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 / Characteristics of study population / Surgical MarginsDefinition & categories for final microscopic margins (from excision or re-excision) / MedT follow-up months / Treatment§
Whole breast radiotherapy (WBR) is an inclusion criterion for this review (all subjects had WBR)
Author year
(country)
[Related study of the same cohortC] / Design,
time-frame / Median age**
(range)
Years / Number of subjects (number excluded) / Eligible subjects/ definition of cohort / Stage distribution (% DCIS if included)
N+ % / Re-excision 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) / Systemic therapy (ST): Chemotherapy (C); Endocrine therapy (E)
WBR / Boost / Total dose / C / E
*Livi 23 2013 (Italy) / R
2000 - 2008 / 58 (22-86) / N=2093 from 2121
(28 NMIC) / Patients with (T1-T2) invasive breast cancer treated with BCS and radiation with boost / I-II in > 90%;
N+ 28% / Positive/close: invasive tumor at margin or within 2mm ; negative >2mm / 62.4 / NR / 50 (46-52) / 10-20
(100%) / NR / 39.6% / 73.3%
*Demirci24 2012 (USA) / R
1985 – 2005 / 56 (18-89) / N=1058
(no exclusions) / Stage I-II breast cancer patients treated with BCT (surgical excision plus radiotherapy) / I-II;
N+ 19.4% / Positive: tumor cells at ink (includes focally positive); close (negative but <2mm); negative margin ( ≥2mm) and negative (width unknown) / 117.6 / NR / Estimate 47.5 (36-50.4) / 15 (6-24)
(97%) / 62 / 31.4% / 61.6%
*Lupe25 2011 (Canada) / R
2001 – 2003 / 57 / N=2264 (no exclusions) / Breast cancer patients with pT1-3, any pN stage, M0, who were treated with BCS and WBR / I-II; N+ 25.8% / Positive: microscopic tumor with invasive carcinoma or
DCIS touching ink; close <2mm; negative ≥2mm / 62.4 / 4.9% / 42.5 / 10
(100%) / NR / 84.6% / 84.6%
*Groot26 2011 (Canada) / R
1991 – 2001 / Mean 57.3 / N=825 (263 NMIC) / Patients with invasive carcinoma of the breast with stage I or II, and had BCT. / I-II;
N+ NR / No positive group; close/narrow (not at ink but ≤ 2mm); negative > 2mm / 86.3 / 29% / NR / NR
(15.3%) / NR / NR / NR
*Liau27 2010 (UK) / R
1999 – 2004 / 58 (29-92) / N=563 (no exclusions) / Patients with unilateral invasive breast carcinoma (T1–3, N0–1, M0) who were treated with BCS and radiation / 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%
*Whipp28 2010 (UK) / R
1997 – 2000 / 53 (25-79) / N=221 (excluded those NMIC) / Consecutive stage I-II breast cancer patients treated with BCS and referred for radiation / I-II; N+ 32% / Positive: at ink; close ≤1mm; negative margin > 1mm / 60 / 17.6% / 46 / 12.5
(62.4%) / NR / NR / 71.5%
Kreike29 2008 (Netherlands) [Borger66 94] / R
1979-88 / Mean 50 (22-85) / N=1024 (2) / Consecutive subjects with stage I-II IBC treated with radiation as part of BCT. / I-II;
N+ 25% / Positive: tumour at surgical margin; close < 1mm; negative ≥ 1mm; unknown / 159.6 / NR / 50 / 15-25 (99.7%) / 50-81 / 15% / 2.5%
Ewertz30 2008
(Denmark) / R
1989-98 / Estimate53.8 / N= 3899 from 4921
(450 NMIC & excluded 639 various reasons) / Women aged ≤75 years at breast cancer diagnosis (in population database/ DBCG) treated with BCS and radiation according to national protocols / I-II in > 90%;
N+ 32% / Microscopic tumour-free margin (inking not specified): positive < 5mm; negative (tumour-free) ≥ 5mm; unknown / 102 / NR / 48 / 10-16 (96%) / NR / 23% / 19%
Varghese31 2008 (UK) / R 1990 -2004 / 57 (33-95) / N = 79 (no exclusions) / Early IBC ≤ 1 cm treated with BCS (data are for group treated with BCS and WBR) / I in > 90%;
N+ 9% / Positive (invasive or in-situ) cancer at inked margin; close < 1mm; negative ≥ 1mm / 110.6 / NR / 40 accelerated WBR / NR / NR / NR (probably 0%) / 80%
*Livi32 2007 (Italy) / R
1980 – 2001 / 55 (30-80) / N=3834 (no exclusions) / Early stage (T1-T2) breast cancer patients treated with BCS and radiation / I-II in > 90%; N+ 29.5% / Positive <1mm; negative ≥1mm / 88.8 / NR / 50 (46-52) / 9-16
(79%) / NR / 24% / 46.8%
Kunos33 2006
(USA) / R
1996-2002 / Mean
59.4 (24-89) / N= 341 (6) / Consecutive women having BCS, axillary dissection and WBR for T1a–T2 stage I or II IBC / I-II;
N+ 28% / Microscopic distance to the closest inked margin: close > 0mm and <2mm; negative ≥2mm (positive at ink not retained in study) / 56 / NR / 46.8 (39.6-54) / 12.6 (0-18) (100%) / Min ≥ 50 / 38% / 70%
*Kasumi34 2006 (Japan) / R
1986 – 2002 / Mean 51 / N= 987 (1462 NMIC) / All patients who had BCS; only cohort receiving radiation considered in this analytic review / I-II in > 90% (NR);
N+ NR / Positive (positive/close) tumor cells (invasive or in-situ) within 5mm of resection margin; negative > 5mm / 78 / NR / 50 (50-50) / 13.5 (10-16)
(100%) / NR / NR / NR
Karasawa35 2005, multicentre
(Japan) / R
1999-2002 / 48 (24-89) / N= 941 (no exclusions) / Clinical stage 0-II breast cancer (tumour diameter < 3 cm), treated with BCS and WBR with follow-up > 2 years. / I 54%,
II 45%, (1%);
N+ 30% / Positive: cancer cells at surgical margins; close ≤ 2mm; negative 2.1-5mm / 58.5 / NR / 50 (34-62) / Estimate 10 (87%) / 60 (34-70) / NR (80% any ST) / NR (80% any ST)
Bellon36 2005
(USA) [Recht65 1996] / RCT 1984-92 / 45 (20-68) / N= 244 (no exclusions) / Clinical stage I-II IBC treated with BCS; RCT of WBR either before or after chemotherapy (node positive or high-risk node negative IBC) / 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%
Santiago37 2004 (USA) [Peterson64 99, Solin63 91] / R
1977-90 / 52 (21-86) / N= 937 (no exclusions) / Consecutive women with clinical and pathologic stage I-II IBC treated with BCS and WBR. / 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 / 121 / 49% / 46 (44.0-52.7) / 16 – 19.7 (100%) / 64 (60.0-72.4);
Min ≥ 60 / 28.6% / 18.7%
*Leong38 2004 (Australia) / R P
1980 – 1994 / 48 / N= 452 (706 NMIC or no path review) / Stage I-II node-negative breast cancer patients who had BCS and radiation therapy and had central pathology review of tumor / I 76.3%, II 21.5%, unknown 2%;
N+ 0% / Positive: invasive or in-situ cancer at inked margin; negative: absence of invasive or in-situ cancer at inked margin / 80 / 22.4% / 46 (40-54) / 16 (8-30)
(84%) / 61 / 0.0% / 0.4%
Neuschatz39 2003 (USA)
[Wazer61 1998] / R
1982-94 / 56 (25-86) / N= 509 breasts in 498 women
(no exclusions) / Women with clinical stage I-II IBC treated with BCS and WBR. / I-II;
N+ 18.1% / Proximity of (invasive or in-situ) tumour to inked margin stratified as: positive; close > 0 but ≤ 2mm; negative 2.1-5mm or negative >5mm; re-excision; unknown / 121 / 55.6% / 50-50.4 / 10-20 (73%) / 65 (50-70) / 24.4% / 26.3%
Goldstein40 2003 (USA) / RP
1980-1996 / 60.6 (29-87) / 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% / 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 / 104.4 / 72.7% / 45 / 15-16 (96%) / 61 / 16.3% / 38.4%
Perez41 2003 (USA) / R 1970-97 / 57 (22-92) / 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% / Positive (at inked margin); close ≤3mm; negative >3mm; unknown (mainly where specimen not inked) / 79.2 / 52.3% / 48-50 / 10-20 based on margins (91.4%) / NR
Estimate
Min ≥ 58 / 18.3% / 38%
Smitt42 2003 (USA)
[Smitt62 1995] / RP
1972-96 / NR (age-group data) / 535
(no exclusions) / Women with stage I-II IBC treated with BCS and radiation therapy / I-II;
N+ 24% / 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) / 60 / 49% / 50.4 / 10 (65%) / < 60 in 43%
≥ 60 in 57% / 27% / 26.2%
Karasawa43 2003 (Japan) / R
1987-2001 / 49 (25-83) / N= 353 breasts in 348 women (9 from 357) / Women with histology-proven stage 0-II breast cancer (and no metastases) treated with wide excision / I 55.0%, II 39.4%, (5.7%);
N+ 18% / Positive margin (inking not specified) ≤5mm further stratified as: focally positive, <2mm free margin, 2-5mm free margin; or negative
tumour-free margin >5mm / 51.6 / NR / 44-50 / 9 (99.4%) / NR
Estimate
Min ≥ 52 / 37.4% / 50.6%
* McBain44 2003 (UK) / R
1989 – 1992 / Mean 53.5 (21-77) / 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 / Positive: resection margins positive for cancer or incomplete excision; otherwise classified as negative (or unknown if NR) / 76.8 / 6.1% / 40 (40-40) / No boost / 40 (40-40) / 5.6% / 57.8%
Mirza45 2002
(USA) [Cabioglu59 2005] / R
1970-94 / 50 (24-86) / N= 947 from 1083 (136 with systemic relapse) / Women with stage I-II IBC treated with BCS and WBR. / I 56%, II 44%;
N+ 21% / Positive <1mm of inked edge59; negative ≥1mm; unknown / 108 / 39% / 45-50 / 10-20 (70%) / NR / 24.6% / 20.4%
Horiguchi46 2002 (Japan) [Horiguchi60 1999] / R
1991-99 / Mean 50.9 (24-78) / N = 217 breasts in 215 women (no exclusions) / Women with clinical stage I-II IBC treated with BCS, ALND, and WBR. / I 51.2%,
II 48.8%;
N+ 26% / Positive: tumour cells ≤5mm from resected margin (inking not specified); negative > 5mm / 54 / NR / 50 / NR / NR / 100% / 59.4%
Voogd47 2001
(EORTC & DBCG) / CDP based on 2 trials 1980- 89 / Estimate53.1 / N = 781 from 879 (98 NMIC) / 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 / 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 / 117.6 / NR / 50 / DBCG:
10-25 (100%);
EORTC 20-25 (100%) / NR / NR / NR
Kokubo48
2000 (Japan) / NR
1987-98 / Mean 48 (21-86) / N= 906 from 928 (22) / Women with breast cancer treated with BCS, ALND, and radiation therapy / I 44.2%,
II 50.9%,
III 0.9% (4%); N+ 28% / Positive: tumour at resected margin; close < 5mm; negative ≥ 5mm / 52 / NR / 50 / 10 (21%) / NR / NR (most had ST) / NR (most had ST)
Park49 2000 (USA)
[Schnitt57 94, Gage58 96] / RP 1968-87 / 53 (23-88) / N = 533 from 2140 (1607 NMIC) / Women with stage I-II IBC for whom histology slides were available to classify margins / I 56%, II 44%;
N+ 26% / 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 / 127 / 48% / 45 / Dose NR (100%) / 62 (60-72.5);
Min ≥ 60 / 28% / 7%
Touboul50 1999 (France) / R
1976 -93 / Mean 52.5 (26-86) / 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% / Tumour-free inked margin stratified as: positive (0mm), close (2mm), negative (>2mm), or indeterminate (unknown or not inked) / 87.2 / NR / 45 / 14.8-15.2 (99%) / Estimate
60 / 22% / 33%
Freedman51 1999 (USA)
[Freedman56 2002] / R
1979-92 / 55 (24-89) / 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 edge; close ≤ 2mm; negative >2mm / 76 / 59% / 46 / Estimate 16 (99%) / 62: 60, 64, or 66 based on margins / 28% / >20% and <48%
Obedian & Haffty52 1999 (USA) / R
1970-90 / 57 (20-86) / 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% / Positive (invasive or in-situ) cancer at margin; close ≤ 2mm; negative >2mm; unknown (mainly where specimen not inked) / 156 / 34% / 46-54 / 10-18 (100%) / 64 / 18% / 19.4%
*Pierce531997 (USA) / R
1984 – 1995 / 55 (22-89) / N=429 (no exclusions) / Patients with clinical stage I-II breast cancer who had BCS and radiation therapy / I-II; N+ 26% / Positive: tumor at inked margin; negative: no tumor at ink / 52.8 / 65% / 40-45 / NR
(95%) / 60-66 / 38% / 38%
*Burke541995 (Australia) / R 1982 – 1989 / 52 (23-81) / N=512 (no exclusions) / Patients with clinical stage I or II invasive breast cancer treated with BCS and radiation therapy / I-II;
N+ 15% / Positive: tumor cells at inked resection margins; negative: no tumor cells at inked margins / 50 / NR / 50 (39-54) / 10 (3.5-18)
(82%) / 60 (46-66) / 7.8% / 49.2%
*Spivack55 1994 (USA) / R
1982 – 1990 / Mean 53.2 (27-76) / N=272 (no exclusions) / Patients with invasive breast cancer who had BCS and radiation therapy / I-II in > 90%;
N+ 35% / Positive: margin had transected microscopic foci of invasive or in-situ cancer; negative: no microscopic foci at inked margins / 48 / NR / 47.7 (45-50.4) / 9-16
(NR) / NR / 40.1% / 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.