2014/11/05

Lancet Oncol 2014; 15: 130310

Introduction
Sentinel node biopsy has replaced ALND as the standard
method for assessment of axillary LN status in cN(-)
breast cancer.
Many studies have proven the accuracy and high
negative predictive value of the sentinel node procedure.
Negative sentinel node no ALND
Positive sentinel node ALND has long been regarded
as standard.
ACOSOG Z0011 (1999-2004)
Randomized. Non-inferiority trial.
Closed prematurely due to low accrual and low rate of
events. 856 of expected 1900 patients
T1-T2, cN0, SLND+ (1 or 2 SLN+ on H&E; SLN+ by IHC
were not eligible). All underwent lumpectomy with
margin- and tangents RT.
Adjuvant systemic therapy 97% (hormones 46%, C/T
58%).
Arm 1) completion ALND.
Arm 2) no further dissection.
ACOSOG Z0011 (1999-2004)
Median f/u: 6.3 years
Outcome: 5-year breast recurrence (ALND arm) 3.1%
vs. (SLND arm) 1.6% (NS); 5-year axilla recurrence
0.5% vs. 0.9% (NS). 5-yr OS 91.8% (ALND) vs. 92.5%
(SLND). 5-yr DFS 82.2% vs. 83.9%.
Median # of nodes removed: 17 (ALND) vs. 2 (SLND).
In ALND group, axillary dissection revealed additional
metastases in 27.3%
Number of positive nodes (not including micromets) -
median: 1 (ALND) vs. 1 (SLND).
SLN micromets: 37.5% (ALND) vs. 44.8% (SLND).

Ann Surg. 2010 Sep;252(3):426-32 & JAMA. 2011 Feb 9;305(6):569-75

ACOSOG Z0011 (1999-2004)
Radiation field design on the ACOSOG Z0011 trial
Among 605 pts completed adjuvant RT, 89% receive
whole breast RT. Of these, 89 patients (15%) also
receiving treatment to the supraclavicular region.
ACOSOG Z0011 (1999-2004)
Detailed RT records available on 228 patients: 104/389
(26.7%) (ALND arm) and 124/404 (30.7%) (SLND arms)
43 (18.9%) received directed regional nodal RT using
3 fields: 22 in the ALND and 21 in the SLND arm.
185 patients (81.1%) received tangent-only treatment:
142 (76.8%) with sufficient data to evaluate tangent
field height. High tangent RT fields (cranial tangent
border within 2 cm of the humeral head) in 52.6%
(40/76) (ALND arm) & 50% (33/66) (SLND arm).
Those receiving directed nodal RT tended to have
greater nodal involvement (p<0.001) Bias.
IBCSG 23-01 (2001-2010)
Axillary dissection vs. no axillary dissection in patients
with sentinel-node micrometastases.
Phase 3 randomized controlled trial.
27 institutions. 931 patients, with tumor 5 cm (T1-2) &
1 micrometastases or isolated tumor cells (ITC) in
sentinel node ( 2 mm), no ECE.
Arm 1) completion axillary dissection.
Arm 2) no further surgery.
Mastectomy 9%. In BCS group, 98% received adjuvant
RT (28% intraoperative)

Lancet Oncol 2013; 14: 297305

IBCSG 23-01 (2001-2010)
Median F/U 5 years
Outcome: Local recurrence ALND (2.1%) vs. OBS
(1.7%), regional recurrence (0.2%) vs. (1%), distant
recurrence (7%) vs. (5%). 5-year DFS 88% vs 84% (NS)
SLND+ ALND: additional metastases in 13%
Toxicity: ALND: 1 Gr 3 neuropathy, 3 Gr 3-4
lymphedema, 3 Gr 3 motor neuropathy vs. OBS 1 Gr 3
motor neuropathy

Lancet Oncol 2013; 14: 297305

Introduction
Patients with limited disease in the sentinel node
treated with breast-conserving surgery, whole breast
RT & adjuvant systemic treatment can be spared ALND
without compromising loco-regional control or survival.
Patients with high risk of axillary involvement still need
axillary treatment. Axillary RT
Methods - Study design and patients
Randomized multicenter, open-label, phase 3 non-
inferiority trial.
T12, unifocal, invasive breast cancer, w/o palpable
LAP.
Bilateral breast cancer not exclude & no age limit.
Ineligible: History of previous malignancy, s/p neoadjuvant
systemic treatment, or s/p axillary surgery or RT.
After Feb 22, 2008, eligibility criteria included T: 3-5cm,
multifocal disease. Sentinel nodes with only isolated
tumor cells (ITC) were not regarded as positive.
Methods - Randomization
Randomly assigned (1:1) by a computer-generated
allocation schedule to ALND or axillary RT before sentinel
node biopsy.
Methods - Procedures
ALND defined as dissection of at least levels I & II
including 10 nodes.
Adjuvant systemic treatment at the discretion of the
treating multidisciplinary team.
Local treatment of the breast consisted of breast-
conserving treatment (including whole-breast RT) or
mastectomy chest wall irradiation.
Axillary RT included all three levels of the axilla and the
medial part of the supraclavicular fossa (SCF), 50Gy/25fr.
Adjuvant axillary RT after ALND when 4 LN(+)
Methods - Assessment
Assessments of lymphoedema & shoulder mobility at
baseline and at 1, 3, 5, and 10 years by study clinicians.
Recording any sign of lymphoedema.
Arm circumference 15 cm above the medial epicondyle
(upper arms) and 15 cm below the medial epicondyle
(lower arms) was measured by study clinicians. An
increase of at least 10% compared with the contralateral
arm was judged to be clinically significant lymphoedema.
For shoulder mobility, the range of motion in both arms
was measured in four excursions: abduction, adduction,
anteversion, and retroversion.
Methods - Assessment
QoL was assessed by the EORTC quality-of-life
questionnaire (EORTC-QLQ-C30; version 3) & breast
cancer module (QLQ-BR23). The selected scales were
pain, body image, and arm symptoms.
Questionnaires were completed at baseline and at years
1, 2, 3, 5, and 10.
Methods - Outcome
Primary endpoint: 5-year axillary recurrence (recurrence
in LNs in the ipsilateral axilla, infraclavicular fossa, or
interpectoral area. Supraclavicular LN recurrences: DM).
Secondary endpoints: Axillary recurrence-free survival,
disease-free survival (DFS), overall survival, shoulder
mobility, lymphoedema, and QoL.
1425 patients (30%) sentinel node positive
Results - Patient Characteristics
Feb 19, 2001 - April 29, 2010, 4823 patients at 34
centers from 9 European countries.
Median follow-up was 6.1 years in the patients with
sentinel node positive & 5.1 years (sentinel node
negative)
Patient and disease baseline characteristics were well
balanced between the 2 treatment groups
33%
Results - Axillary recurrence
Axillary recurrence occurred in 4/744 patients in the
ALND group & 7/681 in the axillary RT group over the
entire follow-up period.
5-year axillary recurrence: 0.43% (ALND group) &
1.19% (axillary RT group).
Among 3131 patients with a sentinel node(-), 25 axillary
recurrences (axillary recurrence rate 0.72%).
 Results - Disease-Free Survival

5-year DFS:
In patients with 86.9% (95% CI 84.189.3) in the ALND
SLN(-), 5-year group & 82.7% (79.385.5) in the axillary
DFS: 87.9% RT group
(95% CI 86.6
89.1)
 Results - Overall Survival

5-year OS:
In patients with 93.3% (95% CI 91.095.0) in the
SLN(-), 5-year ALND group & 925% (90.094.4) in
OS was 954% the axillary RT group.
 39 (6%) of 655 patients in the ALND group & 11 (2%) of
586 patients in the axillary RT group received both RT
and surgery to the axilla.
Lymphoedema was significantly more frequently reported
in this subgroup.
Result Shoulder mobility & QoL
The range of motion (abduction, adduction, anteversion,
and retroversion) did not differ significantly between the
two treatment groups at both timepoints (1 year: p=029;
5 years: p=047).
No statistically significant in QoL.
Interpretation
ALND & axillary RT after a positive sentinel node
provide excellent and comparable axillary control for
patients with clinically T12 primary breast cancer and
no palpable LAP.
Axillary RT results in significantly less morbidity
(Lymphoedema).
Discussion
Axillary RT group having less lymphoedema
However, no clinically significant difference in QoL
The present QoL measures might not be
sensitive enough.
Most cases might be with mild edema
Patients adapt to their disorders and change
their internal standards.
Discussion
Low 5-year axillary recurrence AMAROS trial was not
sufficiently powered to address the primary endpoint
(non-inferiority of 5-year axillary recurrence)
Overtreatment (?) Axillary RT arm: level 3 & the SCV
nodes were also treated.
More patients with SLN(+) were allocated to the ALND
group than to the axillary RT group.
No plausible cause could be identified to explain this
imbalance.
Comment
Many clinically occult low-volume axillary diseases:
77% having only 1 positive SLN & 40% having only
micrometastasis or isolated tumor cells
Extrapolate to 3 SLN(+) ?
Follow-up was short (median f/u of 6.1 years)
Tumor biology information, such as hormonal status,
LVSI, and ECE of the sentinel nodes, were not available
Extrapolate to all biologic subtype (?)
AMAROS trial excluded patients with neoadjuvant C/T.
Management of regional LN in women with limited nodal
involvement:
The role of surgery
The role of comprehensive nodal RT
http://www.mskcc.org/cancer-care/adult/breast/prediction-tools