Margins in Ductal Carcinoma In Situ: Is Bigger Really Better?
Breast cancer is now recognized to be a group of genetically distinct diseases with different behaviors. Outcomes are maximized when therapy is tailored to patient and disease characteristics. Ductal carcinoma in situ (DCIS) can be eliminated with mastectomy, but this approach is considered unnecessarily radical in most cases for an entity that is non–life threatening, usually asymptomatic, and may not progress to invasive cancer. Breast-conserving surgery (BCS) consisting of removal of the DCIS to clear margins (tumor not touching the inked surface) is the minimal standard of care. The need for negative margins is already incorporated in guidelines for DCIS management based on strong evidence from randomized clinical trials ( 1–3 ), as well as a meta-analysis of the individual patient data from the randomized trials of BCS vs BCS and radiotherapy (RT) ( 4 ). The main topic of debate now is whether more widely clear margins of resection can eliminate the need for RT.
In this issue of the Journal, Wang et al. ( 5 ) use a network meta-analysis of the impact of different margin widths on local recurrence (LR) in DCIS to reach the somewhat surprising conclusion that wider margins should be a “priority” for all DCIS patients, regardless of the receipt of RT. This recommendation is based upon an analysis of 24 cohorts from 21 studies (three randomized trials) involving 7564 patients treated over 25 years. A margin width of 10 mm or greater was observed to decrease the risk of LR compared with a margin of 2 mm or greater (odds ratio = 0.46; 95% confidence interval = 0.29 to 0.69), leading to a recommendation by the authors for wide excision. This would represent a major change in the current standard surgical approach to DCIS, as illustrated even by the selected dataset used in the meta-analysis, where margins greater than 1 cm were obtained in only 4% of patients treated with RT and in 9% of those treated with excision alone. Before embarking on such a change in practice, clinicians need to ask whether the observed association between larger margins and lower LR is valid, whether there is evidence of a causal relationship, and whether this change would improve the health of women with DCIS.
In any observational study, there is concern that the results could be influenced by important confounding factors. This is a particularly challenging problem in this meta-analysis incorporating the results of many observational studies where patients were not randomly assigned to the different margin widths. In fact, the authors acknowledge the possibility that bias caused by unobserved selection effects across studies cannot be excluded, particularly when only five of 21 studies included in the meta-analysis reported margin widths of 1 cm or more. This subset of patients may have differed from the much larger cohort used to determine recurrence for patients with smaller margins in ways that could result in the lower rate of LR. For example, they may have been older age ( 4 ), had lower tumor grade ( 4 ), or greater use of boost dose of RT ( 6 ), or tamoxifen ( 3 )—all factors that can have an important effect on risk of LR. Furthermore, the treatment cohorts may have differed with regard to margin processing and evaluation, which was not standardized between institutions or even within institutions over time. The patients in the five studies evaluating 1 cm margins were generally treated in a more recent time period than those in the other 16 studies, and rates of LR have declined over time because of improvements in imaging and pathology independent of margin width ( 7 ). The inability to control for this complex, but potentially powerful, residual confounding may limit the validity of the findings.
Another challenge to this study is the uncertainty in the inference of causality ( 5 ). It is just as clinically plausible to hypothesize that tumors with more favorable prognosis were more likely to result in more widely clear margins. Results from a prospective study of a large group of patients with DCIS conducted by the Eastern Cooperative Oncology Group ( 8 ) do not support a causal relationship between margin width and LR. In that 671-patient study, a minimal margin width of 3 mm was required, complete embedding and sequential sectioning of the specimen were specified, and post-excision mammograms were mandated, removing many of the sources of variation present in retrospective studies. In this context, the actuarial risk of LR at 5 years did not differ statistically significantly between patients with margins of 1 cm or greater (n = 329) compared with those with smaller margins (n = 332), even after stratification by grade.
The final question concerns the potential consequences of adopting a margin threshold of 1 cm as a priority for women with DCIS. Re-excision is already a common procedure; in a recent population-based study ( 9 ), 31% of women with DCIS successfully treated with breast conservation unde (...truncated)