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Are mastectomy resection margins of clinical relevance? A systematic review
The Breast 19 (2010) 14–22
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Review
Are mastectomy resection margins of clinical relevance? A systematic review N.P. Rowell* Kent Oncology Centre, Maidstone Hospital, Hermitage Lane, Maidstone, Kent ME16 9QQ, UK
a r t i c l e i n f o
a b s t r a c t
Article history: Received 11 June 2009 Received in revised form 9 September 2009 Accepted 17 October 2009
Although some guidelines support the use of post-mastectomy radiotherapy where the resection margin is involved or close, the scientific basis of this practice is not established. This systematic review explores the relationship between margin status and subsequent relapse. Pooled data from 22 studies (18,863 women) identified an involved post-mastectomy margin in 2.5%, a close margin in 8.0% and muscle or fascia invasion in 7.2% of patients. In a meta-analysis of five studies of non-inflammatory breast cancer without radiotherapy, local recurrence was increased by an involved or close margin (relative risk 2.6; P < 0.00001). The effect of muscle or fascia invasion was of borderline significance (relative risk 1.7; P ¼ 0.04). In two separate meta-analyses, risk of relapse was related to margin status in women with inflammatory breast cancer (relative risk 3.1; P < 0.0001) but not in those undergoing skin-sparing mastectomy (relative risk 2.1; P ¼ 0.16). Ó 2009 Elsevier Ltd. All rights reserved.
Keywords: Mastectomy Resection margins Margin status Local relapse Systematic review Meta-analysis
Introduction The risk of locoregional recurrence, particularly chest wall recurrence, is related to a number of factors. While nodal status exerts the strongest influence on locoregional recurrence,1 other factors such as the presence of lymphovascular invasion, tumour size or grade or patient age or menopausal status are also important, perhaps more so in node-negative cases.2 The impact of margin status is less clear. Although national and international guidelines recognise the importance of resection margin status in breast conservation surgery, uncertainty remains concerning its significance after mastectomy. UK guidelines are silent on the issue of mastectomy resection margins3,4 while the ASCO guidelines on postmastectomy radiotherapy5 state that ‘‘although postmastectomy radiotherapy is commonly used for patients with close or positive margins, the data supporting this practice are fragmentary and sometimes contradictory’’. Authors of other guidelines support the practice for margins that are involved or close (<1 mm)6 or where there is pectoral muscle or chest wall invasion7 but do not provide supporting evidence. Other reviewers have concluded variously that ‘‘the effect of close/positive margin on locoregional failure is not well defined’’8 or that a positive margin or muscle invasion
are among the principal indications for post-mastectomy radiotherapy.9 The view of the pectoral fascia as a barrier to invasion has to some extent been supported by the two most frequently cited studies, the first10 reporting that ‘‘these data appear to suggest a deep margin consisting of an intact pectoral fascia may be adequate to prevent local recurrence’’ and the second11 that ‘‘the results of this study indicate that tumour to fascia margin, as recorded by the pathologist, is not a strong determinant of local recurrence’’. However, on closer scrutiny the data in these studies do not entirely support this view. Where mastectomy with immediate reconstruction or skin-sparing subcutaneous mastectomy is performed, superficial resection margins, i.e. at the skin surface, may also be relevant. As a consequence of this uncertainty, with the prevailing view that deep resection margin is not of clinical concern, resection margins are in many cases not recorded.12 Additionally, the lack of consensus of what constitutes a close margin serves only to cloud the issue further. As post-mastectomy radiotherapy has been shown to reduce local relapse by at least two-thirds,1,2 it is therefore important to identify those patients at greater risk of relapse and who would have the most to gain from radiotherapy. Aims and objectives
* Tel: þ44 1622 225103; fax: þ44 1622 225074. E-mail address: [email protected] 0960-9776/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved. doi:10.1016/j.breast.2009.10.007
In this systematic review, the relationship between close or involved margins and risk of local or locoregional relapse is
N.P. Rowell / The Breast 19 (2010) 14–22
explored. Limitations of the evidence are discussed and suggestions made regarding further studies in this area. Methods Criteria for considering studies for this review Types of studies Randomised controlled trials Non-randomised studies
Types of participants Women of any age or menopausal status with stage T1-4N1-3M0 breast cancer, including inflammatory breast cancer. Types of interventions Women treated with radical or modified radical mastectomy with or without simultaneous reconstruction, with or without axillary sampling, clearance or sentinel node biopsy. Patients may have received neoadjuvant or adjuvant chemotherapy, endocrine therapy or radiotherapy. Outcome measures Local relapse was defined as persistent or recurrent disease in the chest wall or within the reconstructed breast. Regional relapse was defined as persistent or recurrent disease in the axilla, supraclavicular fossa or internal mammary chain. Locoregional relapse (LRR) was defined as failure in either local or regional sites. Resection margins were characterised as involved or close or by the presence of fascia invasion or muscle infiltration. Involved, or positive, margins were those where tumour was identified at the deep resection margin. Close margins were defined as those where tumour was identified within a defined distance from the resection margin. Data with respect to skin invasion were not included as it was generally unclear whether this represented disease adjacent to a resection margin or skin involvement some considerable distance away.
15
Data analysis Data were extracted from each paper and summarised. Data relating to the incidence of involved or close margins were pooled to give an indication of the frequency of each of these findings. Relative risks for local or locoregional relapse according to margin status (with 95% confidence intervals calculated according to a random effects model) were combined in a meta-analysis using RevMan5 software.23 Studies were aggregated into three distinct clinical groups: studies of non-inflammatory breast cancer treated by radical or modified radical mastectomy with or without radiotherapy (group 1), studies of inflammatory breast cancer (group 2) and studies of skin-sparing mastectomy (group 3). Studies of involved or close margins were analysed together within these categories. Relative risk was chosen in preference to odds ratio as being less open to misinterpretation. Where possible, actual numbers of patients with relapse were used but where these were unavailable24–27 proportions were calculated from actuarial estimates. A similar process was used to evaluate data with respect to the risks of fascia invasion or muscle infiltration. A chi-square test for statistical heterogeneity was applied to each group. Results of multivariate analysis, where performed, were summarised. No attempt was made to combine these results. Data from a single study10 in which rates of relapse were related to distance from the resection margin were analysed further as a means of demonstrating ways in which future research might address the question of ‘‘cut-off’’ for close margins. Firstly, on the assumption that risk of relapse might fall exponentially with distance, rates of relapse were plotted against log of distance. To eliminate the zero value arising from involvement of the resection margin, data were aggregated into 2 mm subgroups (i.e. 0–1 mm, 2–3 mm, 4–5 mm, etc.) and plotted as the maximum distance within each subgroup (i.e. 1, 3, 5 mm, etc.). Secondly, cumulative risk of relapse was plotted against distance in order to demonstrate the proportion of relapses that would be identified by a particular cut-off value. Results For the purpose of summarising data, studies were aggregated into three groups as described above.
Search strategy for identification of studies Electronic searches of the Medline, Embase and ProQuest databases using the terms ‘‘mastectomy’’, ‘‘resection margin’’, ‘‘deep margin’’, ‘‘margin status’’, ‘‘fascia invasion’’ and ‘‘muscle invasion or infiltration’’ were carried out and updated in August 2009 with identification of further studies from references cited in the papers identified by electronic searching. On-line searching of abstracts from ASCO meetings (1998– 2008), San Antonio Breast Cancer Symposia (2005–2008) and St Gallen Consensus Conferences (2003–2007) was also performed. Description of studies Thirty non-randomised studies met the inclusion criteria. Three of these related to inflammatory breast cancer and three to subcutaneous skin-sparing mastectomy. One was a prospective study and the remainder retrospective cohort studies, of which one was conducted as a national audit13 and five were retrospective studies of patients entered into randomised clinical trials.14–18 Three studies from one centre15,16,18 clearly related to separate subsets of patients but three studies from another centre represented subgroup analyses19–21 of patients included within a larger retrospective study.22
Group 1: Non-inflammatory breast cancer treated with radical or modified radical mastectomy Involved or close resection margin Within this group of 25 studies (18,863 women), there was a wide range of node positivity and utilisation of radiotherapy and chemotherapy (Table 1) reflecting both the selection criteria for the study and the time period in which patients had been treated. In most cases chemotherapy was delivered in the adjuvant setting but in two studies neoadjuvant chemotherapy had been given.15,28 The majority of patients in this group underwent radical or modified radical mastectomy with axillary clearance. The presence of an involved margin was recorded in 15 studies (range 0–8%; Table 2). Close margins were reported in 14 studies (range 0–61%). Pooled data from 13,663 patients revealed the presence of an involved margin in 2.5% (data from 12,552 patients) and a close margin in 8.0% (data from 8964 patients). Various definitions of close margin were used, ranging from a margin of 2 mm or less in five studies to a cut-off of 4–10 mm in eight studies. One study10 presented data for rates of recurrence in 1 mm intervals up to 2 cm. In the radical mastectomy group (Table 1), radiotherapy was given to all patients in seven studies and to no patients in a further
16
N.P. Rowell / The Breast 19 (2010) 14–22
Table 1 Details of patients in series reporting incidence of involved or close margins. Reference
Study typea
Years studied
Number of patients
Stage
% with positive nodes
% Receiving chest wall radiotherapy
% Receiving chemotherapy (% neoadjuvant)
Median follow-up (months)
Radical/modified radical mastectomy R 1975–1980 Ahlborn11 R 1990–2003 Alassas28 Atahan29 R 1994–2002 R 1999–2001 Cheng30 19 R 1989–1998 Coulombe 31 R 1978–1998 Feigenberg 14 R,C 1978–1981 Fowble R 1984–1993 Freedman32 Hehr26 R 1989–2004 R 1980–2001 Horiguchi33 Huang15 R,C 1974–2000 34 P 1982–1987 Jager R 1980–2000 Jagsi27 16 R,C 1975–1994 Katz R 1978–1981 Lagios35 R 1971–2003 Livi36 R 1989–1998 Macdonald22 R 1974–1982 Mentzer10 37 Miccoli R 1979–1982 17 R,C 1982–1999 Nielsen 38 R 1997–2002 Punglia R 1989–1998 Truong20 R 1989–1998 Truong21 R,A 2003–2004 van Houtte13 R,C 1975–1994 Woodward18
322 75 952 1010 752 268 627 789 287 1144d 542 608 877 1031 157 2064 4181 100 129 1545 1620 2570 821 110 470
T1–2N0 IIIA/B T1–4N0–3 T1–4N0–3 T1–2N0–1 T1–4N0–3 II–IIIA I–II T1–4N0–3c 0–IIIB II–IIIC T1–3N0–3 T1–3N0 II–IIIA I–II T1–4N0–3 T1–3N0–3 II T2N0–1 II–III I–II T1–2N0 T1–2N1 T1–4N0–3 II–IIIA
0 Not stated 74 51 31 74 100 35b 82 40 82 58 0 86 50 53 43 62 Not stated 91 44 0 100 Not stated 97
0 100 100 26 8 100 0 0b 100 Not stated 100 10 0 0 8 0 22 22 Not stated 0 24 Not stated 0 100 100
0 100 (43) 92 72 62 59 88 68b 27 Not stated 100 (all) 58 15 100 4 27 27 25 Not stated 55 63 Not stated 37 Not stated 100
47 Not stated 61 Not stated 108 96 54 59b 43 81 70 90 100 116 37 199 120 37 Not stated 216 Not stated 92 92 Not stated 120
Inflammatory breast cancer R 1977–2004 Bristol24 Chin39 R 1987–1997 R 1970–1995 Curcio25
192 23e 28
T4N0–3 IIIB/IV IIIB
86 Not stated 90
100 52 Not stated
95 (all) 96 (68) Not stated
64 44 21
38 141d 210f
4 cm or N2–3 0–IIIA 0–III
95 27 28
69 0 20
95 Not stated Not stated
53 71 59
Skin-sparing mastectomy R Downes40 R Horiguchi33 R Vaughan41
1996–2002 1980–2001 1999–2006
Clinical details of patients in studies reporting incidence of involved or close margins. Stage is as reported in the original publication. a Study type: national audit (A); patients entered into randomised clinical trials (C); patients studied prospectively (P); retrospective cohort study (R). b As proportion of the 34 patients with close or positive margins. c Selected series of patients with high risk features. d Included 57/1144 (5%) of patients undergoing radical mastectomy and 20/141 (14%) of patients undergoing skin-sparing mastectomy for in situ disease. e Included 5 patients with stage IV disease; probably some patients included in Curcio.25 f Included 40/210 (19%) mastectomies for in situ disease.
eight studies. Radiotherapy utilisation was not stated in three studies and was 8–26% of patients in the remaining studies. For the purpose of investigating the impact of margin status on rates of relapse, subgroups were identified in which either all patients received radiotherapy or no patients received radiotherapy. Studies differed in their preference for reporting rates of locoregional relapse or local relapse (Table 3). In the subgroup of patients receiving radiotherapy, the risk of LRR was 7–11% (median 9%) and in those with infrequent use of radiotherapy, the risk of local or locoregional relapse was 2–19% (median 8.5%). In the studies where radiotherapy was used infrequently, rates of relapse ranged from 3–16% with clear margins to 6–43% where there were close or involved margins. In seven studies reporting rates of relapse with respect to the presence of an involved or close margin (Table 3), radiotherapy was given to all patients in one study,31 to no patients in five studies11,16,21,27,32 and to 22% of patients in the remaining study.22 Data from these seven studies were combined in a meta-analysis, subdivided according to radiotherapy usage (Fig. 1). For the group of five studies in which radiotherapy had not been given (including 2825 patients), the relative risk of relapse was 2.6 (95% confidence interval 1.8–3.8; P < 0.00001) whereas, individually, only two of these studies had reached statistical significance.16,27 In contrast,
the single study where radiotherapy was given to all patients31 showed no impact of resection margin on rate of relapse (relative risk 0.84; 95% confidence interval 0.25–2.8; P ¼ 0.77). As the incidence of close margins might possibly be affected by other tumour factors, multivariate analysis may more reliably identify the significance of individual risk factors. Multivariate analysis was undertaken in six studies. In four studies with infrequent use of radiotherapy, margin status was identified as a significant independent risk factor in two studies16,27 but not in two others.22,34 Margin status was not identified as a significant risk factor in either of two studies where all patients received radiotherapy.26,31 Muscle or fascia invasion The presence of pectoralis muscle or fascia invasion was recorded in six studies (range 2–20%; Table 2). Pooled data identified the presence of muscle or fascia invasion in 396/5487 patients (7.2%). Involvement of the pectoralis fascia or muscle resulted in a greater risk of LRR in two studies,14,16 but not in two others.17,36 Data from these four studies, in which radiotherapy was not used, are combined in Fig. 2, resulting in a pooled relative risk of 1.7 (95% confidence interval 1.0–2.9; P ¼ 0.04). Significant statistical heterogeneity was present in this group of studies (X2 ¼ 12.6;
N.P. Rowell / The Breast 19 (2010) 14–22
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Table 2 Incidence of involved or close margins. Reference
Definition of margin
Radical/modified radical mastectomy <4 mm Ahlborn11 Involved Alassas28 Atahan29 involved Involved; 2 mm Cheng30 31 Involved; 2 mm Feigenberg 14 Fascia involved Fowble 32 1 cm Freedman 1 cm Hehr26 Hehr26 Muscle infiltration Horiguchi33 <5 mm Huang15 Involved; <5 mmb 34 Involved; <5 mm Jager Involved; <2 mm Jagsi27 16 Involved; <5 mm Katz Fascia involved Katz16 Katz,16 Woodward18 Involved Lagios35 Muscle infiltration Livi36 22 Macdonald Involved 19 Coulombe 20 Truong Truong21 Involved; 5 mm Mentzer10 Muscle infiltration Miccoli37 Fascia involved Nielsen17 38 Involved; <2 mm Punglia 13 van Houtte Involved; <2 mm 18 Involved; <5 mmb Woodward Pooled data Inflammatory breast cancer <2 mm Bristol24 Involved Curcio25 39 Involved Chin Pooled data Skin-sparing mastectomy Downes40 Involved; <5 mm <5 mm Horiguchi33 41 <1 mm Vaughan Pooled data
Subgroup
Number evaluable for margin status
322 75 952 1000 268
Number (%) with involved margin
Number evaluable for muscle or fascia invasion
Number (%) with muscle or fascia invasion
561
21 (4%)
287
57 (20%)a
1010 502
19 (2%) 9 (2%)
1955
31 (2%)
129 1545
8 (6%) 260 (17%)
5487
396 (7.2%)
88 (27%) 1 (1%) 8 (8%) 3 (<1%) 16 (6%)
789 287 1144 537 608 726 994
Number (%) with involved or close margin
24 (2%) 49 (18%) 136 (17%) 78 (27%)a
0 19 6 19 12
(0%) (4%) (1%) (3%) (1%)
0 (0%) 60 (11%) 57 (9%) 64 (9%) 29 (3%)
T1–2N1
Age <50 years T1–2N0 T1–2N1
155
0 (0%)
3804 752 2570 750 100
226 (6%) 45 (6%) 94 (4%) 26 (3%) 8 (8%)
1619 100 470 13,663
18 (1%) 2 (2%) 3 (1%) 341/12,552 (2.5%)
149 28 23 Data not pooled
7 (25%) 4 (17%)
38 141c 210d 389
61 (61%)
40 (2%) 10 (10%) 17 (4%) 713/8964 (8.0%) 16 (11%)
1 (3%)
1/38 (2.6%)
7 (18%) 9 (6%) 29 (14%) 45/389 (11.6%)
Data relating to subgroups within each study are shown in italics. a Selected series of high risk patients. b Close margin not defined in report; <5 mm assumed as institutional standard as reported in another series from the same centre.16 c 20/141 patients (14%) had DCIS. d 40/210 patients (19%) had DCIS.
P ¼ 0.0006). Multivariate analysis was undertaken in two studies, identifying muscle or fascia invasion as a significant independent risk factor in one study26 but not in another.14
Group 2: Inflammatory breast cancer Three studies of inflammatory breast cancer and margin status were identified.24,25,39 As two studies may have overlapped,25,39 these three studies account for approximately 220–240 women undergoing mastectomy as part of multimodality treatment for inflammatory breast cancer (Table 1). Close margins (less than 2 mm) were observed in 11% in one study24 and in the overlapping pair of studies,25,39 involved margins were seen in 17–25% (Table 2). Data were not pooled for this group. Locoregional relapse was seen in 16–30% overall,24,39 with a higher frequency in those with involved or close margins (32– 100% vs 9–40% with clear margins; Table 3). In a meta-analysis, there was a pooled relative risk of LRR of 3.1 (95% confidence interval 1.8–5.4; P < 0.0001; Fig. 1). This result was not substantially
affected (relative risk 2.63; P ¼ 0.004) by exclusion of one of the overlapping studies.39 In one study, three-year overall survival was significantly worse (0% vs 47%) in those with involved margins (relative risk 7.8; 95% confidence interval 2.1–28.6; P ¼ 0.002).25
Group 3: Skin-sparing mastectomy Three studies of skin-sparing mastectomy and margin status were identified33,40,41 (389 women; Table 1). Two of these studies also included some patients with ductal carcinoma in situ (DCIS). Close margins (with either invasive cancer or DCIS) were seen in 45/389 (11.6%); two studies using a cut-off of 5 mm33,40 and one a cut-off of 1 mm41 (Table 2). Local relapse was seen in 5–8% (Table 3) with only one study reporting risk relative to margin status.41 In this study, there was a higher risk of local relapse in those with close margins but this did not reach statistical significance (relative risk 2.1; 95% confidence interval 0.7–5.8; P ¼ 0.16). However, in the single study in which
18
N.P. Rowell / The Breast 19 (2010) 14–22
Table 3 Rates of local or locoregional relapse (LRR) in women with involved or close margins Reference
Definition of margin
Subgroup
Site of Relapse rate relapse overall (%)
Radical/modified radical mastectomy – radiotherapy given to £26% of patients <4 mm from fascia Local Ahlborn11 Fowble14 Fascia invasion LRR Freedman
32
Horiguchi33 Jager34 Jagsi27 Katz16
1 cm 0–2 mm vs >2–6 mm <5 mm <5 mm 2 mm <5 mm
Katz16
Fascia involved
Livi36
All stages T 5 cm N0–1 and margins 1 cm
12/322 (4%)
Local Local
136/789 (17%) 5/34 (15%)
Local Local LRR LRR
19/1144 (2%) 53/608 (9%) 46/877 (5%) 19% at 10 years
1–3 nodes involved
LRR LRR
1–3 nodes involved Muscle invasion
LRR LRR
Macdonald22 Mentzer10 Nielsen17
Involveda 5 mmb Fascia involved
LRR LRR
Truong21
Involved
NS 0.007
4/19 vs 1/14 (21% vs 7%)
NS
Local LRR
LRR
11% at 10 years
Local LRR
31/470 (7%) 41/470 (9%)
Curcio25 Chin39
Involved Involved
Skin-sparing mastectomy Not stated Downes40 <5 mm Horiguchi33 <1 mm Vaughan41
0.0008 0.003
NS
0.99 (0.5–1.95) NS 2.6 0.02 0.0001 not stated
0.0001 NS
0.0001
NS NS
Close or unknownd vs LRR negative LRR LRR Local Local Local
NS 0.05
NS
3/49 vs 16/219 (6% vs 7%) Not stated Not stated Not stated Not stated Not stated
Radical/modified radical mastectomy – subset of two studies with and without RT T1–2N1 Katz,16 Woodward18 <5 mmc Inflammatory breast cancer Bristol24 <2 mm
<0.001 0.0001
P
NS
Huang15 Woodward
5/88 vs 7/234 (6% vs 3%) 6/21 vs 54/540 (29% vs 10%)
8/100 (8%) 7/61 vs 1/39 (11% vs 3%) 456/1545 (30%) 86/260 vs 370/1285 (33% vs 29%) 67/821 (8%) 5/26 vs 100/724 113/821 (14%) (19% vs 14%) 19/268 (7%) 15% at 5 years
<5 mm Chest wall or fascia invasion <5 mmc
Univariate Multivariate analysis analysis P Relative risk (95% c.i.)
Not stated 21% vs 5% at 10 years 12/29 vs 151/965 (41% vs 16%) 43% vs 13% at 10 years 8/19 vs 160/991 (42% vs 16%) 33% vs 13% at 10 years 378/2064 (18%) 7/31 vs 355/1924 (26% vs 23%)
Radical/modified radical mastectomy – radiotherapy given to all patients 2 mm LRR Feigenberg31 1 cm Local Hehr26 Muscle invasion
18
Relapse rate with vs without involved or close margin (%)
not stated 3.2 NS NS
NS
16% at 5 years
32% vs 9% at 5 years
7/23 (30%)
69% vs 40% at 3 years NS 4/4 vs 3/19 (100% vs 16%) 0.02
3/38 (8%) 8/141 (6%)e 9/170 (5%)f
3/11 vs 26/199 (27% vs 13%)
NS NS not stated
4.6 (1.1–19.3)
0.036
7.1 (1.3–38.0)
0.022
0.0005
NS
NS, not significant. a 44/1075 were men. b Assessed from gross specimen in a proportion of cases. c Close margin not defined in report; <5 mm assumed as institutional standard as reported in another series from the same centre.16 d Included 43/192 with unknown margins. e 20/141 patients (14%) had DCIS. f 40/210 patients (19%) had DCIS.
multivariate analysis was performed,33 margin status was confirmed as a significant risk factor (relative risk 7.1; 95% confidence interval 1.3–38.0; P ¼ 0.002; Table 3).
that of all relapses within 5 mm or less, one-third were at the resection margin, a further one-third up to 2 mm and the remaining third between 2 and 5 mm.
Further evaluation of risk of relapse vs distance from the resection margin
Analysis of all groups combined
Further exploratory analysis of data from a single study10 (Fig. 3) demonstrated a significant relationship between risk of relapse and log of distance from the resection margin (r ¼ 0.77; P ¼ 0.024). A simple linear relationship was also found (r ¼ 0.74; P ¼ 0.035; not shown). A plot of cumulative risk (Fig. 4) showed, approximately,
Combining data from all three groups resulted in a relative risk of 2.6 (95% confidence interval 1.9–3.4; P < 0.00001; without significant statistical heterogeneity), indicating the risk of an involved or close margin was broadly consistent across all groups despite the differences in clinical situation.
N.P. Rowell / The Breast 19 (2010) 14–22
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Fig. 1. Meta-analysis of risk of recurrence with respect to involved or close resection margins.
Discussion This review demonstrates that involved margins are relatively uncommon, affecting only 2.5% of patients following mastectomy. However close margins were just over three times more frequent. The relationship between margin status and local relapse included more data from patients with close margins than involved margins. Fig. 1 clearly demonstrates that a close margin is associated with a significantly increased risk of local or locoregional relapse. The relative risk of close margins following mastectomy for inflammatory breast cancer (3.1) or subcutaneous skin-sparing mastectomy (2.1) were broadly consistent with the risk following mastectomy for non-inflammatory breast cancer (2.7) suggesting that in all clinical situations the baseline risk may be modified by the presence of a close margin to a similar extent.
Within the group of studies of non-inflammatory breast cancer, only two had (individually) shown an increased risk from close margins.16,34 These were larger studies with over 1700 patients between them. In contrast, the two older and more frequently cited studies10,11 were smaller and, statistically, much less likely to have produced a positive result. The low frequency of close margins and the generally low risk of recurrence after mastectomy, mean that study size is critical. Small studies, particularly where the result is negative, cannot be relied upon. In these two older studies, the authors’ conclusions of no significant relationship between margin status and subsequent relapse were taken at face value and the possible implications of an increased relative risk overlooked. The relative importance of close margin and fascia involvement requires further scrutiny as in one study, in individual patients there was a disparity between these two factors.16 If a surgeon considers that the tumour may lie close to the fascia, an additional
20
N.P. Rowell / The Breast 19 (2010) 14–22
Fig. 2. Meta-analysis of risk of recurrence with respect to fascia invasion or muscle infiltration. Non-inflammatory breast cancer; radiotherapy not given.
cuff of muscle may be included within the main specimen. In this situation, the fascia might be involved but the resection margin considered clear. This disparity might account for the weaker relationship between fascia or muscle involvement and relapse (relative risk 1.7) as compared to the relationship between resection status and relapse (relative risk 2.6). Meta-analysis was undertaken to investigate the extent to which a number of small studies had produced individually inconclusive results, especially given the low frequency of close margins, when a larger analysis might have revealed a more consistent trend. However, such an analysis is limited by the interdependence of clinical factors and must be interpreted with caution. It is particularly important in any analysis to exclude potential sources of bias and it is possible that an analysis of rates of relapse with respect solely to margin status might be misleading. The possibility that the adverse effect of margin status is itself related to other tumour factors (for example tumour size or nodal status) needs to be considered. However, the group of five studies of non-inflammatory breast cancer without radiotherapy11,16,21,27,32 does not contain a preponderance of more advanced tumours. Out of the 2825 patients included in this analysis, tumours greater than 5 cm were seen in 103 patients (out of 1031) in one study16 and 25 (out of 877) in another.27 Additionally all 1050 patients included in two studies were node-negative,11,27 only one study (with 821 patients) included only node-positive patients21 and the remainder included a mixture of node-positive and node-negative. Multivariate analysis within individual studies provided confirmatory evidence of the significance of margin status. In this case the two larger studies in the meta-analysis showed that margin status was an independent risk factor,16,27 although two other studies22,34
which did not provide data for the meta-analysis (except in the form of a selected subgroup21) found this not to be significant. On the other hand, it is possible that this review underestimates the risk of a close resection margin. A number of studies reported locoregional relapse (LRR) rather than local relapse. In a series of 1545 patients,17 the increased risk of LRR in those with fascia invasion was of borderline significance (18-year probability of LRR 46% vs 40%; P ¼ 0.05) but considering chest wall relapse only this became highly significant (30% vs 20%; P ¼ 0.003). In contrast, the risk of axillary failure alone was not increased. In a study of 627 node-positive women,14 isolated LRR was seen in 70 of which chest wall relapse (with or without concurrent nodal relapse) was seen in 40 (57%). As close margin could only potentially be responsible for just over half of these relapses, the inclusion of data for LRR rather than truly local relapse would be expected to result in lower estimates of risk. The ideal cut-off for the definition of a close margin remains uncertain. On the basis of risk gradually reducing with distance from the margin, there would be a balance between the need to define the minimum distance at greatest risk and the need to include the majority of those who have any additional risk. The further analysis of Mentzer’s data10 (Figs. 3 and 4) demonstrates how this might be achieved. In this case, the use of a 5 mm margin would appear to identify the majority of those at risk. However, this study contained only 100 patients and is unusual for the high proportion of tumours within 5 mm of the resection margin (61%) and therefore the low proportion of those at a larger distance. A higher proportion of tumours at a greater distance would be necessary to establish a baseline risk (i.e. independent of distance) to which can be added the additional risk from proximity to the
y = -0.0948x + 0.1358 r = 0.77; P = 0.024 0.15
0.1
0.05
0 1
3
5
10
20
30
distance from resection margin (mm) Fig. 3. Risk of local recurrence at intervals from resection margin. Reanalysis of data from Mentzer10 relating rate of local relapse to distance from the resection margin. Data have been aggregated into 2 mm groups up to 10 mm, and 5 mm groups thereafter.
cumulative risk of local recurrence
risk of local recurrence
0.2
0.2
0.15
0.1
0.05
0 0
5
10
15
20
25
30
distance from resection margin (mm) Fig. 4. Cumulative risk of local relapse. Cumulative risk of local relapse by distance from the resection margin (8 relapses in 100 patients). Data from Mentzer.10
N.P. Rowell / The Breast 19 (2010) 14–22
resection margin. In Fig. 3, the best fit was obtained by plotting distance on a logarithmic scale, consistent with risk falling exponentially with distance from the resection margin. This demonstration of the significance of close margins supports the use of postoperative radiotherapy where the margins are close, as is normal practice for a number of oncologists.38 Of note is that in the one study where radiotherapy was given to all patients,31 the absence of risk from margin status was clearly demonstrated. This would be consistent with postoperative radiotherapy effectively eliminating the risk from a close margin. The absolute risk from the presence of a close margin needs to be understood in the context of other risk factors. In one study, the presence of either a close margin or a single other risk factor (compared to those without any risk factors) increased the risk of LRR from 1% to 10%.27 In another study, the presence of a positive margin did not increase the risk of LRR except in the presence of either lymphovascular invasion, a grade 3 tumour, T2 tumour or age under 50 when the risk of LRR was 20%.20 A third study32 reported that all LRR occurring in patients with close margins affected those under 50 year of age. Conclusions This systematic review demonstrates that close resection margin is associated with a significantly increased risk of local relapse and that chest wall radiotherapy should be considered especially where other risk factors are present. Implications for practice B
B
B
For women with a close resection margin and one or more additional risk factors, chest wall radiotherapy should be recommended. For women with a close resection margin but without additional risk factors, chest wall radiotherapy should be considered. In the absence of further data, a 5 mm cut-off would seem reasonable.
Implications for research B
Further research is required to explore the relationship between distance from the resection margin and risk of local recurrence. An approach similar to that used above in the reanalysis of Mentzer’s data is suggested. The relative infrequency of close margins and the recognised impact of other risk factors suggests that such a study would need to include many thousands of women.
Conflicts of interest There are no conflicts of interest. Funding sources Dr NP Rowell is employed by Maidstone & Tunbridge Wells NHS Trust. There are no additional sources of funding. Acknowledgements I am indebted to Dr Russell Burcombe and Dr David Fish for their helpful comments and encouragement.
21
References 1. Clarke M, Collins R, Darby S, Davies C, Elphinstone P, Evans V, et al. Effects of radiotherapy and of differences in the extent of surgery for early breast cancer on local recurrence and 15-year survival: an overview of the randomised trials. Lancet 2005;366:2087–106. 2. Rowell NP. Radiotherapy to the chest wall following mastectomy for nodenegative breast cancer: a systematic review. Radiother Oncol 2009;91:23–32. 3. Association of Breast Surgery at BASO, Royal College of Surgeons of England. Guidelines for the management of symptomatic breast disease. Eur J Surg Oncol 2005;31:S1–21. 4. Scottish Intercollegiate Guidelines Network. Management of breast cancer in women. A national clinical guideline. Available at: http://www.sign.ac.uk/ guidelines/published/index.html; 2005. 5. Recht A, Edge SB, Solin LJ, Robinson DS, Estabrook A, Fine RE, et al. Postmastectomy radiotherapy: guidelines of the American Society of Clinical Oncology. J Clin Oncol 2001;19:1539–69. 6. NCCN. Practice guidelines in oncology: invasive breast cancer. Version 1. National Comprehensive Cancer Network. Available at: http://www.nccn.org/ professionals/physician_gls/f_guidelines.asp; 2009. 7. Truong PT, Olivotto IA, Whelan TJ, Levine M. Clinical practice guidelines for the care and treatment of breast cancer: 16. Locoregional post-mastectomy radiotherapy. Can Med Assoc J 2004;170:1263–73. 8. Pierce LJ. The use of radiotherapy after mastectomy: a review of the literature. J Clin Oncol 2005;23:1706–17. 9. Sozzi WJ, Mirimanoff RO. Indications de la radiotherapie dans le cancer du sein non metastatique. Revue Medicale Suisse 2007;130:2398–404. 10. Mentzer SJ, Osteen RT, Wilson RE. Local recurrence and the deep resection margin in carcinoma of the breast. Surg Gynecol Obst 1986;163:513–7. 11. Ahlborn TN, Gump FE, Bodian C, Habif DV, Kister S. Tumour to fascia margin as a factor in local recurrence after modified radical mastectomy. Surg Gynecol Obst 1988;166:523–6. 12. Imperato PJ, Waisman J, Wallen MD, Llewellyn CC, Pryor V. Improvements in breast cancer pathology practices among medicare patients undergoing unilateral extended simple mastectomy. Am J Med Quality 2003;18:164–70. 13. Van Houtte P, Bourgois N, Renard F, Huget P, D’hoore W, Scalliet P. A federal audit of the Belgian radiotherapy departments in breast cancer treatment. Radiother Oncol 2007;83:178–86. 14. Fowble B, Gray R, Gilchrist K, Goodman RL, Taylor S, Tormey DC. Identification of a subgroup of patients with breast cancer and histologically positive axillary nodes receiving adjuvant chemotherapy who may benefit from postoperative radiotherapy. J Clin Oncol 1988;6:1107–17. 15. Huang EH, Tucker SL, Strom EA, McNeese MD, Kuerer HM, Hortobagyi GN, et al. Predictors of locoregional recurrence in patients with locally advanced breast cancer treated with neoadjuvant chemotherapy, mastectomy, and radiotherapy. Int J Radiat Oncol Biol Phys 2005;62:351–7. 16. Katz A, Strom EA, Buchholz TA, Theriault R, Singletary SE, McNeese MD. The influence of pathologic tumour characteristics on locoregional recurrence rates following mastectomy. Int J Radiat Oncol Biol Phys 2001;50:735–42. 17. Nielsen HM, Overgaard M, Grau C, Jensen AR, Overgaard J. Loco-regional recurrence after mastectomy in high-risk breast cancer – risk and prognosis. An analysis of patients from the DBCG 82 b&c randomisation trials. Radiother Oncol 2006;79:147–55. 18. Woodward WA, Strom EA, Tucker SL, Katz A, McNeese MD, Perkins GH, et al. Locoregional recurrence after doxorubicin-based chemotherapy: implications for breast cancer patients with early-stage disease and predictors for recurrence after postmastectomy radiation. Int J Radiat Oncol Biol Phys 2003;57: 336–44. 19. Coulombe G, Tyldesley S, Speers C, Paltiel C, Aquino-Parsons C, Bernstein V, et al. Is mastectomy superior to breast-conserving treatment for young women? Int J Radiat Oncol Biol Phys 2007;67:1282–90. 20. Truong PT, Olivotto IA, Speers CH, Wai ES, Berthelet E, Kader HA. A positive margin is not always an indication for radiotherapy after mastectomy in early breast cancer. Int J Radiat Oncol Biol Phys 2004;58:797–804. 21. Truong PT, Olivotto IA, Kader HA, Panades M, Speers CH, Berthelet E. Selecting breast cancer patients with T1–T2 tumours and one to three positive axillary nodes at high postmastectomy locoregional recurrence risk for adjuvant radiotherapy. Int J Radiat Oncol Biol Phys 2005;61:1337–47. 22. Macdonald G, Paltiel C, Olivotto IA, Tyldesley S. A comparative analysis of radiotherapy use and patient outcome in males and females with breast cancer. Ann Oncol 2005;16:1442–8. 23. Review Manager [Computer program]. Version 5.0. Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration; 2008. 24. Bristol IJ, Woodward WA, Strom EA, Cristofanilli M, Domain D, Singletary SE, et al. Locoregional treatment outcomes after multimodality management of inflammatory breast cancer. Int J Radiat Oncol Biol Phys 2008;72:474–84. 25. Curcio LD, Rupp E, Williams WL, Chu DZJ, Clarke K, Odom-Maryon T, et al. Beyond palliative mastectomy in inflammatory breast cancer – a reassessment of margin status. Ann Surg Oncol 1999;6:249–54. 26. Hehr T, Classen J, Huth M, Durst I, Christ G, Bamberg M, et al. Postmastectomy radiotherapy of the chest wall. Comparison of electron-rotation technique and common tangential photon fields. Strahlenther Onkol 2004;180:629–36. 27. Jagsi R, Raad RA, Goldberg S, Sullivan T, Michaelson J, Powell SN, et al. Locoregional recurrence rates and prognostic factors for failure in node-negative
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N.P. Rowell / The Breast 19 (2010) 14–22 patients treated with mastectomy: implications for postmastectomy radiation. Int J Radiat Oncol Biol Phys 2005;62:1035–9. Alassas M, Chu Q, Burton G, Ampil F, Mizell J, Li BD. Neoadjuvant chemotherapy in stage III breast cancer. Am Surg 2005;71:487–92. Atahan IL, Ozyigit G, Yildiz F, Gurkaynak M, Selek U, Sari S, et al. Percent positive axillary involvement predicts for the development of brain metastasis in high-risk patients with nonmetastatic breast cancer receiving postmastectomy radiotherapy. Breast Journal 2008;14:245–9. Cheng SH, Horng CF, Clarke JL, Tsou MH, Tsai SY, Chen CM, et al. Prognostic index score and clinical prediction model of local regional recurrence after mastectomy in breast cancer patients. Int J Radiat Oncol Biol Phys 2006;64:1401–9. Feigenberg SJ, Mendenhall NP, Benda RK, Morris CG. Postmastectomy radiotherapy: patterns of recurrence and long-term disease control using electrons. Int J Radiat Oncol Biol Phys 2003;56:716–25. Freedman GM, Fowble BL, Hanlon AL, Myint MA, Hoffman JP, Sigurdson ER, et al. A close or positive margin after mastectomy is not an indication for chest wall irradiation except in women aged fifty or younger. Int J Radiat Oncol Biol Phys 1998;41:599–605. Horiguchi J, Koibuchi Y, Yoshida T, Takata D, Kikuchi M, Rokutanda N, et al. Significance of local recurrence as a prognostic factor in the treatment of breast cancer. Anticancer Res 2006;26:569–74. Jager JJ, Volovics L, Schouten LJ, de Jong JMA, Hupperets PSGJ, von Meyenfeldt MF, et al. Loco-regional recurrences after mastectomy in breast
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cancer: prognostic factors and implications for postoperative irradiation. Radiother Oncol 1999;50:267–75. Lagios MD, Richards VE, Rose MR, Yee E. Segmental mastectomy without radiotherapy: short-term follow-up. Cancer 1983;52:2173–9. Livi L, Saieva C, Detti B, Meattini I, Susini T, Paiar F, et al. Loco-regional recurrence in 2064 patients with breast cancer treated with mastectomy without adjuvant radiotherapy. Eur J Surg Oncol 2007;33:977–81. Miccoli P, Iacconi P, Spinelli C, Di Candio G. Ope´ration de Halsted versus mastectomie radicale modifie´e: utilite´ d’une se´lection des patients en fonction du type et de la localisation de la tumeur. Acta Chir Belg 1984;84:39–41. Punglia RS, Hughes ME, Edge SB, Theriault RL, Brookman MA, Wilson JL, et al. Factors associated with guideline-concordant use of radiotherapy after mastectomy in the National Comprehensive Cancer Network. Int J Radiat Oncol Biol Phys 2008;72:1434–40. Chin PL, Andersen JS, Somlo G, Chu DZ, Schwarz RE, Ellenhorn JD. Esthetic reconstruction after mastectomy for inflammatory breast cancer: is it worthwhile? J Am Coll Surg 2000;190:304–9. Downes KJ, Glatt BS, Kanchwala SK, Mick R, Fraker DL, Fox KR, et al. Skin-sparing mastectomy and immediate reconstruction is an acceptable treatment option for patients with high-risk breast carcinoma. Cancer 2005; 103:906–13. Vaughan A, Dietz JR, Aft R, Gillanders WE, Eberlein TJ, Freer P, et al. Patterns of local breast cancer recurrence after skin-sparing mastectomy and immediate breast reconstruction. Am J Surg 2007;194:438–43.
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Review
Are mastectomy resection margins of clinical relevance? A systematic review N.P. Rowell* Kent Oncology Centre, Maidstone Hospital, Hermitage Lane, Maidstone, Kent ME16 9QQ, UK
a r t i c l e i n f o
a b s t r a c t
Article history: Received 11 June 2009 Received in revised form 9 September 2009 Accepted 17 October 2009
Although some guidelines support the use of post-mastectomy radiotherapy where the resection margin is involved or close, the scientific basis of this practice is not established. This systematic review explores the relationship between margin status and subsequent relapse. Pooled data from 22 studies (18,863 women) identified an involved post-mastectomy margin in 2.5%, a close margin in 8.0% and muscle or fascia invasion in 7.2% of patients. In a meta-analysis of five studies of non-inflammatory breast cancer without radiotherapy, local recurrence was increased by an involved or close margin (relative risk 2.6; P < 0.00001). The effect of muscle or fascia invasion was of borderline significance (relative risk 1.7; P ¼ 0.04). In two separate meta-analyses, risk of relapse was related to margin status in women with inflammatory breast cancer (relative risk 3.1; P < 0.0001) but not in those undergoing skin-sparing mastectomy (relative risk 2.1; P ¼ 0.16). Ó 2009 Elsevier Ltd. All rights reserved.
Keywords: Mastectomy Resection margins Margin status Local relapse Systematic review Meta-analysis
Introduction The risk of locoregional recurrence, particularly chest wall recurrence, is related to a number of factors. While nodal status exerts the strongest influence on locoregional recurrence,1 other factors such as the presence of lymphovascular invasion, tumour size or grade or patient age or menopausal status are also important, perhaps more so in node-negative cases.2 The impact of margin status is less clear. Although national and international guidelines recognise the importance of resection margin status in breast conservation surgery, uncertainty remains concerning its significance after mastectomy. UK guidelines are silent on the issue of mastectomy resection margins3,4 while the ASCO guidelines on postmastectomy radiotherapy5 state that ‘‘although postmastectomy radiotherapy is commonly used for patients with close or positive margins, the data supporting this practice are fragmentary and sometimes contradictory’’. Authors of other guidelines support the practice for margins that are involved or close (<1 mm)6 or where there is pectoral muscle or chest wall invasion7 but do not provide supporting evidence. Other reviewers have concluded variously that ‘‘the effect of close/positive margin on locoregional failure is not well defined’’8 or that a positive margin or muscle invasion
are among the principal indications for post-mastectomy radiotherapy.9 The view of the pectoral fascia as a barrier to invasion has to some extent been supported by the two most frequently cited studies, the first10 reporting that ‘‘these data appear to suggest a deep margin consisting of an intact pectoral fascia may be adequate to prevent local recurrence’’ and the second11 that ‘‘the results of this study indicate that tumour to fascia margin, as recorded by the pathologist, is not a strong determinant of local recurrence’’. However, on closer scrutiny the data in these studies do not entirely support this view. Where mastectomy with immediate reconstruction or skin-sparing subcutaneous mastectomy is performed, superficial resection margins, i.e. at the skin surface, may also be relevant. As a consequence of this uncertainty, with the prevailing view that deep resection margin is not of clinical concern, resection margins are in many cases not recorded.12 Additionally, the lack of consensus of what constitutes a close margin serves only to cloud the issue further. As post-mastectomy radiotherapy has been shown to reduce local relapse by at least two-thirds,1,2 it is therefore important to identify those patients at greater risk of relapse and who would have the most to gain from radiotherapy. Aims and objectives
* Tel: þ44 1622 225103; fax: þ44 1622 225074. E-mail address: [email protected] 0960-9776/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved. doi:10.1016/j.breast.2009.10.007
In this systematic review, the relationship between close or involved margins and risk of local or locoregional relapse is
N.P. Rowell / The Breast 19 (2010) 14–22
explored. Limitations of the evidence are discussed and suggestions made regarding further studies in this area. Methods Criteria for considering studies for this review Types of studies Randomised controlled trials Non-randomised studies
Types of participants Women of any age or menopausal status with stage T1-4N1-3M0 breast cancer, including inflammatory breast cancer. Types of interventions Women treated with radical or modified radical mastectomy with or without simultaneous reconstruction, with or without axillary sampling, clearance or sentinel node biopsy. Patients may have received neoadjuvant or adjuvant chemotherapy, endocrine therapy or radiotherapy. Outcome measures Local relapse was defined as persistent or recurrent disease in the chest wall or within the reconstructed breast. Regional relapse was defined as persistent or recurrent disease in the axilla, supraclavicular fossa or internal mammary chain. Locoregional relapse (LRR) was defined as failure in either local or regional sites. Resection margins were characterised as involved or close or by the presence of fascia invasion or muscle infiltration. Involved, or positive, margins were those where tumour was identified at the deep resection margin. Close margins were defined as those where tumour was identified within a defined distance from the resection margin. Data with respect to skin invasion were not included as it was generally unclear whether this represented disease adjacent to a resection margin or skin involvement some considerable distance away.
15
Data analysis Data were extracted from each paper and summarised. Data relating to the incidence of involved or close margins were pooled to give an indication of the frequency of each of these findings. Relative risks for local or locoregional relapse according to margin status (with 95% confidence intervals calculated according to a random effects model) were combined in a meta-analysis using RevMan5 software.23 Studies were aggregated into three distinct clinical groups: studies of non-inflammatory breast cancer treated by radical or modified radical mastectomy with or without radiotherapy (group 1), studies of inflammatory breast cancer (group 2) and studies of skin-sparing mastectomy (group 3). Studies of involved or close margins were analysed together within these categories. Relative risk was chosen in preference to odds ratio as being less open to misinterpretation. Where possible, actual numbers of patients with relapse were used but where these were unavailable24–27 proportions were calculated from actuarial estimates. A similar process was used to evaluate data with respect to the risks of fascia invasion or muscle infiltration. A chi-square test for statistical heterogeneity was applied to each group. Results of multivariate analysis, where performed, were summarised. No attempt was made to combine these results. Data from a single study10 in which rates of relapse were related to distance from the resection margin were analysed further as a means of demonstrating ways in which future research might address the question of ‘‘cut-off’’ for close margins. Firstly, on the assumption that risk of relapse might fall exponentially with distance, rates of relapse were plotted against log of distance. To eliminate the zero value arising from involvement of the resection margin, data were aggregated into 2 mm subgroups (i.e. 0–1 mm, 2–3 mm, 4–5 mm, etc.) and plotted as the maximum distance within each subgroup (i.e. 1, 3, 5 mm, etc.). Secondly, cumulative risk of relapse was plotted against distance in order to demonstrate the proportion of relapses that would be identified by a particular cut-off value. Results For the purpose of summarising data, studies were aggregated into three groups as described above.
Search strategy for identification of studies Electronic searches of the Medline, Embase and ProQuest databases using the terms ‘‘mastectomy’’, ‘‘resection margin’’, ‘‘deep margin’’, ‘‘margin status’’, ‘‘fascia invasion’’ and ‘‘muscle invasion or infiltration’’ were carried out and updated in August 2009 with identification of further studies from references cited in the papers identified by electronic searching. On-line searching of abstracts from ASCO meetings (1998– 2008), San Antonio Breast Cancer Symposia (2005–2008) and St Gallen Consensus Conferences (2003–2007) was also performed. Description of studies Thirty non-randomised studies met the inclusion criteria. Three of these related to inflammatory breast cancer and three to subcutaneous skin-sparing mastectomy. One was a prospective study and the remainder retrospective cohort studies, of which one was conducted as a national audit13 and five were retrospective studies of patients entered into randomised clinical trials.14–18 Three studies from one centre15,16,18 clearly related to separate subsets of patients but three studies from another centre represented subgroup analyses19–21 of patients included within a larger retrospective study.22
Group 1: Non-inflammatory breast cancer treated with radical or modified radical mastectomy Involved or close resection margin Within this group of 25 studies (18,863 women), there was a wide range of node positivity and utilisation of radiotherapy and chemotherapy (Table 1) reflecting both the selection criteria for the study and the time period in which patients had been treated. In most cases chemotherapy was delivered in the adjuvant setting but in two studies neoadjuvant chemotherapy had been given.15,28 The majority of patients in this group underwent radical or modified radical mastectomy with axillary clearance. The presence of an involved margin was recorded in 15 studies (range 0–8%; Table 2). Close margins were reported in 14 studies (range 0–61%). Pooled data from 13,663 patients revealed the presence of an involved margin in 2.5% (data from 12,552 patients) and a close margin in 8.0% (data from 8964 patients). Various definitions of close margin were used, ranging from a margin of 2 mm or less in five studies to a cut-off of 4–10 mm in eight studies. One study10 presented data for rates of recurrence in 1 mm intervals up to 2 cm. In the radical mastectomy group (Table 1), radiotherapy was given to all patients in seven studies and to no patients in a further
16
N.P. Rowell / The Breast 19 (2010) 14–22
Table 1 Details of patients in series reporting incidence of involved or close margins. Reference
Study typea
Years studied
Number of patients
Stage
% with positive nodes
% Receiving chest wall radiotherapy
% Receiving chemotherapy (% neoadjuvant)
Median follow-up (months)
Radical/modified radical mastectomy R 1975–1980 Ahlborn11 R 1990–2003 Alassas28 Atahan29 R 1994–2002 R 1999–2001 Cheng30 19 R 1989–1998 Coulombe 31 R 1978–1998 Feigenberg 14 R,C 1978–1981 Fowble R 1984–1993 Freedman32 Hehr26 R 1989–2004 R 1980–2001 Horiguchi33 Huang15 R,C 1974–2000 34 P 1982–1987 Jager R 1980–2000 Jagsi27 16 R,C 1975–1994 Katz R 1978–1981 Lagios35 R 1971–2003 Livi36 R 1989–1998 Macdonald22 R 1974–1982 Mentzer10 37 Miccoli R 1979–1982 17 R,C 1982–1999 Nielsen 38 R 1997–2002 Punglia R 1989–1998 Truong20 R 1989–1998 Truong21 R,A 2003–2004 van Houtte13 R,C 1975–1994 Woodward18
322 75 952 1010 752 268 627 789 287 1144d 542 608 877 1031 157 2064 4181 100 129 1545 1620 2570 821 110 470
T1–2N0 IIIA/B T1–4N0–3 T1–4N0–3 T1–2N0–1 T1–4N0–3 II–IIIA I–II T1–4N0–3c 0–IIIB II–IIIC T1–3N0–3 T1–3N0 II–IIIA I–II T1–4N0–3 T1–3N0–3 II T2N0–1 II–III I–II T1–2N0 T1–2N1 T1–4N0–3 II–IIIA
0 Not stated 74 51 31 74 100 35b 82 40 82 58 0 86 50 53 43 62 Not stated 91 44 0 100 Not stated 97
0 100 100 26 8 100 0 0b 100 Not stated 100 10 0 0 8 0 22 22 Not stated 0 24 Not stated 0 100 100
0 100 (43) 92 72 62 59 88 68b 27 Not stated 100 (all) 58 15 100 4 27 27 25 Not stated 55 63 Not stated 37 Not stated 100
47 Not stated 61 Not stated 108 96 54 59b 43 81 70 90 100 116 37 199 120 37 Not stated 216 Not stated 92 92 Not stated 120
Inflammatory breast cancer R 1977–2004 Bristol24 Chin39 R 1987–1997 R 1970–1995 Curcio25
192 23e 28
T4N0–3 IIIB/IV IIIB
86 Not stated 90
100 52 Not stated
95 (all) 96 (68) Not stated
64 44 21
38 141d 210f
4 cm or N2–3 0–IIIA 0–III
95 27 28
69 0 20
95 Not stated Not stated
53 71 59
Skin-sparing mastectomy R Downes40 R Horiguchi33 R Vaughan41
1996–2002 1980–2001 1999–2006
Clinical details of patients in studies reporting incidence of involved or close margins. Stage is as reported in the original publication. a Study type: national audit (A); patients entered into randomised clinical trials (C); patients studied prospectively (P); retrospective cohort study (R). b As proportion of the 34 patients with close or positive margins. c Selected series of patients with high risk features. d Included 57/1144 (5%) of patients undergoing radical mastectomy and 20/141 (14%) of patients undergoing skin-sparing mastectomy for in situ disease. e Included 5 patients with stage IV disease; probably some patients included in Curcio.25 f Included 40/210 (19%) mastectomies for in situ disease.
eight studies. Radiotherapy utilisation was not stated in three studies and was 8–26% of patients in the remaining studies. For the purpose of investigating the impact of margin status on rates of relapse, subgroups were identified in which either all patients received radiotherapy or no patients received radiotherapy. Studies differed in their preference for reporting rates of locoregional relapse or local relapse (Table 3). In the subgroup of patients receiving radiotherapy, the risk of LRR was 7–11% (median 9%) and in those with infrequent use of radiotherapy, the risk of local or locoregional relapse was 2–19% (median 8.5%). In the studies where radiotherapy was used infrequently, rates of relapse ranged from 3–16% with clear margins to 6–43% where there were close or involved margins. In seven studies reporting rates of relapse with respect to the presence of an involved or close margin (Table 3), radiotherapy was given to all patients in one study,31 to no patients in five studies11,16,21,27,32 and to 22% of patients in the remaining study.22 Data from these seven studies were combined in a meta-analysis, subdivided according to radiotherapy usage (Fig. 1). For the group of five studies in which radiotherapy had not been given (including 2825 patients), the relative risk of relapse was 2.6 (95% confidence interval 1.8–3.8; P < 0.00001) whereas, individually, only two of these studies had reached statistical significance.16,27 In contrast,
the single study where radiotherapy was given to all patients31 showed no impact of resection margin on rate of relapse (relative risk 0.84; 95% confidence interval 0.25–2.8; P ¼ 0.77). As the incidence of close margins might possibly be affected by other tumour factors, multivariate analysis may more reliably identify the significance of individual risk factors. Multivariate analysis was undertaken in six studies. In four studies with infrequent use of radiotherapy, margin status was identified as a significant independent risk factor in two studies16,27 but not in two others.22,34 Margin status was not identified as a significant risk factor in either of two studies where all patients received radiotherapy.26,31 Muscle or fascia invasion The presence of pectoralis muscle or fascia invasion was recorded in six studies (range 2–20%; Table 2). Pooled data identified the presence of muscle or fascia invasion in 396/5487 patients (7.2%). Involvement of the pectoralis fascia or muscle resulted in a greater risk of LRR in two studies,14,16 but not in two others.17,36 Data from these four studies, in which radiotherapy was not used, are combined in Fig. 2, resulting in a pooled relative risk of 1.7 (95% confidence interval 1.0–2.9; P ¼ 0.04). Significant statistical heterogeneity was present in this group of studies (X2 ¼ 12.6;
N.P. Rowell / The Breast 19 (2010) 14–22
17
Table 2 Incidence of involved or close margins. Reference
Definition of margin
Radical/modified radical mastectomy <4 mm Ahlborn11 Involved Alassas28 Atahan29 involved Involved; 2 mm Cheng30 31 Involved; 2 mm Feigenberg 14 Fascia involved Fowble 32 1 cm Freedman 1 cm Hehr26 Hehr26 Muscle infiltration Horiguchi33 <5 mm Huang15 Involved; <5 mmb 34 Involved; <5 mm Jager Involved; <2 mm Jagsi27 16 Involved; <5 mm Katz Fascia involved Katz16 Katz,16 Woodward18 Involved Lagios35 Muscle infiltration Livi36 22 Macdonald Involved 19 Coulombe 20 Truong Truong21 Involved; 5 mm Mentzer10 Muscle infiltration Miccoli37 Fascia involved Nielsen17 38 Involved; <2 mm Punglia 13 van Houtte Involved; <2 mm 18 Involved; <5 mmb Woodward Pooled data Inflammatory breast cancer <2 mm Bristol24 Involved Curcio25 39 Involved Chin Pooled data Skin-sparing mastectomy Downes40 Involved; <5 mm <5 mm Horiguchi33 41 <1 mm Vaughan Pooled data
Subgroup
Number evaluable for margin status
322 75 952 1000 268
Number (%) with involved margin
Number evaluable for muscle or fascia invasion
Number (%) with muscle or fascia invasion
561
21 (4%)
287
57 (20%)a
1010 502
19 (2%) 9 (2%)
1955
31 (2%)
129 1545
8 (6%) 260 (17%)
5487
396 (7.2%)
88 (27%) 1 (1%) 8 (8%) 3 (<1%) 16 (6%)
789 287 1144 537 608 726 994
Number (%) with involved or close margin
24 (2%) 49 (18%) 136 (17%) 78 (27%)a
0 19 6 19 12
(0%) (4%) (1%) (3%) (1%)
0 (0%) 60 (11%) 57 (9%) 64 (9%) 29 (3%)
T1–2N1
Age <50 years T1–2N0 T1–2N1
155
0 (0%)
3804 752 2570 750 100
226 (6%) 45 (6%) 94 (4%) 26 (3%) 8 (8%)
1619 100 470 13,663
18 (1%) 2 (2%) 3 (1%) 341/12,552 (2.5%)
149 28 23 Data not pooled
7 (25%) 4 (17%)
38 141c 210d 389
61 (61%)
40 (2%) 10 (10%) 17 (4%) 713/8964 (8.0%) 16 (11%)
1 (3%)
1/38 (2.6%)
7 (18%) 9 (6%) 29 (14%) 45/389 (11.6%)
Data relating to subgroups within each study are shown in italics. a Selected series of high risk patients. b Close margin not defined in report; <5 mm assumed as institutional standard as reported in another series from the same centre.16 c 20/141 patients (14%) had DCIS. d 40/210 patients (19%) had DCIS.
P ¼ 0.0006). Multivariate analysis was undertaken in two studies, identifying muscle or fascia invasion as a significant independent risk factor in one study26 but not in another.14
Group 2: Inflammatory breast cancer Three studies of inflammatory breast cancer and margin status were identified.24,25,39 As two studies may have overlapped,25,39 these three studies account for approximately 220–240 women undergoing mastectomy as part of multimodality treatment for inflammatory breast cancer (Table 1). Close margins (less than 2 mm) were observed in 11% in one study24 and in the overlapping pair of studies,25,39 involved margins were seen in 17–25% (Table 2). Data were not pooled for this group. Locoregional relapse was seen in 16–30% overall,24,39 with a higher frequency in those with involved or close margins (32– 100% vs 9–40% with clear margins; Table 3). In a meta-analysis, there was a pooled relative risk of LRR of 3.1 (95% confidence interval 1.8–5.4; P < 0.0001; Fig. 1). This result was not substantially
affected (relative risk 2.63; P ¼ 0.004) by exclusion of one of the overlapping studies.39 In one study, three-year overall survival was significantly worse (0% vs 47%) in those with involved margins (relative risk 7.8; 95% confidence interval 2.1–28.6; P ¼ 0.002).25
Group 3: Skin-sparing mastectomy Three studies of skin-sparing mastectomy and margin status were identified33,40,41 (389 women; Table 1). Two of these studies also included some patients with ductal carcinoma in situ (DCIS). Close margins (with either invasive cancer or DCIS) were seen in 45/389 (11.6%); two studies using a cut-off of 5 mm33,40 and one a cut-off of 1 mm41 (Table 2). Local relapse was seen in 5–8% (Table 3) with only one study reporting risk relative to margin status.41 In this study, there was a higher risk of local relapse in those with close margins but this did not reach statistical significance (relative risk 2.1; 95% confidence interval 0.7–5.8; P ¼ 0.16). However, in the single study in which
18
N.P. Rowell / The Breast 19 (2010) 14–22
Table 3 Rates of local or locoregional relapse (LRR) in women with involved or close margins Reference
Definition of margin
Subgroup
Site of Relapse rate relapse overall (%)
Radical/modified radical mastectomy – radiotherapy given to £26% of patients <4 mm from fascia Local Ahlborn11 Fowble14 Fascia invasion LRR Freedman
32
Horiguchi33 Jager34 Jagsi27 Katz16
1 cm 0–2 mm vs >2–6 mm <5 mm <5 mm 2 mm <5 mm
Katz16
Fascia involved
Livi36
All stages T 5 cm N0–1 and margins 1 cm
12/322 (4%)
Local Local
136/789 (17%) 5/34 (15%)
Local Local LRR LRR
19/1144 (2%) 53/608 (9%) 46/877 (5%) 19% at 10 years
1–3 nodes involved
LRR LRR
1–3 nodes involved Muscle invasion
LRR LRR
Macdonald22 Mentzer10 Nielsen17
Involveda 5 mmb Fascia involved
LRR LRR
Truong21
Involved
NS 0.007
4/19 vs 1/14 (21% vs 7%)
NS
Local LRR
LRR
11% at 10 years
Local LRR
31/470 (7%) 41/470 (9%)
Curcio25 Chin39
Involved Involved
Skin-sparing mastectomy Not stated Downes40 <5 mm Horiguchi33 <1 mm Vaughan41
0.0008 0.003
NS
0.99 (0.5–1.95) NS 2.6 0.02 0.0001 not stated
0.0001 NS
0.0001
NS NS
Close or unknownd vs LRR negative LRR LRR Local Local Local
NS 0.05
NS
3/49 vs 16/219 (6% vs 7%) Not stated Not stated Not stated Not stated Not stated
Radical/modified radical mastectomy – subset of two studies with and without RT T1–2N1 Katz,16 Woodward18 <5 mmc Inflammatory breast cancer Bristol24 <2 mm
<0.001 0.0001
P
NS
Huang15 Woodward
5/88 vs 7/234 (6% vs 3%) 6/21 vs 54/540 (29% vs 10%)
8/100 (8%) 7/61 vs 1/39 (11% vs 3%) 456/1545 (30%) 86/260 vs 370/1285 (33% vs 29%) 67/821 (8%) 5/26 vs 100/724 113/821 (14%) (19% vs 14%) 19/268 (7%) 15% at 5 years
<5 mm Chest wall or fascia invasion <5 mmc
Univariate Multivariate analysis analysis P Relative risk (95% c.i.)
Not stated 21% vs 5% at 10 years 12/29 vs 151/965 (41% vs 16%) 43% vs 13% at 10 years 8/19 vs 160/991 (42% vs 16%) 33% vs 13% at 10 years 378/2064 (18%) 7/31 vs 355/1924 (26% vs 23%)
Radical/modified radical mastectomy – radiotherapy given to all patients 2 mm LRR Feigenberg31 1 cm Local Hehr26 Muscle invasion
18
Relapse rate with vs without involved or close margin (%)
not stated 3.2 NS NS
NS
16% at 5 years
32% vs 9% at 5 years
7/23 (30%)
69% vs 40% at 3 years NS 4/4 vs 3/19 (100% vs 16%) 0.02
3/38 (8%) 8/141 (6%)e 9/170 (5%)f
3/11 vs 26/199 (27% vs 13%)
NS NS not stated
4.6 (1.1–19.3)
0.036
7.1 (1.3–38.0)
0.022
0.0005
NS
NS, not significant. a 44/1075 were men. b Assessed from gross specimen in a proportion of cases. c Close margin not defined in report; <5 mm assumed as institutional standard as reported in another series from the same centre.16 d Included 43/192 with unknown margins. e 20/141 patients (14%) had DCIS. f 40/210 patients (19%) had DCIS.
multivariate analysis was performed,33 margin status was confirmed as a significant risk factor (relative risk 7.1; 95% confidence interval 1.3–38.0; P ¼ 0.002; Table 3).
that of all relapses within 5 mm or less, one-third were at the resection margin, a further one-third up to 2 mm and the remaining third between 2 and 5 mm.
Further evaluation of risk of relapse vs distance from the resection margin
Analysis of all groups combined
Further exploratory analysis of data from a single study10 (Fig. 3) demonstrated a significant relationship between risk of relapse and log of distance from the resection margin (r ¼ 0.77; P ¼ 0.024). A simple linear relationship was also found (r ¼ 0.74; P ¼ 0.035; not shown). A plot of cumulative risk (Fig. 4) showed, approximately,
Combining data from all three groups resulted in a relative risk of 2.6 (95% confidence interval 1.9–3.4; P < 0.00001; without significant statistical heterogeneity), indicating the risk of an involved or close margin was broadly consistent across all groups despite the differences in clinical situation.
N.P. Rowell / The Breast 19 (2010) 14–22
19
Fig. 1. Meta-analysis of risk of recurrence with respect to involved or close resection margins.
Discussion This review demonstrates that involved margins are relatively uncommon, affecting only 2.5% of patients following mastectomy. However close margins were just over three times more frequent. The relationship between margin status and local relapse included more data from patients with close margins than involved margins. Fig. 1 clearly demonstrates that a close margin is associated with a significantly increased risk of local or locoregional relapse. The relative risk of close margins following mastectomy for inflammatory breast cancer (3.1) or subcutaneous skin-sparing mastectomy (2.1) were broadly consistent with the risk following mastectomy for non-inflammatory breast cancer (2.7) suggesting that in all clinical situations the baseline risk may be modified by the presence of a close margin to a similar extent.
Within the group of studies of non-inflammatory breast cancer, only two had (individually) shown an increased risk from close margins.16,34 These were larger studies with over 1700 patients between them. In contrast, the two older and more frequently cited studies10,11 were smaller and, statistically, much less likely to have produced a positive result. The low frequency of close margins and the generally low risk of recurrence after mastectomy, mean that study size is critical. Small studies, particularly where the result is negative, cannot be relied upon. In these two older studies, the authors’ conclusions of no significant relationship between margin status and subsequent relapse were taken at face value and the possible implications of an increased relative risk overlooked. The relative importance of close margin and fascia involvement requires further scrutiny as in one study, in individual patients there was a disparity between these two factors.16 If a surgeon considers that the tumour may lie close to the fascia, an additional
20
N.P. Rowell / The Breast 19 (2010) 14–22
Fig. 2. Meta-analysis of risk of recurrence with respect to fascia invasion or muscle infiltration. Non-inflammatory breast cancer; radiotherapy not given.
cuff of muscle may be included within the main specimen. In this situation, the fascia might be involved but the resection margin considered clear. This disparity might account for the weaker relationship between fascia or muscle involvement and relapse (relative risk 1.7) as compared to the relationship between resection status and relapse (relative risk 2.6). Meta-analysis was undertaken to investigate the extent to which a number of small studies had produced individually inconclusive results, especially given the low frequency of close margins, when a larger analysis might have revealed a more consistent trend. However, such an analysis is limited by the interdependence of clinical factors and must be interpreted with caution. It is particularly important in any analysis to exclude potential sources of bias and it is possible that an analysis of rates of relapse with respect solely to margin status might be misleading. The possibility that the adverse effect of margin status is itself related to other tumour factors (for example tumour size or nodal status) needs to be considered. However, the group of five studies of non-inflammatory breast cancer without radiotherapy11,16,21,27,32 does not contain a preponderance of more advanced tumours. Out of the 2825 patients included in this analysis, tumours greater than 5 cm were seen in 103 patients (out of 1031) in one study16 and 25 (out of 877) in another.27 Additionally all 1050 patients included in two studies were node-negative,11,27 only one study (with 821 patients) included only node-positive patients21 and the remainder included a mixture of node-positive and node-negative. Multivariate analysis within individual studies provided confirmatory evidence of the significance of margin status. In this case the two larger studies in the meta-analysis showed that margin status was an independent risk factor,16,27 although two other studies22,34
which did not provide data for the meta-analysis (except in the form of a selected subgroup21) found this not to be significant. On the other hand, it is possible that this review underestimates the risk of a close resection margin. A number of studies reported locoregional relapse (LRR) rather than local relapse. In a series of 1545 patients,17 the increased risk of LRR in those with fascia invasion was of borderline significance (18-year probability of LRR 46% vs 40%; P ¼ 0.05) but considering chest wall relapse only this became highly significant (30% vs 20%; P ¼ 0.003). In contrast, the risk of axillary failure alone was not increased. In a study of 627 node-positive women,14 isolated LRR was seen in 70 of which chest wall relapse (with or without concurrent nodal relapse) was seen in 40 (57%). As close margin could only potentially be responsible for just over half of these relapses, the inclusion of data for LRR rather than truly local relapse would be expected to result in lower estimates of risk. The ideal cut-off for the definition of a close margin remains uncertain. On the basis of risk gradually reducing with distance from the margin, there would be a balance between the need to define the minimum distance at greatest risk and the need to include the majority of those who have any additional risk. The further analysis of Mentzer’s data10 (Figs. 3 and 4) demonstrates how this might be achieved. In this case, the use of a 5 mm margin would appear to identify the majority of those at risk. However, this study contained only 100 patients and is unusual for the high proportion of tumours within 5 mm of the resection margin (61%) and therefore the low proportion of those at a larger distance. A higher proportion of tumours at a greater distance would be necessary to establish a baseline risk (i.e. independent of distance) to which can be added the additional risk from proximity to the
y = -0.0948x + 0.1358 r = 0.77; P = 0.024 0.15
0.1
0.05
0 1
3
5
10
20
30
distance from resection margin (mm) Fig. 3. Risk of local recurrence at intervals from resection margin. Reanalysis of data from Mentzer10 relating rate of local relapse to distance from the resection margin. Data have been aggregated into 2 mm groups up to 10 mm, and 5 mm groups thereafter.
cumulative risk of local recurrence
risk of local recurrence
0.2
0.2
0.15
0.1
0.05
0 0
5
10
15
20
25
30
distance from resection margin (mm) Fig. 4. Cumulative risk of local relapse. Cumulative risk of local relapse by distance from the resection margin (8 relapses in 100 patients). Data from Mentzer.10
N.P. Rowell / The Breast 19 (2010) 14–22
resection margin. In Fig. 3, the best fit was obtained by plotting distance on a logarithmic scale, consistent with risk falling exponentially with distance from the resection margin. This demonstration of the significance of close margins supports the use of postoperative radiotherapy where the margins are close, as is normal practice for a number of oncologists.38 Of note is that in the one study where radiotherapy was given to all patients,31 the absence of risk from margin status was clearly demonstrated. This would be consistent with postoperative radiotherapy effectively eliminating the risk from a close margin. The absolute risk from the presence of a close margin needs to be understood in the context of other risk factors. In one study, the presence of either a close margin or a single other risk factor (compared to those without any risk factors) increased the risk of LRR from 1% to 10%.27 In another study, the presence of a positive margin did not increase the risk of LRR except in the presence of either lymphovascular invasion, a grade 3 tumour, T2 tumour or age under 50 when the risk of LRR was 20%.20 A third study32 reported that all LRR occurring in patients with close margins affected those under 50 year of age. Conclusions This systematic review demonstrates that close resection margin is associated with a significantly increased risk of local relapse and that chest wall radiotherapy should be considered especially where other risk factors are present. Implications for practice B
B
B
For women with a close resection margin and one or more additional risk factors, chest wall radiotherapy should be recommended. For women with a close resection margin but without additional risk factors, chest wall radiotherapy should be considered. In the absence of further data, a 5 mm cut-off would seem reasonable.
Implications for research B
Further research is required to explore the relationship between distance from the resection margin and risk of local recurrence. An approach similar to that used above in the reanalysis of Mentzer’s data is suggested. The relative infrequency of close margins and the recognised impact of other risk factors suggests that such a study would need to include many thousands of women.
Conflicts of interest There are no conflicts of interest. Funding sources Dr NP Rowell is employed by Maidstone & Tunbridge Wells NHS Trust. There are no additional sources of funding. Acknowledgements I am indebted to Dr Russell Burcombe and Dr David Fish for their helpful comments and encouragement.
21
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