Fast track — ArticlesTamoxifen in treatment of intraductal breast cancer: National Surgical Adjuvant Breast and Bowel Project B-24 randomised controlled trial
Introduction
Until the mid-1980s, mastectomy followed by axillary dissection was the preferred treatment for primary invasive breast cancer and ductal carcinoma in situ (DCIS). That therapeutic approach was challenged, however, as a result of more widespread use of better diagnostic equipment and an increased effort to educate women about the value of early detection of breast tumours. Invasive and non-invasive tumours were found more frequently and at earlier stages, often before they became clinically evident. Before the availability of mammography, fewer than 3% of newly diagnosed breast cancers were DCIS, and most presented as large palpable masses, many with areas of microinvasion.1, 2 Since the introduction of mammography, 20–30% of mammographically detected cancers are DCIS.3
The management of primary invasive breast cancer and DCIS was influenced by a report which showed that the outcome in women with invasive breast cancer treated by lumpectomy and radiation therapy was similar to that of women treated by radical or modified radical mastectomy.1 Mastectomy for the treatment of invasive disease therefore became more difficult to justify for invasive disease, but was frequently advocated for the management of DCIS, a non-invasive cancer. Thus, surgery for removal of localised DCIS was commonly more radical than that for removal of localised invasive disease. Uncertainty therefore arose about the clinical management of women with small, localised DCIS detected by mammography, and prompted the National Surgical Adjuvant Breast and Bowel Project (NSABP) to do the B-17 study, a randomised controlled trial to investigate whether excision of localised DCIS with tumour-free sample margins (referred to as lumpectomy, although most women had no palpable mass) followed by radiation therapy was more effective than lumpectomy alone in prevention of an invasive tumour in the ipsilateral breast.5
The first findings of B-17 reported a significantly better overall 5-year event-free survival because of lower incidence of invasive and non-invasive ipsilateral-breast cancers among women who underwent lumpectomy and radiation therapy.5 At 8 years, findings were confirmed of lower cumulative incidence of both types of ipsilateral-breast cancer because of lumpectomy and radiation therapy for localised mammographically detected DCIS.6 The study concluded that, because of the low recurrence rate of invasive ipsilateral-breast cancer, mastectomy was not warranted in women who had DCIS similar to that of B-17 participants.
Many women were ineligible for participation in B-17 because mammography showed diffuse DCIS and resected sample margins contained DCIS, or scattered calcifications were thought to be benign or associated with unremoved DCIS. Those women were mainly treated by mastectomy. Tamoxifen had been shown in animal studies to have anti-initiator and antipromoter properties.7, 8 We have also reported that tamoxifen prevents tumour recurrences in the ipsilateral breasts and second primary tumours in the contralateral breasts of women who have undergone lumpectomy and radiation therapy for primary invasive breast cancer,9, 10 which suggests that tamoxifen can interfere with development of primary invasive breast cancer from the start or with progression of DCIS to invasive cancer. As a result, we designed the NSABP B-24 randomised controlled trial. The B-17 and B-24 studies were based on the idea that DCIS either progresses from non-invasive to invasive cancer or is a marker of risk rather than a progenitor for the subsequent occurrence of an invasive tumour, or that a focus of invasive cancer existing in conjunction with DCIS might remain after lumpectomy. In the B-24 study, a double-blind randomised controlled trial, we tested the hypothesis that, in patients with non-invasive DCIS, treatment with lumpectomy, postoperative radiation therapy, and tamoxifen would be more effective than lumpectomy and radiation therapy alone in prevention of invasive and non-invasive cancers in the ipsilateral and contralateral breast. We present results from B-24 and relate them to those from B-17 and the NSABP P-l prevention trial.11
Section snippets
Patients
Women with DCIS were eligible for inclusion if their life expectancy was at least 10 years. Women with tumours that consisted of DCIS and lobular carcinoma in situ (LCIS) were also eligible. Although we did not require or recommend axillary dissection in B-24, if it was done, all lymph nodes had to be negative for tumour on histological assessment. Time between surgery and randomisation had to be 56 days or less. Women who had previously been diagnosed with cancer, except for those who had had
Results
1804 women were randomly assigned treatment between May 9, 1991, and April 13, 1994 (figure 1). 29 (1·6%) patients (11 on placebo, 18 on tamoxifen) became ineligible after randomisation because primary tumours showed characteristics other than those of non-invasive intraductal carcinoma (13) or because surgery after diagnosis was delayed, surgical procedures were not done correctly, because of previous cancers, or because of other reasons (16). Of the 1804 randomised patients, 14 (0·8%) did not
First events
There were 295 breast-cancer and non-breast-cancer events among the 1798 patients with follow-up (table 2). At 5 years of follow-up, 83·3% (95% CI 80·8–85·8) of patients who received placebo were event-free compared with 87·4% (85·1–89·6) of tamoxifen-treated patients (data not shown).
Among patients who received placebo, 130 invasive and non-invasive breast-cancer events occurred in the ipsilateral breast, contralateral breast, or presented as metastases at regional or distant sites, compared
Relation of characteristics to outcome
Age at diagnosis was significantly associated with occurrence of ipsilateral-breast tumour. Younger patients in the two groups were at higher risk than older patients for such an event (table 3). The annual rate of ipsilateral-breast tumour per 1000 women aged 49 years or younger who received placebo was 33·3 and 13·03 for those aged 50 years or older. Tamoxifen administration resulted in a 38% reduction in ipsilateral-breast tumours in women younger than 50 years and a 22% reduction in women
Survival
28 women in the placebo group and 26 in the tamoxifen group died. At 5 years from study entry, survival was 97% (96–98) for the two groups (p=0·74, data not shown). Six of the 28 women in the placebo group had invasive breast cancer and two of these six had invasive ipsilateral-breast tumours. Four women on tamoxifen had invasive breast cancer, and three of these four had invasive ipsilateralbreast tumours. One developed a new primary cancer.
Adverse events
Information about toxic events was available for 1781 (98·7%) randomised patients (table 4). No strokes were seen in the two groups. Grade 4 toxic effects not usually associated with tamoxifen occurred with similar rates in the two groups. There was an increase in the rate of endometrial cancer in tamoxifen-treated patients, (1·53 vs 0·45 per 1000 patients per year in the placebo group). No deaths from endometrial cancer occurred in the tamoxifen group.
Discussion
Women with DCIS treated by lumpectomy and radiation therapy showed additional benefit from tamoxifen. The advantage was due mainly to a decrease in the rate of invasive cancer, especially in the ipsilateral breast. That effect was also seen in the rate of invasive and non-invasive tumours in the contralateral breast and at regional or distant sites. When the events of those sites were combined, there was a significantly lower rate and cumulative incidence of all breast-cancer-related events
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