Online-Appendix 2: Summary of studies providing data on local recurrence in relation to quantified categories for surgical margins:
Study-specific characteristics, margins definition, and treatment
Study
Author year
(country)
[Related
study of the
same
cohortC]
Characteristics of study population
Desig
n,
timeframe
Median
age**
(range)
Years
Number
of subjects
(number
excluded)
*Livi 23 2013
(Italy)
R
2000 2008
58 (2286)
N=2093
from 2121
(28 NMIC)
*Demirci24
2012 (USA)
R
1985 –
2005
56 (1889)
N=1058
(no
exclusions)
*Lupe25 2011
(Canada)
R
2001 –
2003
57
N=2264
(no
exclusions)
*Groot26 2011
(Canada)
R
1991 –
2001
Mean
57.3
N=825
(263
NMIC)
*Liau27 2010
(UK)
R
1999 –
2004
58 (2992)
N=563 (no
exclusions)
*Whipp28
2010 (UK)
R
1997 –
2000
53 (2579)
N=221
(excluded
those
Eligible subjects/
definition of cohort
Stage
distribut
ion (%
DCIS if
include
d)
N+ %
Surgical Margins
Definition & categories for
final microscopic margins
(from excision or reexcision)
MedT
followup
Treatment§
Whole breast radiotherapy (WBR) is an inclusion
criterion for this review (all subjects had WBR)
months
Reexcis
ion
rate
Radiotherapy§: Median dose
Gray (Gy) [dose range or
minimum (Min) where given
or calculable] for WBR,
boost, and total dose to
tumour bed (% of subjects
received boost)
WBR
Boost
Total
dose
Systemic
therapy (ST):
Chemotherapy
(C); Endocrine
therapy (E)
C
E
Patients with (T1-T2)
invasive breast cancer
treated with BCS and
radiation with boost
Stage I-II breast cancer
patients treated with BCT
(surgical excision plus
radiotherapy)
I-II in >
90%;
N+ 28%
Positive/close: invasive tumor
at margin or within 2mm ;
negative >2mm
62.4
NR
50 (4652)
10-20
(100%)
NR
39.6%
73.3%
I-II;
N+
19.4%
117.6
NR
Estimate
47.5 (3650.4)
15 (6-24)
(97%)
62
31.4%
61.6%
Breast cancer patients
with pT1-3, any pN stage,
M0, who were treated
with BCS and WBR
Patients with invasive
carcinoma of the breast
with stage I or II, and had
BCT.
Patients with unilateral
invasive breast carcinoma
(T1–3, N0–1, M0) who
were treated with BCS and
radiation
Consecutive stage I-II
breast cancer patients
treated with BCS and
I-II; N+
25.8%
Positive: tumor cells at ink
(includes focally positive);
close (negative but <2mm);
negative margin ( ≥2mm) and
negative (width unknown)
Positive: microscopic tumor
with invasive carcinoma or
DCIS touching ink; close
<2mm; negative ≥2mm
No positive group;
close/narrow (not at ink but ≤
2mm); negative > 2mm
62.4
4.9%
42.5
10
(100%)
NR
84.6%
84.6%
86.3
29%
NR
NR
(15.3%)
NR
NR
NR
I-II in >
90%;
N+
31.3%
No positive group; distance of
invasive or in-situ cancer from
edge of resection sample:
close <5mm; negative ≥5mm
58
10.8
%
Estimate
40
9
(60.4%)
NR
20.2%
78.5%
I-II; N+
32%
Positive: at ink; close ≤1mm;
negative margin > 1mm
60
17.6
%
46
12.5
(62.4%)
NR
NR
71.5%
I-II;
N+ NR
NMIC)
N=1024 (2)
Kreike29 2008
(Netherlands)
[Borger66 94]
Ewertz30 2008
(Denmark)
R
197988
R
198998
Mean 50
(22-85)
Varghese31
2008 (UK)
R
1990 2004
57 (3395)
*Livi32 2007
(Italy)
R
1980 –
2001
R
19962002
55 (3080)
*Kasumi34
2006 (Japan)
R
1986 –
2002
Mean 51
N= 987
(1462
NMIC)
Karasawa35
2005,
multicentre
(Japan)
R
19992002
48 (2489)
N= 941 (no
exclusions)
Bellon36 2005
(USA)
[Recht65
1996]
RCT
198492
45 (2068)
N= 244 (no
exclusions)
Santiago37
2004 (USA)
[Peterson64
99, Solin63
91]
*Leong38
2004
R
197790
52 (2186)
N= 937 (no
exclusions)
RP
1980 –
48
N= 452
(706 NMIC
Kunos33 2006
(USA)
Estimate
53.8
Mean
59.4 (2489)
N= 3899
from 4921
(450 NMIC
& excluded
639 various
reasons)
N = 79 (no
exclusions)
N=3834
(no
exclusions)
N= 341 (6)
referred for radiation
Consecutive subjects with
stage I-II IBC treated with
radiation as part of BCT.
Women aged ≤75 years at
breast cancer diagnosis (in
population database/
DBCG) treated with BCS
and radiation according to
national protocols
Early IBC ≤ 1 cm treated
with BCS (data are for
group treated with BCS
and WBR)
Early stage (T1-T2) breast
cancer patients treated
with BCS and radiation
Consecutive women
having BCS, axillary
dissection and WBR for
T1a–T2 stage I or II IBC
I-II;
N+ 25%
Positive: tumour at surgical
margin; close < 1mm;
negative ≥ 1mm; unknown
Microscopic tumour-free
margin (inking not specified):
positive < 5mm; negative
(tumour-free) ≥ 5mm;
unknown
159.6
NR
50
15-25
(99.7%)
50-81
15%
2.5%
102
NR
48
10-16
(96%)
NR
23%
19%
I in >
90%;
N+ 9%
Positive (invasive or in-situ)
cancer at inked margin; close
< 1mm; negative ≥ 1mm
110.6
NR
40
accelerat
ed WBR
NR
NR
80%
I-II in >
90%; N+
29.5%
I-II;
N+ 28%
Positive <1mm; negative
≥1mm
88.8
NR
50 (4652)
9-16
(79%)
NR
NR
(proba
bly
0%)
24%
Microscopic distance to the
closest inked margin: close >
0mm and <2mm; negative
≥2mm (positive at ink not
retained in study)
Positive (positive/close) tumor
cells (invasive or in-situ)
within 5mm of resection
margin; negative > 5mm
Positive: cancer cells at
surgical margins; close ≤
2mm; negative 2.1-5mm
56
NR
46.8
(39.6-54)
12.6 (018)
(100%)
Min ≥
50
38%
70%
78
NR
50 (5050)
13.5 (1016)
(100%)
NR
NR
NR
58.5
NR
50 (3462)
Estimate
10 (87%)
60 (3470)
NR
(80%
any
ST)
NR
(80%
any
ST)
I 52%, II
46%,
unknown
2%;
N+ 80%
Positive65: tumour at inked
margin; close ≤ 1mm;
negative >1mm; unknown
135
68.5
%
45
16-18
(100%)
61
100%
7.4%
I 55%, II
45%; N+
28.8%
Positive (invasive or in-situ)
tumour at surgical margins;
close ≤ 2mm; negative >2 mm
from surgical margins;
unknown
Positive: invasive or in-situ
cancer at inked margin;
121
49%
46 (44.052.7)
16 – 19.7
(100%)
28.6%
18.7%
80
22.4
%
46 (4054)
16 (8-30)
(84%)
64
(60.072.4);
Min ≥
60
61
0.0%
0.4%
I-II in >
90%;
N+ 32%
All patients who had BCS;
only cohort receiving
radiation considered in
this analytic review
Clinical stage 0-II breast
cancer (tumour diameter <
3 cm), treated with BCS
and WBR with follow-up
> 2 years.
Clinical stage I-II IBC
treated with BCS; RCT of
WBR either before or after
chemotherapy (node
positive or high-risk node
negative IBC)
Consecutive women with
clinical and pathologic
stage I-II IBC treated with
BCS and WBR.
I-II in >
90%
(NR);
N+ NR
I 54%,
II 45%,
(1%);
N+ 30%
Stage I-II node-negative
breast cancer patients who
I 76.3%,
II 21.5%,
46.8%
(Australia)
1994
or no path
review)
had BCS and radiation
therapy and had central
pathology review of tumor
Women with clinical stage
I-II IBC treated with BCS
and WBR.
unknown
2%;
N+ 0%
I-II;
N+
18.1%
Neuschatz39
2003 (USA)
[Wazer61
1998]
R
198294
56 (2586)
N= 509
breasts in
498 women
(no
exclusions)
Goldstein40
2003 (USA)
RP
19801996
60.6 (2987)
N= 607
breasts in
583 women
(no
exclusions)
Women with IBC (and
with follow-up data)
treated with BCS and
radiation therapy.
I-II in >
90%;
N+ 23%
Perez41 2003
(USA)
R
197097
57 (2292)
N=1347
(no
exclusions)
Women with pathologic
T1 or T2 breast carcinoma
treated with wide local
excision and WBR.
I-II in >
90%;
N+
17.1%
Smitt42 2003
(USA)
[Smitt62 1995]
RP
197296
NR (agegroup
data)
535
(no
exclusions)
Women with stage I-II
IBC treated with BCS and
radiation therapy
I-II;
N+ 24%
Karasawa43
2003 (Japan)
R
19872001
49 (2583)
N= 353
breasts in
348 women
(9 from
357)
Women with histologyproven stage 0-II breast
cancer (and no metastases)
treated with wide excision
I 55.0%,
II 39.4%,
(5.7%);
N+ 18%
* McBain44
2003 (UK)
R
1989 –
1992
Mean
53.5 (2177)
N= 2159
(no
exclusions)
Patients with clinical stage
I or II invasive breast
cancer treated with BCS
and radiation therapy
I-II in >
90%;
N+ NR
Mirza45 2002
(USA)
[Cabioglu59
2005]
R
197094
50 (2486)
Women with stage I-II
IBC treated with BCS and
WBR.
Horiguchi46
R
Mean
N= 947
from 1083
(136 with
systemic
relapse)
N = 217
Women with clinical stage
negative: absence of invasive
or in-situ cancer at inked
margin
Proximity of (invasive or insitu) tumour to inked margin
stratified as: positive; close >
0 but ≤ 2mm; negative 2.15mm or negative >5mm; reexcision; unknown
Positive (invasive or in-situ)
cancer at inked margin; close
≤ 2.1mm but not at ink;
negative >2.1mm; or
unknown [based on half LPF]
– subset stratified by margin
width from 0-10 mm
Positive (at inked margin);
close ≤3mm; negative >3mm;
unknown (mainly where
specimen not inked)
121
55.6
%
50-50.4
10-20
(73%)
65 (5070)
24.4%
26.3%
104.4
72.7
%
45
15-16
(96%)
61
16.3%
38.4%
79.2
52.3
%
48-50
10-20
based on
margins
(91.4%)
18.3%
38%
60
49%
50.4
10 (65%)
27%
26.2%
51.6
NR
44-50
9
(99.4%)
NR
Estimat
e
Min ≥
52
37.4%
50.6%
76.8
6.1%
40 (4040)
No boost
40 (4040)
5.6%
57.8%
I 56%, II
44%;
N+ 21%
Positive (invasive or in-situ)
cancer at inked margin; close
≤2 mm from ink; negative >2
mm from ink; unknown
(specimen not inked, or
removed in pieces)
Positive margin (inking not
specified) ≤5mm further
stratified as: focally positive,
<2mm free margin, 2-5mm
free margin; or negative
tumour-free margin >5mm
Positive: resection margins
positive for cancer or
incomplete excision;
otherwise classified as
negative (or unknown if NR)
Positive <1mm of inked
edge59; negative ≥1mm;
unknown
NR
Estimat
e
Min ≥
58
< 60 in
43%
≥ 60 in
57%
108
39%
45-50
10-20
(70%)
NR
24.6%
20.4%
I 51.2%,
Positive: tumour cells ≤5mm
54
NR
50
NR
NR
100%
59.4%
2002 (Japan)
[Horiguchi60
1999]
199199
50.9 (2478)
Voogd47 2001
(EORTC &
DBCG)
CDP
based
on 2
trials
198089
NR
198798
Estimate
53.1
I-II IBC treated with BCS,
ALND, and WBR.
II 48.8%;
N+ 26%
from resected margin (inking
not specified); negative >
5mm
I-II;
N+ 37%
Positive (invasive or in-situ)
cancer on specimen surface;
doubtful: cancer at < 1 HPF
from resection margin;
negative ≥1 HPF from
margin; or unknown
Positive: tumour at resected
margin; close < 5mm;
negative ≥ 5mm
117.6
NR
50
N= 906
from 928
(22)
Women with stage I-II
IBC in two RCTs of BCS
and mastectomy: BCS
cohorts from each trial
combined in a prospective
evaluation of margins
Women with breast cancer
treated with BCS, ALND,
and radiation therapy
Mean 48
(21-86)
52
NR
50
Park49 2000
(USA)
[Schnitt57 94,
Gage58 96]
RP
196887
53 (2388)
N = 533
from 2140
(1607
NMIC)
Women with stage I-II
IBC for whom histology
slides were available to
classify margins
127
48%
R
1976 93
Mean
52.5 (2686)
N = 528
(no
exclusions)
Women with stage I-II
IBC ≤ 3 cm treated with
BCS, ALND, and
radiation therapy
I 76.5%,
II 23.5%;
N+ 25%
87.2
Freedman51
1999 (USA)
[Freedman56
2002]
R
197992
55 (2489)
N=1262
(no
exclusions)
Women with clinical stage
I-II IBC treated with BCS,
ALND, and radiation.
I-II;
N+ 27%
Positive (invasive or in-situ)
cancer at inked margin
[further classified as focally or
extensively positive]; close
≤1mm; negative >1mm or
negative NOS; stratified by
distance from ink
Tumour-free inked margin
stratified as: positive (0mm),
close (<2mm), negative
(>2mm), or indeterminate
(unknown or not inked)
Positive (invasive or in-situ)
cancer at inked edge; close ≤
2mm; negative >2mm
Touboul50
1999 (France)
Obedian &
Haffty52 1999
(USA)
R
197090
57 (2086)
N= 871
from 984
(113
NMIC)
Women with IBC treated
with BCS and WBR, and
had available pathology
reports
I-II in >
90%;
N+ 28%
*Pierce531997
(USA)
R
1984 –
1995
R
1982 –
1989
55 (2289)
N=429 (no
exclusions)
I-II; N+
26%
52 (2381)
N=512 (no
exclusions)
Patients with clinical stage
I-II breast cancer who had
BCS and radiation therapy
Patients with clinical stage
I or II invasive breast
cancer treated with BCS
Positive (invasive or in-situ)
cancer at margin; close ≤
2mm; negative >2mm;
unknown (mainly where
specimen not inked)
Positive: tumor at inked
margin; negative: no tumor at
ink
Positive: tumor cells at inked
resection margins; negative:
no tumor cells at inked
Kokubo48
2000 (Japan)
*Burke541995
(Australia)
breasts in
215 women
(no
exclusions)
N = 781
from 879
(98 NMIC)
I 44.2%,
II 50.9%,
III 0.9%
(4%);
N+ 28%
I 56%, II
44%;
N+ 26%
I-II;
N+ 15%
DBCG:
10-25
(100%);
EORTC
20-25
(100%)
10 (21%)
NR
NR
NR
NR
NR
(most
had
ST)
NR
(most
had
ST)
45
Dose NR
(100%)
62 (6072.5);
Min ≥
60
28%
7%
NR
45
14.815.2
(99%)
Estimat
e
60
22%
33%
76
59%
46
Estimate
16 (99%)
28%
>20%
and
<48%
156
34%
46-54
10-18
(100%)
62: 60,
64, or
66
based
on
margins
64
18%
19.4%
52.8
65%
40-45
NR
(95%)
60-66
38%
38%
50
NR
50 (3954)
10 (3.518)
(82%)
60 (4666)
7.8%
49.2%
*Spivack55
1994 (USA)
R
1982 –
1990
Mean
53.2 (2776)
N=272 (no
exclusions)
and radiation therapy
Patients with invasive
breast cancer who had
BCS and radiation therapy
I-II in >
90%;
N+ 35%
margins
Positive: margin had
transected microscopic foci of
invasive or in-situ cancer;
negative: no microscopic foci
at inked margins
48
NR
47.7 (4550.4)
9-16
(NR)
NR
Key (Appendix 1): IBC = invasive breast cancer; IDC = invasive ductal cancer; DCIS = ductal carcinoma in situ; BCS = breast conserving surgery; BCT =
breast conserving therapy; WBR = whole breast radiotherapy; NMIC = not meeting inclusion criteria for the study cohort; ALND = axillary lymph node
dissection; N+ = node-positive; LPF = low-power microscopic field; HPF = high-power microscopic field; EORTC = European Organization for Research and
Treatment of Cancer; DBCG = Danish Breast Cancer Cooperative Group; NOS = not otherwise specified.
Study Design: RCT (Randomised controlled trial); R (observational, retrospective); CD (combination of design and cohorts); NR (not reported and unclear); the
superscript P for study design indicates that study has used (or is interpreted as having used) prospective review of histology slides to classify margins.
* Studies added in updated meta-analysis
C
Related study of same cohort: where 2 or more papers reported on the same cohort, the most recent study was preferentially used (details in text and Figure 1).
**Age: median (or mean) age where reported, or estimated based on descriptive data for age-groups (median age could not be estimated in 1 study).
Nodes (N+ %): Proportion of positive nodes (N+ %) is based on percentage from all subjects (retaining subjects whose node status is unknown in calculation).
Stage: Summary table specifies, where reported, whether clinical or pathologic staging has been described. Most studies used either the American Joint
Committee for Cancer (AJCC) staging system (version 4, or 5, or 6) or did not specify a staging system, and a few studies used International Union against
Cancer (UICC) staging (1987 or 2002 classification). The use of T1, T2 refers to tumor size categorization used in staging systems.
Surgical Margins (details in Methods): Most studies considered the presence of tumour cells at the resection or inked margin as positive, with a negative margin
defined quantitatively as the absence of tumour cells within a specified distance or width (mm) of the margin – a close margin indicated that tumour cells were
within that defined distance (but not at the inked margin) as an intermediate category to positive and negative margins.
T
Median follow-up time in months: A minimum median (or mean) follow-up time of 48 months was an inclusion criterion in this systematic review; additional
data on range of follow-up and losses to follow-up are available from the authors.
§
Treatment: Data on radiation to regional nodes were extracted but were inconsistently and infrequently reported and have not been included in the above table.
40.1%
NR