Download Margins in Ductal Carcinoma In Situ: Is Bigger

DOI: 10.1093/jnci/djs165
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EDITORIALS
Margins in Ductal Carcinoma In Situ: Is Bigger Really Better?
Monica Morrow, Steven J. Katz
Correspondence to: Monica Morrow, MD, Breast Service, Department of Surgery, Memorial Sloan-Kettering Cancer Center, 300 E. 66th St, New York,
NY 10065 (e-mail: [email protected]).
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 metaanalysis 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
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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 populationbased study (9), 31% of women with DCIS successfully treated with
breast conservation underwent re-excision (9). This proportion
would undoubtedly increase if a policy of more widely clear margins
is adopted because approximately half of the re-excisions in a recent
report were performed to achieve an arbitrary margin width greater
than tumor cells not touching ink (10). More importantly, this recommendation may result in more women being deemed ineligible
for BCS by their surgeons initially and more women choosing to
undergo mastectomy after an initial BCS attempt fails to achieve the
“best” margin width because fear of LR is strongly associated with
mastectomy use (11). Prospective trials have not identified a subset
of women not benefiting from RT, and more accurate estimates of
RT use in DCIS than the 50% cited by Wang et al. (5) suggest rates
above 70% (11,12). This suggests that aggressive surgical treatment
will do more harm than good because only a minority of patients
treated without RT might benefit from a wider margin, whereas a
much larger group would be subject to overtreatment.
Vol. 104, Issue 7 | April 4, 2012
Ultimately, this article illustrates the challenges to making
clinical policy recommendations based on observational data.
Meta-analyses, regardless of the sophistication of the analytic
technique used, are only as good as the data they include. The
Early Breast Cancer Trialists Collaborative overview analysis has
been such a powerful force in invasive breast cancer management
because it includes patient-level analysis of data from prospective
randomized trials. This approach resulted in the identification of
the survival benefit associated with local control that was not seen
in any of the individual trials of BCS with and without RT (13) and
clarified estimates of the effect of many of the systemic therapies
used today. Although trials are generally superior to retrospective
approaches, we must ask in the end whether a study of margin
width is worthy of the large investment such a trial would necessitate. This is not an ethical issue, as suggested by Wang et al. (5),
because the “right” margin width remains uncertain. But there is
an issue of feasibility. Although margin width remains a clinical
dilemma, in the National Surgical Adjuvant Breast and Bowel Project
B17 and B24 trials that required margins of tumor not touching ink,
only 72 (2.8%) of 2612 participants treated with BCS with and
without RT died of breast cancer after 15 years of follow-up (3).
Thus, any net benefit of more widely clear margins on the overall
health of women with DCIS would be extremely small or negligible.
The patient and financial resources needed for a study to quantify
such a small difference are likely to do more good if devoted to
identifying those factors that result in the progression of DCIS to
invasive cancer—knowledge that is critical to our ability to tailor the
extent of treatment and optimize net benefit in individual patients.
Observational research on the margin question would be greatly
facilitated by the adoption of a standard method of specimen processing and examination. At present, there is no compelling evidence
that bigger is better for margins in DCIS, and physicians should be
cautious about the routine use of large resections or re-excision to
achieve an arbitrary negative margin width.
2. Holmberg L, Garmo H, Granstrand B, et al. Absolute risk reductions for
local recurrence after postoperative radiotherapy after sector resection for
ductal carcinoma in situ of the breast. J Clin Oncol. 2008;26(8):
1247–1252.
3. Wapnir IL, Dignam JJ, Fisher B, 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. J Natl Cancer Inst. 2011;
103(6):478–488.
4. Correa C, McGale P, Taylor C, et al. Overview of the randomized trials
of radiotherapy in ductal carcinoma in situ of the breast. J Natl Cancer Inst
Monogr. 2010;2010(41):162–177.
5. Wang SY, Chu H, Shamliyan T, et al. Network meta-analysis of margin
threshold for women with ductal carcinoma in situ. J Nat Can Inst.
2012;104(7):507–516.
6. Omlin A, Amichetti M, Azria D, et al. Boost radiotherapy in young
women with ductal carcinoma in situ: a multicentre, retrospective study of
the Rare Cancer Network. Lancet Oncol. 2006;7(8):652–656.
7. Rudloff U, Jacks LM, Goldberg JI, et al. Nomogram for predicting
the risk of local recurrence after breast-conserving surgery for ductal
carcinoma in situ. J Clin Oncol. 2010;28(23):3762–3769.
8. Hughes LL, Wang M, Page DL, et al. Local excision alone without
irradiation for ductal carcinoma in situ of the breast: a trial of the
Eastern Cooperative Oncology Group. J Clin Oncol. 2009;27(32):
5319–5324.
9. Morrow M, Jagsi R, Alderman AK, et al. Surgeon recommendations and
receipt of mastectomy for treatment of breast cancer. JAMA. 2009;
302(14):1551–1556.
10. McCahill LE, Single RM, Aiello Bowles EJ, et al. Variability in reexcision
following breast conservation surgery. JAMA. 2012;307(5):467–475.
11. Katz SJ, Lantz PM, Janz NK, et al. Patterns and correlates of local therapy
for women with ductal carcinoma-in-situ. J Clin Oncol. 2005;23(13):
3001–3007.
12. Jagsi R, Abrahamse P, Hawley ST, et al. Underascertainment of
radiotherapy receipt in Surveillance, Epidemiology, and End Results
registry data. Cancer. 2012;118(2):333–341.
13. Darby S, McGale P, Correa C, et al. Effect of radiotherapy after breastconserving surgery on 10-year recurrence and 15-year breast cancer death:
meta-analysis of individual patient data for 10,801 women in 17 randomised
trials. Lancet. 2011;378(9804):1707–1716.
References
The authors declare no conflicts of interest.
1. Bijker N, Meijnen P, Peterse JL, et al. Breast-conserving treatment with or
without radiotherapy in ductal carcinoma-in-situ: ten-year results of European
Organisation for Research and Treatment of Cancer randomized phase III
trial 10853—a study by the EORTC Breast Cancer Cooperative Group and
EORTC Radiotherapy Group. J Clin Oncol. 2006;24(21):3381–3387.
jnci.oxfordjournals.org Notes
Affiliations of authors: Breast Service, Department of Surgery, Memorial
Sloan-Kettering Cancer Center, New York, NY (MM); Department of
Medicine and Department of Health Management and Policy, University of
Michigan, Ann Arbor, MI (SJK).
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