The use of axillary lymph node dissection

is declining for women with a low volume

of nodal disease.

Photo courtesy of Lisa Scholder. Fetally Free, 28 36.

Evolution of Axillary Nodal Staging in Breast Cancer:

Clinical Implications of the ACOSOG Z0011 Trial
Miraj Shah-Khan, MD, and Judy C. Boughey, MD
Background: Management of the axilla in breast cancer patients has evolved from routine axillary lymph node
dissection (ALND) for all patients to a highly selective approach based on the assessment of the sentinel lymph
nodes (SLNs) as well as tumor and patient characteristics. Although ALND continues to have an important
role in staging and regional control for many breast cancer patients, recent trial results question the need for
routine ALND in patients who have positive SLNs.
Methods: Not all axillary disease becomes clinically detectable or relevant with respect to recurrence and survival.
Therefore, recent trends indicate that many surgeons have omitted ALND in subgroups of patients, particularly
those with clinically node-negative, SLN-positive, early-stage breast cancer undergoing breast-conserving therapy
with postoperative irradiation. This review explores trends in axillary management, focusing primarily on the
clinical implications of the results from the American College of Surgeons Oncology Group (ACOSOG) Z0011
randomized controlled trial.
Results: According to the results of the ACOSOG Z0011 trial, the use of SLN dissection alone did not result
in inferior survival compared with ALND in patients with limited SLN disease treated with breast-conserving
therapy. This subgroup of women was spared the morbidity associated with ALND. However, several points
of debate, including the smaller than anticipated sample size, the older study population, and the length of
follow-up, suggest caution when applying these findings to all women with breast cancer.
Conclusions: Although the findings of ACOSOG Z0011 are impressive, in clinical practice they are applicable
to a limited number of women with breast cancer: those with T1-2 primary tumors with clinically negative
axilla and 1 to 2 positive SLNs undergoing breast-conserving surgery and adjuvant whole-breast irradiation.
The next generation of clinical trials may answer some of the remaining questions regarding how best to manage
the axilla in additional subsets of patients undergoing treatment of breast cancer.

A Historical Surgical Perspective

From the Department of Surgery at the Mayo Clinic, Rochester,
Minnesota.
Submitted December 1, 2011; accepted March 1, 2012.
Address correspondence to Judy C. Boughey, MD, Department of
Surgery, Mayo Clinic, 200 First Street SW, Rochester, MN 55905.
E-mail: boughey.judy@mayo.edu
No significant relationship exists between the authors and the
companies/organizations whose products or services may be referenced in this article.
October 2012, Vol. 19, No. 4

Traditionally, surgical oncologic principles have been

based on obtaining an R0 resection. This principle
led to the development of Halsteds radical mastectomy for treatment of breast cancer.1 Radical mastectomy was predicated on the belief that disease
spreads in an orderly fashion from the breast to the
regional lymph nodes and then to distant sites. Thus,
aggressive local tumor control might prevent systemic
Cancer Control 267

tumor spread and potentially prevent death from

breast cancer.
Alternatively, the hypothesis by Fisher et al2,3
centered on the concept that breast cancer becomes
systemic early in its course, although the systemic
disease may remain subclinical. Thus, the presence
of regional nodal involvement may be a manifestation
of metastatic disease elsewhere, and aggressive local
tumor control may not affect overall survival. This
view represents a pivotal question in breast cancer
management. In accepting the latter hypothesis, the
surgical management of breast cancer has evolved
to develop conservative (less extensive) approaches.
Although several groups have reported their experience with partial mastectomy or breast-conserving
surgery, Fisher et al4 and Veronesi et al5 demonstrated
that breast-conserving surgery followed by irradiation of the primary tumor was a feasible option for
women with early-stage breast cancer in randomized prospective trials. These studies showed that
breast-conserving surgery offered patients equivalent
long-term survival as traditional mastectomy.4,5 Just
as the surgical management of the primary tumor has
evolved, management of the axilla has evolved as well.

The Changing Role of

Axillary Lymph Node Dissection
In 1990, the National Institutes of Health Consensus
Conference concluded that the treatment of potentially curable breast cancer should include levels I and
II axillary lymph node dissection (ALND).6 The need
for routine ALND was challenged by the introduction
of the sentinel lymph node (SLN) biopsy. This concept had a tremendous effect on management of the
axilla. In 1994, Giuliano et al7 demonstrated that the
status of the SLN accurately reflected the status of the
entire axillary basin draining a primary breast tumor.
Since these initial reports, the accuracy of SLN
surgery has been validated by multiple groups, sparing patients with negative sentinel nodes an ALND
and its associated morbidity.8,9 Although risks such
as lymphedema are present with SLN surgery, the
incidence of arm lymphedema is significantly less
than with ALND (7% vs 25%).10-12 The false-negative
rate of SLN biopsy has been demonstrated to be approximately 9.8%,13 and the rate of locoregional tumor
recurrence in patients with negative SLNs who did
not have ALND has ranged from 0.1% to 1.5%.14-17
Smidt et al14 evaluated a series of 439 patients with a
negative SLN. After a median follow-up of 26 months,
axillary tumor recurrence was detected in 2 of 439
patients (0.46%). In addition, a meta-analysis of 3,184
patients with a negative SLN from 13 studies was
performed, with a median follow-up of 21 months.
Axillary tumor recurrence was detected in 8 of these
patients (0.25%).14
In cases of a positive SLN, standard treatment has
been a completion ALND, as outlined by the consensus statement from the American Society of Clinical
268 Cancer Control

Oncology (ASCO) and the National Comprehensive

Cancer Network (NCCN).18,19 These guidelines stem
from a meta-analysis of 69 trials including 8,059 patients who underwent SLN biopsy and subsequent
ALND. The results demonstrated that 53% of patients
with a positive SLN were found to have disease in
non-SLNs.20
The incidence of non-SLN involvement changes
considerably with the extent of disease in the SLN.
For patients whose SLN was involved by macrometastatic disease (tumor metastases greater than 2 mm),
the incidence of non-SLN involvement is reported to
be 40% to 58%.21 When the SLN is involved by micrometastatic disease (nodal metastasis 0.2 to 2 mm),
the incidence of non-SLN involvement is 20%,22 and
in the case of the SLN with isolated tumor cells ( 0.2
mm), the incidence decreases to 12%.23
Factors that influence the degree of non-SLN involvement are tumor histology and grade, primary
tumor size, multifocality, lymphovascular invasion,
estrogen receptor (ER) status, and the ratio of positive SLNs to the total number of sentinel nodes removed.24-26 These findings have been important components in the developing trend of forgoing ALND
in certain patients, particularly those thought to be
at a lower likelihood of having additional disease
in the non-SLNs. The American Society of Breast
Surgeons issued a consensus statement in 2005 acknowledging this trend27: Outside of clinical trials,
usual treatment for SLN-positive patients is a level I-II
ALND. However, since axillary node metastases are
limited to the SLN in more than half of SLN-positive
individuals, there may be low-risk subsets for whom
a completion ALND is not required. The decision to
omit completion axillary dissection in such a case
requires a balanced discussion between the surgeon
and the patient regarding the risks of further surgery
and any potential for improved outcome with more
complete information and/or axillary clearance.
The American College of Surgeons Oncology
Group (ACOSOG) Z0011 study28,29 was a practicechanging trial that questioned the need for completion
ALND in patients with early-stage disease undergoing breast conservation who were found to be SLNpositive. The study concept considered a number
of factors, including the overall change in the extent
of disease on initial presentation, the changes in the
recommendations for adjuvant therapy based more
heavily on primary tumor characteristics, and the demonstration of a low incidence of positive non-SLNs.29
As previously discussed, the SLN has been demonstrated to be the only positive lymph node in many
cases. Data from high-volume breast centers indicate
that the SLN is the only site of nodal metastasis in
40% to 60% of axillary dissections.30 Veronesi et al31
reported on a series of 376 patients who underwent
SLN surgery and subsequent ALND. In 73 of 168 patients with a positive SLN (44%), the SLN was the only
site of metastatic disease. In a series of 443 patients
October 2012, Vol. 19, No. 4

undergoing SLN and ALND, Krag et al32 noted a 97%

accuracy in identifying the SLNs. In this group, 95
patients had 1 to 3 positive SLNs, and the SLN was
the only positive node in 62% of cases. Similarly,
Giuliano et al33 reported a study of 107 patients who
underwent SLN surgery and subsequent axillary dissection. Forty-two patients were found to have positive SLNs, and in 67% of cases, the SLN was the only
site of metastatic disease.
These findings may reflect a trend in identifying
disease at an earlier stage and therefore at a lower
nodal tumor burden. Expanded use of screening
and increased awareness of breast cancers have led
to a decreased size of primary tumors at presentation. Cady et al34 reported that the mean maximum
diameter of breast cancers at diagnosis was 3 cm
from 1979 to 1983 and 2 cm from 1989 to 1993. This
downward trend in the size of tumors at presentation,
coupled with the high incidence of SLN-only positive
axillary disease, suggests that adequate local tumor
control and staging in early-stage breast cancer may
be accomplished by treating the primary tumor and
removing the SLNs.
ALND has been associated with significant morbidity compared with SLN biopsy alone; the risk
of lymphedema reported with SLN biopsy is 2% to
7% compared with a lifetime risk of lymphedema
with ALND of 25%.10,35,36 Lucci et al12 compared the
postoperative complication rate of women undergoing SLN vs SLN and ALND in the ACOSOG Z0011
study. They found that women in the ALND group
had a significantly greater incidence of postoperative
complications than did the SLN-only group (70% vs
25%). Complications included wound infection, axillary seromas, axillary paresthesias, brachial plexus
injury, and lymphedema. As reported subjectively by
study participants, the development of lymphedema
was 13% at 1 year in the ALND group vs 2% in the
SLN-only group.

Trends to Omit ALND

The use of completion ALND in patients with positive SLNs was decreasing prior to the presentation of
the results of the ACOSOG Z0011 trial. This trend
was evaluated retrospectively in a number of studies. Bilimoria et al37 reviewed patients from the National Cancer Data Base (NCDB) between 1998 and
2005. The 97,314 patients identified were clinically
node-negative and found to have nodal metastasis on SLN biopsy. Approximately 20.8% of these
node-positive patients underwent SLN biopsy alone
without completion ALND. From 1998 to 2005, the
proportion of patients who underwent SLN biopsy
alone for macroscopic disease declined from 24.2%
to 16.7%. However, the proportion of patients who
underwent SLN biopsy alone for micrometastatic disease increased from 24.7% to 45.3%. Patients who
underwent SLN biopsy alone were older (mean age,
58 vs 56 years), had lower-grade disease (58.8% grade
October 2012, Vol. 19, No. 4

I/II vs 32.5% grade III), had a smaller tumor size (1.8

vs 2.1 cm), and were undergoing breast-conserving
surgery (81%). In this retrospective review, axillary
recurrence and survival data were obtained for the
cohort of patients diagnosed between 1998 and 2000.
No significant difference was detected with respect
to axillary tumor recurrence or survival between the
patients undergoing SLN alone and those undergoing
SLN and completion ALND, with a median follow-up
of 63 months.
Yi et al38 reviewed patients from the Surveillance,
Epidemiology, and End Results (SEER) database from
1998 to 2004. A total of 26,986 patients with breast
cancer underwent SLN biopsy and were found to have
nodal metastasis. Of these patients with a positive
SLN, 4,425 (16.4 %) underwent SLN biopsy alone, and
22,561 (83.6%) underwent ALND. When the investigators evaluated the trend of patients undergoing SLN
biopsy alone, there was a difference among patients
who had micrometastatic vs macrometastatic disease.
From 1998 to 2004, the proportion of patients with
micrometastases who underwent SLN biopsy alone
increased from 21% to 38%. However, in patients with
macrometastasis, the proportion of patients who underwent SLN biopsy alone increased (5.7% to 13.1%)
from 1998 to 2002 and then decreased slightly (13.1%
to 10.6%) from 2002 to 2004.
Similar to the NCDB report, the cohort of patients
who underwent SLN biopsy alone in the SEER report
were older (59 vs 56 years of age), had a smaller tumor size (16 vs 20 mm), or had lower-grade tumors
(21% grade I or II vs 13% grade III). Also, the majority of patients who had SLN biopsy alone underwent
breast-conserving surgery (78.8%). This trend may
reflect the increased comfort of physicians to forgo
completion ALND in patients who are candidates for
postoperative radiotherapy. The authors noted that
patients with micrometastasis had no difference in
ipsilateral regional events among the groups. Patients
with macrometastasis who underwent SLN biopsy
with ALND had a lower risk of ipsilateral regional
events than did those who underwent SLN biopsy
alone (0.08% vs 0.2%; P = .02). However, no significant difference in survival was noted between the two
groups at 50 months.
One of the factors that may have influenced the
decrease in completion ALND for SLN-positive disease
after the year 2000 may be the availability of online
nomograms to predict non-SLN involvement. Currently, several nomograms have been developed to predict
non-SLN involvement for patients with SLN-positive
disease. The Memorial Sloan-Kettering Cancer Center
(MSKCC) online nomogram,39 which has been externally validated, is one of the most commonly used.40-42
Other available nomograms have been developed at
the Mayo Clinic, MD Anderson Cancer Center, and
Stanford University.40,43,44 The MSKCC nomogram is
an online calculator that provides a risk estimate of
non-SLN metastasis based on 9 histopathological variCancer Control 269

ables: frozen section analysis, primary tumor size, primary tumor type (ductal/lobular) and nuclear grade,
number of positive SLNs, number of negative SLNs,
method of SLN detection (routine hematoxylin and
eosin [H&E], serial H&E, or immunohistochemistry
[IHC]), presence of lymphovascular invasion, multifocality, and ER positivity (greater than 10%).
Park et al26 reported on a group of patients from
MSKCC in which 1,960 patients with positive SLNs
were evaluated from 1997 to 2004. A total of 287
patients (15%) did not undergo completion ALND.
In concordance with the aforementioned studies,
these patients were older and had more favorable
tumors, and the majority underwent breast-conserving
therapy. In addition, the median nomogram scores
were significantly different between the groups (9%
vs 37%), indicating a selection bias in the use of
ALND for SLN-positive patients with a higher prediction of non-SLN disease. Eighty-six percent of
patients forgoing ALND had nomogram scores of
20%, whereas 74% of patients undergoing ALND had
nomogram scores of > 20%. The authors pointed out
that the prediction nomogram became fully utilized
in their practice in 2003. When evaluating the prevs post-nomogram trends, the proportion of patients
not undergoing completion ALND for SLN metastasis
increased from 31% from 1997 to 2002 to 38% from
2004 to 2005. The limitation of information obtained
from retrospective reviews such as inherent selection
bias due to lack of randomization highlights the need
for a prospective randomized trial addressing the
question of completion ALND.

The Inception of the ACOSOG Z0011 Trial

The aim of the ACOSOG Z0011 study was to examine
the impact of ALND on regional control and survival
in women with early-stage breast cancer undergoing
breast-conserving therapy. The goal was to identify
whether ALND can be safely omitted in women with
early-stage disease. The hypothesis of the trial was
that patients with H&E-detected metastases in the SLN
would have similar outcomes with completion ALND
and SLN biopsy alone.28
Eligibility criteria included age older than 18 years
and clinical T1 or T2, N0, M0 invasive breast cancer
in women electing to undergo breast-conserving surgery. Patients had to have tumors that were 5 cm
or smaller on clinical examination and imaging and
were clinically node negative (ie, without palpable
lymphadenopathy). Patients underwent lumpectomy
and SLN biopsy. Those found to have 1 or 2 positive
SLNs were randomized to receive either no additional
axillary surgery (SLN-only group) or completion ALND
(SLN plus ALND group). All patients were required
to have negative margins for the lumpectomy specimen and were to undergo whole-breast irradiation
following surgery. The trial recommended 45 to 50
Gy of breast radiation, in fractions of 1.8 to 2.0 Gy per
day delivered via tangential fields without third-field
270 Cancer Control

axillary radiation. Patients underwent systemic adjuvant therapy at the discretion of the treating medical
oncologist as indicated. Patients excluded from the
study were those with known node-positive disease
prior to surgery, patients with 3 or more positive
nodes, and patients with SLN metastases identified
on IHC only.
The trial was activated in May 1999, with a planned
target accrual of 1,900 patients. Due to slow accrual
and, more importantly, the low event rate in both
groups, recruitment was closed in December 2004,
with a total of 891 patients enrolled.28 The number
of patients who ultimately received treatment in the
study were 388 patients in arm 1 (completion ALND)
and 425 patients in arm 2 (SLN alone). Patients were
stratified with respect to age (younger or older than
50 years), ER status, and tumor size (< 1 cm, 1 to 2
cm, or > 2 cm). The median age of patients enrolled
was 56 and 54 years for arms 1 and 2, respectively.
Patients older than 50 years comprised 67.4% of those
in arm 1 and 62.6% of those in arm 2. The majority of
tumors were T1 (67.1% and 70.5%), infiltrating ductal
type (82.1% and 84%), and ER+ (82.2% and 82.8%)
for arms 1 and 2, respectively.
Patients randomized to arm 1 had a median of 17
nodes removed compared with a median of 2 nodes
removed in the SLN-only group. The median number
of positive nodes in both groups was 1. A total of 41%
of SLNs were determined to have micrometastases
( 2 mm) or isolated tumor cells. It is important to
note the differences in tumor burden between the two
groups. The percentage of SLN micrometastasis was
37.5% in the ALND group vs 44.8% in the SLN-only
group, with this difference being statistically significant (P = .05). This finding suggests that patients in
the SLN-only group may have had a more favorable
tumor burden. Comparison of the two groups at 6.3
years of follow-up revealed no difference in the rate
of axillary tumor recurrence (0.5% vs 0.9% for arms
1 and 2, respectively), in-breast recurrence (3.6% vs
1.9%), or overall locoregional tumor recurrence (4.1%
vs 2.8%). The 5-year disease-free survival rates were
82.2% in the ALND group and 83.9% in the SLN-only
group, and 5-year overall survival rates were 91.8%
and 92.5%, respectively.
By intent-to-treat analysis, adjuvant systemic therapy was delivered to 403 patients in the ALND group
(96%) and 423 in the SLN-only arm (97%). Hormonal
therapy was given to 195 patients in the ALND group
(46.4%) compared with 203 patients in the SLN-only
arm (46.6%). Chemotherapy was administered to 243
patients in the ALND arm (57.9%) and 253 patients in
the SLN-only arm (58%). Locoregional tumor recurrence was 3.4% in patients who received adjuvant
systemic therapy and 3.3% in those who did not.
The trial recommended whole-breast radiation be
administered to all patients; however, all patients did
not undergo adjuvant radiation therapy. Whole-breast
radiation was administered to 88.9% of patients in
October 2012, Vol. 19, No. 4

the ALND group and 89.6% of patients in the SLNonly group. In the group of patients who underwent
ALND, 27% had additional nodal metastasis identified
on histopathological assessment of the axillary contents. Ten percent of patients with micrometastasis on
SLN biopsy who underwent ALND had additional involved nodes removed. We may presume that a similar
number of patients in the SLN-only arm had residual
non-SLN metastasis. However, this conclusion may
not be entirely accurate, as a greater percentage of the
SLN-only cohort had micrometastasis and patients with
micrometastasis had lower rates of additional nodal
metastasis. Failure to stratify patients based on the
size of SLN metastasis is a limitation of this trial. The
axillary tumor recurrence rate for this arm was less
than 1% at 6.3 years. Although subclinical disease may
have been treated by adjuvant systemic therapy and
irradiation, this finding suggests that not all non-SLN
metastasis develops into clinically detectable disease.
Removing additional involved nodes with an axillary
dissection in this group of patients did not improve
locoregional tumor recurrence or overall survival.

Supporting Data From Other Clinical Trials

The recently reported update by Galimberti et al45 of
the International Breast Cancer Study Group (IBCSG)
trial 23-01 sheds light on the issue of ALND in patients
with SLN micrometastasis. The study was a randomized, multicenter, phase III clinical trial comparing
axillary dissection with no axillary dissection in patients with micrometastasis in the SLN. A total of 934
patients were randomized: about half to ALND and
the other half to SLN only. Patients were clinically
node-negative, had a primary tumor < 5 cm, and had
a minimal (< 2 mm) tumor burden in 1 to 2 SLNs.
The majority of patients (67%) had tumors < 2 cm,
and 89% were ER+. Disease-free survival was the
studys primary endpoint, and overall survival and
systemic disease-free survival were secondary endpoints. The 5-year disease-free survival and overall
survival rates in the ALND vs SLN-only groups were
87.3% vs 88.4% (P = .48) and 97.6% vs 98% (P = .35),
respectively. Of note, 25% of patients included in this
study underwent mastectomy.
The fact that R0 resection to remove all positive
lymph nodes may not be required and does not affect
overall survival is not a new idea. The National Surgical Adjuvant Breast and Bowel Project (NSABP) B-04
study provided insight into the natural progression
of axillary disease and the clinical consequences of
axillary nontreatment.2 In this study, clinically nodenegative patients were randomized to undergo total
mastectomy with ALND (n = 354), total mastectomy
with regional irradiation (n = 282), or total mastectomy alone (no treatment to the axilla, n = 344). The
total mastectomy-alone arm provides information on
the consequences of no treatment to the axilla, neither
surgery nor irradiation, and no systemic therapy. Of
note, 40% of patients randomized to undergo total
October 2012, Vol. 19, No. 4

mastectomy with axillary dissection were found to

have positive axillary lymph nodes on final pathology
review. This finding indicates that the mastectomy-only arm also had a similarly high percentage of lymphnode positivity, even though they were clinically N0.
Of the patients in the mastectomy-only arm, 18.6%
presented with clinically palpable axillary nodes on
follow-up and underwent delayed ALND. This study
result is remarkable in that it is less than half the
presumed number of patients with subclinical positive nodes. After assessing for these salvage axillary
surgeries, no significant difference in the rates of
uncontrolled regional tumor recurrence and overall
survival among these clinically node-negative patients
was demonstrated, with a 25-year follow-up.3 These
results support Fishers concept that the biology of
breast cancer will dictate its disease progression, as
opposed to the mere presence of nodal involvement.

Controversies Surrounding the

ACOSOG Z0011 Trial
Several points of debate about the ACOSOG Z0011
trial have been explored: the smaller than anticipated sample size and the low event rate; the older
(> 50 years) study population (raising the question
of applicability to younger women); the largely ER+
study population (again raising the question of applicability to women with ER or HER-2+ tumors);
the applicability to invasive lobular carcinoma, which
comprised a minority of the study cohort; and the
length of follow-up.
The planned target accrual for the ACOSOG
Z0011 trial was 1,900 patients, as previously mentioned. This number was calculated using a prediction of overall survival rate of 80% at 5 years for
women with optimally treated node-positive breast
cancer, and clinical noninferiority was defined as the
SLN-only group having a 5-year survival rate of not
less than 75% of that observed in the ALND group.
An estimated 500 deaths were needed for the study
to have 90% power to confirm noninferiority of SLN
alone compared with ALND.
The first patient was enrolled in May 1999. Due
to the low mortality rate observed, the ACOSOG Data
and Safety Monitoring Committee closed the study to
new patients in December 2004.28 Even if the trial
had accrued the target 1,900 patients, it would have
taken more than 20 years of follow-up to observe 500
deaths due to the slower-than-predicted event rate.
No preliminary analysis had been performed at the
time of closure of the study.
It could be argued that the information obtained
from the study is limited, based on a smaller sample
size than anticipated and a low event rate. At a median follow-up of 6.3 years, there were 94 deaths: 42
in the SLN-alone group and 52 in the ALND group.
Despite the low event rate and significantly lower
number of patients enrolled than expected, the study
authors maintain that the predefined statistical analyCancer Control 271

sis plan was able to demonstrate the noninferiority

of SLN biopsy alone for overall survival, with a P
value of .008.46
The majority of women in the ACOSOG Z0011
study were older than 50 years. In the multivariate
analysis, tumor grade and patient age were associated with locoregional tumor recurrence in either arm.
Upon closer evaluation, the majority of locoregional
tumor recurrences in young women were in-breast
recurrences as opposed to nodal recurrences.46 In
patients younger than age 50, the SLN-only group experienced 5 locoregional recurrence events: 4 in the
breast and 1 nodal. The ALND group had 11 locoregional recurrence events: 9 in the breast and 2 nodal.
The tendency of young women to have a higher
rate of in-breast tumor recurrence has been demonstrated in previous reports.47,48 One retrospective
review evaluating 3,064 patients who underwent
breast-conserving therapy demonstrated that age < 40
years was an independent risk factor for local tumor
recurrence.48 Based on the fact that the observed locoregional tumor recurrences in women younger than
age 50 were primarily breast recurrences as opposed
to nodal recurrences, the authors of ACOSOG Z0011
maintain that the study does not provide evidence
that young women have a higher rate of nodal tumor
recurrence.46 However, as the majority of women
enrolled in the study were older than age 50, the findings may not be widely applicable to younger women.
Another question raised about the ACOSOG
Z0011 data is their applicability to subgroups of patients with tumors who are ER or HER-2/neu+. The
development and use of targeted adjuvant endocrine
therapy have been demonstrated to significantly reduce the rate of locoregional tumor recurrence as
well as improve the rates of disease-free survival and
overall survival in women with ER+ tumors.49-51 The
remarkably low locoregional tumor recurrence rate
reported in the ACOSOG Z0011 trial is in part due
to the use of targeted adjuvant therapy, which likely
treats subclinical disease in the axillary nodal basin.
According to the multivariate analysis in the ACOSOG
Z0011 trial, there was no difference in the rate of
locoregional tumor recurrence in patients who had
ER vs ER+ tumors. However, only 16% of patients
in each arm were ER, which raises the question of
whether these results can be extrapolated to patients
with ER disease.
Information with respect to HER-2 status was
not included within the study design. When the trial
opened in 1999, routine testing of HER-2 was not uniformly practiced. Tumors that express HER-2 tend to
be more aggressive.52 However, patients with HER-2+
tumors may benefit from the use of targeted adjuvant
therapy such as trastuzumab (Herceptin). In randomized controlled trials, the use of adjuvant trastuzumab
has been demonstrated to improve the disease-free
and overall survival rates in patients with HER-2+
breast cancer.53,54 Thus, HER-2 positivity may not be a
272 Cancer Control

reason to omit or proceed with ALND but rather must

be weighed along with the rest of the data available
for a patient.55 The findings of ACOSOG Z0011 may
not apply to patients who have not had the benefit of
targeted adjuvant therapy, such as those with triplenegative disease. However, the authors suggest that
although the prognosis of patients with triple-negative
breast cancer is poor, these tumors are less likely to
metastasize to lymph nodes,56 and thus their prognosis
may not rely on a heavy nodal burden.46
A subset of patients not clearly defined in the
ACOSOG Z0011 study consists of those with invasive
lobular carcinoma. These patients represented only
7% of the trial population. The concern with evaluation of SLNs in patients with lobular histology is that
these tumors are more likely to have multiple smaller
foci of disease and isolated tumor cells in the SLN,
which may not be detected by standard H&E analysis.
These nodal metastases may require IHC for detection.57 Although isolated tumor cells represent a low
tumor burden, they may have clinical relevance undetected in this study. This factor must be taken into
consideration when evaluating patients with invasive
lobular carcinoma with respect to performing ALND.55
Routine IHC analysis of SLNs has not been supported by ASCO or the College of American Pathologists and was abandoned by many institutions after
the data from ACOSOG Z0010 and NSABP B-32 were
reported.13,35 The ACOSOG Z0010 observational study
sought to determine the association between metastases detected by IHC staining of SLNs and bone
marrow specimens from patients with early-stage
breast cancer and survival. Of the 3,326 SLN specimens that were negative by H&E staining, 10.5% were
found to be positive for metastasis on IHC. There was
no significant difference in overall survival between
patients with IHC-negative disease compared with
IHC-positive disease (95.7% vs 95.1%; P =.64). NSABP
B-32, which randomized clinically node-negative
breast cancer patients to receive SLN alone or SLN
plus ALND, identified lymph node metastases by IHC
in 15.9% of patients who were SLN-negative on H&E
staining. The absolute difference in overall survival
between IHC-positive and IHC-negative patients was
1.2% (94.6% vs 95.8%; P = .03).
Another issue regarding the validity of the data
from ACOSOG Z0011 is related to the length of followup for the enrolled patients and whether it is adequate
for assessing recurrence and survival.46 We looked at
previous studies to answer this question. In NSABP
B-04, the median time to axillary tumor recurrence
was 14.8 months in clinically node-negative women
who did not undergo ALND. At 5 years, the rate of
tumor recurrence was 16.2% (55 of 344 patients). On
10-year follow-up evaluation, 75% of patients who
remained free of disease at the end of 5 years continued to be free of disease.58 Similarly, with respect to
overall survival, about 75% of patients with negative
nodes who were alive at 5 years remained alive at 10
October 2012, Vol. 19, No. 4

years. Additionally, there was no significant difference

between overall survival among the 3 node-negative
groups over the entire follow-up. At 10 years, overall
survival was 58% for the radical mastectomy group,
59% for patients treated with total mastectomy plus
irradiation, and 54% for those undergoing total mastectomy alone. Furthermore, there was no difference
in disease-free, distant relapse-free, or overall survival
rates among these groups at 25 years.
Greco et al59 evaluated a series of 401 breast cancer patients prospectively. Patients had tumors up
to 3 cm and clinically negative axilla. A total of 383
patients underwent quadrantectomy with no axillary
dissection. Of these patients, 67% received postoperative adjuvant radiation therapy. The median time to
axillary tumor recurrence was 30.6 months.
Martelli et al60 reported on a group of 671 patients
over the age of 70 with clinically node-negative axilla who underwent breast-conserving therapy with
or without axillary dissection (172 patients vs 499
patients). All patients received adjuvant tamoxifen
therapy for at least 2 years. The median time from
primary surgery to axillary tumor recurrence was 33
months. Upon 15-year follow-up, 90% of patients
who developed axillary disease did so within 6 years
of surgery. With respect to survival, there was no
advantage to axillary dissection in terms of breast
cancer mortality.
Grills et al61 demonstrated that in a group of 568
node-positive, ER+ patients treated with breast-conserving therapy or axillary dissection, with or without nodal irradiation, the incidence of nodal tumor
recurrence increased only slightly after 5 years. Thus,
based on data available from reported studies, the
ACOSOG investigators maintain that a follow-up of
6.3 years is sufficient to capture the majority of axillary tumor recurrences.46

Whole-Breast Radiation Fields and

Management of the Axilla
The ACOSOG Z0011 trial recommended whole-breast
radiation therapy without the addition of a third field
to treat the axilla. The standard technique of wholebreast radiation therapy applied to breast cancer
patients following breast-conserving therapy is the
two-portal opposed tangential approach. In addition to radiating all the breast tissue, this technique
applies radiation to some extent to the low-lying axillary lymph nodes. When treating high-risk patients,
some radiation oncologists advocate the use of high
tangential fields to improve axillary coverage.62
Data from Reznik et al62 demonstrated that the
average doses of radiation delivered to axillary levels
1, 2, and 3 with tangential fields are 66%, 44%, and
31% of the prescribed dose, respectively. With these
normal tangents, 51% of level 1 and 26% of level 2
axillary nodes receive 95% of the prescribed dose.
With minor variation in the field design, radiation can
be delivered via high tangential fields. This technique
October 2012, Vol. 19, No. 4

achieves almost complete axillary coverage by field

edge at least extending the superior field border to
within 2 cm of the humeral head and by setting the
deep field edge at least 2 cm posterior to the lung/
chest wall interface.63 In this scenario, 79%, 51%, and
49% of levels I, II, and III receive 95% of the therapeutic dose, respectively.
A limitation of the ACOSOG Z0011 trial is that
data concerning features of the field design were not
captured for patients enrolled in the study. In addition, all patients did not undergo whole-breast radiation therapy as planned. As previously discussed,
88.9% of patients in the ALND group and 89.6% of
patients in the SLN-alone group underwent adjuvant
radiation therapy. Due to the potentially therapeutic
effect of tangential field radiation on the axilla, the
fact that this was not standardized among patients
enrolled raises questions regarding the radiation fields
for these patients. Therefore, when incorporating
ACOSOG Z0011 results into clinical practice, radiation
oncologists may question whether tangents should be
raised to direct radiation to the axilla.
The delivery of radiation to the axilla for treatment of nodal disease is not novel. Gadd et al64 evaluated the outcome of patients with a positive SLN who
underwent axillary radiation therapy in lieu of ALND.
The study included 73 patients with clinically T1-2 N0
disease who underwent breast-conserving therapy
with a finding of a positive SLN. These patients underwent adjuvant axillary radiation therapy as well as
systemic therapy. Of the 73 patients, 1.4% developed
an axillary tumor recurrence, with a median follow-up
of 32 months. Although this study did not compare
ALND and axillary radiation therapy, it does suggest
that radiation therapy may be an acceptable alternative to ALND in a subset of patients with early-stage
disease. However, the data from this study have been
published only in abstract format.
This topic is being addressed further in a prospective randomized study by the European Organisation for Research and Treatment of Cancer (EORTC)
in the AMAROS (After Mapping of the Axilla: Radiotherapy or Surgery) trial.65 The AMAROS trial
is a phase III study comparing ALND with axillary
radiation therapy in patients with proven axillary
metastasis by SLN biopsy. The main objective of the
trial is to prove equivalent locoregional tumor control
and reduced morbidity for axillary radiation therapy.
This study will evaluate the axillary recurrence rate as
the primary outcome measure. Secondary outcome
measures include axillary recurrence-free survival,
disease-free survival, overall survival, and qualityof-life measures.
The recently reported results from the NCIC-CTG
MA.20 intergroup trial of regional nodal irradiation
in early breast cancer have raised the question of additional nodal radiation therapy for high-risk patients
undergoing breast-conserving therapy and wholebreast irradiation.66,67 The hypothesis for this trial
Cancer Control 273

was that adding regional nodal radiation therapy may

improve survival compared with breast-alone irradiation after breast-conserving therapy and systemic
therapy. The concern with extending the radiation
volume is that it may increase the risk of adverse
side effects, such as pneumonitis, lymphedema, and
cardiac disease (particularly after anthracycline-based
chemotherapy). This study included patients who
underwent breast-conserving therapy with ALND.
Patients were eligible for additional nodal radiation
therapy if they had involved nodes. If the nodes were
negative, they were eligible if the primary tumor was
> 2 cm, if they had < 10 nodes retrieved during ALND,
or if they had either grade 3 histology, an ER tumor,
or the presence of lymphovascular tumor invasion.
The 1,832 women were randomized to receive
either whole-breast and regional nodal radiation
therapy or standard whole-breast irradiation. The
whole-breast and regional nodal radiation group experienced improved isolated locoregional disease-free
survival (96.8% vs 94.5%; P = .02), improved distant
disease-free survival (92.4% vs 87.0%; P = .002), and
a trend toward improved overall survival (92.3% vs
90.7%; P = .07) at 5 years. The whole-breast and
regional nodal irradiation group also experienced
an increase in pneumonitis (1.3% vs 0.2%; P = .01)
and lymphedema (7.3% vs 4.1%; P = .004) over the
standard whole-breast radiation group.

Although the findings of ACOSOG Z0011 are impressive, in practice we must remember that the data
are applicable to a limited number of cancer patients:
those with T1-2 primary tumors with clinically negative axilla and 1 to 2 positive SLN(s) who underwent
breast-conserving surgery and adjuvant whole-breast
irradiation. The majority of patients were older and
had invasive ductal carcinoma, ER+ disease, and a
low nodal tumor volume. This patient cohort does
not represent the breadth of patients who present
with breast cancer. Surgeons must use discretion
when applying these data to younger patients or to
those with invasive lobular carcinoma, ER, and HER2+ disease. The trial did not address (and therefore
should not be translated to) patients with early-stage
disease who elect mastectomy, patients undergoing
neoadjuvant chemotherapy, or patients who may be
receiving partial-breast radiation therapy, intraoperative radiation therapy, or whole-breast irradiation in
the prone position.68 Additionally, these data cannot
be extrapolated to advise axillary radiation therapy in
lieu of ALND. For patients with known positive lymph
node metastasis preoperatively, those with palpable
adenopathy, and those with more than 2 positive SLNs
or lymph nodes with extracapsular tumor extension,
ALND should be recommended.
Although nodal staging has become less invasive
for more women, ALND still plays an important role
for regional tumor control and staging for many breast

Conclusions
Management of the axilla in breast cancer patients has
evolved over the past several decades. We have transitioned from the era of performing routine axillary
lymph node dissection (ALND) on all breast cancer
patients to identifying patients who need ALND based
on results from sentinel lymph node (SLN) biopsy
(Table). In doing so, many patients have been spared
the morbidity associated with ALND. Currently, the
approach to the axilla has become even more selective, as the choice of ALND may be based not only on
the SLN result but also on tumor and patient characteristics. Evaluation of the SLN has also evolved, as
data from recent trials support abandoning the routine
use of IHC to identify occult metastasis.
The findings from the ACOSOG Z0011 trial are
practice-changing, and they evoke the principle demonstrated in NSABP B-04: not all axillary disease
becomes clinically detectable or relevant with respect
to recurrence and survival. The recurrence and survival rates demonstrated in ACOSOG Z0011 are far
superior to those in NSABP B-04, representing the
evolution of breast cancer care received by contemporary women. These improved outcomes can be
explained by improvements in screening and imaging, which have led to more women presenting with
earlier-stage disease. In addition, improved pathological analysis, targeted adjuvant systemic therapy,
and radiation therapy have improved locoregional
tumor recurrence and overall survival.
274 Cancer Control

Table. Guidelines for Management of Sentinel Lymph Node Findings

Biopsy Results

Guidelines

Negative sentinel lymph node(s)

No further axillary surgery required.

ALND may be omitted.

Positive lymph node at presentation

(proven by FNA or core needle biopsy)

ALND should be performed.

Positive sentinel lymph node(s)

1 or 2 positive sentinel lymph nodes

ALND may be omitted if:

Primary tumor 5 cm
Clinically negative axilla
Successful breast conservation
Will receive whole-breast
radiation therapy and likely
systemic therapy
ACOSOG Z0011 data do not apply to
the following patients:
Those undergoing mastectomy
Those receiving neoadjuvant
chemotherapy
Those receiving partial-breast
radiation therapy or radiation
therapy in the prone position
For these patients, the standard of
care is completion ALND.

3 or more positive
sentinel lymph nodes

Completion ALND should

be performed.

ALND = axillary lymph node dissection, FNA = fine-needle aspiration.

October 2012, Vol. 19, No. 4

cancer patients. As the understanding of breast cancer biology deepens and adjuvant therapies become
more effective, more individualized treatment via a
multidisciplinary approach is possible. Important
questions with regard to management of the axilla
in additional subsets of patients may be answered in
the future, with the next generation of trials. These
trials may include patients undergoing mastectomy,
neoadjuvant chemotherapy, axillary radiation therapy,
or partial-breast irradiation.
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