Research

JAMA | Original Investigation

Effect of Axillary Dissection vs No Axillary Dissection

on 10-Year Overall Survival Among Women With
Invasive Breast Cancer and Sentinel Node Metastasis
The ACOSOG Z0011 (Alliance) Randomized Clinical Trial
Armando E. Giuliano, MD; Karla V. Ballman, PhD; Linda McCall, MS; Peter D. Beitsch, MD; Meghan B. Brennan, RN, ONP, PhD; Pond R. Kelemen, MD;
David W. Ollila, MD; Nora M. Hansen, MD; Pat W. Whitworth, MD; Peter W. Blumencranz, MD; A. Marilyn Leitch, MD; Sukamal Saha, MD;
Kelly K. Hunt, MD; Monica Morrow, MD

Editorial page 909

IMPORTANCE The results of the American College of Surgeons Oncology Group Z0011 Author Audio Interview
(ACOSOG Z0011) trial were first reported in 2005 with a median follow-up of 6.3 years.
Longer follow-up was necessary because the majority of the patients had estrogen Supplemental content

receptor–positive tumors that may recur later in the disease course (the ACOSOG
is now part of the Alliance for Clinical Trials in Oncology).

OBJECTIVE To determine whether the 10-year overall survival of patients with sentinel lymph
node metastases treated with breast-conserving therapy and sentinel lymph node dissection
(SLND) alone without axillary lymph node dissection (ALND) is noninferior to that of women
treated with axillary dissection.

DESIGN, SETTING, AND PARTICIPANTS The ACOSOG Z0011 phase 3 randomized clinical trial
enrolled patients from May 1999 to December 2004 at 115 sites (both academic and community
medical centers). The last date of follow-up was September 29, 2015, in the ACOSOG Z0011
(Alliance) trial. Eligible patients were women with clinical T1 or T2 invasive breast cancer,
no palpable axillary adenopathy, and 1 or 2 sentinel lymph nodes containing metastases.

INTERVENTIONS All patients had planned lumpectomy, planned tangential whole-breast

irradiation, and adjuvant systemic therapy. Third-field radiation was prohibited.

MAIN OUTCOMES AND MEASURES The primary outcome was overall survival
with a noninferiority hazard ratio (HR) margin of 1.3. The secondary outcome was
disease-free survival.

RESULTS Among 891 women who were randomized (median age, 55 years), 856 (96%)
completed the trial (446 in the SLND alone group and 445 in the ALND group). At a median
follow-up of 9.3 years (interquartile range, 6.93-10.34 years), the 10-year overall survival was
86.3% in the SLND alone group and 83.6% in the ALND group (HR, 0.85 [1-sided 95% CI,
0-1.16]; noninferiority P = .02). The 10-year disease-free survival was 80.2% in the SLND
alone group and 78.2% in the ALND group (HR, 0.85 [95% CI, 0.62-1.17]; P = .32). Between
year 5 and year 10, 1 regional recurrence was seen in the SLND alone group vs none in the
ALND group. Ten-year regional recurrence did not differ significantly between the 2 groups.

CONCLUSIONS AND RELEVANCE Among women with T1 or T2 invasive primary breast cancer,
no palpable axillary adenopathy, and 1 or 2 sentinel lymph nodes containing metastases,
10-year overall survival for patients treated with sentinel lymph node dissection alone was
noninferior to overall survival for those treated with axillary lymph node dissection. These
findings do not support routine use of axillary lymph node dissection in this patient Author Affiliations: Author
affiliations are listed at the end of this
population based on 10-year outcomes. article.
Corresponding Author: Armando E.
TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00003855 Giuliano, MD, Department of Surgery,
Cedars-Sinai Medical Center, 8700
Beverly Blvd, Los Angeles, CA 90048
JAMA. 2017;318(10):918-926. doi:10.1001/jama.2017.11470 (armando.giuliano@cshs.org).

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 Effect of Sentinel Lymph Node vs Full Axillary Dissection on Overall Breast Cancer Survival Original Investigation Research

F
or more than 100 years, the extent of breast cancer sur-
gery was based on the Halstedian concept of breast can- Key Points
cer as a locoregional disease that spread via the lym-
Question Is there any diminution in 10-year overall survival for
phatic system and was cured by resection.1,2 Since then, it has women with cT1-2N0 breast cancer and metastases to 1 or 2
been recognized that breast cancer biology, rather than the ex- sentinel lymph nodes undergoing breast-conserving surgery,
tent of surgery, is a major risk determinant of both systemic whole-breast irradiation, and adjuvant systemic therapy treated
and locoregional recurrence,3,4 opening the door to new sur- with sentinel node dissection alone compared with that of patients
gical approaches to management. treated with axillary dissection?
Axillary lymph node dissection (ALND), long used to iden- Findings In this randomized clinical trial including 856 women,
tify women with axillary nodal metastases, was replaced as a after median follow-up of 9.3 years, overall survival for patients
staging procedure by the less morbid sentinel lymph node dis- treated with sentinel lymph node dissection alone was not inferior
section (SLND).5-7 Between 1998 and 2004, the use of ALND to those treated with completion axillary lymph node dissection
(86.3% vs 83.6%, respectively; noninferiority hazard ratio
declined from 94% to 36% in women with no axillary nodal
margin of 1.3).
metastases, whereas 68% of patients with sentinel node me-
tastases underwent ALND in 2004.8 Axillary lymph node dis- Meaning These findings do not support the use of axillary lymph
section is an effective method of maintaining regional con- node dissection when metastases are found with sentinel lymph
node sampling in women with cT1-2M0 breast cancer.
trol but it is associated with a significant risk of complications
such as lymphedema, numbness, axillary web syndrome, and
decreased upper-extremity range of motion.6 Changes in the tional review boards at participating centers. All patients pro-
presentation and management of breast cancer and the selec- vided written informed consent. Adult women with histologi-
tion of systemic therapy based on tumor biology raised ques- cally confirmed invasive breast carcinoma clinically 5 cm or
tions regarding the necessity of ALND for some patients with less in size, no palpable adenopathy, and with sentinel nodes
sentinel lymph node metastases. containing metastatic breast cancer detected without immu-
The American College of Surgeons Oncology Group Z0011 nohistochemical stains were eligible for participation. The eli-
(ACOSOG Z0011) randomized clinical trial was designed to de- gibility criteria have been reported.9,10
termine whether SLND alone yielded survival outcomes that
were noninferior to that obtained with ALND in women with Study and Design End Points
a limited number of sentinel node metastases undergoing The study and design end points have been described else-
breast-conserving surgery and receiving adjuvant whole- where.9,10 Briefly, after stratification based on age, hormone
breast irradiation with adjuvant systemic therapy. The ACOSOG receptor status, and tumor size, patients with 1 or 2 sentinel
is now part of the Alliance for Clinical Trials in Oncology nodes with metastases detected by hematoxylin and eosin
(Alliance). The trial protocol appears in the Supplement. stain were randomized to no further axillary-specific treat-
The initial study results, reported after a median follow-up ment including no axillary third-field irradiation (SLND
of 6.3 years,9,10 demonstrated that the overall survival in pa- alone group) or completion ALND (ALND group). Patients
tients randomized to SLND alone was no worse than patients were assessed for disease recurrence with a history and
randomized to ALND with a noninferiority hazard ratio (HR) physical examination every 6 months for the first 36
margin of 1.3. It also showed no statistically significant differ- months and yearly thereafter. Annual mammography was
ence in disease-free survival between patients randomized to required; other testing was based on individual symptoms
SLND alone or ALND, and nodal recurrence occurred in fewer or by investigator preference.
than 1% of patients in either study group. Follow-up was planned for 10 years. The primary study
A serious criticism of the study was the relatively short end point was overall survival, which was defined as the
follow-up that may have not detected late death. Breast cancer, time from randomization until death from any cause.
particularly hormone receptor–positive breast cancer, is a dis- Disease-free survival, which was defined as the time from
ease with a long natural history11,12 and a substantial risk of randomization to death or first breast cancer recurrence,
locoregional and systemic relapses occurring after 5 years. Pa- was a secondary end point along with morbidity and locore-
tients enrolled in ACOSOG Z0011 reflected the demographics gional recurrence. Locoregional recurrence was defined as a
of patients with breast cancer in the United States. The major- tumor in the breast or in ipsilateral axillary, internal mam-
ity of patients were postmenopausal with hormone receptor– mary, subclavicular, or supraclavicular nodes. All other dis-
positive breast cancer, raising concern that additional follow- ease sites were defined as distant metastases. Secondary
up beyond 6 years was needed to document noninferiority of end points have been reported.6,13
overall survival with SLND alone in this node-positive cohort.
Statistical Analysis
The primary end point was overall survival as a measure of
noninferiority of no further axillary-specified interventions
Methods (SLND alone group) compared with the ALND group. The
Patient Characteristics study design hypothesized that overall survival would be
This multicenter randomized phase 3 trial was registered with 80% at 5 years for optimally treated women in this node-
the National Cancer Institute and approved by the institu- positive cohort. The SLND alone group would be considered

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 Research Original Investigation Effect of Sentinel Lymph Node vs Full Axillary Dissection on Overall Breast Cancer Survival

clinically noninferior to the ALND group if the 5-year sur-

Figure 1. Flow of Patients Through Treatment and Follow-up in the
vival rate was 75% or greater and the HR was 1.3 or less. ACOSOG Z0011 (Alliance) Trial
A 1-sided 95% CI for the HR from a Cox regression model
was used to confirm noninferiority of SLND alone compared
891 Randomizeda
with ALND. An estimated 500 deaths were needed for the
study to have 90% power.14
Enrollment of 1900 patients in 4 years with a minimum 446 Randomized to receive sentinel 445 Randomized to receive axillary
lymph node dissection alone lymph node dissection
follow-up period of 5 years was initially planned. The trial 436 Received sentinel lymph 420 Received axillary lymph
closed early because of low accrual rates and fewer than an- node dissection alone node dissection as
as randomized randomized
ticipated events. The protocol specified that patients were to 10 Withdrew prior to surgery 25 Withdrew prior to surgery
be followed up for a minimum of 10 years. However, the analy-
sis of overall survival after the completion of study follow-up 74 Lost to follow-up 92 Lost to follow-up
was not prespecified. 3 Discontinued intervention 2 Discontinued intervention
2 Refused after randomization 1 Refused after randomization
Analyses were performed on the intent-to-treat sample but prior to surgery but prior to surgery
(436 patients in the SLND alone group and 420 patients in 1 Opted for alternative therapy 1 Consent obtained after patient
registered
the ALND group) as well as on the patients who actually
received treatment. Both analyses yielded similar results so 436 Included in primary analysis 420 Included in primary analysis
only the intent-to-treat results are reported. Kaplan-Meier
survival curves for overall survival were compared using ACOSOG indicates American College of Surgeons Oncology Group; Alliance,
the log-rank test for noninferiority. The unadjusted HR Alliance for Clinical Trials in Oncology.
(95% CI) was calculated using a Cox regression analysis. a
Data are not available for the number of patients screened for eligibility.
Patients who were lost to follow-up (ie, missing data) were
censored at the time of their last follow-up in the time-to-
event analyses (disease-free survival and overall survival). formed with a 2-sided, .05 significance level, and 95% CIs.
Most patients were lost to follow-up because the site inves- SAS version 9.4 (SAS Institute Inc) was used for all analyses.
tigator left an institution and the institution stopped active
follow-up on the patients. Hence, the missing data were not
associated with outcome.
Patients who withdrew consent for use of their informa-
Results
tion were omitted from the analyses. All secondary analyses Patient Characteristics
were tested for differences. As a secondary analysis, known Enrollment began in May 1999 with a planned accrual of 1900
prognostic factors (including adjuvant treatment) were patients and closed in December 2004 due to a lower than ex-
included in the Cox regression model to generate an adjusted pected event rate.9 There were 891 patients randomized from
HR for overall survival. Disease-free survival was analyzed 115 institutions (both academic and community medical cen-
with a log-rank analysis using Kaplan-Meier curves and ters); 35 withdrew consent (Figure 1). Demographic and dis-
unadjusted and multivariable Cox regression analyses. The ease characteristics at baseline were well balanced between the
proportional hazards assumptions for the Cox models were SLND alone group and the ALND group (Table 1).9
evaluated using Schoenfeld residual plots, and none of the
reported models appeared to violate the proportional haz- Treatment Results
ards assumption. Fewer lymph nodes were removed in the SLND alone group
An exploratory analysis was conducted to determine the (median, 2; interquartile range [IQR], 1-4) than in the ALND
effect of treatment (SLND alone vs ALND) on overall survival group (median, 17; IQR, 13-22) (P < .001), and the total num-
for patients with hormone receptor–positive tumors. A com- ber of involved nodes was greater in the ALND group. The me-
parison was done among 4 groups of patients (hormone dian total number of nodes containing metastases in both
receptor–positive treated with ALND, hormone receptor– groups was 1 (IQR, 1-2).
positive treated with SLND alone, hormone receptor– Micrometastases (≤2 mm) were identified in the sentinel
negative treated with ALND, hormone receptor–negative nodes of 164 patients (44.8%) in the SLND alone group com-
treated with SLND alone) using a log-rank test. In addition, pared with 137 patients (37.5%) in the ALND group (P = .046).
a log-rank test was used to determine whether hormone In addition, 27.3% of patients in the ALND group had macro-
receptor status was associated with overall survival in the metastases (>2 mm) in nonsentinel nodes removed during
ALND group. ALND, including 10% of patients with micrometastases in a sen-
Data collection and statistical analyses in the ACOSOG tinel node.
Z0011 (Alliance) trial were conducted by the Alliance Statis- Adjuvant systemic therapy was delivered to 423 women
tics and Data Center. Data quality was ensured by review of (97.0%) in the SLND alone group and 403 women (96.0%) in
data by the Alliance Statistics and Data Center and by the the ALND group, with no between-group difference in the type
study chairperson following Alliance policies. The study of chemotherapy or the proportion receiving endocrine
database was frozen on September 29, 2015. Except for the therapy, chemotherapy, or both. The majority of women re-
primary overall survival analysis, each analysis was per- ceived radiation therapy (277 women [89.6%] in the SLND alone

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 Effect of Sentinel Lymph Node vs Full Axillary Dissection on Overall Breast Cancer Survival Original Investigation Research

Table 1. Baseline Participant Characteristics

Lymph Node Dissection

Sentinel Alone Axillary
(n = 436) (n = 420)
Age, median (range), y 54 (25-90) 56 (24-92)
Age group, No. (%)
≤50 y 160 (36.7) 135 (32.1)
>50 y 266 (61.0) 278 (66.2)
Missing 10 (2.3) 7 (1.7)
Clinical stage, No. (%)
T1 303 (69.5) 284 (67.6)
T2 126 (28.9) 134 (31.9)
Missing 7 (1.6) 2 (0.5)
Tumor size, median (range), cma 1.6 (0-5.0) 1.7 (0.4-7.0)
Receptor status, No. (%)
ER and PR positive 270 (61.9) 256 (61.0)
ER positive and PR negative 54 (12.4) 61 (14.5)
ER negative and PR positive 4 (0.9) 3 (0.7)
ER and PR negative 64 (14.7) 63 (15.0)
Missing 44 (10.1) 37 (8.8)
Lymphovascular invasion, No. (%)
Present 113 (25.9) 129 (30.7)
Absent 208 (47.7) 189 (45.0)
Missing 115 (26.4) 102 (24.3)
Grade, No. (%)b
1 81 (18.6) 71 (16.9)
2 148 (33.9) 158 (37.6)
Abbreviations: ER, estrogen receptor;
3 87 (20.0) 94 (22.4) PR, progesterone receptor.
Missing 120 (27.5) 97 (23.1) a
There were missing data for 14
Histological type, No. (%) patients in the sentinel lymph node
dissection alone group and for 6
Ductal 356 (81.7) 344 (81.9)
patients in the axillary lymph node
Lobular 36 (8.3) 27 (6.4) dissection group.
Mixed ductal and lobular 10 (2.3) 23 (5.5) b
Defined using the modified
Other 22 (5.0) 22 (5.2) Bloom-Richardson system.
Patients with lower grades have
Missing 12 (2.7) 4 (1.0)
a better prognosis.

group vs 263 women [88.9%] in the ALND group). An inde- tion, or a combination of these 3) and age for the SLND
pendent analysis of radiation fields in a subset of participants alone group compared with the ALND group was 0.93
demonstrated no between-group difference in the use of high (1-sided 95% CI, 0-1.28) (Table 2).
tangents, nodal irradiation, or no irradiation; 18.9% received In a multivariable analysis of overall survival, type of treat-
protocol-prohibited nodal-field irradiation.15 Eleven percent ment was not significantly associated with overall survival
received no irradiation. (Table 3). An exploratory analysis of the effect of treatment and
hormone receptor status revealed no statistically significant
Overall Survival difference in overall survival among the 4 groups (log-rank
At a median follow-up of 9.3 years (IQR, 6.93-10.34 years), P = .14; Figure 2B). Operation had no significant effect on over-
there were 110 deaths (51 in the SLND alone group and 59 in all survival with respect to estrogen receptor and progester-
the ALND group). Compared with ALND, SLND alone was one receptor status.
found to be noninferior for overall survival (log-rank
P = .02; Figure 2A). The 10-year overall survival rate was Disease-Free Survival
86.3% (95% CI, 82.2%-89.5%) in the SLND alone group and Disease-free survival and locoregional recurrence have been
83.6% (95% CI, 79.1%-87.1%) in the ALND group. The unad- reported.13 The 10-year disease-free survival was 80.2% (95%
justed HR comparing overall survival between the SLND CI, 75.6%-84.1%) for the SLND alone group and 78.2% (95%
alone group and the ALND group was 0.85 (1-sided 95% CI, CI, 73.5%-82.2%) for the ALND group (log-rank P = .32;
0-1.16), which did not cross the prespecified noninferiority Figure 2C). The unadjusted HR comparing the SLND alone
HR margin of 1.3. The HR for overall survival adjusting for group with the ALND group was 0.85 (95% CI, 0.62-1.17)
adjuvant therapy (chemotherapy, endocrine therapy, radia- (Table 2). Only 1 nodal recurrence was observed in a patient

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 Research Original Investigation Effect of Sentinel Lymph Node vs Full Axillary Dissection on Overall Breast Cancer Survival

Figure 2. Overall and Disease-Free Survival in the ACOSOG Z0011 (Alliance) Trial

A Overall survival

100

SLND alone
80 ALND

60
Alive, %

40

20
Hazard ratio, 0.85 (1-sided 95% CI, 0-1.16); noninferiority P = .02
0
0 1 2 3 4 5 6 7 8 9 10
Time, y
No. at risk
SLND alone 436 411 391 317 246 146
ALND 420 398 381 317 248 134

B Overall survival by estrogen receptor (ER) and progesterone receptor (PR) status
100
ALND (ER and PR positive)

SLND alone (ER and PR positive)

80 SLND alone (ER and PR negative)
ALND (ER and PR negative) ACOSOG indicates American College
of Surgeons Oncology Group;
60 Alliance, Alliance for Clinical Trials in
Alive, %

Oncology. In part A, there were 51

40 events in the sentinel lymph node
dissection (SLND) alone group
(n = 436) during a median follow-up
20
of 9.3 years (interquartile range
Log-rank P = .14 [IQR], 6.8-10.3 years) vs 59 events in
0 the axillary lymph node dissection
0 1 2 3 4 5 6 7 8 9 10 (ALND) group (n = 420) during a
Time, y median follow-up of 9.4 years
No. at risk (IQR, 7.2-10.3 years). In part B,
SLND alone there were 12 events in the ER-
ER and PR Negative 64 60 56 45 37 19 and PR-negative SLND alone group
ER and PR Positive 270 254 240 196 147 92
(n = 64) during a median follow-up
ALND of 9.3 years (IQR, 7.7-10.7 years) with
ER and PR Negative 63 58 54 45 31 19
a hazard ratio of 1.71 (95% CI,
ER and PR Positive 256 243 238 201 163 85
0.88-3.34); 33 events in the ER- and
PR-positive SLND alone group
C Disease-free survival (n = 270) during a median follow-up
100 of 9.3 years (IQR, 6.7-10.4 years) with
a hazard ratio of 1.10 (95% CI,
0.67-1.80); 13 events in the ER- and
80 SLND
ALND PR-negative ALND group (n = 63)
during a median follow-up of 9.3
60 years (IQR, 7.1-10.4 years) with
Alive, %

a hazard ratio of 1.91 (95% CI,

1.00-3.66); and 30 events in the
40
ER- and PR-positive ALND group
(n = 256) during a median follow-up
20 of 9.5 years (IQR, 7.7-10.3 years) with
Hazard ratio, 0.85 (95% CI, 0.62-1.17); log-rank P = .32 a hazard ratio of 1 [Reference].
In part C, there were 73 events in the
0
0 1 2 3 4 5 6 7 8 9 10 SLND alone group (n = 435) during
Time, y a median follow-up of 9.3 years
(IQR, 6.8-10.3 years) vs 82 events in
No. at risk
SLND alone 435 399 374 303 237 137 the ALND group (n = 418) during
ALND 418 376 352 295 233 126 a median follow-up of 9.4 years
(IQR, 7.2-10.3 years).

in the SLND alone group after 5 years and none in the ALND with nodal-field irradiation experienced no difference in dis-
group. In an unplanned analysis of the subset of the 228 pa- ease-free survival, overall survival, or locoregional recur-
tients with detailed radiation records available, those treated rence compared with those who did not receive irradiation.

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 Effect of Sentinel Lymph Node vs Full Axillary Dissection on Overall Breast Cancer Survival Original Investigation Research

Table 2. Survival Outcomes by Study Group

Lymph Node Dissection

Sentinel Alone Axillary P Value
Primary End Point: Overall Survival
10-y Disease-free survival Kaplan-Meier estimate 86.3 (82.2-89.5) 83.6 (79.1-87.1)
(95% CI)
No. of events/No. of patients 51/436 59/420
Unadjusted HR (1-sided 95% CI) 0.85 (0-1.16) 1 [Reference] .02a
b
Adjusted HR (1-sided 95% CI) 0.93 (0-1.28) 1 [Reference] .72
Disease-Free Survival
10-y Kaplan-Meier estimate (95% CI) 80.2 (75.6-84.1) 78.2 (73.5-82.2)
No. of events/No. of patients 73/435 82/418
Unadjusted HR (95% CI) 0.85 (0.62-1.17) 1 [Reference] .32
Adjusted HR (95% CI)b 0.90 (0.68-1.18) 1 [Reference] .51
Locoregional Relapse-Free Survival
10-y Kaplan-Meier estimate (95% CI) 83.0 (78.6-86.6) 81.2 (76.7-84.9) Abbreviation: HR, hazard ratio.
a
No. of events/No. of patients 64/436 71/418 Indicates noninferiority for primary
end point.
Unadjusted HR (95% CI) 0.87 (0.62-1.22) 1 [Reference] .41
b
Model includes study group, age,
Adjusted HR (95% CI)b 0.93 (0.66-1.31) 1 [Reference] .66
and adjuvant therapy.

Table 3. Multivariable Analysis of the Association of Treatment and Prognostic Variables With Overall Survival
No. of No. of
Patients Deaths Adjusted HR (95% CI)a P Value
Lymph node dissection group
Sentinel alone 426 51 0.93 (0.64-1.36)
.72
Axillary 413 56 1 [Reference]
Age group, y
≤50 295 23 1 [Reference]
.002
>50 544 84 2.08 (1.31-3.30)
Estrogen receptor and progesterone
receptor status
Both negative 101 25 1 [Reference]
.02
≥1 Positive 514 61 0.57 (0.36-0.91)
Lymphovascular invasion
Absent 238 31 1 [Reference]
.74
Present 387 48 0.92 (0.59-1.46)
Sentinel lymph node met size
Micrometastases (≤2 mm) 296 37 1 [Reference]
.97
Macrometastases (>2 mm) 418 53 1.01 (0.66-1.54)
Pathological tumor size, cm (continuous) 1.19 (1.07-1.32) .001
Histological type
Ductal 687 86 1 [Reference]
Lobular 63 9 1.04 (0.52-2.07)
.25
Mixed ductal and lobular 32 8 2.06 (0.99-4.27)
Other 41 4 0.79 (0.29-2.16) Abbreviation: HR, hazard ratio.
Gradeb a
Model includes study group, age,
1 150 20 1 [Reference] and adjuvant therapy.
2 300 31 0.74 (0.42-1.30) b
Defined using the modified
.46 Bloom-Richardson system.
3 178 26 1.07 (0.60-1.92)
Patients with lower grades have a
Unknown or missing 144 21 1.06 (0.58-1.96)
better prognosis.

vival outcomes compared with ALND for patients with clini-

Discussion cal T1 or T2 node-negative (by palpation) breast cancer and 1
or 2 positive sentinel nodes treated with breast-conserving
Even with follow-up extended to a median of 9.3 years, the therapy and adjuvant systemic therapy. Before publication
ACOSOG Z0011 (Alliance) randomized clinical trial demon- of the initial ACOSOG Z0011 trial results,9 there was a gen-
strated that SLND alone did not result in inferior overall sur- eral consensus that axillary dissection was necessary for

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 Research Original Investigation Effect of Sentinel Lymph Node vs Full Axillary Dissection on Overall Breast Cancer Survival

better cancer control when metastases were identified in development of a guideline using ACOSOG Z0011 eligibility
sentinel lymph nodes. criteria and age of 50 years or older as indications for
Axillary dissections are associated with considerable SLND alone.20
morbidity, and the results of this trial demonstrated that In a National Cancer Database study of 74 309 patients, Yao
this morbidity can be avoided without decreasing cancer et al21 observed that use of SLND in patients meeting ACOSOG
control. The long-term outcome of this study provides addi- Z0011 eligibility criteria increased from 23% to 56% between
tional support that axillary dissection is not necessary for 2009 and 2011. In that study, age younger than 50 years and a
long-term disease control and survival for patients with triple-negative subtype predicted a greater use of ALND, a prac-
positive sentinel nodes, even for those with generally late- tice neither supported by the reported 5-year outcomes of
recurring hormone receptor–positive tumors. ACOSOG Z0011,9 nor by the findings of the current report. In
In addition, there was no significant difference in ACOSOG Z0011, age was not significantly associated with lo-
disease-free survival between patients treated with SLND coregional recurrence after controlling for other factors.13 Stud-
alone and ALND. This confirms that although distant recur- ies examining the application of findings from ACOSOG Z0011
rence among hormone receptor–positive tumors is a later among young women or among those with triple-negative
event, nodal recurrence among these patients is primarily an breast cancer have found neither a greater need for ALND in
early event. The stability of these results over time is impor- these groups, nor heavier axillary tumor burdens in those un-
tant because patients with hormone receptor–positive breast dergoing ALND.19,22
cancer, who comprise the majority of study participants and The role of nodal irradiation, specifically in ACOSOG
the majority of breast cancer patients in the United States, Z0011 and in the management of patients with node-
are known to be at prolonged risk for disease recurrence. positive breast cancer, is controversial. Although 19% of
Although the annual rate of distant recurrence after patients received prohibited third-field irradiation, nodal
completion of 5 years of endocrine therapy has been irradiation was distributed similarly by treatment group, as
reported to range from 0.9% to 1.5% through year 15 after was omission of irradiation and the use of high–tangent-
diagnosis,12 regional recurrence in the ACOSOG Z0011 (Alli- field irradiation,15 indicating that choice of radiotherapy
ance) trial was rare after either SLND alone or ALND between fields was unlikely to have affected the study outcome. In
years 5 and 10 even though more than 80% of patients had addition, the unplanned analysis showed that no survival
hormone receptor–positive tumors. 13 These findings are differences were observed among patients treated with con-
compatible with those of the International Breast Cancer ventional tangent-field irradiation or nodal-field irradiation.
Study Group in which rates of regional recurrence in patients Since the initial publication of ACOSOG Z0011,9 2 stud-
with estrogen receptor–positive tumors were seen to ies (the MA.20 2 3 and the European Organization for
increase minimally from 5% to 6.2% between years 5 and 10, Research and Treatment of Cancer24 [EORTC] 22922/10925)
with substantially greater increases in the rates of late local examined the role of regional nodal irradiation in patients
(8.8%-11. 2%) and distant rec urrence (23.4%-31.9%) with similar characteristics (T1 or T2 and 1, 2, or 3 axillary
observed.16 nodal metastases) and their findings have caused some25 to
Because the patient characteristics were well balanced, question whether comprehensive nodal irradiation should
any decrease in disease-free survival or overall survival in be routine. In the MA.20 study, 23 patients with node-
the SLND alone group would have been anticipated to occur positive tumors were randomized to axillary dissection or
due to an increase in regional recurrences; however, only a axillary dissection plus extensive postoperative nodal irra-
single regional recurrence was observed in the SLND alone diation, including supraclavicular and internal mammary
group with additional follow-up in the ACOSOG Z0011 (Alli- nodal basins. The EORTC 22922/10925 study24 randomized
ance) trial. Consistent with this finding, the incremental high-risk women postoperatively to whole-breast or chest-
decreases in disease-free survival (3.7% for the SLND alone wall irradiation alone or with regional nodal irradiation.
group and 4.0% for the ALND group) and overall survival These studies, with 10 years of follow-up and 5836 enrolled
(6.2% for the SLND alone group and 8.2% for the ALND patients, demonstrate a very modest 1% to 1.5% decrease in
group) between years 5 and 10 among patients undergoing regional recurrence with nodal irradiation, and no signifi-
either SLND alone or ALND were not meaningfully different. cant difference in overall survival.
In an adjusted analysis, well documented prognostic factors The 10-year rates of overall survival in the SLND alone
such as age, hormone receptor status, tumor size, and the and ALND groups of the ACOSOG Z0011 (Alliance) trial were
use of adjuvant therapy (but not elimination of ALND) were 86.3% and 83.6%, respectively, compared with 82.8% in the
associated with overall survival. nodal irradiation group in MA.20 and 82.3% in EORTC
Although the initial results of the ACOSOG Z0011 study 22922/10925, suggesting that the ACOSOG Z0011 eligibility
generated controversy,17,18 management of women in the criteria identified a population that may not benefit from
United States with sentinel node metastases changed sub- comprehensive nodal irradiation. Thus, although nodal irra-
stantially as a result of the study. Among 701 consecutive diation may be added to the management of some patients
patients with node-positive tumors at Memorial Sloan with node-positive tumors based on an evaluation of their
Kettering Cancer Center who met ACOSOG Z0011 eligibility overall risk profile, the routine use of nodal irradiation for
criteria, 83% did not have to undergo ALND.19 In a 12-hospital all patients with 1 or 2 sentinel node metastases managed
network, use of ALND decreased from 71% to 17% after with SLND alone may not be justified.

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 Effect of Sentinel Lymph Node vs Full Axillary Dissection on Overall Breast Cancer Survival Original Investigation Research

Ten years of follow-up confirm that women with 1 or 2 Limitations

positive sentinel nodes and clinical T1 or T2 tumors under- This study has several limitations. Like most large ran-
going lumpectomy with whole-breast irradiation and sys- domized trials in breast cancer management, not all bio-
temic therapy experience no worse local control, disease- logical subtypes are represented in large numbers. Differ-
free survival, or overall survival with elimination of ALND. ences in outcomes may be seen for patients with different
Application of these findings in clinical practice has the individual circumstances. However, not all biological
potential to avoid the morbidity of ALND without diminu- subtypes can be analyzed for small variations in locore-
tion of survival outcomes in 61% to 83% of women with gional treatment. Furthermore, due to low accrual and
these characteristics.19,26 The routine use of ALND for all the low event rate, the study did not reach the prespecified
patients with positive sentinel nodes is no longer justified sample size of 1900 participants or 500 deaths. In addition,
based on these 10-year overall survival results. some patients had irradiation protocol variations that
However, these conclusions apply only to patients meet- could have resulted in a small alteration of outcomes;
ing ACOSOG Z0011 eligibility criteria and should not be however, these patients were distributed similarly in both
extrapolated to the management of patients with positive study groups.
palpable nodes, those with metastases in more than 2 senti-
nel nodes, patients forgoing whole-breast irradiation, those
treated with mastectomy without radiation, or patients
receiving neoadjuvant therapy because all of these are cir-
Conclusions
cumstances in which the elimination of ALND is not known Among women with T1 or T2 invasive primary breast cancer,
to be safe. The ongoing Positive Sentinel Node-Adjuvant no palpable axillary adenopathy, and 1 or 2 sentinel lymph
Therapy Alone vs Adjuvant Therapy Plus Clearance or nodes containing metastases, 10-year overall survival for
Axillary Radiotherapy trial for women with metastases in 1 or patients treated with sentinel lymph node dissection alone
2 sentinel nodes treated with breast-conserving surgery or was noninferior to overall survival for those treated with axil-
mastectomy will provide important information about the lary lymph node dissection. These findings do not support
safety of omitting ALND after mastectomy, but this study is routine use of axillary lymph node dissection in this patient
not expected to complete accrual until 2018.17 population based on 10-year outcomes.

ARTICLE INFORMATION Kelemen, Ollila, Hansen, Whitworth, Blumencranz, Role of the Funder/Sponsor: The National Cancer
Accepted for Publication: July 28, 2017. Leitch, Saha, Hunt, Morrow. Institute had a role in the design and conduct of the
Drafting of the manuscript: Giuliano, Ballman, study; collection, management, analysis, and
Author Affiliations: Department of Surgery, McCall, Brennan, Morrow. interpretation of the data; preparation, review, or
Cedars-Sinai Medical Center, Los Angeles, California Critical revision of the manuscript for important approval of the manuscript; and decision to submit
(Giuliano); Alliance Statistics and Data Center, Weill intellectual content: All authors. the manuscript for publication. Neither the Alliance
Cornell Medicine/New York–Presbyterian Hospital, Statistical analysis: Ballman, McCall. nor the National Cancer Institute had the right to
New York, New York (Ballman); Alliance Statistics Obtained funding: Giuliano. veto the submission of the manuscript.
and Data Center, Duke University, Durham, North Administrative, technical, or material support:
Carolina (McCall); Dallas Surgical Group, Dallas, Disclaimer: The content is solely the responsibility
Giuliano. of the authors and does not necessarily represent
Texas (Beitsch); Clinical Research Unit/TRIO-US Supervision: Giuliano.
Network, Jonsson Comprehensive Cancer Center, the official views of the National Institutes
University of California, Los Angeles (Brennan); Conflict of Interest Disclosures: The authors have of Health.
Ashikari Breast Center, Dobbs Ferry, New York completed and submitted the ICMJE Form for Meeting Presentation: This study was presented
(Kelemen); Department of Surgery, University of Disclosure of Potential Conflicts of Interest. in part at the American Society of Clinical Oncology
North Carolina, Chapel Hill (Ollila); Department of Dr Giuliano reported receiving travel support from annual meeting; June 3-7, 2016; Chicago, Illinois.
Surgery, Feinberg School of Medicine, the American College of Surgeons Oncology Group
Northwestern University, Chicago, Illinois (Hansen); (ACOSOG) to attend Alliance for Clinical Trials in REFERENCES
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