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Articles

Axillary dissection versus no axillary dissection in patients


with breast cancer and sentinel-node micrometastases
(IBCSG 23-01): 10-year follow-up of a randomised,
controlled phase 3 trial
Viviana Galimberti, Bernard F Cole, Giuseppe Viale, Paolo Veronesi, Elisa Vicini, Mattia Intra, Giovanni Mazzarol, Samuele Massarut, Janez Zgajnar,
Mario Taffurelli, David Littlejohn, Michael Knauer, Carlo Tondini, Angelo Di Leo, Marco Colleoni, Meredith M Regan, Alan S Coates, Richard D Gelber,
Aron Goldhirsch, for the International Breast Cancer Study Group Trial 23-01*

Summary
Background We previously reported the 5-year results of the phase 3 IBCSG 23-01 trial comparing disease-free survival Lancet Oncol 2018
in patients with breast cancer with one or more micrometastatic (≤2 mm) sentinel nodes randomly assigned to either Published Online
axillary dissection or no axillary dissection. The results showed no difference in disease-free survival between the September 5, 2018
http://dx.doi.org/10.1016/
groups and showed non-inferiority of no axillary dissection relative to axillary dissection. The current analysis presents
S1470-2045(18)30380-2
the results of the study after a median follow-up of 9∙7 years (IQR 7∙8–12∙7).
See Online/Comment
http://dx.doi.org/10.1016/
Methods In this multicentre, randomised, controlled, open-label, non-inferiority, phase 3 trial, participants were S1470-2045(18)30416-9
recruited from 27 hospitals and cancer centres in nine countries. Eligible women could be of any age with clinical, *Investigators, leadership, and
mammographic, ultrasonographic, or pathological diagnosis of breast cancer with largest lesion diameter of 5 cm or staff of the Group are listed in
smaller, and one or more metastatic sentinel nodes, all of which were 2 mm or smaller and with no extracapsular the appendix (pp 2,3)

extension. Patients were randomly assigned (1:1) before surgery (mastectomy or breast-conserving surgery) to no Division of Senology
(V Galimberti MD,
axillary dissection or axillary dissection using permuted blocks generated by a web-based congruence algorithm, with Prof P Veronesi MD, E Vicini MD,
stratification by centre and menopausal status. The protocol-specified primary endpoint was disease-free survival, M Intra MD, M Colleoni MD) and
analysed in the intention-to-treat population (as randomly assigned). Safety was assessed in all randomly assigned International Breast Cancer
patients who received their allocated treatment (as treated). We did a one-sided test for non-inferiority of no axillary Study Group (IBCSG) Central
Pathology Office, Division of
dissection by comparing the observed hazard ratios (HRs) for disease-free survival with a margin of 1·25. This 10-year Pathology and Laboratory
follow-up analysis was not prespecified in the trial’s protocol and thus was not adjusted for multiple, sequential Medicine (Prof G Viale MD,
testing. This trial is registered with ClinicalTrials.gov, number NCT00072293. G Mazzarol MD), IEO, European
Institute of Oncology IRCCS,
Milan, Italy; IBCSG Statistical
Findings Between April 1, 2001, and Feb 8, 2010, 6681 patients were screened and 934 randomly assigned to no axillary Center and Department of
dissection (n=469) or axillary dissection (n=465). Three patients were ineligible and were excluded from the trial after Mathematics and Statistics,
randomisation. Disease-free survival at 10 years was 76∙8% (95% CI 72∙5–81∙0) in the no axillary dissection group, University of Vermont,
compared with 74∙9% (70∙5–79∙3) in the axillary dissection group (HR 0∙85, 95% CI 0∙65–1∙11; log-rank p=0∙24; Burlington, VT, USA
(Prof B F Cole PhD); University
p=0∙0024 for non-inferiority). Long-term surgical complications included lymphoedema of any grade in 16 (4%) of of Milan, Milan, Italy
453 patients in the no axillary dissection group and 60 (13%) of 447 in the axillary dissection group, sensory neuropathy (Prof G Viale, Prof P Veronesi);
of any grade in 57 (13%) in the no axillary dissection group versus 85 (19%) in the axillary dissection group, and motor Centro di Riferimento
Oncologico, Aviano, Italy
neuropathy of any grade (14 [3%] in the no axillary dissection group vs 40 [9%] in the axillary dissection group).One
(S Massarut MD); Department
serious adverse event (postoperative infection and inflamed axilla requiring hospital admission) was attributed to of Surgical Oncology, Institute
axillary dissection; the event resolved without sequelae. of Oncology, Ljubljana,
Slovenia (Prof J Zgajnar MD);
Orsola Hospital and University
Interpretation The findings of the IBCSG 23-01 trial after a median follow-up of 9∙7 years (IQR 7∙8–12∙7) corroborate
of Bologna, Bologna, Italy
those obtained at 5 years and are consistent with those of the 10-year follow-up analysis of the Z0011 trial. Together, (Prof M Taffurelli MD); Riverina
these findings support the current practice of not doing an axillary dissection when the tumour burden in the sentinel Cancer Care Centre, Wagga
nodes is minimal or moderate in patients with early breast cancer. Wagga, NSW, Australia
(D Littlejohn MBBS); Breast
Center St Gallen, Kantonsspital,
Funding International Breast Cancer Study Group. St Gallen, Switzerland
(Prof M Knauer MD);
Copyright © 2018 Elsevier Ltd. All rights reserved. Department of Medical
Oncology, Ospedale Papa
Giovanni XXIII, Bergamo, Italy
Introduction side-effects of axillary dissection were always of concern.2–4 (C Tondini MD); Hospital of
Up to the 1990s, the surgical treatment of invasive breast Sentinel-node biopsy accurately predicted axillary status Prato-AUSL Toscana Centro,
cancer included axillary lymph-node dissection.1 Axillary and quickly replaced axillary dissection in patients with a Istituto Toscano Tumori, Prato,
Italy (A Di Leo MD); IBCSG
dissection served both as a regional staging procedure clinically negative axilla because this method provided Statistical Center, Department
and as treatment. However, the short-term and long-term enough information to guide adjuvant treatment, and

www.thelancet.com/oncology Published online September 5, 2018 http://dx.doi.org/10.1016/S1470-2045(18)30380-2 1


Articles

of Biostatistics and
Computational Biology, Research in context
Dana-Farber Cancer Institute,
Harvard Medical School, Evidence before this study patients received whole-breast radiotherapy and systemic
Boston, MA, USA We did a literature search before publication of the 5-year treatment.
(M M Regan ScD, results of the IBCSG 23-01 trial in 2013. We searched PubMed
Prof R D Gelber PhD); IBCSG and Added value of this study
using the terms “breast cancer”, “axillary dissection”, “sentinel
University of Sydney, Sydney, The 10-year results of the IBCSG 23–01 trial provide important,
NSW, Australia node”, “sentinel node involvement”, “sentinel node biopsy”,
additional level-1 evidence that omitting axillary dissection
(Prof A S Coates MD); “micrometastases”, and “prognosis”. We retrieved papers
Harvard T H Chan School of when the sentinel nodes contain only micrometastases is safe,
published in English only. The ACOSOG Z0011 trial had been
Public Health, Boston, MA, USA supporting the avoidance of potentially serious and chronic
published indicating that limited macrometastatic
(Prof R D Gelber); Frontier sequelae of this surgery in women with early breast cancer.
Science and Technology involvement of the sentinel node could be left untreated
Research Foundation, Boston, provided patients received whole-breast irradiation and Implications of all the available evidence
MA, USA (Prof R D Gelber); and systemic treatment. In preparing the present report, we again Evidence that axillary dissection is not needed when the
IBCSG and European Institute
of Oncology, Milan, Italy
searched PubMed on Dec 15, 2017, using the same previous sentinel node is minimally involved (ie, in patients with no
(Prof A Goldhirsch MD) terms as well as “sentinel lymph node”, “sentinel lymph node more than two sentinel lymph node macrometastases) is now
Correspondence to: dissection”, “sentinel lymph node biopsy”, and “complete abundant and high quality. These results support the clinical
Dr Viviana Galimberti, axillary dissection.” The 10-year follow-up data of the practice of omitting axillary dissection when disease burden in
Department of Surgery, ACOSOG Z0011 trial confirmed that when the sentinel nodes the sentinel nodes is moderate. Ongoing clinical trials are now
European Institute of Oncology,
Milan, 20141, Italy
had little macrometastatic involvement, further surgical assessing whether sentinel node biopsy is necessary in patients
viviana.galimberti@ieo.it treatment of the axilla was not necessary provided that with breast cancer.
See Online for appendix

also reduced axillary morbidity and hospital stay in disease-free survival, or overall survival between the
patients with a negative sentinel node.5–11 However, the axillary dissection group and the no axillary dissection
more exhaustive histological methods developed to assess group were observed.20
sentinel nodes often revealed minimal nodal involvement Another randomised, phase 3 trial, the EORTC 10981-
(eg, micrometastasis and isolated tumour cells) of which 22023 AMAROS trial,21 compared axillary dissection with
the prognostic significance was unclear.12–15 Viale and axillary radiotherapy in 1425 women with T1–2 breast
colleagues16 and Galimberti and colleagues17 also sug­ cancer, clinically negative axilla, and at least one
gested that for patients with a low disease burden in the metastatic sentinel node who were enrolled between
sentinel nodes, axillary dissection might be overtreatment. Feb 19, 2001, and April 29, 2010. After a median follow-up
The phase 3 International Breast Cancer Study Group of 6∙1 years (IQR 4·1–8·0), both axillary dissection and
(IBCSG) 23-01 multicentre, randomised, non-inferiority axillary radiotherapy provided similar axillary control,
trial was designed to investigate this issue, comparing but radio­therapy was associated with significantly lower
disease-free survival in patients with resectable breast morbidity. In this report, we present the analysis of
cancer and one or more micrometastatic (ie, ≤2 mm) IBCSG 23-01 trial outcomes after a median follow-up of
sentinel nodes who were recruited between April 1, 2001, 9·7 years (IQR 7∙8–12∙7). The longer follow-up, with
and Feb 28, 2010. Patients could receive conservative more events, provides further data to support the primary
surgery or mastectomy. Eligible patients were randomly and secondary endpoints of the trial.
assigned to no axillary dissection or axillary dissection.
After a median follow-up of 5·0 (IQR 3·6–7·3) years, Methods
results showed no between-group differences in disease- Study design and participants
free survival, overall survival, or recurrence.18 Other The IBCSG 23-01 study design and related aspects are
studies also addressed this issue: the randomised, described in detail elsewhere.18 Briefly, IBCSG 23-01 was
phase 3 Z0011 trial19 enrolled women who had stage T1–2 a multicentre, randomised, controlled, open-label, non-
breast cancer and one or two metastatic nodes from inferiority, phase 3 trial comparing no axillary dissection
May, 1999, to December, 2004. Patients were randomly with axillary dissection in patients with breast cancer
assigned to either complete axillary lymph node and sentinel-node micrometastases. Patients were
dissection or no further axillary treatment. All patients recruited from 27 hospitals and cancer centres in nine
received breast-conserving surgery plus whole-breast countries (Australia, Belgium, Denmark, France, Italy,
irradiation. Almost all women in the Z0011 trial received New Zealand, Peru, Slovenia, and Switzerland) between
systemic therapy, and 301 (35%) of 856 randomly April 1, 2001, and Feb 8, 2010. Ethical committees of all
assigned patients had micrometastatic sentinel node participating centres and the IBCSG approved the
involvement and thus were similar to patients enrolled in protocol, and all patients provided written informed
the IBCSG 23-01 trial. The 10-year follow-up results of consent before enrolment.
the Z0011 trial confirmed the initial results observed: no Eligible women could be of any age with clinical,
significant differences in locoregional recurrence, mammographic, ultrasonographic, or pathological

2 www.thelancet.com/oncology Published online September 5, 2018 http://dx.doi.org/10.1016/S1470-2045(18)30380-2


Articles

diagnosis of breast cancer, with a diameter of 5 cm or (every 4 months from the date of randomisation for the
smaller, and only micrometastases in the sentinel nodes. first year, and every 6 months during years 2–5) based on
Key exclusion criteria were a previous or concomitant the National Cancer Institute Common Toxicity Criteria
malignancy, pure ductal carcinoma in situ, previous version 2. Serious adverse events were recorded as they
systemic therapy for breast cancer, cancer chemo­ occurred, and were defined as any event that occurred
prevention treatment in the preceding year, distant during surgery or within 4 weeks of surgery (or occurred
metastases, palpable axillary nodes, or Paget’s disease later but was considered related to the surgery) and met
without invasive cancer. Pregnant or lactating women any of the following criteria: was fatal or life threatening,
were also ineligible. required hospitalisation, resulted in disability, was a
In June, 2006, to increase accrual, and in line with the congenital anomaly or birth defect, was a secondary
2005 American Society of Clinical Oncology guidelines,22 cancer, or required significant medical intervention.
eligibility criteria were broadened to include patients
with one or more positive sentinel nodes (formerly only Outcomes
one), multicentric or multifocal tumours (formerly only The primary endpoint was disease-free survival, defined
unicentric), and largest lesion size of 5 cm or smaller as the time from randomisation to first evidence of
(formerly ≤3 cm). relapse at any site, appearance of a second contralateral
Patients could be scheduled for mastectomy or breast primary tumour, appearance of a second, non-
conservative breast surgery, and were included in the breast, primary tumour, or death from any cause,
trial and randomly assigned to treatment if, during or whichever occurs first. Each reported disease-free survival
after surgery, they were found to have a cancer of a event was centrally reviewed by IBCSG Medical Affairs.
maximum diameter of 5 cm or smaller, one or more Secondary endpoints were overall survival, defined as
micrometastatic foci (≤2 mm), including isolated tumour the time from randomisation to death from any cause;
cells23 in the sentinel nodes, and no macro-metastatic systemic disease-free survival, defined as the time
axillary disease. from randomisation to systemic relapse (any recurrent
or metastatic disease in sites other than the local
Randomisation and masking mastectomy scar, chest wall, or skin, the ipsilateral breast
Patients were randomly assigned (1:1) to either no axillary in case of breast conservation, or the contralateral breast),
dissection or axillary dissection using permuted blocks appearance of second, non-breast primary tumour, or
generated by a congruence algorithm, with stratification death, whichever occurs first (we do not report this
by participating centre and menopausal status. The endpoint because conclusions based on it are very similar
system assigned a patient identification number, treat­ to those based on disease-free survival); axillary failure,
ment group, and date of randomisation. The IBCSG data
management centre developed and maintained the
randomisation system. The study involved no masking— 6681 patients screened before surgery

patients, participating centre staff, trial management


staff, and surgeons were all aware of assigned treatments. 5747 ineligible

Procedures
934 randomly assigned
Patients receiving breast-conserving surgery were required
to undergo radiotherapy to the residual breast, which could
be either conventional whole-breast irradiation or partial-
breast irradiation given intra-operatively. The protocol 469 assigned to no axillary dissection 465 assigned to axillary dissection
specified that locoregional radiotherapy should not be
given to patients scheduled for mastectomy. However,
radiotherapy to internal mammary lymph nodes was 2 excluded 1 excluded (ineligible)
1 ineligible
permitted if any of these nodes were metastatic. Randomly 1 withdrew consent
assigned patients were scheduled for examinations every
4 months for the first year, every 6 months during
467 analysed for efficacy (as randomly 464 analysed for efficacy (as randomly
years 2–5, and yearly thereafter. Each follow-up visit assigned) assigned)
included a physical examination with specific attention to
the possible presence of palpable (ie, metastatic) axillary
lymph nodes. Mammography was to be done on a yearly 14 received axillary dissection 17 did not receive axillary dissection

basis; other investigations were to be done as clinically


indicated and in the presence of focal symptoms. 453 analysed for safety (as treated) 447 analysed for safety (as treated)
The treating physician assessed and reported long-
term surgical events (sensory neuropathy, lymphoedema,
Figure 1: Trial profile
and motor neuropathy) at each follow-up visit

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Statistical analysis
A
100 No axillary dissection
Patients enrolled in IBCSG 23-01 were followed up for
Axillary dissection longer-term outcomes, based on the existing study protocol
HR=0·85 (95% CI 0·65–1·11) that was in place for the 5-year analysis (appendix p 6), as
80
Log-rank p=0·24; pnon-inferiority=0·0024
Disease-free survival (%)

were analyses of the primary and secondary endpoints;


60 however, the protocol did not specifically prespecify plans
for a 10-year analysis. The purpose of the 10-year analysis
40 was to further assess the primary and secondary endpoints
of the trial after longer follow-up and for comparison with
20
10-year results from the Z0011 trial.20 Patient follow-up for
0
this final trial analysis was completed on Feb 17, 2017, after
0 2 4 6 8 10 requesting all centres to provide a final follow-up form for
Number at risk each patient not deceased or lost to follow-up. The data
(number censored)
No axillary dissection 467 (0) 443 (5) 412 (18) 367 (40) 278 (113) 168 (206)
cutoff date for this analysis was May 16, 2017.
Axillary dissection 464 (0) 433 (5) 392 (15) 353 (35) 282 (97) 169 (193) As originally designed, target accrual was 1960 patients
with analysis planned after 558 events. These targets were
B
based on having 90% power to detect non-inferiority of no
20 HR=0·98 (95% CI 0·71–1·36)
Log-rank p=0·92 axillary dissection with a one-sided significance level of
10% (α=0·10) assuming that 5-year disease-free survival
Cumulative incidence of breast

15 with axillary dissection was 70% and defining non-


cancer events (%)

inferiority as a hazard ratio (HR) of less than 1·25 (ie,


10 no axillary dissection relative to axillary dissection)
assessed by Z test applied to log HR. We did a one-sided
5 test for non-inferiority of no axillary dissection by com­
paring the observed HR for disease-free survival with a
margin of 1·25 (ie, a null hypothesis that HR ≥1·25).
0
0 2 4 6 8 10 All analyses, except those for adverse events, were based
Number at risk on the intention-to-treat population, defined as all eligible,
(number censored) randomised patients, regardless of what treatment they
No axillary dissection 467 (0) 443 (5) 412 (18) 367 (40) 278 (113) 168 (206)
Axillary dissection 464 (0) 433 (5) 392 (15) 353 (35) 282 (97) 169 (193) received (as randomly assigned). Long-term surgical
adverse events were analysed in the safety population,
C which excluded patients from the intention-to-treat
100
population who did not receive the treatment allocated by
HR 0·78 (95% CI 0·53–1·14)
Log-rank p=0·20 randomisation (as treated).
80
We assessed disease-free survival and overall survival
Overall survival (%)

60 using the product-limit method and used the log-rank


test, stratified by menopausal status, to compare the
40 treatment groups. We converted the log-rank test statistic
(observed minus expected numbers of events [O–E]) and
20 its variance (V) into an HR comparing no axillary
dissection with axillary dissection using the following
0
0 2 4 6 8 10 formula:
Time (years) [O – E]
Number at risk
(number censored) HR = exponential
No axillary dissection 467 (0) 460 (5) 441 (19) 405 (43) 314 (125) 197 (235) V
Axillary dissection 464 (0) 456 (5) 438 (16) 401 (41) 319 (112) 199 (221)

Figure 2: Disease-free survival, cumulative incidence of breast-cancer events, and overall survival Fisher’s exact test was used to compare the overall
Figure shows (A) disease-free survival, (B) cumulative incidence of breast-cancer events (exploratory analysis), incidence of long-term surgical adverse events (of any
and (C) overall survival in the intention-to-treat population with a median follow-up of 9∙7 years (IQR 7∙8–12∙7). grade) between the groups.
We assessed and compared the cumulative incidence
defined as a regional recurrence in the ipsilateral axilla or of breast cancer events using the Gray method,24
axillary nodes; and assessment of sites of first failure and treating second primaries and other-cause death as
long-term surgical com­ plications up to 5-years after competing risks. We estimated 95% CIs and p values
treatment. We also assessed any breast cancer event, for HRs on the basis of a normal distribution following
defined as the time from randomisation to any ipsilateral natural logarithm transformation. To assess the non-
breast cancer recurrence or contralateral breast cancer inferiority of no axillary dissection versus axillary
development in an exploratory analysis. dissection, we did subgroup analyses of disease-free

4 www.thelancet.com/oncology Published online September 5, 2018 http://dx.doi.org/10.1016/S1470-2045(18)30380-2


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survival defined by age at diagnosis (<50, 50–59, or


No axillary Axillary
≥60 years), tumour size (<2, 2–2·9, or ≥3 cm), dissection dissection
oestrogen-receptor status, progesterone-receptor status, (n=467) (n=464)
tumour grade, size of largest metastatic sentinel node Disease-free survival events* 101 (22%) 117 (25%)
(≤1 or >1 mm), number of metastatic sentinel nodes Breast cancer events 74 (16%) 75 (16%)
(1 or ≥2), tumour centricity, HER2 status, histological Local recurrences 14 (3%) 13 (3%)
subtype of primary tumour (invasive ductal, invasive Regional events 9 (2%) 3 (1%)
lobular, or all other types), type of surgery, and adjuvant Ipsilateral axillary failures 8 (2%) 2 (<1%)
therapy; subgroup-specific HRs were assessed with Distant 41 (9%) 47 (10%)
99% CIs and overall disease-free survival HR with
Contralateral breast 10 (2%) 12 (3%)
95% CI.
Non-breast cancer events 27 (6%) 42 (9%)
Additional post-hoc exploratory analyses compared
Second (non-breast) primary 17 (4%) 23 (5%)
outcomes among patients who received a mastectomy
Death without previous cancer event 6 (1%) 2 (<1%)
versus those who received breast-conserving surgery,
Death with unknown cancer status 4 (<1%) 17 (4%)
including disease-free survival, overall survival, and the
Deaths 45 (10%) 58 (13%)
cumulative incidence of breast-cancer events assessed as
described above. We compared the two surgery groups Data are n (%) in the intention-to-treat population after a median follow-up of
on baseline factors using Fisher’s exact test (for categorical 9∙7 years (IQR 7∙8–12∙7). *Includes breast-cancer events and non-breast cancer events.

variables) and the rank-sum test (for continuous Table 1: Disease-free survival events and number of deaths
variables). We used proportional-hazards regression
analysis to estimate HRs for surgery type and systemic
therapy received after adjustment for the baseline factors up shortly after randomisation), thus the intention-to-treat
listed above. We assessed interactions between baseline population consisted of 931 patients, 467 assigned to no
factors by including the appropriate product terms in the axillary dissection and 464 assigned to axillary dissection
regression models. CIs and significance tests for adjusted (figure 1).
HRs were based on Wald statistics. The proportional The groups were well balanced for baseline char­
hazards assumption was assessed by including time- acteristics (appendix p 4).18 42 (5%) of 931 patients received
varying covariates to ascertain whether HRs exhibited radiotherapy to the axillary lymph nodes (22 [5%] of 467 in
any heterogeneity over time. the no axillary dissection group and 20 [4%] of 464 in the
An independent data monitoring committee reviewed axillary dissection group). Two (5%) of the 42 patients who
accrual, safety, and number of events every 6 months received radiotherapy to the axillary lymph nodes had
during the first 5-years of follow-up. No monitoring was metastatic internal mam­mary lymph nodes and received
done during the exploratory extended follow-up. Analyses radiotherapy to these nodes only; the remaining
were done with SAS (version 9.4) and R (version 3.4.1). 40 (95%) patients received lymph node irradiation in
This study is registered with ClinicalTrials.gov, number violation of protocol (21 [4%] of 467 in the no axillary
NCT00072293. dissection group and 19 [4%] of 464 in the axillary
dissection group).
Role of the funding source For this final analysis, median follow-up for the
The funder of the study had no role in study design, data 931 patients in the intention-to-treat population was
collection, data analysis, data interpretation, and writing 9∙7 years (IQR 7∙8–12∙7). Disease-free survival at 10 years
of the report. VG, BFC, MMR, and RDG had full access was 76∙8% (95% CI 72∙5–81∙0) in the no axillary
to all the data in the study, and the corresponding author dissection group compared with 74∙9% (70∙5–79∙3) in
had final responsibility for the decision to submit for the axillary dissection group (HR 0∙85, 95% CI 0∙65–1∙11;
publication. log-rank p=0∙24; p=0∙0024 for non-inferiority; figure 2A).
The proportion of patients with local recurrences was
Results similar in the two groups (table 1); however, regional
As described previously,18 between April 1, 2001, and events were more frequent in the no axillary dissection
Feb 8, 2010, 6681 patients were screened for enrolment group. Ipsilateral axillary events were also more frequent
before surgery. Accrual was stopped early because in the no axillary dissection group; however, there were
micrometastases were lower than expected and the fewer non-breast cancer events in the no axillary
projected time to complete accrual was too long. Accrual dissection group (table 1). There were no differences in
stopped after 934 patients met the requirement of the cumulative incidence of breast cancer events (post-
micrometastatic sentinel nodes and were randomly hoc exploratory analysis) or overall survival in this final
assigned to treatment. Three of 934 patients assigned to analysis. 10-year cumulative incidence of breast cancer
treatment were excluded from the analysis (two had no events was 17∙6% (95% CI 13∙8–21∙5) in the no axillary
data submitted because no tumour was found in a sentinel dissection group and 17∙3% (13∙4–21∙1) in the axillary
node, and one withdrew consent for treatment and follow- dissection group (HR 0∙98; 95% CI 0∙71–1∙36; log-rank

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Events/patients HR (95% CI) pnon-inferiority

No axillary dissection Axillary dissection

Age at diagnosis (years)


<50 31/165 45/183 0·75 (0·42–1·36) 0·014
50–59 26/148 30/140 0·89 (0·45–1·79) 0·11
≥60 44/154 42/141 0·90 (0·52–1·58) 0·067
Tumour size (cm)
<2 65/322 68/316 0·94 (0·60–1·46) 0·048
2–2·9 28/112 35/106 0·75 (0·39–1·44) 0·022
≥3 8/28 14/36 0·74 (0·24–2·24) 0·11
Oestrogen-receptor status
Negative 18/40 18/51 1·29 (0·53–3·10) 0·53
Positive 82/425 99/409 0·80 (0·55–1·17) 0·0013
Progesterone-receptor status
Negative 41/115 35/108 1·21 (0·67–2·19) 0·45
Positive 58/350 82/352 0·70 (0·45–1·09) 0·0003
Tumour grade
I 12/90 22/118 0·66 (0·27–1·63) 0·035
II 45/241 49/214 0·83 (0·49–1·42) 0·025
III 44/135 46/129 0·86 (0·50–1·48) 0·038
Size largest metastatic sentinel node (mm)
≤1 62/319 81/323 0·77 (0·50–1·18) 0·0017
>1 39/146 36/141 1·04 (0·57–1·88) 0·21
Number metastatic sentinel nodes
1 98/450 111/440 0·86 (0·60–1·23) 0·0037
≥2 3/17 6/24 0·78 (0·12–4·93) 0·26
Tumour centricity
Unicentric 33/204 37/202 0·90 (0·48–1·66) 0·082
Multicentric 5/39 11/41 0·46 (0·13–1·69) 0·024
Unknown 63/224 69/221 0·90 (0·57–1·41) 0·030
HER2 status
Negative 68/335 83/332 0·81 (0·53–1·24) 0·0043
Borderline 10/33 10/33 0·87 (0·27–2·82) 0·21
Positive 12/47 18/49 0·60 (0·23–1·54) 0·022
Unknown 11/52 6/50 1·77 (0·50–6·20) 0·76
Histological subtype
Invasive ductal 84/399 103/400 0·81 (0·56–1·19) 0·0017
Invasive lobular 13/37 9/35 1·29 (0·43–3·89) 0·53
All other types 4/31 5/29 0·79 (0·14–4·47) 0·25
Type of surgery
Mastectomy 8/42 15/44 0·45 (0·15–1·39) 0·0097
Breast conserving 93/425 102/420 0·91 (0·63–1·31) 0·013
Adjuvant therapy
None 5/16 7/22 1·29 (0·26–6·47) 0·52
Chemotherapy alone 13/32 17/41 1·00 (0·38–2·66) 0·28
Hormonal therapy alone 63/315 64/292 0·93 (0·59–1·47) 0·047
Combination 20/104 29/109 0·69 (0·33–1·44) 0·018
All patients 101/467 117/464 0·85 (0·65–1·11) 0·0024

99% CI 0·25 0·5 0·75 1·0 1·5 2·0 2·5


95% CI
Favours no axillary dissection Favours axillary dissection

Figure 3: Forest plot of the subgroup analysis of disease-free survival


Subgroups were defined by baseline characteristics in the intention-to-treat population (n=931). Each subgroup HR is shown as a black square, with the size of the
square being inversely proportional to the variance of the corresponding log-HR estimate (ie, larger squares indicate lower variability in the estimate). The HR for all
patients is shown as a diamond. The dashed line corresponds to an HR of 1·25, which was the threshold for non-inferiority for no axillary dissection. The horizontal
axis is on a logarithmic scale. HR=hazard ratio.

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p=0∙92; figure 2B). 45 (10%) of 467 patients in the no


No axillary Axillary dissection p value*
axillary dissection group and 58 (13%) of 464 in the dissection (n=453) (n=447)
axillary dissection group died during follow-up. 10-year
Sensory neuropathy 57 (13%) 85 (19%) 0∙010
overall survival was 90∙8% (95% CI 87∙9–93∙8) in the no
Grade 1–2 48 (11%) 78 (17%) ∙∙
axillary dissection group and 88∙2% (84∙8–91∙6) in the
Grade 3 0 1 (<1%) ∙∙
axillary dissection group (HR 0∙78; 95% CI 0∙53–1∙14;
Grade 4 0 0 ∙∙
log-rank p=0∙20; figure 2C).
Unknown grade 9 (2%) 6 (1%) ∙∙
Disease-free survival did not differ between treatments
Lymphoedema 16 (4%) 60 (13%) <0∙0001
in the subgroup analysis by patient characteristics
Grade 1–2 14 (3%) 56 (13%) ∙∙
(figure 3). 16 (3%) of 467 patients allocated to no axillary
Grade 3 0 2 (<1%) ∙∙
dis­section and 22 (5%) of 464 patients allocated to axillary
dissection received no adjuvant systemic therapy. A Grade 4 0 1 (<1%) ∙∙

post-hoc exploratory multi­variable analysis to assess the Unknown grade 2 (<1%) 1 (<1%) ∙∙

effect of systemic therapy, comparing any systemic Motor neuropathy 14 (3%) 40 (9%) 0∙0002
therapy with no systemic therapy, resulted in an adjusted Grade 1–2 13 (3%) 37 (8%) ∙∙
HR of 0∙81 (95% CI 0∙45–1∙48; p=0∙50) for disease-free Grade 3 1 (<1%) 3 (<1%) ∙∙
survival. Grade 4 0 0 ∙∙
In the complete cohort, irrespectively of allocated Unknown grade 0 0 ∙∙
treatment, 86 (9%) of 931 patients received a mastectomy All surgical adverse events recorded after a median follow-up of 9∙7 years
and 845 (91%) received breast-conserving surgery. (IQR 7∙8–12∙7). There were no fatal events in any of the above categories. *Based
Five (6%) of 86 patients who had mastectomy received on Fisher’s exact test applied to the occurrence of any long-term surgical event.
chest-wall radiotherapy (which was a protocol violation). Table 2: Incidence of long-term surgical adverse events in the safety
None of the 22 patients who had breast-conserving population
surgery without radiotherapy had axillary failure.
Post-hoc exploratory analyses showed that patients who
had a mastectomy were younger than those who mastectomy group than in the breast-conserving group
had breast-conserving surgery (median age 50 years (HR 2∙56, 95% CI 1∙36–4∙85; p=0∙0038).
[IQR 44–57] vs 54 years [47–62]; difference of 3·9 years Long-term surgical adverse events (ie, sensory
[95% CI 1·4–6·5]; p=0∙0027) and had larger tumours neuropathy, lymphoedema, and motor neuropathy) were
(median tumour size 2∙2 cm [IQR 1·5–3·0] in the monitored only until year 5. Therefore, our updated
mastectomy group vs 1∙5 cm [1·1–2·0] in the breast- 10-year analysis is nearly identical to that presented at
conserving surgery group; difference of 0·6 cm [95% CI 5 years18 (table 2). Adverse events of grade 3 or worse
0·4–0·8]; p<0∙0001). 10-year disease-free survival was occurred in less than 1% of all patients in the safety
70∙5% (95% CI 58∙8–82∙3) in the mastectomy group and population (table 2). There was one report of a serious
76∙4% (73∙2–79∙6) in the breast-conserving-surgery adverse event (postoperative infection and inflamed axilla
group (HR 1·39, 95% CI 0·85–2·26; log-rank p=0∙19). requiring hospital admission) attributed to axillary
After adjustment for baseline factors, the HR for 10-year dissection 27 days after the procedure. The event resolved
disease-free survival was 1∙23 (95% CI 0∙76–1∙98; without sequelae.
p=0∙40) comparing mastectomy with breast-conserving
surgery. Results were similar for breast-cancer events Discussion
(treating all other events as competing risks). There were This 10-year follow-up study provides additional, high-
17 (20%) of 86 breast-cancer events in the mastectomy level evidence that omission of axillary dissection in
group and 132 (16%) of 845 in the breast-conserving patients with minimal disease burden in the sentinel
surgery group (adjusted HR 1∙11; 95% CI 0∙63–1∙97; nodes is an acceptable treatment, because it confirms
p=0∙71). Of the 845 patients who received breast- that, long term, the primary outcome of disease-free
conserving surgery, seven (<1%) had axillary failure; survival in the no axillary dissection group was non-
five (71%) of these seven patients were given experimental inferior to that in the axillary dissection group, which was
partial-breast radiotherapy (ie, single-dose intraoperative also the case in most of the subgroups studied.
radiotherapy with electrons). There were two axillary Furthermore, the frequency of axillary lymph node failure
failures (2%) among the 86 patients who received a in the no axillary dissection group was low, though higher
mastectomy. 14 (16%) of the 86 patients who received a than in the axillary dissection group. Of the 845 patients
mastectomy died, as did 89 patients (10%) of the 845 given who received breast-conserving surgery, only seven had
breast-conserving surgery. 10-year overall survival was axillary lymph node failure, but five of these patients
82∙1% (95% CI 73∙4–90∙8) in the mastectomy group received experimental partial breast irradiation. We
and 90∙4% (88∙1–92∙7) in the breast-conserving group speculate that if all patients had received conventional
(log-rank p=0∙0029). After adjustment for baseline radiotherapy instead, there might have been fewer axillary
factors, overall survival was significantly worse in the failures.25 In the patients who received a mastectomy, the

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proportion of axillary lymph node failure was slightly with axillary failure in the no axillary dissection was
higher, but still acceptably low. acceptably low. These findings are consistent with those
Omission of axillary dissection when the sentinel node of the 10-year follow-up analysis of the Z0011 trial, and
disease burden is low is becoming standard clinical support the omission of axillary dissection in breast cancer
practice and has been recommended since 2013,26 after patients with minimal sentinel node involvement.
the publication of the Z0011 study and the 5-year results Contributors
of this trial. Although in the Z0011 trial only VG, RDG, AG, and PV participated in the design and conception of the
301 (35%) of 856 patients had micrometastatic involve­ study. GV and GM participated in the pathology review. VG, PV, EV, MI,
JZ, SM, MT, ADL, DL, MK, CT, and MC participated in the data collection
ment of the sentinel nodes, and most patients had macro­ and enrolment of patients.VG did the literature searches. BFC, RDG,
metastases (in up to two sentinel nodes), early and and MMR participated in the data analyses. VG, BFC, ASC, and RDG
long-term data (median follow-up 6∙3 years [IQR 5·2–7·7]19 were involved in interpreting the results. All authors were involved in
and 9∙3 years [6·9–10·3])20 indicated non-inferior overall drafting and finalising the report.
survival, and no differences in loco­ regional recurrence Declaration of interests
between the axillary dissection and no axillary dissection ADL reports grants from AstraZeneca, Pierre Fabre, and Pfizer; and
personal fees from AstraZeneca, Bayer, Celgene, Daichii-Sankyo, Eisai,
groups. In this 10-year follow-up analysis of the IBCSG 23- Genomic Health, Ipsen, Lilly, Novartis, Pierre Fabre, Pfizer, and Roche.
01 study, we assessed non-inferiority in subgroups at MC reports advisory board fees from AstraZeneca, Pierre Fabre, Pfizer,
increased risk of a breast-cancer event to inform whether OBI Pharma, Puma Biotechnology, and Celldex; and honoraria from
no axillary dissection might be less advantageous in some Novartis. MMR reports grants from the International Breast Cancer
Study Group. All other authors declare no competing interests.
cases. In most subgroups, the HR for a disease-free
survival event indicated non-inferiority of no axillary Acknowledgments
IBCSG 23-01 was supported by the centres that enrolled the women,
dissection to axillary dissection. Additionally, similar and the International Breast Cancer Study Group that is partly funded
results in the breast-conserving surgery and mastectomy by: the Swiss Group for Clinical Cancer Research; the Swiss Cancer
group suggest that no axillary dissection might be League/Cancer Research Switzerland/Oncosuisse, Frontier Science and
Technology Research Foundation; The Cancer Council Australia;
acceptable treatment in patients scheduled for mastectomy.
The Australian New Zealand Breast Cancer Trials Group (National
Altogether, the results of these trials provide important Health Medical Research Council); The Swedish Cancer Society; and
additional support to the change in clinical practice that The Foundation for Clinical Cancer Research of Eastern Switzerland.
started after the early findings were published to omit There was no pharmaceutical company support for this trial. We thank
the patients, physicians, nurses, and data managers who participated in
axillary dissection in patients with minimal lymph
the trial.
node involvement.18 Accordingly, the 2017 National
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