|Ahead of print publication
Comparison of local recurrence after mastectomy for pure ductal carcinoma in situ with close or positive margins: A meta-analysis
Donghyun Kim1, Yongkan Ki2, Wontaek Kim1, Dahl Park1, Jihyeon Joo2, Hosang Jeon2, Jiho Nam1
1 Department of Radiation Oncology, Biomedical Research Institute, Pusan National University Hospital and Pusan National University School of Medicine, Busan, Korea
2 Department of Radiation Oncology, Pusan National University Yangsan Hospital and Pusan National University School of Medicine, Yangsan, Korea
|Date of Submission||07-Mar-2019|
|Date of Decision||24-Aug-2019|
|Date of Acceptance||17-Oct-2019|
|Date of Web Publication||09-Jun-2020|
Department of Radiation Oncology, Pusan National University Yangsan Hospital and Pusan National University School of Medicine, Yangsan 50612
Source of Support: None, Conflict of Interest: None
Background: There is controversy regarding the relationship between margin status and risk of local recurrence (LR) in patients with Ductal carcinoma in situ(DCIS) treated by mastectomy.
Purpose: We sought to assess the LR rates for patients with DCIS breast cancer treated by mastectomy with respect to the resection margin (RM) status.
Materials and Methods: Systematic search of MEDLINE, EMBASE, and Cochrane library published was performed. Studies of pure DCIS breast cancer with treatment of mastectomy and studies that reported surgical RM and LR were included.
Results:A total of 12 retrospective studies were included, encompassing 2902 patients with a mean follow-up of 86.4 months. Overall LR rates were 5.3% (27/508) for positive or close margins and 1.6% (37/2367) for negative margin, and most of the recurrences (93.7%) are invasive cancers. Patients with positive or close margins showed a 3.72-fold (95% confidence interval [CI] = 2.30–6.01,P < 0.01, I = 11%) higher risk of LR than patients with negative margin. Patients with positive margin showed a 2.91-fold (95% CI = 1.14–7.41,P = 0.03, I = 0%) higher risk of LR than patients with close margin. Postmastectomy radiation therapy (RT) was not associated with a decreased risk of LR (Risk ratio 0.50; 95% CI = 0.06–4.08,P= 0.52, I = 0%) in patients with positive or close margins.
Conclusions: The RM status after mastectomy has a great impact on LR. However, the recurrence rate was insufficient to warrant a recommendation for postmastectomy RT in patients with close or positive margins.
Keywords: Ductal carcinoma in situ, local recurrence, margin, mastectomy, meta-analysis
|How to cite this URL:|
Kim D, Ki Y, Kim W, Park D, Joo J, Jeon H, Nam J. Comparison of local recurrence after mastectomy for pure ductal carcinoma in situ with close or positive margins: A meta-analysis. J Can Res Ther [Epub ahead of print] [cited 2020 Sep 27]. Available from: http://www.cancerjournal.net/preprintarticle.asp?id=286250
| > Introduction|| |
Ductal carcinoma in situ (DCIS) is a noninvasive form of breast cancer where proliferating malignant cells are confined within the basement membrane of the mammary ductal system. The incidence of DCIS is increasing with the widespread use of population-based screening mammography. The surgical treatment for DCIS includes breast conserving surgery with or without adjuvant radiation therapy (RT) and mastectomy. For an increasing proportion of patients with DCIS, breast conserving therapy has been favored. Nevertheless, up to 30% of pure DCIS patients still undergo mastectomy for a variety of reasons that include extensive or multicentric disease, BRCA mutation carriers, not candidates for RT, and the patient's preference.
Mastectomy for DCIS offers excellent outcomes in terms of survival and local control. Local recurrence (LR) after mastectomy for DCIS has historically been demonstrated as low, with the UK SLOANE audit reporting a 1% LR rate, and a meta-analysis incorporating 9391 patients demonstrating a 10 years LR rate of 2.6%. Due to the rare incidence of recurrence, there is very little information regarding factors predictive of chest wall recurrence in women undergoing mastectomy for DCIS.
The status of the resection margin (RM) in patients from the National Surgical Adjuvant Breast and Bowel Project B-24 trial is significant predictor of ipsilateral invasive breast tumor recurrence in DCIS who undergo breast-conserving surgery with radiation. However, there is controversy regarding the relationship between margin status and risk of LR in patients with DCIS treated by mastectomy. Owing to rarity of recurrent cases, there have been a limited number of studies published, and meta-analysis regarding the prognostic value of margin status has not been performed.
The purpose of this meta-analysis was to evaluate the incidence of LR rates in pure DCIS patients with a focus on close or positive mastectomy margins and to assess the potential role of postmastectomy RT (PMRT) in these patients.
| > Materials and Methods|| |
Our study followed Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines. Systematic search of MEDLINE, EMBASE, and Cochrane library for English-language publications were conducted on January 31, 2019. We searched these databases using the following keywords: (”ductal carcinoma in situ” OR “DCIS” OR “intraductal carcinoma”) AND “mastectomy.” Reference lists of related articles were also searched. All searches were limited to human studies.
Eligible studies for this meta-analysis should meet all of the following inclusion criteria: (1) Clinical trials, prospective studies, or retrospective studies; (2) studies of pure DCIS (without microinvasion) breast cancer treated with mastectomy; and (3) LR was documented in relation to RM status. Abstracts, reviews, conference papers, case reports, and editorial materials were excluded. After reviewing titles of searched studies to remove duplicated studies, abstracts of the remaining studies were reviewed to filter studies that were irrelevant to the study subject or not meeting the inclusion criteria. If there were multiple studies from a single center, the report with the information most relevant to this study was included. Finally, full-text review was conducted for the remaining studies to determine if they were relevant to the study subject and whether they fully met inclusion criteria. Two authors independently examined the titles and abstracts of articles identified in the search as potentially relevant trials, and discrepancies were resolved by consensus.
Data extraction was performed by two independent reviewers. In case of any disagreement, we consulted a third review author to help resolve disagreements. Data extraction was performed in standardized form: (1) general information of the study including institution, country, first author, data-accrual period, and year of publication was collected; (2) patients' characteristics including the number of patients, age, mastectomy type, and surgical margin status were obtained; and (3) treatment results including length of follow-up and LR were obtained.
Since all included studies were retrospective in nature, the quality of included studies was assessed using the Newcastle–Ottawa Scale (NOS). A score of 7–9 on NOS was assessed as a high-quality report.
The primary endpoint for meta-analysis was LR, defined as subsequent ipsilateral chest wall, skin, or subcutaneous tissues (DCIS or invasive) disease. Surgical margins were categorized as negative (>1 or 2 mm), close (≤1 or 2 mm), or positive. The effects of margin status on LR were assessed using risk ratios (RRs) with 95% confidence interval (CI). Forest plot was generated to display the result of each analysis. Random effects model was used if data were significantly heterogeneous (I >50%). Otherwise, fixed effects model was used for calculation. Funnel plots were used to assess publication bias. The data from each study were analyzed using Review Manager software version 5.3 (USA), and P < 0.05 was considered to be statistically significant.
| > Results|| |
In the literature search via electronic databases, 2228 studies were found. In the first screening, duplicated studies, reviews, letters, conference abstracts, and case reports were excluded. Titles and abstracts of the remaining 1065 studies were then carefully reviewed and 1038 studies were excluded due to irrelevant subject. Full text contents of the remaining 27 articles were reviewed to evaluate whether they fully met the inclusion criteria. Finally, 12 studies,,,,,,,,,,, encompassing 2902 patients were eligible for inclusion in the study. The detailed procedure is described in [Figure 1].
All 12 studies were retrospective in nature. Of these 12 studies, eight were published in United States. Regarding the definition of close margin, 8 out of 12 studies defined <2 mm, while the remaining 4 studies defined <1 mm. Two studies, reported outcomes of combined treatment of mastectomy and PMRT. The median F/U time ranged from 61 to 144 months. According to NOS scale, the quality of all twelve studies fallen into the high-quality category. Characteristics of included studies are summarized in [Table 1]. Visual inspection of the funnel plot suggested no evidence of publication bias [Figure 2].
In total, there were 64 events in 2902 women who had undergone mastectomy and most of the LR (93.7%) are invasive cancers. The LR occurred in 27 of 508 (5.3%) women in the positive or close margins and 37 of 2367 (1.6%) women in the negative margin. Fixed effect model was used to analyze RR due to their low heterogeneity (RR 3.72, 95% CI = 2.30–6.01, P < 0.01 and I = 11%). Forest plot of RR is shown at [Figure 3].
|Figure 3: Forest plot of the risk ratio for local recurrence comparison: positive or close margins versus negative margin|
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The pooled RR for LR was 2.91 (95% CI = 1.14-7.41, P = 0.03, I = 0%) for positive margin (7.4%) and close margin (2.7%) [Figure 4]. Subgroup meta-analyses were assessed according to the definition of close RM (<1 mm and <2 mm) [Figure 5]. Studies with a close RM <1 mm,,, had a RR of 7.06 (95% CI = 2.81–17.71, P < 0.01, I = 10%), whereas those with a close RM <2 mm,,,,,,, had a RR of 3.09 (95% CI = 1.75–5.46, P < 0.01, I = 12%). However, PMRT was not associated with a decreased risk of LR (RR 0.50; 95% CI = 0.06–4.08, P = 0.52, I = 0%) in patients with positive or close margins [Figure 6].
|Figure 4: Forest plot of the risk ratio for local recurrence comparison: positive margin versus close margin|
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|Figure 5: Subgroup meta-analyses for local recurrence according to the definition of close RM ([A] <1 mm and [B] <2 mm): positive or close margins versus negative margin|
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|Figure 6: Subgroup meta-analyses for local recurrence in patients with positive or close margins: Postmastectomy radiation therapy versus observation|
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| > Discussion|| |
This meta-analysis evaluated the impact of margin status on LR in patients treated with mastectomy for pure DCIS. Outcome of 2902 DCIS cases confirms that mastectomy margin is associated with LR. The pooled LR rate analyzed in this meta-analysis was 5.3% for positive or close margins and 1.6% for negative margin. In addition, there was a 2.3-fold difference in RR of LR depending on the definition of close margin (<1 mm or 2 mm).
LR after mastectomy for DCIS has been reported, but the reported impact of close or positive RMs on the risk of chest wall recurrence is less consistent. Owen et al. from British Columbia reported an overall 10-year LR rate of 1% in 637 patients with a median follow-up time of 12 years. Although relatively high proportion of patients (4.9%) had positive margins, only two of these patients developed a LR and none of these patients received PMRT. Meanwhile, Rashtian et al. evaluated 84 patients with DCIS treated with mastectomy (RM <10 mm). After excluding 4 patients who were treated with PMRT, they reported a 7.5% overall LR rate and a 16% LR rate for patients with margins m2 mm. This high LR rate among patients with close or positive margins has led some clinicians to consider PMRT. In a survey of 226 surgeons in the UK, they would consider the use of PMRT in 19% of respondents, with 66% saying RM status was the key factor, but there is not enough evidence for its use.
The definition of a close margin varies between institutions, from 1 to 2 mm. In this study, both 1 and 2 mm margin width were included in overall comparison of LR. Subgroup meta-analysis was assessed according to the close margin width (<1 mm and 2 mm) and 1 mm showed 2.3-fold higher risk of LR than patients with w2 mm. Further work is required to evaluate differences in LR rate between a margin of 1 and 2 mm to better inform risks of LR with margin width.
PMRT is often considered when the risk of LR is above 10%. The LR rate in our series of 5.3% for patients with close or positive margins and 7.4% for patients with positive margin are all below this threshold. Further, Kim et al. reported that 90% (9/10) of patients treated with mastectomy for DCIS who developed a chest wall relapse were successfully salvaged with excision and RT at the time of relapse. On the basis of these data, we would not recommend routine PMRT for patients with close or positive margins.
In addition to margin status, there may be other risk factors for LR. Kelley et al. assigned Van Nuys Prognostic Index (VNPI) scores to 496 patients with DCIS treated with mastectomy. At 12 years, the overall LR rate was 2.2%, but patients with VNPI scores of 10–12 had a higher LR rate risk of 9.6%, compared with 0 in those with scores of 4–9. Patients with positive or close margins who have additional unfavorable features such as high-grade disease, comedo necrosis, and age <60 years are particularly at risk of LR. These patients might benefit from PMRT and further research related to this will be helpful.
Close or positive margins after mastectomy for DCIS is rare, thus a meta-analysis might be one of the few available research approaches to assess prognostic factor. There are no prospective studies examining this question, and only limited single institution retrospective analyses are available. Combining studies increases the number of cases for analysis and thus will reduce stochastic variation. However, the interpretation should be cautious because the research bias could not be completely ruled out. Heterogeneity among the included studies with different patient characteristics, definition of close margin, and follow-up periods were included in this study, which is a weakness for meta-analysis. There may also be variable mastectomy type among these studies, leaving behind variable amounts of residual breast tissue. Despite the outlined limitations, summarizing published data using meta-analysis may assist clinicians in estimating LR rates after mastectomy.
| > Conclusions|| |
We found a very low rate of chest wall recurrences for patients with DCIS treated by mastectomy, even among patients who had positive or close mastectomy margins. It seems unlikely that PMRT would yield any significant benefit in these patients. Therefore, in clinical practice, the application of PMRT remains limited to an individualized risk determined at the discretion of the treating physicians. Such individualized assessment should include surgical technique used, age, extent of margin involvement, DCIS grade, and extent of tumor. Further studies of risk assessment establishing strategies for aggressive postmastectomy therapy are needed.
This work was supported by clinical research grant from Pusan National University Hospital in 2019.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| > References|| |
Barnes NL, Ooi JL, Yarnold JR, Bundred NJ. Ductal carcinoma in situ
of the breast. BMJ 2012;344:e797.
National Cancer Intelligence Network. The Second all Breast Cancer Report; 2007.
Clements K, Dodwell D, Lawrence G, Ball G, Francis A, Pinder S, et al.
Radiotherapy after mastectomy for screen-detected ductal carcinoma in situ
. Eur J Surg Oncol 2015;41:1406-10.
Stuart KE, Houssami N, Taylor R, Hayen A, Boyages J. Long-term outcomes of ductal carcinoma in situ
of the breast: A systematic review, meta-analysis and meta-regression analysis. BMC Cancer 2015;15:890.
Wapnir IL, Dignam JJ, Fisher B, Mamounas EP, Anderson SJ, Julian TB, 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;103:478-88.
Cochran WG. The combination of estimates from different experiments. Biometrics 1954;10:101-29.
Egger M, Davey Smith G, Schneider M, Minder C. Bias in meta-analysis detected by a simple, graphical test. BMJ 1997;315:629-34.
Weng EY, Juillard GJ, Parker RG, Chang HR, Gornbein JA. Outcomes and factors impacting local recurrence of ductal carcinoma in situ
. Cancer 2000;88:1643-9.
Spiegel AJ, Butler CE. Recurrence following treatment of ductal carcinoma in situ
with skin-sparing mastectomy and immediate breast reconstruction. Plast Reconstr Surg 2003;111:706-11.
Carlson GW, Page A, Johnson E, Nicholson K, Styblo TM, Wood WC. Local recurrence of ductal carcinoma in situ
after skin-sparing mastectomy. J Am Coll Surg 2007;204:1074-8.
Rashtian A, Iganej S, Amy Liu IL, Natarajan S. Close or positive margins after mastectomy for DCIS: Pattern of relapse and potential indications for radiotherapy. Int J Radiat Oncol Biol Phys 2008;72:1016-20.
Chan LW, Rabban J, Hwang ES, Bevan A, Alvarado M, Ewing C, et al.
Is radiation indicated in patients with ductal carcinoma in situ
and close or positive mastectomy margins? Int J Radiat Oncol Biol Phys 2011;80:25-30.
Chadha M, Portenoy J, Boolbol SK, Gillego A, Harrison LB. Is there a role for postmastectomy radiation therapy in ductal carcinoma in situ
? Int J Surg Oncol 2012;2012:423520.
Owen D, Tyldesley S, Alexander C, Speers C, Truong P, Nichol A, et al.
Outcomes in patients treated with mastectomy for ductal carcinoma in situ
. Int J Radiat Oncol Biol Phys 2013;85:e129-34.
Childs SK, Chen YH, Duggan MM, Golshan M, Pochebit S, Punglia RS, et al.
Impact of margin status on local recurrence after mastectomy for ductal carcinoma in situ
. Int J Radiat Oncol Biol Phys 2013;85:948-52.
Fitzsullivan E, Lari SA, Smith B, Caudle AS, Krishnamurthy S, Lucci A, et al.
Incidence and consequence of close margins in patients with ductal carcinoma-in situ
treated with mastectomy: Is further therapy warranted? Ann Surg Oncol 2013;20:4103-12.
Frank S, Dupont A, Teixeira L, Porcher R, De Roquancourt A, Giacchetti S, et al.
Ductal carcinoma in situ
(DCIS) treated by mastectomy, or local excision with or without radiotherapy: A monocentric, retrospective study of 608 women. Breast 2016;25:51-6.
Timbrell S, Al-Himdani S, Shaw O, Tan K, Morris J, Bundred N. Comparison of local recurrence after simple and skin-sparing mastectomy performed in patients with ductal carcinoma in situ
. Ann Surg Oncol 2017;24:1071-6.
Silverstein MJ, Barth A, Poller DN, Gierson ED, Colburn WJ, Waisman JR, et al.
Ten-year results comparing mastectomy to excision and radiation therapy for ductal carcinoma in situ
of the breast. Eur J Cancer 1995;31A: 1425-7.
Mallon PT, McIntosh SA. Post mastectomy radiotherapy in breast cancer: A survey of current United Kingdom practice. J BUON 2012;17:245-8.
Kim JH, Tavassoli F, Haffty BG. Chest wall relapse after mastectomy for ductal carcinoma in situ
: A report of 10 cases with a review of the literature. Cancer J 2006;12:92-101.
Kelley L, Silverstein M, Guerra L. Analyzing the risk of recurrence after mastectomy for DCIS: A new use for the USC/Van nuys prognostic index. Ann Surg Oncol 2011;18:459-62.
Torresan RZ, dos Santos CC, Okamura H, Alvarenga M. Evaluation of residual glandular tissue after skin-sparing mastectomies. Ann Surg Oncol 2005;12:1037-44.
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