Two randomized trials on DCIS treatment: fifteen year followup
Study Design: Two prospective randomized trials conducted by the National Surgical Adjuvant Breast and Bowel Project (NSABP). In the first trial, NSABP B-17, patients with localized DCIS were randomly assigned to lumpectomy only (LO) group or lumpectomy followed by radiation (LRT). The second trial, NSABP B-24, was a double-blinded, placebo-controlled trial that compared LRT + tamoxifen (TAM) versus LRT + placebo. The primary endpoint was event-free survival.
Study Eligibility: B-17: Women with localized DCIS detected by physical examination or mammography were eligible for the study. Exclusion criteria consisted of women with previous cancers or tumor-positive axillary nodes on clinical examination. B-24: Women with DCIS were eligible for inclusion if their life expectancy was at least 10 years. Also, unlike B-17, patients whose tumor margin status was involved or uncertain with DCIS were eligible, as well as women whose mammograms contained foci of calcifications that were not excised, as long as their radiological appearance was not suggestive of invasive cancer.
Enrollment: B-17: 818 total randomized, 405 with LO and 413 with LRT; B-24: 1,804 total randomized, 902 with LRT + placebo and 902 with LRT + TAM. Ten patients were dropped for various reasons.
Research Question: What is the impact of invasive ipsilateral breast tumor recurrence (I-IBTR) on the long-term prognosis of patients receiving breast-conserving treatments for DCIS?
Invasive ipsilateral breast tumor recurrence (IBTR), or invasive breast cancer in the same breast that was previously treated, is the most common event that disrupts disease-free survival for DCIS patients after lumpectomy. The NSABP B-17 study began in 1985, comparing IBTR after lumpectomy only (LO) and lumpectomy followed by radiation (LRT) for DCIS patients. At the time, the study was groundbreaking, and the findings showed a 60% reduced risk of IBTR in women treated by LRT compared to LO alone. A second prospective randomized trial, the NSABP B-24 trial, added tamoxifen (TAM) to LRT, and compared IBTR after LRT + TAM versus LRT + placebo. The results showed a 31% reduction in risk of IBTR in patients treated with LRT + TAM versus LRT + placebo. In the current study, these two trials are compared to investigate the 15-year incidence of invasive IBTR (I-IBTR) and other local or regional failures. Failures were defined as any event that disrupted event-free survival (i.e. tumors, death).
In the NSABP B-17, 403 patients with localized DCIS were randomly assigned to lumpectomy only (LO) and 410 patients to a lumpectomy followed by radiation (LRT). In NSABP B-24, there were 899 patients randomly assigned to the LRT + tamoxifen (TAM) and 900 to the LRT + placebo arm. The two trials consisted of populations with similar disease characteristics. With respect to age, 50% of women were 55 years or older and 22% of women 65 years of age and older. More than 75% of tumors measured less than 1 cm in diameter, and 80% of patients had their cancers detected by mammography. The radiation therapy began 8 weeks after surgery and lasted 5 weeks.
After a median follow-up of 207 months and 162 months for the B-17 trial and B-24 trial, respectively, 490 IBTR events occurred, 263 (53.7%) of which were invasive. The 15-year cumulative incidence of I-IBTR for LO, LRT, LRT + placebo, and LRT + TAM were 19.4%, 8.9%, 10.0%, and 8.5% respectively. Both radiation and tamoxifen were found to reduce the risk of I-IBTR, with LRT yielding a 52% risk reduction compared to LO, and the LRT + TAM have a 32% reduced risk compared to the LRT + placebo arm. In terms of non-invasive IBTR (DCIS-IBTR), rates appeared to diminish after 5 years, while I-IBTR rates remained relatively constant over time. In addition, radiation and tamoxifen reduced contralateral breast cancers (CBC) but did not appear to effect cumulative incidence. Local, regional, and distant failure events did not prove to be significantly associated with treatment, nor did tumor characteristics and risk of I-IBTR. However, the risk of I-IBTR was shown to be significant with age, with women younger than 45 years exhibiting a 2.1-fold increased risk compared to women 65 and older. Finally, the 15-year cumulative incidence of breast cancer death was not much difference between treatment groups and was below 5% all groups.
Although I-IBTR increases the risk of breast cancer-specific death, the advantages of radiation treatment and tamoxifen in addition to a lumpectomy are apparent, with LRT + TAM treatment regimes resulting in a reduced risk of future I-IBTR compared to lumpectomy alone. While the NSABP trials include a large number of participants, one of the limitations of this study was the sample size difference of nearly 1,000 patients between the B-17 and B-24 trials. Ideally, sample populations should be similar in size to increase confidence in results. In addition, the authors cite other limitations such as the inferior diagnostic technologies that existed 20 years ago at the beginning of the study. Hormone receptor and HER-2 status information were also not available due to the dated trials. Lastly, the difference in tumor margins also differed between B-17 and B-24, which may have an unknown bias on the results.
Irene L. Wapnir, James J. Dignam, Bernard Fisher, Eleftherios P. Mamounas, Stewart J. Anderson et al. Long-Term Outcomes of Invasive Ipsilateral Breast Tumor Recurrences After Lumpectomy in NSABP B-17 and B-24 Randomized Clinical Trials for DCIS. JNCI. 2011 Mar 16; 103 (6): 478-88.
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