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Management of the axilla in patients with breast cancer and positive sentinel
lymph node biopsy: An evidence-based update in a European breast center

Article in European Journal of Surgical Oncology · August 2019

DOI: 10.1016/j.ejso.2019.08.013

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 European Journal of Surgical Oncology xxx (xxxx) xxx

Contents lists available at ScienceDirect

European Journal of Surgical Oncology

journal homepage: www.ejso.com

Management of the axilla in patients with breast cancer and positive

sentinel lymph node biopsy: An evidence-based update in a European
breast center
Carlos A. Garcia-Etienne*, Alberta Ferrari, Angelica Della Valle, Marco Lucioni,
Elisa Ferraris, Giuseppe Di Giulio, Luigi Squillace, Elisabetta Bonzano, Angioletta Lasagna,
Gianpiero Rizzo, Richard Tancredi, Andrea Scotti Foglieni, Francesca Dionigi,
Maurizia Grasso, Eloisa Arbustini, Giorgio Cavenaghi, Paolo Pedrazzoli, Andrea R. Filippi,
Paolo Dionigi, Adele Sgarella
Breast Center, Fondazione IRCCS Policlinico San Matteo, Universita
! degli Studi di Pavia, Pavia, Italy

a r t i c l e i n f o a b s t r a c t

Article history: The surgical approach to the axilla in breast cancer has been a controversial issue for more than three
Received 27 January 2019 decades. Data from recently published trials have provided practice-changing recommendations in this
Received in revised form scenario. However, further controversies have been triggered in the surgical community, resulting in
22 June 2019
heterogeneous diffusion of these recommendations.
Accepted 12 August 2019
The development of clinical guidelines for the management of the axilla in patients with breast cancer
Available online xxx
is a work in progress. A multidisciplinary team discussion was held at the research hospital Policlinico
San Matteo from the Universit! a degli Studi di Pavia with the aim to update recommendations for the
Keywords:
Axillary lymph node dissection
management of the axilla in patients with breast cancer. An evidence-based approach is presented.
Axillary dissection Our multidisciplinary panel determined that axillary dissection after a positive sentinel lymph node
Axillary lymphadenectomy biopsy may be avoided in cN0 patients with micro/macrometastasis to !2 sentinel nodes, with age "40y,
Sentinel lymph node biopsy lesions !3 cm, who have not received neoadjuvant chemotherapy and have planned breast conservation
Positive sentinel node (BCS) with whole breast radiotherapy (WBRT). Cases with gross (>2 mm) ECE in SLNs are evaluated on
Surgery for breast cancer individual basis for completion ALND, axillary radiotherapy or omission of both. Patients fulfilling the
criteria listed above who undergo mastectomy, may also avoid axillary dissection after multidisciplinary
discussion of individual cases for consideration of axillary irradiation. Women 70 years or older with
hormone receptors positive invasive lesions !3 cm, clinically negative nodes, and serious or multiple
comorbidities who undergo BCS with WBRT, may forgo axillary staging/surgery (if mastectomy or larger
tumor, comorbidities and life expectancy are taken into account).
© 2019 Published by Elsevier Ltd.

Introduction heterogeneous diffusion of these recommendations.

The surgical approach to the axilla in breast cancer has been a
controversial issue for more than three decades [1]. Data from
recently published trials have provided practice-changing recom-
mendations in this scenario. However, further controversies have
been triggered in the surgical community in Italy, resulting in
A multidisciplinary team (hereinafter called panel) discussion
was held at the research hospital Policlinico San Matteo from the
Universita
! degli Studi di Pavia with the aim to update recommen-
dations for the management of the axilla in patients with breast
cancer and positive sentinel lymph node biopsy. An evidence-based
approach is presented.

* Corresponding author. Breast Surgery, Fondazione IRCCS Policlinico San Matteo,
Universita
! degli Studi di Pavia, Viale Camillo Golgi 19, Pavia, 27100, Italy.
E-mail address: carlos.garciaetienne@unipv.it (C.A. Garcia-Etienne).
Historic background
Sentinel lymph node biopsy (SLNB) is a reliable method for
staging the axilla in most breast cancer cases and axillary

https://doi.org/10.1016/j.ejso.2019.08.013
0748-7983/© 2019 Published by Elsevier Ltd.

Please cite this article as: Garcia-Etienne CA et al., Management of the axilla in patients with breast cancer and positive sentinel lymph node
biopsy: An evidence-based update in a European breast center, European Journal of Surgical Oncology, https://doi.org/10.1016/
j.ejso.2019.08.013
2 C.A. Garcia-Etienne et al. / European Journal of Surgical Oncology xxx (xxxx) xxx
recurrence is a rare event in patients with a positive sentinel node
who undergo axillary lymph node dissection (ALND) [2e5].
Seminal studies have shown that axillary recurrence is much
lower than expected in patients with positive axillary status who
forgo ALND. In the NSABP B-04 study, only 18% of patients in whom
ALND was spared presented axillary recurrence, even though
approximately 40% of these cases harbored axillary metastasis [6].
In this study, that recruited patients between 1971 and 1974 with
higher disease stages than those currently seen in countries with
available screening programs, differences in the surgical manage-
ment of the axilla did not show an impact in DFS or OS [6].
Trials validating the use of SLNB technique with a false negative
rate for detecting axillary metastasis ranging from 5% to 8%, have
consistently resulted in a much lower axillary recurrence rate (<1%)
and no impact on survival outcomes, showing the same findings
from the NSABP-04 translated to the current era [4,5].
These observations called into question the need for ALND in the
presence of a positive sentinel node. Improved understanding of
the disease and the current trend in placing more emphasis on
tumor biology, where lymph node status may influence but not
necessarily dictate the indication for chemotherapy, further justi-
fied the need to reassess potentially harmful surgical interventions
that may be unnecessary in selected cases.
A retrospective study from the US National Cancer Database
with more than 97,000 women with a positive SLNB documented
that 19% of cases with macroscopic metastasis to the sentinel node
and 36% of cases with microscopic nodal disease did not complete
ALND. No significant differences in axillary recurrence rates and 5-
year relative survival were observed after omission of ALND in
cases with microscopic or macroscopic disease to the sentinel node
[7]. Despite its large patient sample, the retrospective nature of this
study precluded definitive conclusions at the time of publication,
due to potential confounding factors that may have resulted from
selection bias.
Recently published prospective trials
Table 1 shows 10-year outcomes of randomized controlled trials
(RCTs) evaluating different options of axillary management in pa-
tients with early breast cancer and positive sentinel node biopsy.
The Z0011 study, a RCT from the American College of Surgeons
Oncology Group (ACOSOG), represents the most discussed evi-
dence on this topic. It included patients with T1-2 lesions who were
candidates for breast-conserving surgery (BCS) with whole breast
radiotherapy (WBRT) and had 1 to 2 positive sentinel nodes (micro
or macroscopic disease). Four hundred forty-six cases were ran-
domized to no further surgical treatment of the axilla (SLNB-only)
and 445 cases to completion ALND. Their first reports after a me-
dian follow-up of 6.3 years showed no statistically significant dif-
ferences in local recurrence (p ¼ 0.11), regional recurrence
(p ¼ 0.45), disease-free survival (DFS; p ¼ 0.14), and overall survival
(OS; p ¼ 0.25) between the two groups [8,9].
A recent update of the Z0011 with a median follow-up of 9.25
years confirms positive results on locoregional disease control. The
cumulative incidence of regional recurrences at 10 years in the
ipsilateral axilla was similar in both arms with 2 (0.5%) in the ALND
group compared with 5 (1.5%) patients in the SLNB-only group
(p ¼ 0.28). Ten-year cumulative locoregional recurrence was 6.2%
with ALND and 5.3% with SLNB-only (p ¼ 0.36). Of note, SLN was
the only site of metastasis in 73% of cases in the ALND group. After
multivariable analyses adjusted for treatment arm; hormone re-
ceptor status, pathologic tumor size and tumor grade were asso-
ciated with locoregional recurrences [10]. The 10-year OS was 86.3%
in the SLND-only group and 83.6% in the ALND group (HR 0.85 [1-
sided 95% CI, 0e1.16]; non-inferiority p ¼ 0.02). The 10-year DFS
Please cite this article as: Garcia-Etienne CA et al., Management of the axilla in patients with breast cancer and positive sentinel lymph node
biopsy: An evidence-based update in a European breast center, European Journal of Surgical Oncology, https://doi.org/10.1016/
j.ejso.2019.08.013
was 80.2% in the SLND-only group and 78.2% in the ALND group
(HR, 0.85 [95% CI, 0.62e1.17]; p ¼ 0.32) [11].
Some caveats that concerned the validity of Z0011 results were
pointed out since the first report such as low patient accrual (the
trial was closed with 891 cases before reaching the planned accrual
size of 1900 patients), and limited follow-up (6.3 years). However,
the study was closed because the event rate was much lower than
anticipated in both arms and updated reports with longer median
follow-up of 9.25 and 9.3 years, respectively, have confirmed its
findings [10,11].
Additional recently published trials have also questioned the
impact of ALND in early-stage breast cancer. A prospective RCT
from the International Breast Cancer Study Group (IBCSG), the trial
23-01, included patients with T1-2 lesions with a positive SLNB for
micrometastasis or isolated tumor cells (ITCs) and randomized
cases to completion ALND (n ¼ 465) or no further surgical treat-
ment (n ¼ 469). With a median follow-up of 9.7 years, 10-year DFS
was 76.8% (95% CI, 72.5e81.0) in the non-ALND group compared
with 74.9% (70.5e79.3) in the ALND group (HR 0.85; 95% CI,
0.65e1.11; log-rank p ¼ 0.24; p ¼ 0.0024 for non-inferiority). 10-
year OS was 90.8% (95% CI, 87.9e93.8) in the non-ALND group
and 88.2% (84.8e91.6) in the ALND group (HR 0.78; 95% CI,
0.53e1.14; log-rank p ¼ 0.20) [12].
The AMAROS (After Mapping of the Axilla: Radiotherapy Or
Surgery?) trial from the EORTC (European Organisation for
Research and Treatment of Cancer), selected patients with similar
criteria to Z011, but also included cases operated with mastectomy.
Patients were randomized to completion ALND (n ¼ 744) or axillary
radiotherapy (n ¼ 681). After a median follow-up of 10 years, there
were no significant differences in 10-year (10y)-axillary recurrence,
10y-DMFS (Distant metastasis-free survival) and 10y-OS between
the two groups (p ¼ 0.37; p ¼ 0.19; p ¼ 0.26, respectively). More
second primaries were observed after axillary radiotherapy: 75/681
(21 contralateral breast) as compared to ALND: 57/744 (11 contra-
lateral breast) (p ¼ 0.035) [13]. The 5 year report showed a statis-
tically significant difference in the 5-year incidence of measured
arm lymphedema, with 13% after ALND and 5% in the radiotherapy
group (p ¼ 0.0009) [14]. Approximately 80% of lesions were !2 cm
with a resulting 82% of cases being treated with BCS and approxi-
mately 18% with mastectomy in both arms [13,14].
Another recently published trial, the INT09/98, from Agresti and
colleagues addressed whether ALND could be safely avoided and
whether tumor biology could be adequate to guide adjuvant
treatment. This study was not conducted in patients with a positive
SLN, but in cases with cT1 cN0 disease and randomized patients to
breast conservation with or without ALND [15]. All patients
received WBRT with no attempt to irradiate the axilla. Decisions for
adjuvant treatment were based on clinicopathologic factors that
took into account information form axillary nodes in the ALND
group and from an experimental biological panel-only in the non-
ALND group. This resulted in unbalanced receipt of adjuvant sys-
temic treatment between both arms, with 51% of cases in the ALND
group receiving chemotherapy compared to 35% in the non-ALND
group (p < 0.001). However, despite this difference that could
have favored the ALND arm, after a median follow-up of 127
months, no statistically significant differences were observed in
10y-DFS, with 92.4% in the ALND group vs. 91.3% in the non-ALND
group (log-rank p ¼ 0.97) and 10y-OS, with 93.3% in the ALND
group vs. 91.5% in the non-ALND group (log-rank p ¼ 0.436). Non-
inferiority p values for DFS (p ¼ 0.029) and OS (p ¼ 0.037) with
90% confidence intervals showed that patients in the non-ALND
group did not appear to have unacceptably worse outcomes
compared to cases in the ALND group. This study was designed
before sentinel lymph node biopsy was routinely introduced in
clinical practice and included cases with small tumors, with 98%
 C.A. Garcia-Etienne et al. / European Journal of Surgical Oncology xxx (xxxx) xxx 3

comprising pT1 lesions and a mean size of 1.5 cm. The study did

0.02 (non-inf)
show a higher rate of axillary recurrence in the non-ALND group
(9%) vs. the ALND group (0%). Patients with axillary recurrence
underwent ALND and no significant relationship was observed
86.3%
83.6%

90.8%
88.2%

81.4%
84.6%
0.20

0.26
between OS and the number of involved lymph nodes in these
DFS OS

78.2%d cases. Of note, although up to 29% of cases had a positive axillary

81.7%d
80.2%
78.2%

76.8%
74.9%
No. of patients Median follow-up Treatment arm/P value 10-year Outcomes

status, as demonstrated in the ALND group, there was only 9%

0.32

0.24

0.19
axillary recurrence rate in the non-ALND group [15]. Again, an
1.5%
0.5%

0.4%

1.8%
0.9%
0.28

0.37

observation that parallels findings from the seminal NSABP B-04

LRR axR

2%

study [6].
5.3%
6.2%

3.5%
0.36

0.69
5%
3%

4%
e

Change in practice
No ALND (N ¼ 436)

No ALND (N ¼ 467)

The first Z0011 report had an immediate effect on practice

ax-RT (N ¼ 681)
ALND (N ¼ 420)

ALND (N ¼ 464)

ALND (N ¼ 744)

guidelines in the USA. Since 2011, the Memorial Sloan-Kettering

10-year outcomes of randomized controlled trials evaluating different options of axillary management in patients with early breast cancer and positive sentinel node biopsy.

Cancer Center (MSKCC) and the MD Anderson Cancer Center

adopted a change in practice to omit ALND in patients who meet
the Z0011 selection criteria (T1-2 lesions, 1e2 positive SLNs, can-
P

didates for BCS with WBRT, no neoadjuvant chemotherapy) [16,17].

From 2011 to 2012, the National Comprehensive Cancer Network
(NCCN) guidelines were modified to consider no further axillary
surgery in these cases [18]. Likewise, the American Society of
9.25y10

Clinical Oncology (ASCO) states that clinicians should not recom-

9.3y11

9.7y

10y

mend ALND for women who have one or two sentinel lymph node
ITCs: Isolated tumor cells; small clusters of cells !0.2 mm, or single tumor cells, or fewer than 200 cells in a single histologic cross-section.

metastasis and will receive BCS with WBRT [19]. These changes in
recommendations have generated controversy in some groups,
arguing that omitting ALND should be based on individual cases
enrolled

and that more evidence is needed to inform practice [20,21].

cT1-2 cN0 with 1e2 (þ)SLNs (microa/macrometastasisb), for BCS þ WBRT or Mastectomy 1,425
891

cT1-2 cN0 with 1 or more (þ)SLNs (micrometastasisa/ITCsc only), for BCS or Mastectomy 934

A recent study by Yao and colleagues from the National Cancer

Data Base in the USA studied the trend of lymph node removal from
1998 to 2011 of 74,309 patients fulfilling Z0011 selection criteria.
They categorized cases with not more than 4 lymph nodes removed
as having had sentinel node biopsy-only (n ¼ 17,630 patients). The
proportion of patients receiving sentinel node biopsy-only
increased from 23% in 2009 to 56% in 2011 (p < 0.001), after the
cT1-2 cN0 with 1e2 (þ)SLNs (microa/macrometastasisb), for BCS þ WBRT

publication of Z0011 results [22].

A more recent report by Morrow on a survey that aimed to
determine surgeon acceptance of Z0011 findings in the US showed
that still 49% (175/357) of surgeons would definitively or probably
recommend ALND for 1 SLN macrometastasis and 62.6% (221/353)
would definitively or probably recommend ALND for 2 SLNs with
macrometastasis. Lower propensity for ALND was significantly
associated with surgeons who treated a higher volume of cases per
year (21e50 cases: $0.19; 95% CI, $0.39 to 0.02; >51 cases: $0.48;
95% CI, $0.71 to $0.24; p < 0.001), surgeons who follow the
recommendation of “no ink on tumor” as a negative margin
(1e5 mm margin: $0.10; 95% CI, $0.43 to 0.22; no ink on
tumor: $0.53; 95% CI,$0.82 to $0.24; p < 0.001), and surgeons with
a higher proportion of cases discussed in a multidisciplinary tumor
Tumor deposit >0.2e2.0 mm in largest dimension.

board (1%e9% of cases: $0.25; 95% CI, $0.55 to 0.05; >9% of

cases: $0.37; 95% CI, $0.63 to $0.11; p ¼ 0.02), indicating the need
No ALND vs. ALND

No ALND vs. ALND

Tumor deposit >2.0 mm in largest dimension.

for education targeted toward lower-volume breast surgeons [23].

randomized to

randomized to

randomized to
ax-RT vs. ALND

Practice patterns in Europe seem to be heterogeneous across

DMFS: Distant metastasis-free survival.

countries. A study by Gondos et al., that included patients from four

Design

ALND: Axillary lymph node dissection.

population-based and four institute-specific cancer registries in

WBRT: Whole breast radiotherapy.
(þ)SLNs: Positive sentinel node/s.

Denmark, Norway, Sweden, Netherlands, Belgium, Italy and Ger-

BCS: Breast-conserving surgery.

many showed that for pT1 tumors, ALND use declined over time
LRR: Locoregional recurrence.

ax-RT: Axillary radiotherapy.

from a wide range of 27e75% in 2003, to a remaining heteroge-

DFS: Disease-free survival.
Z0011 [10,11] (2016/17)

axR: Axillary recurrence.

neous range of 12e47% in 2010 [24]. This study also included a

AMAROS [13] (2018)

OS: Overall survival.

23-01 [12] (2018)

questionnaire to compare the surgical approach to the axilla during

year 2014 among centers in these countries (adding one more
center from Hungary) and showed important different practice
ACOSOG

patterns. As of 2014, ALND was performed after micrometastasis-

EORTC
IBCSG
Study
Table 1

only in the SLN at the Institut Jules Bordet in Brussels while the
a
b
c
d

Netherlands Cancer Institute was carrying out its own trial. The

Please cite this article as: Garcia-Etienne CA et al., Management of the axilla in patients with breast cancer and positive sentinel lymph node
biopsy: An evidence-based update in a European breast center, European Journal of Surgical Oncology, https://doi.org/10.1016/
j.ejso.2019.08.013
4 C.A. Garcia-Etienne et al. / European Journal of Surgical Oncology xxx (xxxx) xxx
Hospital at the University of Heidelberg adopted Z0011 modified
criteria to avoid ALND since September 2010, while the Istituto
Nazionale dei Tumori from Milan incorporated a similar approach
since 2013. Z0011 criteria had not been implemented in Denmark,
the Institut Jules Bordet or the National Institute of Oncology in
Hungary [24].
A recent Dutch population-based study by Poodt and colleagues
carried out a subgroup analysis that aimed to assess the impact of
Z0011 and AMAROS studies on ALND in patients with cT1-2 N0
disease and 1 to 2 positive SLNs who underwent BCS or mastec-
tomy from 2011 to 2015. The analysis included 8,191 patients and
showed a decrease in ALND from 75% in 2011 to 17% in 2015
(p < 0.001) for both groups, with a more pronounced and sustained
decrease for cases receiving BCS (72% ALND in 2011 to 11% in 2015).
Factors associated with increased probability of performing ALND
were earlier year of diagnosis, younger age, primary mastectomy,
invasive lobular carcinoma, increasing tumor grade and having
surgery at a nonteaching hospital (p < 0.001) [25].
In Italy, the Associazione Senonetwork Italia Onlus, a national
network of Breast Centers, has published a review of data deriving
from recent trials in an effort to reach a national consensus [26].
However, in spite of the evidence presented, the document does
not reach clear recommendations and there is a generalized reti-
cence to adopt new guidelines and a sense of disagreement among
centers in the country. Accordingly, a recent study from the euso-
maDB, the database of the European Society of Breast Cancer Spe-
cialists, demonstrated in a dataset of 6,671 patients fulfilling Z0011-
criteria deriving from 34 Breast Centers located in 6 European
countries (Germany, Italy, Belgium, Switzerland, Austria, and
Netherlands.), a statistically significant decrease in rates of ALND
that started after publication of the trial from 2010 (89%) to 2011
(73%), reaching 46% in 2016 (p < 0.001). After multivariable anal-
ysis, factors associated with higher probability of ALND were earlier
year of surgery, younger age, increasing tumor size and grade, and
being operated in Italy (p < 0.001) [27].
Ongoing trials
Many randomized trials, which extensive discussion is not the
scope of this article, have recently emerged in Europe (see Table 2
for description).
On one end, the SOUND trial takes one step forward the Z0011
and aims to determine if axillary staging could even be omitted in
selected cases with invasive breast cancer (cT1 cN0) [28]. On the
other end, reluctance to fully accept evidence from the Z0011 study
and/or interest in solving new questions have recently initiated the
following trials: POSNOC, INSEMA, BOOG 2013-07, SINODAR ONE,
and SENOMAC [29e35].
The POSNOC and SINODAR ONE trials represent delayed repe-
titions of the Z0011 study that claim to have a different design by
excluding cases with micrometastasis and including cases treated
with mastectomy [29,33]. However, it is likely that accrual for both
studies will be difficult to reach, as a change in practice to avoid
ALND is progressively gaining acceptance. Moreover, the predict-
able selection bias for recruiting early-stage cases prior to
randomization may pose a problem for accruing mastectomy cases.
With a patient selection similar to Z0011, it will be difficult for these
trials to provide crucial additional information.
INSEMA trial approaches more than one clinical question with a
statistically ambitious design by first randomizing cT1-2 BCS can-
didates to either no axillary surgery or SLNB (1:4 allocation), for
then a second randomization of cases with 1e3 positive SLNs to
either no further surgery or completion ALND (1:1) [30,31].
BOOG 2013-07 and SENOMAC trials propose to answer addi-
tional questions not addressed by the Z0011 study by selecting
Please cite this article as: Garcia-Etienne CA et al., Management of the axilla in patients with breast cancer and positive sentinel lymph node
biopsy: An evidence-based update in a European breast center, European Journal of Surgical Oncology, https://doi.org/10.1016/
j.ejso.2019.08.013
patients with higher tumor burden (up to 3 þ SLNs in the former
and up to cT3 lesions in the latter) [32,34,35].
TAXIS trial represents the only European study for patients with
a clinically biopsy-proven positive axilla aiming to prove that
tailored axillary surgery (removal of detectable positive nodes)
with axillary radiotherapy is non-inferior than complete ALND [36].
Management of the axilla with positive SLNB at the breast
center of the Policlinico San Matteo, University of Pavia
The development of clinical guidelines for the management of
the axilla in patients with breast cancer is a work in progress.
Recently published trials have differences in design, patient selec-
tion, treatment approach and length of follow-up, making it un-
likely to reach definitive conclusions. Still, what seems to be clear
from older trials and confirmed by recent studies, is that lymph
node metastasis are indicators, but not governors of survival [37].
Study limitations do not necessarily invalidate their findings, but
may endorse modifications to selection criteria before translating
them to clinical practice.
After a collegial discussion of our multidisciplinary team, we
formulated our decision-making algorithm for the management of
the axilla in patients with early breast cancer and positive SLNB,
effective since 2015 with further recent modifications. A database
prospectively collects patient information, clinicopathologic char-
acteristics and treatment modalities to assess patient outcomes
(local and regional recurrence, distant metastasis, breast cancer-
specific death) during follow-up.
Avoiding ALND in cases with positive axillary status: learnings from
NSABP B-04, Z0011, 23-01 and AMAROS trials
San Matteo Hospital criteria are the result of modified Z0011
selection criteria that take into account additional evidence re-
ported in the literature.
Extracapsular extension (ECE) of tumor in sentinel lymph nodes
was not a component considered in the Z0011 or any other recent
trial. A study reported by Gooch et al., looked for the correlation of
ECE in SLNs and disease burden in the axilla in patients meeting
Z0011 criteria in a 7-year period. From 1,109 cases fulfilling the
criteria, ECE was present in 331 (30%). In this group, microscopic
extension (!2 mm) was observed in 180 (54%) cases and gross
extension (>2 mm) in 151 (46%). Forty (33%) patients with gross
ECE (>2 mm) had "4 additional positive nodes at completion ALND
compared with 11 (9%) cases with microscopic ECE (!2 mm)
(p < 0.0001). Gross ECE was the strongest predictor of "4 additional
positive nodes at completion ALND (odds ratio 14.2) after multi-
variable analysis [38]. Whether or not the increased likelihood of
axillary disease burden in these cases translates into poorer out-
comes was not demonstrated by this study. A recent report from
Barrio and colleagues presented at the San Antonio Breast Cancer
Symposium evaluated the impact of ECE on nodal recurrence in 685
patients with 1e2 positive SLNs in whom ALND was spared. Two
hundred and ten (31%) cases had microscopic ECE (defined as any
ECE, !2 mm or >2 mm) in the SLN. Patients with ECE were more
likely to receive nodal irradiation (39% vs 17%; p < 0.0001). The
median follow-up was 41 months, the 5-year rate of any nodal
recurrence was 1.6% and did not differ by the presence of ECE (2.3%
vs 1.3%; p ¼ 0.31). No differences were observed in local or distant
recurrence rates by ECE status, questioning the routine indication
of ALND in cases with ECE to the SLN [39]. Based on these data and
the need to mature more evidence, the panel determined that cases
with gross (>2 mm) ECE in SLNs should be evaluated on individual
basis for completion ALND, axillary radiotherapy or omission of
both. As this information is only available on definitive pathology
 C.A. Garcia-Etienne et al. / European Journal of Surgical Oncology xxx (xxxx) xxx 5

Table 2
Ongoing or recently closed European trials on management of the axilla in patients with operable invasive breast cancer.

Study Country of origin Design Target Start-End dates

patient
accrual

SOUND Italy cT1 cN0, for BCS þ WBRT 1,560 Mar 2012eJun 2017
(Sentinel node vs. Observation after axillary UltrasouND) [28] randomized to
No axillary surgery vs. SLNB
POSNOC UK cT1-2 cN0 with 1e2 (þ)SLNs (macrometastasisa 1,900 Jan 2014eDec 2023
(POsitive Sentinel NOde: adjuvant therapy alone versus adjuvant only), for BCS or Mastectomy
therapy plus Clearance or axillary radiotherapy) [29] randomized to
No ALND vs. ALND or ax-RT
INSEMA Germany cT1-2 cN0, for BCS þ WBRT 7,095 Sep 2015eSep 2024
(Intergroup Sentinel Mamma) [30,31] randomized to
No axillary surgery vs.SLNB (1:4 allocation) cases with
1e3 (þ)SLNs (macrometastasisa only)
2nd randomization to
No ALND vs. ALND (1:1 ratio)
BOOG 2013-07 Netherlands cT1-2 cN0 with 1e3 (þ)SLNs (microb or 878 Jun 2014eJun 2027
(The value of completion axillary treatment in sentinel node macrometastasisa), for Mastectomy
positive breast cancer patients undergoing a mastectomy) randomized to
[32] No ALND vs. ALND or ax-RT
SINODAR ONE Italy cT1-2 cN0 with 1e2 (þ)SLNs (macrometastasisa 2,000 Apr 2015eMar 2018
(Randomized Clinical Trial to Assess the Role of Axillary Surgery only), for BCS or Mastectomy
in Breast Cancer Patients with One or Two Macrometastatic randomized to
Sentinel Nodes) [33] No ALND vs. ALND
SENOMAC Sweden cT1-3 cN0 with 1e2 (þ)SLNs (macrometastasisa 3,500 Jan 2015eJan 2022
(Omission of Axillary Clearance in Breast Cancer Patients with only), including also patients prior to neoadjuvant
Sentinel Node Macrometastases) [34,35] chemo, for BCS or Mastectomy
randomized to
No ALND vs. ALND
TAXIS Switzerland Any cT cN1-2(f), þ/$ neoadjuvant chemo, also 1,500 Aug 2018eMar 2029
(Tailored axillary surgery with or without axillary lymph node isolated rcT, for BCS þ WBRT or Mastectomy þ chest
dissection followed by radiotherapy in patients with clinically wall RT
node-positive breast cancer) [36] randomized to
TAS þ ALND þ RN-RT vs. TAS þ RNax-RT

BCS: Breast-conserving surgery.

WBRT: Whole breast radiotherapy.
SLNB: Sentinel lymph node biopsy.
(þ)SLNs: Positive sentinel node/s.
ALND: Axillary lymph node dissection.
ax-RT: Axillary radiotherapy.
TAS: Tailored axillary surgery.
RN-RT: Regional nodal radiotherapy (excluding ax-RT).
RNax-RT: Regional nodal/axillary radiotherapy (including ax-RT).
a
Tumor deposit >2.0 mm in largest dimension or defined as macrometastasis on molecular assay.
b
Tumor deposit >0.2e2.0 mm in largest dimension.

report, this should translate in no more than 15% of cases with a
positive SLN having gross ECE.
Regarding age, our panel considered that patients under 40
years were weakly represented in the 23-01, Z0011 and AMAROS
trials. This is due to the natural history of the disease that tends to
present in older women and a selection bias before enrollment that
tends to exclude young patients. In the Z0011 study close to 65% of
patients were older than 50 years, leaving about 35% of its popu-
lation below age 50, from which it can be assumed that the largest
proportion was above 40 years [8e11]. Although the trial accepted
patients starting from age 18 years, young women, and especially
the very young group (<35 years) were underrepresented. An un-
planned analysis has suggested that younger patients (defined as
premenopausal) should not have different outcomes when omit-
ting ALND [40]. However, this post hoc analysis would need further
validation.
A more recent study by Mamtani et al., from the MSKCC reports
their experience after adopting the Z0011 criteria for avoiding
ALND. One of the aims of this study was to determine if age could be
an indicator for the need of ALND. Among 701 consecutive cases
with cT1e2 cN0 disease and positive sentinel nodes, 242 (35%)
were classified as high-risk patients (age <50 years, HER2-positive
or triple negative tumors) and 459 (65%) as average-risk. Criteria for
avoiding ALND were met by 205 high-risk patients (85%) and 377
average-risk patients (82%) (p ¼ 0.39). Indications for ALND were
similar in both groups and it was performed for more than two
positive SLNs in 70% of the high-risk cases and 62% of the average-
risk cases, and for gross ECE in 24% of the high-risk cases and 30% of
the average-risk cases (p ¼ 0.69). After a median follow-up of 31
months, no patients experienced isolated axillary recurrences [41].
This study provides information on how likely patients below age
50 who meet Z0011 criteria are acceptable candidates for avoiding
ALND, but it likely included few patients under 40 years of age and
did not provide long-term outcomes.
It is fair to state that currently, there are no data demonstrating
that young patients (<40 years) who avoid ALND after a positive
SLNB have increased risk for axillary recurrence, distant recurrence
or poorer survival; however, the panel concluded that evidence is
still insufficient to exclude this possibility and determined that
eligible age for avoiding ALND fulfilling all other criteria is at least
40 years old.
Regarding tumor size, although patient selection in Z0011, 23-01
and AMAROS trials could include cases with tumors up to
5 cm (cT1-2), it must be pointed out that the great majority of pa-
tients actually recruited had small to medium size lesions, so large
tumors were underrepresented in these studies. In trial 23-01, 92%

Please cite this article as: Garcia-Etienne CA et al., Management of the axilla in patients with breast cancer and positive sentinel lymph node
biopsy: An evidence-based update in a European breast center, European Journal of Surgical Oncology, https://doi.org/10.1016/
j.ejso.2019.08.013
6 C.A. Garcia-Etienne et al. / European Journal of Surgical Oncology xxx (xxxx) xxx
of cases had tumors <3 cm and only 7% (63/931) had tumors "3 cm
(only 28 [6%, 28/467] cases in the non-ALND group) [12]. In the
AMAROS trial, approximately 80% of patients had lesions !2 cm
[13,14]. In the Z0011 study, close to 70% of patients had lesions
!2 cm with a median clinical tumor size of 1.7 cm, which translated
to SNL(s) being the only site of metastasis in 73% of cases in the
ALND group [8e11]. This distribution likely obeys a selection bias
prior to randomization due to concerns for the inclusion of patients
with higher tumor burden.
Our panel considered that, in order to translate results to clinical
practice, focus should not only be placed in study inclusion criteria,
but in cases who were actually recruited in these studies.
It has been well documented by nomograms that larger tumor
size increases the probability of metastasis to non-sentinel lymph
nodes [42]. Concerned was raised by members of the panel
regarding the potential omission of ALND in patients with high
axillary disease burden. It must be noted that an older seminal
study omitting ALND did include patients with larger tumors. In
the NASBP B-04 study the mean tumor size was 3.3 cm in cN0
patients. This group included 1,079 patients randomized in three
treatment arms: radical mastectomy, total mastectomy with
postoperative radiation to the chest wall and draining lymph node
areas, and total mastectomy-alone with delayed ALND reserved
for cases who presented regional recurrences. The study showed
18% axillary recurrence rate in the total mastectomy-alone arm
with no difference in survival outcomes among the three arms.
Patients in this study did not receive chemo or endocrine therapy
[6]. Nevertheless, this seminal study was not exempt of critics,
such as low patient accrual, extent of axillary surgery in cases
recorded as not receiving ALND (35% received limited ALND), and
inclusion of patients with high risk for distant metastasis. All
factors affecting the statistical power for the evaluation of cases
with untreated axillary nodes (type II statistical error) [1]. More-
over, the panel determined that extrapolation of data for imple-
mentation in our center should derive from more recent trials that
reflect similar scenarios and patient characteristics as those seen
in current practice.
Based on the evidence mentioned above, our multidisciplinary
panel decided to lower the tumor size for the selection of patients
that may forgo ALND and determined 3 cm as a reasonable cutoff.
Furthermore, this size grossly parallels our institutional indication
for neoadjuvant chemo or endocrine therapy (which in addition
takes into account tumor biology and breast-to-tumor size ratio),
hence, rendering cases with larger tumors in the scenario of de-
escalated axillary surgery rather infrequent.
It has been hypothesized that high-tangent fields extending to
the lower level of the axilla may have played a role in regional
control in the Z0011 trial. Jagsi and colleagues ascertained RT
coverage of regional nodes in this study [43]. From cases with
available information, 107 patients did not receive RT and 228 had
detailed RT records. Although 19% of patients received prohibited
third-field irradiation, nodal irradiation was distributed similarly
by treatment group, as was omission of irradiation and the use of
highetangent field irradiation (cranial tangent border !2 cm from
humeral head used in 50% of patients [33/66] assigned to ALND and
52.6% [40/76] assigned to SLNB-only). There were no statistically
significant differences in local or regional recurrence between pa-
tients with high-tangent and patients without high-tangent fields.
Further analysis revealed that only ‘‘no radiation’’ was associated
with an increased risk of local recurrence (p ¼ 0.004) but not
regional recurrence (p ¼ 0.80) [43]. The impact of off-protocol
nodal irradiation on rates of regional control could not be deter-
mined from this study, so it cannot be suggested from this data that
nodal irradiation was necessary or beneficial. After discussion of
available data, the panel established to recommend standard WBRT
Please cite this article as: Garcia-Etienne CA et al., Management of the axilla in patients with breast cancer and positive sentinel lymph node
biopsy: An evidence-based update in a European breast center, European Journal of Surgical Oncology, https://doi.org/10.1016/
j.ejso.2019.08.013
for patients with a positive SLN avoiding ALND according to our
defined criteria.
Avoiding ALND after mastectomy and a positive SLNB
Even though cases receiving mastectomy were also candidates
for recruitment in the 23-01 and AMAROS trials, only 9% had
mastectomy in the former study and about 17% in the latter,
providing low representation of this type of procedure. Moreover,
the type of surgery should not be regarded a reliable surrogate for
tumor size. In the 23-01 trial, only 28 (6%, 28/467) cases in the non-
ALND group had tumors "3 cm and in the AMAROS study, only
about 20% of patients had T2 lesions [12e14].
Based on these findings, our panel decided to also lower the
tumor size to !3 cm for the selection of patients treated with
mastectomy that may be considered to forgo ALND after a positive
SLNB. Patients fulfilling the criteria listed in Table 3 who undergo
mastectomy, may also avoid ALND after multidisciplinary discus-
sion of individual cases for consideration of axillary irradiation.
ALND avoidance is still debated in this scenario. Ongoing trials may
help elucidate this issue.
Cases with tumors larger than 3 cm with a positive SLN for
micrometastasis are evaluated on individual basis for ALND, axil-
lary radiotherapy or omission of both.
Elderly patients
Old series reporting not routinely performing ALND in patients
over age 70 with early breast cancer have shown no significant
impact on OS [44,45]. In patients with T1 tumors, ALND had not
been demonstrated to influence postoperative treatment, decrease
recurrence, or improve survival [46].
Subsequent reports have confirmed that avoiding ALND in older
patients with small tumors and clinically negative axilla do not
adversely affect breast cancer mortality or OS [47,48]. Based on this
evidence, the NCCN guidelines recommend that in the absence of
definitive data demonstrating superior survival, the performance of
axillary staging may be considered optional in the elderly or in
those with serious comorbid conditions [18].
A RCT from the IBCSG carried out between 1993 and 2002
randomized patients older than 60 years to ALND (n ¼ 234) versus
observation (n ¼ 239) [48]. Tamoxifen was prescribed to all patients
for 5 years. Eighty percent of cases had estrogen-receptor positive
disease; 263 (56%) patients had lesions !2 cm and 200 (42%) had
tumors >2 cm. BCS with radiotherapy was performed in 33% of
cases and without radiotherapy in 23%, whereas 44% of cases
received mastectomy. After a median follow-up of 6.6 years, there
were no differences in DFS (6-year DFS, 67% vs. 66%; HR ALND/
observation, 1.06; 95% CI, 0.79 to 1.42; p ¼ 0.69) and OS (6-year OS,
75% vs. 73%; HR ALND/observation, 1.05; 95% CI, 0.76 to 1.46;
p ¼ 0.77). Moreover, 28% of patients in the ALND arm had meta-
static axillary nodes, whereas only 3% of observation arm patients
developed overt axillary disease, and breast cancer mortality was
unaffected. This study was interrupted before its accrual was
completed due to slow recruitment, therefore, it was underpow-
ered to establish treatment equivalence. However, a predictive
power calculation indicated that the chance that a fully accrued
trial would have found a statistically significant benefit in DFS for
patients with ALND was less than 3% [48].
Another RCT conducted from 1996 to 2000 by Martelli and co-
workers included 219 patients aged 65e80 years with cT1 cN0
breast cancer who were randomized to BCS with (n ¼ 109) or
without (n ¼ 110) ALND [49]. All patients received WBRT with no
radiation to the axilla and took tamoxifen for 5 years regardless of
hormone-receptor status. Median age was 70 (range 60e80), 191
 C.A. Garcia-Etienne et al. / European Journal of Surgical Oncology xxx (xxxx) xxx 7

Table 3
San Matteo Criteria for avoiding axillary dissection after a positive sentinel lymph node biopsy in early-stage breast cancer.

Axillary dissection after a positive sentinel lymph node biopsy may be avoided in patients with cN0 and:
& Microa/Macrometastasisb to ≤2 SLNs and:
e Age ≥40yc
e Tumor size ≤3 cm
e No neoadjuvant chemotherapy
e Planned BCS with WBRT (no APBI)
& Cases fulfilling the above criteria who receive mastectomy may avoid ALND with consideration of axillary radiotherapy

SLNs: sentinel lymph nodes; BCS: Breast-conserving surgery; WBRT: whole breast radiotherapy; APBI: accelerated partial breast irradiation; ALND: axillary lymph node
dissection; HRþ: hormone (estrogen/progesterone) receptors positive.
a
Micrometastasis: tumor deposit >0.2e2.0 mm in largest dimension. Cases with micrometastasis to the SLN and tumor >3 cm are evaluated on individual basis for
completion ALND, axillary radiotherapy or omission of both.
b
Macrometastasis: tumor deposit >2.0 mm in largest dimension. Cases with gross (>2 mm) ECE (extracapsular extension) in SLNs are evaluated on individual basis for
completion ALND, axillary radiotherapy or omission of both.
c
Age "70y with cN0, serious/multiple comorbidities, HR þ tumor of !3 cm undergoing BCS with WBRT may consider no axillary staging/surgery. If mastectomy or larger
tumor, comorbidities and life expectancy are taken into account.

(87.6%) cases were positive for estrogen or progesterone receptors
and 25 (11.4%) were negative for both hormone receptors. Twenty-
three percent of the 109 patients in the ALND group had positive
axillary nodes and in the majority of cases (72%), only one node was
involved. Four (4%) patients of the 110 cases without ALND devel-
oped axillary recurrence and underwent delayed dissection; none
of the cases with ALND developed regional recurrence, for a 15-year
crude cumulative incidence of 6% (95% CI, 0%e12.6%) and 0,
respectively. The 15-year crude cumulative incidence of ipsilateral
breast tumor recurrence was 4% (95% CI, 0.1%e7.8%) in the ALND
arm and 8.3% (95% CI, 2.1%e14.5%) in the non-ALND arm. After a
median follow-up of 150 months, crude cumulative incidence
curves for breast cancer mortality and distant metastases did not
differ significantly between the 2 groups (Gray 2-sided test;
p ¼ 0.64 for breast cancer mortality and p ¼ 0.95 for distant me-
tastases) [49].
A more recent report by Chung and Giuliano evaluated the safety
of not performing a sentinel node biopsy in elderly patients with
clinically node-negative breast cancer. In a prospectively maintained
database, they identified 140 women 70 years of age or older with
cT1-2 cN0 disease who underwent BCS without SLNB. The median
age was 83 years (70e97), 74% of cases had T1 lesions and 26% T2
tumors. Most cases (86%) had estrogen-receptor positive tumors,
98% of patients did not receive chemotherapy, 76% did not receive
radiotherapy and 59% did not receive endocrine therapy. After a
median follow-up of 4.5 years, 5 (4%) patients had a breast-cancer
related event; 1 had an axillary recurrence and 4 died of breast
cancer. The 5-year breast cancer-specific survival rate was 96%. Tu-
mor size was the only factor that correlated with survival [50].
In agreement with this evidence, the Society of Surgical
Oncology recently released the recommendation: "Do not routinely
use sentinel node biopsy in clinically node negative women "70
years of age with hormone receptor positive invasive breast cancer"
[51].
Considering that survival is not dependent on nodal tumor
burden in elderly patients with early-stage breast cancer, our
multidisciplinary panel determined that women 70 years or older
with hormone receptors positive invasive lesions !3 cm, clinically
negative nodes, and serious or multiple comorbidities who un-
dergo BCS with WBRT, may forgo axillary staging/surgery. In pa-
tients undergoing mastectomy or with larger tumors, axillary
management is defined at the discretion of the surgeon at time of
surgery taking into account patient comorbidities and life
expectancy.
Conclusions
The development of clinical guidelines for the management of
the axilla in patients with breast cancer is a work in progress. After
extensive multidisciplinary discussion of current available evi-
dence, our panel determined that ALND may be avoided in patients
with a clinically negative axilla who have micro or macrometastasis
to no more than two sentinel lymph nodes, who are at least 40
years old, with lesions not larger than 3 cm, who have not received
neoadjuvant chemotherapy and have planned BCS with WBRT (San
Matteo Criteria Table 3). Patients fulfilling the criteria listed above
who undergo mastectomy, may also avoid ALND after multidisci-
plinary discussion of individual cases for consideration of axillary
irradiation. Cases with tumors larger than 3 cm and micrometa-
stasis to the SLN and cases with gross (>2 mm) extracapsular
extension in SLNs are evaluated on individual basis for completion
ALND, axillary radiotherapy or omission of both.
Women 70 years or older with hormone receptors positive
invasive lesions !3 cm, clinically negative nodes, and serious or
multiple comorbidities who undergo BCS with WBRT, may forgo
axillary staging/surgery. In elderly patients undergoing mastec-
tomy or with larger tumors, axillary management is defined at the
discretion of the surgeon at time of surgery taking into account
patient comorbidities and life expectancy.
Conflict of interest statement
No conflicts declared.
Funding/support
This research did not receive any specific grant from funding
agencies in the public, commercial, or not-for-profit sectors.
Acknowledgements
Special acknowledgements to Vincenza Pratico!, R.N. and case
manager for participation during discussions and to Patrizia Xerri
for clerical assistance.
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Please cite this article as: Garcia-Etienne CA et al., Management of the axilla in patients with breast cancer and positive sentinel lymph node
biopsy: An evidence-based update in a European breast center, European Journal of Surgical Oncology, https://doi.org/10.1016/
j.ejso.2019.08.013

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