Breastcancerchoices.org |
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| Scrutinizing the evidence for breast cancer procedures and treatments |
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Previous Report JUNE 2010 NY TIMES Read Article Lymph Node Dissection Provides No Benefit to Lumpectomy Patients Some 82.2 percent of the women who had the dissection were alive and disease free compared with 83.8 percent of those who did not. Cancer recurred in the breast or nearby in 4.3 percent of those who had the operation and 3.4 percent in those who did not. |
Patients had more distant recurrences with axillary dissection. excerpt from full text To the surprise of most, Fisher's study of 1700 patients failed to reveal any statistically significant survival advantage for patients undergoing ELND. Although the lymph node dissection group experienced fewer recurrences in the treated lymph node basin, this improvement in local control did not translate to a benefit in overall survival. In fact, when these patients did have recurrences, these were more likely to be distant disease. Since Fisher's landmark study, five RCTs evaluating ELND in breast cancer patients have failed to reveal a statistically significant survival advantage for patients treated with ELND.[16] The lack of evidence supporting the value of ELND for breast cancer patients in these five trials raised significant questions regarding the dogmatic but unproven traditional approach to surgical management in patients with cancer. |
Axillary Dissection vs No Axillary Dissection in Women With
Invasive Breast Cancer and Sentinel Node Metastasis: A
Randomized Clinical Trial Go to JAMA website with graphics
Journal of the American Medical Association
February 9, 2011, Vol 305, No. 6, pp 535-634
Armando E. Giuliano, MD; Kelly K. Hunt, MD; Karla V. Ballman, PhD; Peter D. Beitsch, MD; Pat
W. Whitworth, MD; Peter W. Blumencranz, MD; A. Marilyn Leitch, MD; Sukamal Saha, MD; Linda
M. McCall, MS; Monica Morrow, MD
Author Affiliations: John Wayne Cancer Institute at Saint John’s Health Center, Santa Monica,
California (Dr Giuliano); M. D. Anderson Cancer Center, Houston, Texas (Dr Hunt); Mayo Clinic
Rochester, Rochester, Minnesota (Dr Ballman); Dallas Surgical Group, Dallas, Texas (Dr
Beitsch); Nashville Breast Center, Nashville, Tennessee (Dr Whitworth); Morton Plant Hospital,
Clearwater, Florida (Dr Blumencranz); University of Texas Southwestern Medical Center, Dallas
(Dr Leitch); McLaren Regional Medical Center, Michigan State University, Flint (Dr Saha);
American College of Surgeons Oncology Group, Durham, North Carolina (Ms McCall); and
Memorial Sloan-Kettering Cancer Center, New York, New York (Dr Morrow).
Corresponding Author: Armando E. Giuliano, MD, John Wayne Cancer Institute at Saint John’s
Health Center, 2200 Santa Monica Blvd, Santa Monica, CA 90404 (giulianoa@jwci.org).
Abstract
Sentinel lymph node dissection (SLND) accurately identifies nodal metastasis of early breast
cancer, but it is not clear whether further nodal dissection affects survival.
Objective To determine the effects of complete axillary lymph node dissection (ALND) on survival
of patients with sentinel lymph node (SLN) metastasis of breast cancer.
Design, Setting, and Patients
The American College of Surgeons Oncology Group Z0011 trial, a phase 3 noninferiority trial
conducted at 115 sites and enrolling patients from May 1999 to December 2004. Patients were
women with clinical T1-T2 invasive breast cancer, no palpable adenopathy, and 1 to 2 SLNs
containing metastases identified by frozen section, touch preparation, or hematoxylin-eosin
staining on permanent section. Targeted enrollment was 1900 women with final analysis after
500 deaths, but the trial closed early because mortality rate was lower than expected.
Interventions
All patients underwent lumpectomy and tangential whole-breast irradiation. Those with SLN
metastases identified by SLND were randomized to undergo ALND or no further axillary
treatment. Those randomized to ALND underwent dissection of 10 or more nodes. Systemic
therapy was at the discretion of the treating physician.
Main Outcome Measures
Overall survival was the primary end point, with a noninferiority margin of a 1-sided hazard ratio
of less than 1.3 indicating that SLND alone is noninferior to ALND. Disease-free survival was a
secondary end point.
Results Clinical and tumor characteristics were similar between 445 patients randomized to
ALND and 446 randomized to SLND alone. However, the median number of nodes removed was
17 with ALND and 2 with SLND alone. At a median follow-up of 6.3 years (last follow-up, March 4,
2010), 5-year overall survival was 91.8% (95% confidence interval [CI], 89.1%-94.5%) with ALND
and 92.5% (95% CI, 90.0%-95.1%) with SLND alone; 5-year disease-free survival was 82.2%
(95% CI, 78.3%-86.3%) with ALND and 83.9% (95% CI, 80.2%-87.9%) with SLND alone. The
hazard ratio for treatment-related overall survival was 0.79 (90% CI, 0.56-1.11) without
adjustment and 0.87 (90% CI, 0.62-1.23) after adjusting for age and adjuvant therapy.
Conclusion Among patients with limited SLN metastatic breast cancer treated with breast
conservation and systemic therapy, the use of SLND alone compared with ALND did not result in
inferior survival.
Trial Registration clinicaltrials.gov Identifier: NCT00003855
Axillary lymph node dissection (ALND) has been part of breast cancer surgery since the
description of the radical mastectomy.1 ALND reliably identifies nodal metastases and maintains
regional control,2,3 but the contribution of local therapy to breast cancer survival is controversial.
4,5 The Early Breast Cancer Trialists' Collaborative Group synthesized findings from 78
randomized controlled trials, concluding that local control of breast cancer was associated with
improved disease-specific survival.6
ALND, as a means for achieving local disease control, carries an indisputable and often
unacceptable risk of complications such as seroma, infection, and lymphedema.7,8,9 Sentinel
lymph node dissection (SLND) was therefore developed to accurately stage tumor-draining
axillary nodes with less morbidity than ALND.10 SLND alone is the accepted management for
patients whose sentinel lymph nodes (SLNs) are histologically free of tumor, while ALND remains
the standard of care for patients whose SLNs contain metastases.11
Cancer biology is much better understood now than it was when ALND was introduced. Biological
factors may affect the predilection of some malignant cells to selectively invade lymph nodes
rather than visceral organs, just as certain tumor types metastasize to certain organs and not
others.12 Recognition of the complexity of tumor biology has changed cancer treatment, with
more liberal use of systemic therapy to treat occult cancer cells wherever they may be in the
body. Consequently, the decision to administer systemic therapy is influenced by a variety of
patient- and tumor-related factors, with lymph node tumor status influencing13,14 but not
necessarily dictating the use of chemotherapy.15,16,17,18 Other factors, such as early cancer
detection by screening mammography, have led to earlier intervention in breast cancer,
reducing the incidence of nodal metastases and even the number of tumor-involved lymph
nodes.19
These evolving concepts have called into question the need for ALND.20,21 A variety of
algorithms have been developed to help clinicians decide which patients would benefit from
ALND.22,23,24 Review of Surveillance, Epidemiology, and End Results data has shown that the
use of ALND for SLN metastases has decreased in recent years.25 No study has conclusively
demonstrated a survival benefit or detriment for omitting ALND when metastatic breast cancer is
identified by SLND. In the late 1990s, the American College of Surgeons Oncology Group
designed and began the multicenter Z0011 trial. The primary aim of this study was to determine
the effects of ALND on overall survival in patients with SLN metastases treated in the
contemporary era with lumpectomy, adjuvant systemic therapy, and tangential-field radiation
therapy.
METHODS
Patient Characteristics
This multicenter, randomized phase 3 trial was registered with the National Cancer Institute and
approved by the institutional review boards of participating centers. All patients provided written
informed consent. Adult women with histologically confirmed invasive breast carcinoma clinically
5 cm or less, no palpable adenopathy, and an SLN containing metastatic breast cancer
documented by frozen section, touch preparation, or hematoxylin-eosin staining on permanent
section were eligible for participation. Patients with metastases identified initially or solely with
immunohistochemical staining were ineligible. Treatment with lumpectomy to negative margins
(no tumor at ink) was required. Women were ineligible if they had 3 or more positive SLNs,
matted nodes, or gross extranodal disease, or if they had received neoadjuvant hormonal
therapy or chemotherapy.
Study Design and Treatment
Before randomization, all women underwent SLND and were stratified according to age (≤50 and
>50 years), estrogen-receptor status, and tumor size (≤1 cm, >1 cm and ≤2 cm, or >2 cm).
Eligible women were randomly assigned to ALND or no further axillary-specific intervention—
specifically, no third-field nodal irradiation. ALND was defined as an anatomical level I and II
dissection including at least 10 nodes. All women were to receive whole-breast opposing
tangential-field radiation therapy. The use of adjuvant systemic therapy was determined by the
treating physician and was not specified in the protocol.
Patients most commonly entered the study post-SLND following identification of metastases on
final pathology report. However, of the 891 registered patients, 287 were registered pre-SLND
and assigned to treatment after intraoperative documentation of SLN metastases. Patients in this
group subsequently found to have 3 or more tumor-involved lymph nodes were included in the
analysis. Patients were assessed for disease recurrence according to standard clinical practice.
History and physical examination were performed every 6 months for the first 36 months and
yearly thereafter. Annual mammography was required; other testing was based on symptoms
and investigator preference.
Study End Points
The primary end point was overall survival, defined as the time from randomization until death
from any cause. A short-term primary end point was occurrence of surgical morbidities. The
study plan was to report surgical morbidities following the completion of accrual and prior to
overall survival reporting after receiving permission from the data and safety monitoring
committee. These morbidities have been reported.10
A secondary end point was disease-free survival, defined as the time from randomization to
death or first documented recurrence of breast cancer. Breast cancer recurrence was
categorized as locoregional disease (tumor in the breast or ipsilateral supraclavicular,
subclavicular, internal mammary, or axillary nodes) or distant metastases. Disease-free survival
and its components (locoregional disease and distant metastases) are reported instead of the
protocol-specified secondary end point (eg, distant disease–free survival) to facilitate
comparison with other studies.
Statistical Analysis
The primary end point was overall survival as a measure of noninferiority of no further axillary
specified interventions (SLND-alone group) compared with the ALND group. Based on the
literature at the time of study design, we hypothesized that overall survival was 80% at 5 years
for optimally treated women with positive nodes.26,27,28 Clinical noninferiority was defined as
the SLND-alone group having a 5-year survival of not less than 75% of that observed in the
ALND group. Noninferiority of the SLND-alone treatment was also considered if the hazard ratio
(HR) for mortality was less than 1.3 when compared with ALND. An estimated 500 deaths were
needed for the study to have 90% power to confirm noninferiority of SLND alone compared with
ALND, with the use of a 2-sided 90% confidence interval (CI) for the HR from a Cox regression
model.29 Specifically, if the 90% CI for the HR was below 1.3, this would indicate that patients
undergoing SLND alone do not have an unacceptably worse overall survival than patients
undergoing SLND plus ALND.
The use of a 2-sided 90% CI corresponds to a 1-sided significance level of .05.30 The
enrollment of 1900 patients in 4 years with a minimum follow-up period of 5 years was initially
planned. Four formal interim analyses and 1 final analysis were planned for overall survival, and
the O’Brien-Flemming α-spending strategy was used to generate stopping boundaries for each
planned analysis. The overall study significance was maintained at .05. However, none of the
planned interim analyses were performed before the study was closed based on the
recommendation of the data and safety monitoring committee. Because of this, a single terminal
hypothesis test with an α of .05 is applied to the data, which makes it consistent with the planned
overall significance level of .05 in the original study plan.
Ineligible patients were retained in all analyses (ie, both the intent-to-treat analyses and the
treatment-received analyses). Kaplan-Meier survival curves for overall survival were compared
by log-rank test. The unadjusted HR (and 90% CI) was calculated using a Cox regression
analysis, and noninferiority P values are reported. As a secondary analysis, known prognostic
factors including adjuvant treatment were included in the Cox regression model to generate an
adjusted HR for overall survival (with a 90% CI and noninferiority P values). Disease-free survival
was analyzed using Kaplan-Meier curves and univariable and multivariable Cox regression
analyses with 95% CIs. The fact that there were only 94 deaths limited the number of variables
that could be used in a multivariable model without affecting model stability. We created a base
model that included the treatment group (SLND alone vs ALND), age (≤50 vs >50 years), and
whether the patient received adjuvant therapy (yes vs no) and added prognostic variables to this
model individually. Only variables obtained on 90% or more of the patients were included in the
multivariable analysis. Locoregional recurrence rates were compared with the Fisher exact test.
Each analysis, other than analysis for the primary end point of overall survival, was performed
with 2-sided P values, 5% significance, and a 95% CI; all analyses were performed using SAS
release 9.1 (SAS Institute Inc, Cary, North Carolina).
RESULTS
Patient Characteristics
The first patient was enrolled in May 1999, and accrual closed in December 2004 based on a
recommendation of the independent data and safety monitoring committee because of concerns
regarding the extremely low mortality rate. Even if the trial had accrued the targeted 1900
patients, it would have taken more than 20 years of follow-up to observe 500 deaths at the
realized event rate. At the time of the decision to terminate the study there had been no formal
analysis comparing the survival experience between the 2 groups; the decision was based solely
on the observed mortality rate for pooled data from the 2 groups. The date of last follow-up for
this analysis was March 4, 2010.
Patients were enrolled from 115 institutions, which included affiliates of the Cancer Trials
Support Unit and the North Central Cancer Treatment Group. Of 891 patients, 445 were
randomly assigned to the ALND group and 446 to the SLND-alone group (Figure 1). Thirty-five
patients were excluded after withdrawing consent prior to surgery. The 103 ineligible patients
were included in the analyses reported here. Because this was a noninferiority trial, a more
conservative analysis was performed on the treatment-received sample (n = 813 patients); 32
patients in the ALND group did not have ALND, and 11 patients in the SLND-alone group had
ALND. No qualitative differences were observed between treatment-received sample and intent-
to-treat sample analyses, so only intent-to-treat results are reported. Disease characteristics at
baseline were well balanced between the 2 groups (Table 1).
Treatment Results
There was an expected difference between ALND and SLND-alone treatment groups in total
number of removed lymph nodes and total number of tumor-involved nodes; the median total
number of nodes removed was 17 (interquartile range [IQR], 13-22) in the ALND group and 2
(IQR, 1-4) in the SLND-alone group.31 The median total number of nodes with histologically
demonstrated tumor involvement (including SLNs) in the ALND group and SLND-alone group
was equal (1 [IQR, 1-2] for both groups). Hematoxylin-eosin–stained tumor deposits no larger
than 2 mm were defined as micrometastases and were identified in SLNs of 137 of 365 patients
(37.5%) in the ALND group compared with 164 of 366 (44.8%) in the SLND-alone group (P = .
05). In the ALND group, 97 of 355 patients (27.3%) had additional metastasis in lymph nodes
removed by ALND, including 10% of patients with SLN micrometastasis who had macroscopically
involved non-SLNs removed. Total nodal involvement is summarized in Table 1; 21.0% of
patients undergoing ALND had 3 or more involved nodes compared with 3.7% undergoing SLND
alone. Four or more involved nodes were seen in 13.7% of patients receiving ALND and 1.0% of
those receiving SLND alone.
Adjuvant systemic therapy was delivered to 403 women (96.0%) in the ALND group and 423
women (97.0%) in the SLND-alone group.31 No differences in the proportion of women receiving
endocrine therapy, chemotherapy, or both were observed. The type of chemotherapy
administered was similar in the 2 groups; anthracycline- and taxane-based combination
regimens were the most common. The majority of the women (n = 605) received whole-breast
radiation therapy: 263 of 296 (88.9%) in the ALND group and 277 of 309 (89.6%) in the SLND-
alone group.
Overall Survival
At a median follow-up of 6.3 years (IQR, 5.2-7.7), there were 94 deaths (SLND-alone group, 42;
ALND group, 52). The use of SLND alone compared with ALND did not appear to result in
statistically inferior survival (Figure 2) (P = .008 for noninferiority). The unadjusted HR
comparing overall survival between the SLND-alone group and the ALND group was 0.79 (90%
CI, 0.56-1.10), which did not cross the specified boundary of 1.3 (Figure 3). The 5-year overall
survival rates were 92.5% (95% CI, 90.0%-95.1%) in the SLND-alone group and 91.8% (95% CI,
89.1%-94.5%) in the ALND group. This was substantially greater than the 80% anticipated at
protocol design. The HR for overall survival adjusting for adjuvant therapy (chemotherapy,
endocrine therapy, and/or radiation therapy) and age for the SLND-alone group compared with
the ALND group was 0.87 (90% CI, 0.62-1.23). The adjusted HRs comparing the SLND-alone
group with the ALND group in the other multivariable models ranged from 0.86 to 0.92 (Table 2),
all similar to the unadjusted rate of 0.79. An exploratory analysis revealed that treatment with
ALND vs SLND alone produced no statistically significant difference in outcome among patients
grouped by receptor status of the primary tumor (ER+/PR+ or ER−/PR−).
Disease-Free Survival
Disease-free survival (Figure 2) did not differ significantly between treatment groups. The 5-year
disease-free survival was 83.9% (95% CI, 80.2%-87.9%) for the SLND-alone group and 82.2%
(95% CI, 78.3%-86.3%) for the ALND group (P = .14). The unadjusted HR comparing the SLND-
alone group with the ALND group was 0.82 (95% CI, 0.58-1.17), and the HR adjusted for
adjuvant treatment and age was 0.88 (95% CI, 0.62-1.25) (Table 3). The adjusted HRs
comparing the SLND-alone group with the ALND group in the other multivariable models ranged
from 0.84 to 0.89 (Table 3), all similar to the unadjusted rate of 0.82. Locoregional recurrence
and its correlates have been previously reported.31 The 5-year rates of local recurrence were
1.6% (95% CI, 0.7%-3.3%) in the SLND-alone group and 3.1% (95% CI, 1.7%-5.2%) in the ALND
group (P = .11). Locoregional recurrence–free survival at 5 years was 96.7% (95% CI, 94.7%
-98.6%) in the SLND-alone group and 95.7% (95% CI, 93.6%-97.9%) in the ALND group (P = .
28).
Surgical Morbidities
Paresthesias, shoulder pain, weakness, lymphedema, and axillary web syndrome are recognized
morbidities of ALND.7,8,9 As previously reported,10 the rate of wound infections, axillary
seromas, and paresthesias among patients in the Z0011 trial was higher for the ALND group
than for the SLND-alone group (70% vs 25%, P < .001). Lymphedema in the ALND group was
significantly more common by subjective report (P < .001) and also tended to be higher by
objective assessment of arm circumference. These findings are in accordance with other
randomized comparisons of SLND with vs without ALND.32,33
COMMENT
In the American College of Surgeons Oncology Group Z0011 randomized trial, ALND did not
significantly affect overall or disease-free survival of patients with clinical T1-T2 breast cancer
and a positive SLN who were treated with lumpectomy, adjuvant systemic therapy, and tangential-
field whole-breast radiation therapy. These survival findings are consistent with those of the
National Surgical Adjuvant Breast and Bowel Project B04 trial, in which women with clinically
negative nodes were randomized to treatment by radical mastectomy, total mastectomy plus
nodal irradiation, or total mastectomy with delayed ALND if nodal recurrence was observed.4
Initially and at each interim analysis for up to 25 years of follow-up, no statistically significant
survival differences were observed between any of the groups. For patients treated in the
modern era, the relevance of the B04 study, which included patients with larger tumors
undergoing mastectomy without adjuvant systemic therapy, is uncertain, because an axillary
recurrence after SLND in patients with a lower risk of death from distant disease might negatively
affect survival. The findings from Z0011 document the high rate of locoregional control achieved
with modern multimodality therapy, even without ALND.
In contrast to B04, in which about 40% of patients in the radical mastectomy group were node-
positive and the same number in the total mastectomy group were assumed to be node-positive
and 5-year overall survival was only about 60%, 100% of patients in Z0011 had nodal
involvement; yet the 5-year overall survival was more than 90%. Furthermore, a 19% rate of
axillary first failure was observed in B04,4 whereas the axillary nodal recurrence rate was only
0.9% in the SLND-alone group in Z0011.31 The excellent local and distant outcomes in this
study highlight the effects of multiple changes in breast cancer management during the interval
between the 2 studies. These changes, which include improved imaging, more detailed
pathological evaluation, improved planning of surgical and radiation approaches, and more
effective systemic therapy, emphasize the need for ongoing reevaluation of “standard” local
therapy.
The well-documented morbidity from ALND has led other investigators to explore alternative
methods of axillary treatment in patients with clinically negative nodes, including radiation,
systemic therapy, and axillary observation. These have consistently demonstrated low axillary
failure rates, with no significant differences in survival.34,35 The International Breast Cancer
Study Group trial of ALND vs observation is noteworthy because more than half of the patients
did not receive breast or axillary radiotherapy. In women 60 years and older receiving adjuvant
tamoxifen but no axillary treatment, the rate of axillary recurrence was only 3%, and overall
survival was 73% at a median follow-up of 6.6 years.36
The low rates of locoregional recurrence at 5 years and the nearly identical overall and disease-
free survival between treatment groups in Z0011 would suggest that differences in survival
between study groups are unlikely to emerge with longer follow-up, because ALND would only
affect survival by virtue of improved locoregional control. In the Early Breast Cancer Trialists'
Collaborative Group overview, statistically significant survival differences between treatments at
15 years were seen only when differences in locoregional recurrence between treatments were
greater than 10% at 5 years.6 Axillary recurrence is usually an early event, occurring at a
median of 14.8 months in B04; in that trial, only 7 of 68 axillary recurrences occurred more than
5 years after study entry.4 Greco et al37 reported that median time to axillary recurrence was
30.6 months for 401 patients who underwent breast-conserving procedures and radiation
therapy with no axillary surgery. Recent reports of long-term follow-up in randomized trials
confirm these findings.38,39 Because the total locoregional recurrence rate in the Z0011 SLND-
alone group at 5 years is only 2.5% compared with 3.6% in the ALND group, it is unlikely that
further follow-up would result in enough additional recurrences to generate a clinically
meaningful survival difference between groups. The absolute difference in 5-year overall
survival between the treatment groups in Z0011 is 0.7%, numerically favoring the SLND-alone
group. The HR for overall survival comparing the SLND-alone group with the ALND group was
0.79 (90% CI, 0.56-1.10). The worst HR (1.10) is less than 1.3, which was hypothesized as the
inferiority margin threshold. In essence, this means that the 5-year overall survival for the SLND-
alone group might be as low as 90.3% if the true 5-year overall survival for the ALND group was
91.8% and the HR as high as 1.10. Most importantly, there is no suggestion that rates of
locoregional recurrence, the mechanism by which variations in local therapy result in survival
differences, differ between groups to the extent needed to produce survival differences or are
likely to do so in the future. Taken together, this suggests that contemporary women may sustain
the morbidity of ALND without any meaningful improvement in survival rates. Limitations of the
study, such as failure to achieve target accrual and possible randomization imbalance favoring
the SLND-alone group, must be considered. However, even in high-risk women (ER−/PR−) in
Z0011, preliminary analysis suggests no effect of elimination of ALND on survival.
Despite limitations of the Z0011 trial, its findings could have important implications for clinical
practice. Examination of the regional nodes with SLND can identify hematoxylin-eosin–detected
metastases that would indicate a higher risk for systemic disease and the need for systemic
therapy to reduce that risk. Results from Z0011 indicate that women with a positive SLN and
clinical T1-T2 tumors undergoing lumpectomy with radiation therapy followed by systemic
therapy do not benefit from the addition of ALND in terms of local control, disease-free survival,
or overall survival. The only additional information gained from ALND is the number of nodes
containing metastases. This prognostic information is unlikely to change systemic therapy
decisions and is obtained at the cost of a significant increase in morbidity.10 The only rationale
for ALND in these patients would be if the finding of additional nodal metastases would result in
changes in systemic therapy. Because current guidelines do not support differences in adjuvant
systemic therapy based on the number of positive lymph nodes, except in some uncommon
select subgroups,40 ALND does not appear to be warranted in this patient population.
The Z0011 trial did not include patients undergoing mastectomy, those undergoing lumpectomy
without radiotherapy, those treated with partial-breast irradiation, those receiving neoadjuvant
therapy, and those receiving whole-breast irradiation in the prone position, in which the low axilla
is not treated. In those patients, ALND remains standard practice when SLND identifies a positive
SLN. However, ALND may no longer be justified for women who have clinical T1-T2 breast
cancer and hematoxylin-eosin–detected metastasis in the SLN and who are treated with breast-
conserving surgery, whole-breast irradiation, and adjuvant systemic therapy. Implementation of
this practice change would improve clinical outcomes in thousands of women each year by
reducing the complications associated with ALND and improving quality of life with no diminution
in survival.
Author Affiliations: John Wayne Cancer Institute at Saint John’s Health Center, Santa Monica,
California (Dr Giuliano); M. D. Anderson Cancer Center, Houston, Texas (Dr Hunt); Mayo Clinic
Rochester, Rochester, Minnesota (Dr Ballman); Dallas Surgical Group, Dallas, Texas (Dr
Beitsch); Nashville Breast Center, Nashville, Tennessee (Dr Whitworth); Morton Plant Hospital,
Clearwater, Florida (Dr Blumencranz); University of Texas Southwestern Medical Center, Dallas
(Dr Leitch); McLaren Regional Medical Center, Michigan State University, Flint (Dr Saha);
American College of Surgeons Oncology Group, Durham, North Carolina (Ms McCall); and
Memorial Sloan-Kettering Cancer Center, New York, New York (Dr Morrow).
Corresponding Author: Armando E. Giuliano, MD, John Wayne Cancer Institute at Saint John’s
Health Center, 2200 Santa Monica Blvd, Santa Monica, CA 90404 (giulianoa@jwci.org).
Author Contributions: Dr Giuliano had full access to all of the data in the study and takes responsibility for the integrity of the data
and the accuracy of the data analysis.
Study concept and design: Giuliano.
Acquisition of data: Giuliano, Beitsch, Whitworth, Blumencranz, Leitch, Saha, Morrow.
Analysis and interpretation of data: Giuliano, Hunt, Ballman, Whitworth, Leitch, McCall, Morrow.
Drafting of the manuscript: Giuliano, Ballman, Beitsch, Whitworth, Morrow.
Critical revision of the manuscript for important intellectual content: Giuliano, Hunt, Ballman, Beitsch, Whitworth, Blumencranz,
Leitch, Saha, McCall, Morrow.
Statistical analysis: Ballman, McCall.
Administrative, technical, or material support: Giuliano, Hunt, Whitworth, Leitch, Saha.
Study supervision: Giuliano, Whitworth.
Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of
Interest and none were reported.
Funding/Support: This study was supported by National Cancer Institute grant U10 CA 76001 to the American College of
Surgeons Oncology Group (ACOSOG).
Role of the Sponsor: The National Cancer Institute had no role in the design and conduct of the study; the collection, analysis,
and interpretation of the data; or the preparation, review, or approval of the manuscript.
Additional Contributions: We thank the ACOSOG staff, in particular the leadership of Heidi Nelson, MD (Mayo Clinic, Rochester,
Minnesota), David Ota, MD (Duke University, Durham, North Carolina), and Samuel A. Wells Jr, MD (National Cancer Institute,
Bethesda, Maryland). All 3 of these individuals contributed to study design, manuscript review, or both; none received
compensation for their contributions. We also thank all of the investigators and their site research teams. Lastly, we wish to thank
the brave patients with breast cancer who participated in this study and their caregivers.
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Invasive Breast Cancer and Sentinel Node Metastasis: A
Randomized Clinical Trial Go to JAMA website with graphics
Journal of the American Medical Association
February 9, 2011, Vol 305, No. 6, pp 535-634
Armando E. Giuliano, MD; Kelly K. Hunt, MD; Karla V. Ballman, PhD; Peter D. Beitsch, MD; Pat
W. Whitworth, MD; Peter W. Blumencranz, MD; A. Marilyn Leitch, MD; Sukamal Saha, MD; Linda
M. McCall, MS; Monica Morrow, MD
Author Affiliations: John Wayne Cancer Institute at Saint John’s Health Center, Santa Monica,
California (Dr Giuliano); M. D. Anderson Cancer Center, Houston, Texas (Dr Hunt); Mayo Clinic
Rochester, Rochester, Minnesota (Dr Ballman); Dallas Surgical Group, Dallas, Texas (Dr
Beitsch); Nashville Breast Center, Nashville, Tennessee (Dr Whitworth); Morton Plant Hospital,
Clearwater, Florida (Dr Blumencranz); University of Texas Southwestern Medical Center, Dallas
(Dr Leitch); McLaren Regional Medical Center, Michigan State University, Flint (Dr Saha);
American College of Surgeons Oncology Group, Durham, North Carolina (Ms McCall); and
Memorial Sloan-Kettering Cancer Center, New York, New York (Dr Morrow).
Corresponding Author: Armando E. Giuliano, MD, John Wayne Cancer Institute at Saint John’s
Health Center, 2200 Santa Monica Blvd, Santa Monica, CA 90404 (giulianoa@jwci.org).
Abstract
Sentinel lymph node dissection (SLND) accurately identifies nodal metastasis of early breast
cancer, but it is not clear whether further nodal dissection affects survival.
Objective To determine the effects of complete axillary lymph node dissection (ALND) on survival
of patients with sentinel lymph node (SLN) metastasis of breast cancer.
Design, Setting, and Patients
The American College of Surgeons Oncology Group Z0011 trial, a phase 3 noninferiority trial
conducted at 115 sites and enrolling patients from May 1999 to December 2004. Patients were
women with clinical T1-T2 invasive breast cancer, no palpable adenopathy, and 1 to 2 SLNs
containing metastases identified by frozen section, touch preparation, or hematoxylin-eosin
staining on permanent section. Targeted enrollment was 1900 women with final analysis after
500 deaths, but the trial closed early because mortality rate was lower than expected.
Interventions
All patients underwent lumpectomy and tangential whole-breast irradiation. Those with SLN
metastases identified by SLND were randomized to undergo ALND or no further axillary
treatment. Those randomized to ALND underwent dissection of 10 or more nodes. Systemic
therapy was at the discretion of the treating physician.
Main Outcome Measures
Overall survival was the primary end point, with a noninferiority margin of a 1-sided hazard ratio
of less than 1.3 indicating that SLND alone is noninferior to ALND. Disease-free survival was a
secondary end point.
Results Clinical and tumor characteristics were similar between 445 patients randomized to
ALND and 446 randomized to SLND alone. However, the median number of nodes removed was
17 with ALND and 2 with SLND alone. At a median follow-up of 6.3 years (last follow-up, March 4,
2010), 5-year overall survival was 91.8% (95% confidence interval [CI], 89.1%-94.5%) with ALND
and 92.5% (95% CI, 90.0%-95.1%) with SLND alone; 5-year disease-free survival was 82.2%
(95% CI, 78.3%-86.3%) with ALND and 83.9% (95% CI, 80.2%-87.9%) with SLND alone. The
hazard ratio for treatment-related overall survival was 0.79 (90% CI, 0.56-1.11) without
adjustment and 0.87 (90% CI, 0.62-1.23) after adjusting for age and adjuvant therapy.
Conclusion Among patients with limited SLN metastatic breast cancer treated with breast
conservation and systemic therapy, the use of SLND alone compared with ALND did not result in
inferior survival.
Trial Registration clinicaltrials.gov Identifier: NCT00003855
Axillary lymph node dissection (ALND) has been part of breast cancer surgery since the
description of the radical mastectomy.1 ALND reliably identifies nodal metastases and maintains
regional control,2,3 but the contribution of local therapy to breast cancer survival is controversial.
4,5 The Early Breast Cancer Trialists' Collaborative Group synthesized findings from 78
randomized controlled trials, concluding that local control of breast cancer was associated with
improved disease-specific survival.6
ALND, as a means for achieving local disease control, carries an indisputable and often
unacceptable risk of complications such as seroma, infection, and lymphedema.7,8,9 Sentinel
lymph node dissection (SLND) was therefore developed to accurately stage tumor-draining
axillary nodes with less morbidity than ALND.10 SLND alone is the accepted management for
patients whose sentinel lymph nodes (SLNs) are histologically free of tumor, while ALND remains
the standard of care for patients whose SLNs contain metastases.11
Cancer biology is much better understood now than it was when ALND was introduced. Biological
factors may affect the predilection of some malignant cells to selectively invade lymph nodes
rather than visceral organs, just as certain tumor types metastasize to certain organs and not
others.12 Recognition of the complexity of tumor biology has changed cancer treatment, with
more liberal use of systemic therapy to treat occult cancer cells wherever they may be in the
body. Consequently, the decision to administer systemic therapy is influenced by a variety of
patient- and tumor-related factors, with lymph node tumor status influencing13,14 but not
necessarily dictating the use of chemotherapy.15,16,17,18 Other factors, such as early cancer
detection by screening mammography, have led to earlier intervention in breast cancer,
reducing the incidence of nodal metastases and even the number of tumor-involved lymph
nodes.19
These evolving concepts have called into question the need for ALND.20,21 A variety of
algorithms have been developed to help clinicians decide which patients would benefit from
ALND.22,23,24 Review of Surveillance, Epidemiology, and End Results data has shown that the
use of ALND for SLN metastases has decreased in recent years.25 No study has conclusively
demonstrated a survival benefit or detriment for omitting ALND when metastatic breast cancer is
identified by SLND. In the late 1990s, the American College of Surgeons Oncology Group
designed and began the multicenter Z0011 trial. The primary aim of this study was to determine
the effects of ALND on overall survival in patients with SLN metastases treated in the
contemporary era with lumpectomy, adjuvant systemic therapy, and tangential-field radiation
therapy.
METHODS
Patient Characteristics
This multicenter, randomized phase 3 trial was registered with the National Cancer Institute and
approved by the institutional review boards of participating centers. All patients provided written
informed consent. Adult women with histologically confirmed invasive breast carcinoma clinically
5 cm or less, no palpable adenopathy, and an SLN containing metastatic breast cancer
documented by frozen section, touch preparation, or hematoxylin-eosin staining on permanent
section were eligible for participation. Patients with metastases identified initially or solely with
immunohistochemical staining were ineligible. Treatment with lumpectomy to negative margins
(no tumor at ink) was required. Women were ineligible if they had 3 or more positive SLNs,
matted nodes, or gross extranodal disease, or if they had received neoadjuvant hormonal
therapy or chemotherapy.
Study Design and Treatment
Before randomization, all women underwent SLND and were stratified according to age (≤50 and
>50 years), estrogen-receptor status, and tumor size (≤1 cm, >1 cm and ≤2 cm, or >2 cm).
Eligible women were randomly assigned to ALND or no further axillary-specific intervention—
specifically, no third-field nodal irradiation. ALND was defined as an anatomical level I and II
dissection including at least 10 nodes. All women were to receive whole-breast opposing
tangential-field radiation therapy. The use of adjuvant systemic therapy was determined by the
treating physician and was not specified in the protocol.
Patients most commonly entered the study post-SLND following identification of metastases on
final pathology report. However, of the 891 registered patients, 287 were registered pre-SLND
and assigned to treatment after intraoperative documentation of SLN metastases. Patients in this
group subsequently found to have 3 or more tumor-involved lymph nodes were included in the
analysis. Patients were assessed for disease recurrence according to standard clinical practice.
History and physical examination were performed every 6 months for the first 36 months and
yearly thereafter. Annual mammography was required; other testing was based on symptoms
and investigator preference.
Study End Points
The primary end point was overall survival, defined as the time from randomization until death
from any cause. A short-term primary end point was occurrence of surgical morbidities. The
study plan was to report surgical morbidities following the completion of accrual and prior to
overall survival reporting after receiving permission from the data and safety monitoring
committee. These morbidities have been reported.10
A secondary end point was disease-free survival, defined as the time from randomization to
death or first documented recurrence of breast cancer. Breast cancer recurrence was
categorized as locoregional disease (tumor in the breast or ipsilateral supraclavicular,
subclavicular, internal mammary, or axillary nodes) or distant metastases. Disease-free survival
and its components (locoregional disease and distant metastases) are reported instead of the
protocol-specified secondary end point (eg, distant disease–free survival) to facilitate
comparison with other studies.
Statistical Analysis
The primary end point was overall survival as a measure of noninferiority of no further axillary
specified interventions (SLND-alone group) compared with the ALND group. Based on the
literature at the time of study design, we hypothesized that overall survival was 80% at 5 years
for optimally treated women with positive nodes.26,27,28 Clinical noninferiority was defined as
the SLND-alone group having a 5-year survival of not less than 75% of that observed in the
ALND group. Noninferiority of the SLND-alone treatment was also considered if the hazard ratio
(HR) for mortality was less than 1.3 when compared with ALND. An estimated 500 deaths were
needed for the study to have 90% power to confirm noninferiority of SLND alone compared with
ALND, with the use of a 2-sided 90% confidence interval (CI) for the HR from a Cox regression
model.29 Specifically, if the 90% CI for the HR was below 1.3, this would indicate that patients
undergoing SLND alone do not have an unacceptably worse overall survival than patients
undergoing SLND plus ALND.
The use of a 2-sided 90% CI corresponds to a 1-sided significance level of .05.30 The
enrollment of 1900 patients in 4 years with a minimum follow-up period of 5 years was initially
planned. Four formal interim analyses and 1 final analysis were planned for overall survival, and
the O’Brien-Flemming α-spending strategy was used to generate stopping boundaries for each
planned analysis. The overall study significance was maintained at .05. However, none of the
planned interim analyses were performed before the study was closed based on the
recommendation of the data and safety monitoring committee. Because of this, a single terminal
hypothesis test with an α of .05 is applied to the data, which makes it consistent with the planned
overall significance level of .05 in the original study plan.
Ineligible patients were retained in all analyses (ie, both the intent-to-treat analyses and the
treatment-received analyses). Kaplan-Meier survival curves for overall survival were compared
by log-rank test. The unadjusted HR (and 90% CI) was calculated using a Cox regression
analysis, and noninferiority P values are reported. As a secondary analysis, known prognostic
factors including adjuvant treatment were included in the Cox regression model to generate an
adjusted HR for overall survival (with a 90% CI and noninferiority P values). Disease-free survival
was analyzed using Kaplan-Meier curves and univariable and multivariable Cox regression
analyses with 95% CIs. The fact that there were only 94 deaths limited the number of variables
that could be used in a multivariable model without affecting model stability. We created a base
model that included the treatment group (SLND alone vs ALND), age (≤50 vs >50 years), and
whether the patient received adjuvant therapy (yes vs no) and added prognostic variables to this
model individually. Only variables obtained on 90% or more of the patients were included in the
multivariable analysis. Locoregional recurrence rates were compared with the Fisher exact test.
Each analysis, other than analysis for the primary end point of overall survival, was performed
with 2-sided P values, 5% significance, and a 95% CI; all analyses were performed using SAS
release 9.1 (SAS Institute Inc, Cary, North Carolina).
RESULTS
Patient Characteristics
The first patient was enrolled in May 1999, and accrual closed in December 2004 based on a
recommendation of the independent data and safety monitoring committee because of concerns
regarding the extremely low mortality rate. Even if the trial had accrued the targeted 1900
patients, it would have taken more than 20 years of follow-up to observe 500 deaths at the
realized event rate. At the time of the decision to terminate the study there had been no formal
analysis comparing the survival experience between the 2 groups; the decision was based solely
on the observed mortality rate for pooled data from the 2 groups. The date of last follow-up for
this analysis was March 4, 2010.
Patients were enrolled from 115 institutions, which included affiliates of the Cancer Trials
Support Unit and the North Central Cancer Treatment Group. Of 891 patients, 445 were
randomly assigned to the ALND group and 446 to the SLND-alone group (Figure 1). Thirty-five
patients were excluded after withdrawing consent prior to surgery. The 103 ineligible patients
were included in the analyses reported here. Because this was a noninferiority trial, a more
conservative analysis was performed on the treatment-received sample (n = 813 patients); 32
patients in the ALND group did not have ALND, and 11 patients in the SLND-alone group had
ALND. No qualitative differences were observed between treatment-received sample and intent-
to-treat sample analyses, so only intent-to-treat results are reported. Disease characteristics at
baseline were well balanced between the 2 groups (Table 1).
Treatment Results
There was an expected difference between ALND and SLND-alone treatment groups in total
number of removed lymph nodes and total number of tumor-involved nodes; the median total
number of nodes removed was 17 (interquartile range [IQR], 13-22) in the ALND group and 2
(IQR, 1-4) in the SLND-alone group.31 The median total number of nodes with histologically
demonstrated tumor involvement (including SLNs) in the ALND group and SLND-alone group
was equal (1 [IQR, 1-2] for both groups). Hematoxylin-eosin–stained tumor deposits no larger
than 2 mm were defined as micrometastases and were identified in SLNs of 137 of 365 patients
(37.5%) in the ALND group compared with 164 of 366 (44.8%) in the SLND-alone group (P = .
05). In the ALND group, 97 of 355 patients (27.3%) had additional metastasis in lymph nodes
removed by ALND, including 10% of patients with SLN micrometastasis who had macroscopically
involved non-SLNs removed. Total nodal involvement is summarized in Table 1; 21.0% of
patients undergoing ALND had 3 or more involved nodes compared with 3.7% undergoing SLND
alone. Four or more involved nodes were seen in 13.7% of patients receiving ALND and 1.0% of
those receiving SLND alone.
Adjuvant systemic therapy was delivered to 403 women (96.0%) in the ALND group and 423
women (97.0%) in the SLND-alone group.31 No differences in the proportion of women receiving
endocrine therapy, chemotherapy, or both were observed. The type of chemotherapy
administered was similar in the 2 groups; anthracycline- and taxane-based combination
regimens were the most common. The majority of the women (n = 605) received whole-breast
radiation therapy: 263 of 296 (88.9%) in the ALND group and 277 of 309 (89.6%) in the SLND-
alone group.
Overall Survival
At a median follow-up of 6.3 years (IQR, 5.2-7.7), there were 94 deaths (SLND-alone group, 42;
ALND group, 52). The use of SLND alone compared with ALND did not appear to result in
statistically inferior survival (Figure 2) (P = .008 for noninferiority). The unadjusted HR
comparing overall survival between the SLND-alone group and the ALND group was 0.79 (90%
CI, 0.56-1.10), which did not cross the specified boundary of 1.3 (Figure 3). The 5-year overall
survival rates were 92.5% (95% CI, 90.0%-95.1%) in the SLND-alone group and 91.8% (95% CI,
89.1%-94.5%) in the ALND group. This was substantially greater than the 80% anticipated at
protocol design. The HR for overall survival adjusting for adjuvant therapy (chemotherapy,
endocrine therapy, and/or radiation therapy) and age for the SLND-alone group compared with
the ALND group was 0.87 (90% CI, 0.62-1.23). The adjusted HRs comparing the SLND-alone
group with the ALND group in the other multivariable models ranged from 0.86 to 0.92 (Table 2),
all similar to the unadjusted rate of 0.79. An exploratory analysis revealed that treatment with
ALND vs SLND alone produced no statistically significant difference in outcome among patients
grouped by receptor status of the primary tumor (ER+/PR+ or ER−/PR−).
Disease-Free Survival
Disease-free survival (Figure 2) did not differ significantly between treatment groups. The 5-year
disease-free survival was 83.9% (95% CI, 80.2%-87.9%) for the SLND-alone group and 82.2%
(95% CI, 78.3%-86.3%) for the ALND group (P = .14). The unadjusted HR comparing the SLND-
alone group with the ALND group was 0.82 (95% CI, 0.58-1.17), and the HR adjusted for
adjuvant treatment and age was 0.88 (95% CI, 0.62-1.25) (Table 3). The adjusted HRs
comparing the SLND-alone group with the ALND group in the other multivariable models ranged
from 0.84 to 0.89 (Table 3), all similar to the unadjusted rate of 0.82. Locoregional recurrence
and its correlates have been previously reported.31 The 5-year rates of local recurrence were
1.6% (95% CI, 0.7%-3.3%) in the SLND-alone group and 3.1% (95% CI, 1.7%-5.2%) in the ALND
group (P = .11). Locoregional recurrence–free survival at 5 years was 96.7% (95% CI, 94.7%
-98.6%) in the SLND-alone group and 95.7% (95% CI, 93.6%-97.9%) in the ALND group (P = .
28).
Surgical Morbidities
Paresthesias, shoulder pain, weakness, lymphedema, and axillary web syndrome are recognized
morbidities of ALND.7,8,9 As previously reported,10 the rate of wound infections, axillary
seromas, and paresthesias among patients in the Z0011 trial was higher for the ALND group
than for the SLND-alone group (70% vs 25%, P < .001). Lymphedema in the ALND group was
significantly more common by subjective report (P < .001) and also tended to be higher by
objective assessment of arm circumference. These findings are in accordance with other
randomized comparisons of SLND with vs without ALND.32,33
COMMENT
In the American College of Surgeons Oncology Group Z0011 randomized trial, ALND did not
significantly affect overall or disease-free survival of patients with clinical T1-T2 breast cancer
and a positive SLN who were treated with lumpectomy, adjuvant systemic therapy, and tangential-
field whole-breast radiation therapy. These survival findings are consistent with those of the
National Surgical Adjuvant Breast and Bowel Project B04 trial, in which women with clinically
negative nodes were randomized to treatment by radical mastectomy, total mastectomy plus
nodal irradiation, or total mastectomy with delayed ALND if nodal recurrence was observed.4
Initially and at each interim analysis for up to 25 years of follow-up, no statistically significant
survival differences were observed between any of the groups. For patients treated in the
modern era, the relevance of the B04 study, which included patients with larger tumors
undergoing mastectomy without adjuvant systemic therapy, is uncertain, because an axillary
recurrence after SLND in patients with a lower risk of death from distant disease might negatively
affect survival. The findings from Z0011 document the high rate of locoregional control achieved
with modern multimodality therapy, even without ALND.
In contrast to B04, in which about 40% of patients in the radical mastectomy group were node-
positive and the same number in the total mastectomy group were assumed to be node-positive
and 5-year overall survival was only about 60%, 100% of patients in Z0011 had nodal
involvement; yet the 5-year overall survival was more than 90%. Furthermore, a 19% rate of
axillary first failure was observed in B04,4 whereas the axillary nodal recurrence rate was only
0.9% in the SLND-alone group in Z0011.31 The excellent local and distant outcomes in this
study highlight the effects of multiple changes in breast cancer management during the interval
between the 2 studies. These changes, which include improved imaging, more detailed
pathological evaluation, improved planning of surgical and radiation approaches, and more
effective systemic therapy, emphasize the need for ongoing reevaluation of “standard” local
therapy.
The well-documented morbidity from ALND has led other investigators to explore alternative
methods of axillary treatment in patients with clinically negative nodes, including radiation,
systemic therapy, and axillary observation. These have consistently demonstrated low axillary
failure rates, with no significant differences in survival.34,35 The International Breast Cancer
Study Group trial of ALND vs observation is noteworthy because more than half of the patients
did not receive breast or axillary radiotherapy. In women 60 years and older receiving adjuvant
tamoxifen but no axillary treatment, the rate of axillary recurrence was only 3%, and overall
survival was 73% at a median follow-up of 6.6 years.36
The low rates of locoregional recurrence at 5 years and the nearly identical overall and disease-
free survival between treatment groups in Z0011 would suggest that differences in survival
between study groups are unlikely to emerge with longer follow-up, because ALND would only
affect survival by virtue of improved locoregional control. In the Early Breast Cancer Trialists'
Collaborative Group overview, statistically significant survival differences between treatments at
15 years were seen only when differences in locoregional recurrence between treatments were
greater than 10% at 5 years.6 Axillary recurrence is usually an early event, occurring at a
median of 14.8 months in B04; in that trial, only 7 of 68 axillary recurrences occurred more than
5 years after study entry.4 Greco et al37 reported that median time to axillary recurrence was
30.6 months for 401 patients who underwent breast-conserving procedures and radiation
therapy with no axillary surgery. Recent reports of long-term follow-up in randomized trials
confirm these findings.38,39 Because the total locoregional recurrence rate in the Z0011 SLND-
alone group at 5 years is only 2.5% compared with 3.6% in the ALND group, it is unlikely that
further follow-up would result in enough additional recurrences to generate a clinically
meaningful survival difference between groups. The absolute difference in 5-year overall
survival between the treatment groups in Z0011 is 0.7%, numerically favoring the SLND-alone
group. The HR for overall survival comparing the SLND-alone group with the ALND group was
0.79 (90% CI, 0.56-1.10). The worst HR (1.10) is less than 1.3, which was hypothesized as the
inferiority margin threshold. In essence, this means that the 5-year overall survival for the SLND-
alone group might be as low as 90.3% if the true 5-year overall survival for the ALND group was
91.8% and the HR as high as 1.10. Most importantly, there is no suggestion that rates of
locoregional recurrence, the mechanism by which variations in local therapy result in survival
differences, differ between groups to the extent needed to produce survival differences or are
likely to do so in the future. Taken together, this suggests that contemporary women may sustain
the morbidity of ALND without any meaningful improvement in survival rates. Limitations of the
study, such as failure to achieve target accrual and possible randomization imbalance favoring
the SLND-alone group, must be considered. However, even in high-risk women (ER−/PR−) in
Z0011, preliminary analysis suggests no effect of elimination of ALND on survival.
Despite limitations of the Z0011 trial, its findings could have important implications for clinical
practice. Examination of the regional nodes with SLND can identify hematoxylin-eosin–detected
metastases that would indicate a higher risk for systemic disease and the need for systemic
therapy to reduce that risk. Results from Z0011 indicate that women with a positive SLN and
clinical T1-T2 tumors undergoing lumpectomy with radiation therapy followed by systemic
therapy do not benefit from the addition of ALND in terms of local control, disease-free survival,
or overall survival. The only additional information gained from ALND is the number of nodes
containing metastases. This prognostic information is unlikely to change systemic therapy
decisions and is obtained at the cost of a significant increase in morbidity.10 The only rationale
for ALND in these patients would be if the finding of additional nodal metastases would result in
changes in systemic therapy. Because current guidelines do not support differences in adjuvant
systemic therapy based on the number of positive lymph nodes, except in some uncommon
select subgroups,40 ALND does not appear to be warranted in this patient population.
The Z0011 trial did not include patients undergoing mastectomy, those undergoing lumpectomy
without radiotherapy, those treated with partial-breast irradiation, those receiving neoadjuvant
therapy, and those receiving whole-breast irradiation in the prone position, in which the low axilla
is not treated. In those patients, ALND remains standard practice when SLND identifies a positive
SLN. However, ALND may no longer be justified for women who have clinical T1-T2 breast
cancer and hematoxylin-eosin–detected metastasis in the SLN and who are treated with breast-
conserving surgery, whole-breast irradiation, and adjuvant systemic therapy. Implementation of
this practice change would improve clinical outcomes in thousands of women each year by
reducing the complications associated with ALND and improving quality of life with no diminution
in survival.
Author Affiliations: John Wayne Cancer Institute at Saint John’s Health Center, Santa Monica,
California (Dr Giuliano); M. D. Anderson Cancer Center, Houston, Texas (Dr Hunt); Mayo Clinic
Rochester, Rochester, Minnesota (Dr Ballman); Dallas Surgical Group, Dallas, Texas (Dr
Beitsch); Nashville Breast Center, Nashville, Tennessee (Dr Whitworth); Morton Plant Hospital,
Clearwater, Florida (Dr Blumencranz); University of Texas Southwestern Medical Center, Dallas
(Dr Leitch); McLaren Regional Medical Center, Michigan State University, Flint (Dr Saha);
American College of Surgeons Oncology Group, Durham, North Carolina (Ms McCall); and
Memorial Sloan-Kettering Cancer Center, New York, New York (Dr Morrow).
Corresponding Author: Armando E. Giuliano, MD, John Wayne Cancer Institute at Saint John’s
Health Center, 2200 Santa Monica Blvd, Santa Monica, CA 90404 (giulianoa@jwci.org).
Author Contributions: Dr Giuliano had full access to all of the data in the study and takes responsibility for the integrity of the data
and the accuracy of the data analysis.
Study concept and design: Giuliano.
Acquisition of data: Giuliano, Beitsch, Whitworth, Blumencranz, Leitch, Saha, Morrow.
Analysis and interpretation of data: Giuliano, Hunt, Ballman, Whitworth, Leitch, McCall, Morrow.
Drafting of the manuscript: Giuliano, Ballman, Beitsch, Whitworth, Morrow.
Critical revision of the manuscript for important intellectual content: Giuliano, Hunt, Ballman, Beitsch, Whitworth, Blumencranz,
Leitch, Saha, McCall, Morrow.
Statistical analysis: Ballman, McCall.
Administrative, technical, or material support: Giuliano, Hunt, Whitworth, Leitch, Saha.
Study supervision: Giuliano, Whitworth.
Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of
Interest and none were reported.
Funding/Support: This study was supported by National Cancer Institute grant U10 CA 76001 to the American College of
Surgeons Oncology Group (ACOSOG).
Role of the Sponsor: The National Cancer Institute had no role in the design and conduct of the study; the collection, analysis,
and interpretation of the data; or the preparation, review, or approval of the manuscript.
Additional Contributions: We thank the ACOSOG staff, in particular the leadership of Heidi Nelson, MD (Mayo Clinic, Rochester,
Minnesota), David Ota, MD (Duke University, Durham, North Carolina), and Samuel A. Wells Jr, MD (National Cancer Institute,
Bethesda, Maryland). All 3 of these individuals contributed to study design, manuscript review, or both; none received
compensation for their contributions. We also thank all of the investigators and their site research teams. Lastly, we wish to thank
the brave patients with breast cancer who participated in this study and their caregivers.
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