; the EORTC trial reported 9% and 16%, respectively, at 4 years. Our results show lower rates (4 8% vs 13 7%, respectively), which might be because of our older patient population, but could also be explained by the fact that guidelines produced for management of patients within the UK national screening programme provided greater motivation to achieve clear margins. A detailed pathological study might provide more information. Contralateral event rates did not differ in irradiated and control patients. In the NSABP B-17 trial, at a mean follow-up of 9 months 32 patients reported contralateral disease as a first event (radiotherapy 19; control 13). However in the EORTC trial, with a median follow-up period much the same as that in the UK/ANZ trial, there were 21 contralateral events in the radiotherapy group compared with eight in the no radiotherapy group. Although this difference might be attributable to the requirement in the EORTC trial for a compensatory filter or wedge during radiotherapy, this explanation seems unlikely because the latent interval was too short. Chance is the most likely explanation. To judge the overall benefits of treatment, long-term follow-up of all patients randomised into these trials is needed. The effects of radiotherapy in our trial were much the same whether or not patients received concurrent tamoxifen and irrespective of their age (data not shown). In terms of the number needed to treat, our results indicate that in patients with ductal carcinoma in situ detected by mammography, treatment of 36 women with a 5-week course of radiotherapy will prevent the development of one invasive tumour in the ipsilateral breast in the first 5 years of follow up. Although to have radiotherapy is a personal choice made by a woman and her oncologist, our data and those from the two previously reported trials lend support to its use after breast conserving surgery for localised ductal carcinoma in situ. Results from all three trials leave a number of issues outstanding. Do all women need radiotherapy irrespective of the pathological features of the tumour? Pathological review of the NSAPB B-17 trial 11 showed that radiotherapy is of substantial benefit in patients whose tumours included moderate to marked comedonecrosis and a non-significant benefit in those tumours of poor nuclear grade. In the same pathological review, 17% of patients had uncertain or involved margins despite the fact that clear margins were a prerequisite for trial entry. The benefit of radiotherapy was most striking in patients with uncertain or involved margins. The importance of margin status is also apparent in the non-randomised study from Silverstein and colleagues, 12 which showed that the most significant effect of radiotherapy was in those patients with margins of less than 1 mm. Pathological review of specimens from our trial will probably show that, like those in B-17, some patients had involved margins because at inception the importance of margin status and its assessment was not fully understood. When complete, this pathological review might shed light on questions about the grade and to some extent on margin status. By contrast, our results for tamoxifen differ from the only other trial to investigate this drug after complete excision. 11 We had about the same number of patients as the NSABP B-24 trial, but noted only a slight effect of tamoxifen that seemed to be restricted to a reduction in recurrent ductal carcinoma in situ. In the B-24 trial, total number of new breast cancer events was significantly lower in patients taking tamoxifen than in the control group and this was most striking for invasive disease. There was also a non-significant trend for a reduction in non-invasive disease. In the B-24 trial, all patients had radiotherapy before to tamoxifen, whereas in our trial only 523 (33%) in the tamoxifen comparison received radiotherapy. Although this difference could provide an explanation of the differences between the two trials, our sub-group analyses show the same pattern of results for tamoxifen both in the absence and in the presence of radiation (table 4). There was no evidence of an interaction for any of the endpoints. There was no evidence of an interaction for any of the endpoints. Thus, the data are consistent with a number of interpretations: (1) that the tamoxifen effect is similar in patients who did or did not receive radiotherapy; or (2) that tamoxifen did not produce additional benefit over and above that provided by radiotherapy; or indeed (3) that the study is not large enough to reliably detect any differences. The variation in findings of the two trials, therefore, cannot be explained by the difference in background therapy. The number of new breast events was much the same in both trials (256 for our trial vs 214 in the B-24 trial), indicating that the discrepancies are not likely to be caused by differences in power. However, they might be partly explained by the different age distributions in the trials in the B-24 trial 33 5% of patients were younger than 5 years, compared with only 9 5% in our trial. In the B- 24 trial, the main effect of tamoxifen was in those patients under the age of 5 years, who had a reduction in ipsilateral event rate from 3 33 to 2 8. In the group of women older than 5 years, the reduction in ipsilateral event rate was much less obvious, falling from 1 3 to 1 2 per 1 woman-years. When results of our trial and the B-24 trial are stratified by age (greater than or less than 5 years), the results for each trial are much the same (table 5). The number of patients younger than 5 years in the UK/ANZ trial is small, but the pattern of events in the two agegroups and between the trials are broadly the same. THE LANCET Vol 362 July 12,

8 However, tamoxifen was associated with a greater reduction in hazard for women under 5 years than it was in those older than 5 years. In Europe, most ductal carcinoma in situ is diagnosed in women older than 5 years because of the age-group that is offered screening. Because our results show no significant difference in the ipsilateral event rates between patients in the control and tamoxifen groups, we do not support the routine use of tamoxifen in women over 5 years who have localised ductal carcinoma in situ. Further follow-up of patients from these trials (and new trials designed to specifically address this question) might provide more information about the role of tamoxifen for such patients. In trials to evaluate the role of tamoxifen, another important endpoint is undoubtedly the incidence of subsequent gynaecological cancer, especially of the endometrium. Eight gynaecological tumours have been diagnosed and seven of these (including two endometrial) arose in the 883 patients who received tamoxifen, compared with one non-endometrial gynaecological cancer in the patients who did not have tamoxifen. This difference was not significant. In B-24, there were seven endometrial cancers in the tamoxifen group and two in the placebo group (non-significant); further follow-up of patients in both trials is needed. The results of our trial confirm the previously reported benefit of radiotherapy after breast conserving surgery for ductal carcinoma in situ. However, unresolved issues remain, especially about whether radiotherapy is necessary for patients at low risk of recurrence. Our results do not lend support to the use of tamoxifen in women older than 5 years with ductal carcinoma in situ, apart from in randomised trials. Longer follow-up might clarify the situation. Trials of tamoxifen or of newer endocrine agents such as the aromatase inhibitors, perhaps with stratified by hormone receptor status, are needed to assess the true role of endocrine agents in prevention of ipsilateral recurrence and the prevention of contralateral disease. Contributors All members of the working party contributed to the concept of the trial, trial design, and interpretation of data analysis. J Cuzick and C Duggan did the data analysis. The writing group drafted and revised the manuscript, but all members of the working party reviewed major revisions and contributed to the intellectual content of the manuscript. Conflict of interest statement None declared. Acknowledgments We thank patients who participated in this trial and their clinicians who undertook the additional work to complete trial documentation; all other staff (especially nurses and data managers) at the clinical centres who assisted with the trial; trial coordinators, data managers, and support staff at the three trial centres, without whom the trial would not have been completed; members of the working party who are now retired, particularly Prof C A Joslin and H J Stewart (H J Stewart was responsible for the coordination of the trial before it was transferred to the Scottish Cancer Therapy Network); members of the data monitoring committee who regularly reviewed the trial; P Twentyman (died August, 21) and J Hearn of the UKCCCR for their support and help with the trial. In Australia and New Zealand the trial was funded by a grant from the Royal Australasian College of Surgeons. In the UK it was funded through the UK Coordinating Committee on Cancer Research (UKCCCR) by grants from the Cancer Research Campaign, the Imperial Cancer Research Fund, and the Medical Research Council. UK Coordinating Committee on Cancer Research (UKCCCR) Ductal Carcinoma in situ (DCIS) working party W D George* (chair), Western Infirmary, Glasgow, UK; Joan Houghton* (Secretary) University College, London, UK; Joan Austoker, Institute of Health Sciences, Oxford University, UK; Hugh Bishop, Royal Bolton Hospital, UK; Jack Cuzick* (Statistician), ICRF, London; Catherine Duggan*, ICRF, London; Ian S Fentiman*, Guy s Hospital, London; John F Forbes, Mater Misericordiae Hospital, Newcastle, Australia; Elizabeth Foster, Scottish Cancer Therapy Network Central Office, Edinburgh, UK; Ian Ellis, Nottingham City Hospital, UK; Samuel Leinster, University of East Anglia, UK; Margaret Spittle*, The Middlesex Hospital and Norman Williams, University College, London, UK. *Were also members of the writing group Former members of the working party were C Joslin (previous chair), H Stewart (previous secretary), M Baum, R Campbell, C Elston, P Stroner, I Taylor, C Teasdale. Data monitoring committee T Cooke (chair) Glasgow Royal Infirmary, UK; K MacPherson, London School of Hygiene and Tropical Medicine, UK; T Priestman, New Cross Hospital, Wolverhampton, UK; and J Sloane (died May, 2), Royal Liverpool Infirmary. Trials office staff For the Cancer Research UK and UCL Cancer Trials Centre J Houghton, N Williams, D Riley, S Moritz, U Wells, K Bellenger, E Coles, J Chan; for Scottish Cancer Therapy Network (SCTN) E Foster, P Stroner, C MacDonald, A Douglas, R Campbell; for ANZBCTG: J F Forbes, A Wilson, S Hornery and D Lindsay. A list of participating physicians can be seen at References 1 Anderson TJ, Lamb J, Donnan P, et al. Comparative pathology of breast cancer in a randomised trial of screening. Br J Cancer 1991; 64: Veronesi U, Salvadori B, Luini A, et al. Breast conservation is a safe method in patients with small cancer of the breast. Long-term results of three randomised trials on 1,973 patients. Eur J Cancer 1995; 31A: Fisher B, Redmond C, Poisson R, et al. Eight-year results of a randomized clinical trial comparing total mastectomy and lumpectomy with or without irradiation in the treatment of breast cancer. N Engl J Med 1989; 32: Van Dongen JA, Bartelink H, Fentiman IS, et al. Factors influencing local relapse and survival and results of salvage treatment after breastconserving therapy in operable breast cancer: EORTC Trial 181, breast conservation compared with mastectomy in TNM stage I and II breast cancer. Eur J Cancer 1992; 28A : Jacobson JA, Danforth DN, Cowan KH, et al. Ten-year results of a comparison of conservation with mastectomy in the treatment of stage I and II breast cancer. N Engl J Med 1995; 332: Cuzick J, Baum M. and contralateral breast cancer. Lancet 1985, 2: Fornander T, Cedermark B, Mattson A, et al. Adjuvant tamoxifen in early breast cancer: occurrence of new primary cancers. Lancet 1989; 2: Fisher B, Dignam J, Wolmark N. in the treatment of intraductal breast cancer: National Surgical Adjuvant Breast and Bowel Project B-24 randomised control trial. Lancet 1999; 353: Fisher B, Dignam J, Wolmark N, et al. Lumpectomy and radiation therapy for the treatment of intraductal breast cancer: findings from National Surgical Adjuvant Breast and Bowel Project B-17. J Clin Oncol 1998; 16: Julien JP, Bijker N, Fentiman IS. in breast conserving treatment for ductal carcinoma in situ: first results of the EORTC randomised phase 3 trial Lancet 2; 355: Fisher ER, Dignam J, Tan-Chiu E et al. Pathologic findings from the National Surgical Adjuvant Breast Project (NSABP) 8 year up-date of protocol B-17. Cancer 1999; 86: Silverstein MJ, Lagios MD, Groshen S, et al. The influence of margin width on local control of ductal carcinoma in situ of the breast. N Engl J Med 1999; 34: THE LANCET Vol 362 July 12, 23