Perspective

Current Status of Radiotherapy for

the Management of Regional Nodes in
Breast Cancer
Ana Manterola, Gemma Asin, Fernando Arias, Marta Errasti, Marta Barrado,
Maider Campo, Ignacio Visus, Miguel Angel Dominguez
Abstract
Worldwide, breast cancer is the most common invasive cancer in women. Breast cancer constitutes about 23% of
invasive cancers in women. The management of breast cancer depends on various factors, including the cancer stage
and patient age. Breast cancer is usually treated with surgery, which can be followed by chemotherapy or radiation
therapy, or both. Until recently, the standard procedure for axillary study was axillary dissection. Sentinel lymph node
biopsy has been validated as a less-aggressive axillary treatment without an impact on survival. In the present report,
we review the current management of the axillary lymph nodes, especially from the viewpoint of an oncology
radiotherapist.
Clinical Breast Cancer, Vol. 16, No. 1, 1-7 2016 Elsevier Inc. All rights reserved.
Keywords: Axilla management, Lymphadenectomy, Regional radiotherapy, Sentinel lymph node biopsy, Sentinel node biopsy

Introduction
Lymphatic drainage of the breast is preferably produced by the
axillary lymph nodes. It has been estimated that about 15% of the
drainage ends up in the lymph nodes located in the internal
mammary gland and the remaining 85% in the territory of the
axilla. Although both the internal mammary lymph nodes and those
located in the axilla receive drainage from the entire breast, drainage
in internal mammary lymph nodes occurs more frequently in tumors located in the medial part of the breast.1
From the start of breast cancer treatment, the action on the
regional lymph nodes ows inseparably from the local treatment of
the tumor in the breast. Until recently, breast cancer surgery always
involved axillary lymph node dissection (ALND) as a part of the
surgical procedure.

located below and outside the muscle; level II, those located at the
same height; and level III (or the infraclavicular), those inside and
above it (Figure 1). The nodal drainage level, beyond level III, is the
supraclavicular area. The effect on the supraclavicular chain is
restricted to tumors with extensive effects in the axillary area and is
frequently associated with disseminated disease. The internal mammary chain extends to the fth intercostal space; however, its effect is
more common in the lymph nodes in the rst 3 levels.
The risk of axillary dissemination depends on different factors.
Among the best known and most widely studied are the size of the
primary tumor, its histologic grade, the histologic tumor type, the
presence of lymphovascular invasion (LVI), and the location of the
primary tumor in the breast.

Tumor Size

Discussion
For the practical management of the axilla, 3 levels have been
distinguished according to the location of the lymph nodes with
respect to the minor pectoralis muscle. Level I encompasses those
Department of Radiation Oncology, Complejo Hospitalario de Navarra, Pamplona,
Spain
Submitted: Jul 17, 2015; Revised: Aug 25, 2015; Accepted: Sep 11, 2015; Epub:
Sep 25, 2015
Address for correspondence: Ana Manterola, MD, Department of Radiation Oncology,
Complejo Hospitalario de Navarra, Irunlarrea 3, Pamplona 31008, Spain
E-mail contact: ana-manterola@hotmail.com

1526-8209/$ - see frontmatter 2016 Elsevier Inc. All rights reserved.

http://dx.doi.org/10.1016/j.clbc.2015.09.011

Large tumors have been associated with an increased risk of

axillary dissemination, and various studies have shown that as the
size of the primary tumor increases, the odds of positive axillary
lymph nodes increases.2,3 A greater risk has also been demonstrated
in patients who require repeat excision of residual tumor with
positive margins after surgery compared with those with enlargement but negative margins after the rst surgery.4 This effect has
been attributed to an underestimation of the initial tumor size.

Histologic Characteristics
The greater the histologic grade, the greater the risk of lymph
node invasion.5 Tumors with a focus of inltration < 5 mm, those

Clinical Breast Cancer February 2016

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Current Status of Radiotherapy for Regional Nodes

Figure 1 Axillary Lymph Node Levels I, II, and III

that are grade 1 without LVI, and tumors with pure mucinous or
tubular features < 1 cm have a risk of lymph node positivity of <
5%. The same is true for intraductal carcinoma.6

Tumor Localization
The risk of axillary dissemination is increased for tumors located
in the outer quadrants of the breast and there is a greater tendency
of internal mammary tumors in the internal quadrants to drain.7

Assessment of the Axilla

As stated, since the start of treatment for breast cancer, a surgical
approach to the axilla has been the norm. With the advent of radiation
therapy (RT), hormonal treatment, and chemotherapy (CT),
knowledge of the status of the axillary lymph nodes has become critical
for the indication of such procedures. Furthermore, with advances in
early diagnosis, the discovery of patients without nodal involvement
has been greater. Thus, these patients can avoid radical surgical
treatment, such as ALND, which are not without morbidity.
Physical examination of the axilla is not a reliable method for
assessing lymph node involvement in this area. Many of the positive
lymph nodes for breast cancer are not clinically palpable. Also, other
benign pathologic features can produce an enlarged lymph node.
The positive predictive value has varied from 61% to 84%, and the
probability of no involvement after normal examination ndings has
been 50% to 60%.8

Axillary Ultrasonography

In the presence of suspicious lymph nodes found on an ultrasound scan, an axillary echo scan allows for ne needle aspiration
(FNA) or biopsy, which will lead to an accurate diagnosis of lymph
node involvement. The morphologic alterations found on ultrasound scanning have a low predictive value in themselves.9 Thus,

Clinical Breast Cancer February 2016

surgical staging with a histologic examination of resected lymph

nodes is necessary to accurately diagnose the existence of involvement in the axilla, especially because additional treatment also depends on these ndings.
Until recently, the standard procedure for axillary lymph node
study was ALND. ALND includes the removal of level I and II
axillary lymph nodes, which has diagnostic, prognostic, and therapeutic purposes, and is the most accurate and secure method of
diagnosing axillary lymph node involvement. However, this treatment is not without morbidity, such as lymphedema and neurologic
damage. The latter can result in a decit in mobility and sensitivity,
which results in a compromise in functionality and quality of life.10
The development of the sentinel lymph node biopsy (SNB) has
allowed for less-aggressive axillary surgery. The American College of
Surgeons Oncology Group (ACOSOG) Z10 study showed that it is
possible to identify the sentinel lymph node (SLN) in
95% of
cases. Factors that could decrease the percentage of identication
include an increased body mass index, patient age, and studies
with < 50 patients.11
Several studies have shown that SNB is a safer and less morbid
procedure.12-14 These studies have shown that if the SLN is negative, the likelihood of further axillary lymph node involvement will
be very low (5%-10% false-negative results), with very low values of
recurrence in the axilla (range, 0%-4.5%), eliminating the necessity
for lymphadenectomy. A condition for entry in the studies was that
the axilla would be clinically negative.
In a recent review of axillary treatment because of breast cancer,15
the morbidity in patients after SNB was compared with that in those
who had undergone ALND. The risk of lymphedema, pain and
numbness of the arm, and quality of life scores were clearly favorable
for the SNB, with the values showing a doubling or tripling of complications for treatments involving lymphadenectomy.
In 2005, the rst American Society of Clinical Oncology (ASCO)
guide for performing SNB in cases involving early-stage breast cancer
was published.16 This guide acknowledged SNB as an acceptable
treatment of stage T1 and T2 tumors, when these are treated with
conservative surgery and RT to the entire breast. The ASCO guidelines allow performance of the procedure in cases involving multicentricity, cases of intraductal carcinoma with the risk of
microinvasion, and cases for which mastectomy was scheduled. SNB
is not recommended if the patient has undergone previous surgery in
the axilla or previous CT. The axillary lymph nodes should always be
clinically negative. The update published in 2014 allows for SNB after
neoadjuvant systemic treatment and in patients with previous surgical
procedures in the axilla or breast.17 Treatment guidelines, such as the
National Comprehensive Care Network (NCCN) guide and the
Consensus of St Gallen,18 also introduced the option of SNB as a
standard treatment in these patient groups, without ALND necessary
in the case of negative SNB ndings.
Furthermore, the possibility of more detailed study of the lymph
nodes signicantly increases the detection of small tumor deposits
not detected in the initial pathologic study (occult metastasis).
These can be isolated tumor cells (ITCs), micrometastasis, and,
infrequently, macrometastasis.
In the National Surgical Adjuvant Breast and Bowel Project
(NSABP) B32 study, 15.9% of occult metastases were detected.
The differences in prognosis were small, with a difference in overall

55
49
75
74
95
97
2
6
3
1
5.2
<1.5
1995-1998
Veronesi et al,24 2005

Data in parentheses are percentages.

Abbreviations: ALND axillary lymph node dissection; RT radiation therapy.

Not clinically suspicious

5
<3
Not clinically suspicious
1982-1987
Louis-Sylvestre et al,23 2004

50
52
57

Recurrence (n)

e
e
(0.6)
(1.8)
(1.5)
(0.5)
219
206
326
332
214
221
RT
ALND
ALND
RT
None
RT
5
Clinically suspicious
1951-1957
Johansen et al,22 1990

50

Any

Sample
Size (n)
Axillary
Treatment
Median Follow-up
Period (years)
Tumor
Size (cm)
Axillary Status
Patient Age
(years)
Study Period
Investigator

Table 1 Randomized Trials of Axillary Lymph Node Dissection versus Axillary Radiation (Level A Evidence)

survival (OS) of 1.2% (94.6% vs. 95.8%) and in metastasis-free

survival and disease-free survival (DFS) of 2.8%. The ACOSOG
Z0010 study found no association between survival and lymph
node involvement detected by immunohistochemistry (IHC) only
(negative hematoxylin-eosin staining).19 The ASCO 2014 guidelines for SNB expressly stated that neither the NSABP B32 nor the
ACOSOG Z0010 study endorses the use of IHC for the detection
of ICTs or micrometastasis after a routine, initial evaluation of
parafn blocks that showed no involvement in the lymph node.
Thus, based on current knowledge, it can be agreed that if the SNB
is negative, it is not necessary to perform ALND and treatment
should follow the recommendations for a tumor stage of pN0.
However, in the event that involvement appears in the SLN, the
subsequent treatment will depend on the volume of involvement
and the number of affected lymph nodes.
The American Joint Committee on Cancer (AJCC), 7th ed,
guidelines have dened ICT involvement as a lymph node size of 
0.2 mm or  200 cells affected. In such cases, a broad consensus has
been reached to treat such patients the same as any other patients
with stage N0 disease. The disease should be classied as pN0i,
with treatment the same as for stage pN0.
Regarding involvement by micrometastases, a prospective study
(International Breast Cancer Study Group [IBCSG] 23-01), evaluated such patients. A total of 935 patients with stage pT1-pT2N0
clinically and in whom SNB showed micrometastasis were randomized to undergo or not undergo ALND. The results were
published in 2013, with a follow-up study lasting 5 years. No difference between the 2 arms was found in OS or DFS, despite the
discovery of additional metastases in 13% of the patients in the
ALND group. However, in 90% of cases, conservative breast surgery and RT to the breast was performed and 95% of patients
received systemic treatment.20 Moreover, the degree of motor and
sensory neuropathy and lymphedema was signicantly greater in the
ALND group. Thus, the investigators concluded that in this group
of patients, ALND can be safely avoided.
The standard treatment for patients with lymph node involvement has traditionally been ALND. The AJCC (7th ed) guidelines
have dened stage pN1a as inltration of 1 to 3 axillary nodes, with
involvement of
2 mm. Patients who underwent radical mastectomy in the NSABP B04 trial21 presented with excellent local
control, with an incidence of isolated axillary recurrence of only
1.4% in a 10-year follow-up period. However, a signicant degree
of morbidity was reported, as previously mentioned.21 Moreover,
regional RT, as an alternative to ALND, has demonstrated excellent
regional control without impairing survival (Table 1), as multiple
randomized studies have shown.
The largest study, conducted at the Curie Institute and published
in 2004, with 15 years of follow-up data, had randomized 658
patients with clinically negative axillary lymph nodes and tumors <
3 cm in diameter, who had undergone CT and RT to the breast, to
ALND versus axillary RT. No differences were found in either OS
or DFS, with an incidence of isolated axillary lymph node failure of
1% versus 3%, indicating that axillary RT is an excellent alternative
to lymphadenectomy, with the disadvantage of losing the information gained by surgical staging.23
As previously stated, the standard treatment for patients with
lymph node involvement has been ALND. However, since

Survival (n)

Ana Manterola et al

Clinical Breast Cancer February 2016

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Current Status of Radiotherapy for Regional Nodes

publication of the ACOSOG 00Z11 study, this assumption has

been under review. That study included 891 patients with clinically
negative axillary lymph nodes, stage T1-T2. The patients had undergone conservative surgery and breast RT and had presented with
involvement of 1 or 2 sentinel nodes. These patients were randomized, with only 1 group undergoing ALND. The results after a
5-year follow-up period were published in 2011.25 No differences in
either DFS or OS were found in either of the 2 groups after 6 years.
The incidence of axillary lymph node recurrence was very low in
both treatment arms (0.5% vs. 0.9% with vs. without ALND),
always remembering the 27% rate of additional axillary involvement
in the ALND group. The investigators recommended not performing ALND in such cases, because the patients had undergone
whole breast RT and a part of the axilla would have been included
in RT elds. Also, this group of selected patients had a good
prognosis: 41% had micrometastasis as axillary involvement, 71%
had involvement in just 1 node, 69% had stage T1 disease, and
96.5% had received systemic treatment.
The ACOSOG Z0011 study has been widely criticized because
the analysis was undertaken with few patients and events, because of
the statistical parameters applied, and because of the imbalance
between the patients with micrometastasis in the SNB arm and such
patients in the ALND arm (44.8% vs. 37.5%; P .05). Furthermore, a review of RT performed in that study demonstrated that
19% of patients had undergone nodal RT. However, this had
occurred equally in both arms; thus, the investigators believed that
this did not invalidate the data presented.26
Although the degree of morbidity associated with not performing
ALND is lower and the results in disease control in these studies have
been similar, the question of determining which patients can avoid
ALND remains. Many recommendations have been published. In
2013, a meta-analysis15 was published that concluded that it is
possible to avoid ALND in patients undergoing breast conservation
treatment that includes RT if the breast tumor measures < 3 cm, with
a maximum involvement of 3 SLNs. The NCCN guidelines also
included the possibility of performing ALND in cases that meet all the
following criteria: stage T1-T2 and involvement of a maximum of 2
lymph nodes, breast-conserving treatment with whole-breast RT, and
no neoadjuvant CT. The National Cancer Institute Physician Data
Query guidelines give the same recommendations.
Thus, we can conclude that ALND is not necessary after SNB
with a nding of ITCs or micrometastasis, although it is necessary
in patients with clinically positive axillary lymph nodes, involvement of
3 SLNs, and those not receiving RT to the whole breast.
It might be an acceptable option but requires individualized
assessment for patients with stage T1-T2cN0, estrogen receptorpositive cancer, with involvement of 1 to 2 lymph nodes in the
SNB, who have undergone RT to the entire breast and systemic
treatment.
Randomized studies have demonstrated equivalence between
survival after axillary RT and ALND, with good regional disease
control and a lower risk of lymphedema. The AMAROS study
(After Mapping of the Axilla: Radiotherapy or Surgery?), by the
European Organization for Research and Treatment of Cancer
(EORTC), presented at the ASCO 2013 annual meeting, randomized patients with cT1-2cN0 and positive SNB ndings to
receive ALND or lymph node RT. After a 5-year follow-up period,

Clinical Breast Cancer February 2016

axillary recurrence was very low in both groups (ALND, 0.54% vs.
RT, 1.03%), with no signicant difference in DFS (86.9% vs.
82.7%; P .1788) or OS (93.3% vs. 92.5%; P .3386). The
probability of lymphedema in the surgical group was 28%
compared with 14% in the RT group.27 These results show that
nodal RT is equivalent to ALND after positive SNB ndings.
However, another question is whether regional RT is indicated
after SNB with an affected lymph node found if ALND will not be
performed. Complete consensus has been reached on the need for
nodal RT in patients with involvement of > 3 affected lymph nodes
after ALND, with a strong recommendation by international guidelines to radiate nodal areas in which 1 to 3 lymph nodes are affected.
This recommendation has recently been reinforced by the publication
in 2014 of the data from the Early Breast Cancer Trialists Collaborative Group overview in relation to postmastectomy RT.28 In the
3800 patients included in 14 randomized trials with long follow-up
periods comparing mastectomy and ALND with and without RT
(RT wall and regional areas), patients with nodal involvement showed
improvement in DFS (10 years) and OS (20 years) when treated with
postmastectomy RT. This benet was observed in patients with > 3
affected nodes and in patients with 1 to 3 nodes. Given that these
studies were initiated before 2000, an analysis was also performed to
conrm whether the benet of RT was lower in patients with systemic
treatment. However, no differences were found. In fact, the group
with systemic treatment beneted more from RT, although the difference was without statistical signicance (Table 2).
Other studies supporting the need for nodal RT in node-positive
patients include the MA.20 study29 and the EORTC 22922 trial.30
These studies included patients who had undergone surgery for
breast cancer with a follow-up period of 10 years. The patients had
been randomized to local RT only or both local and nodal RT.
Although the 2 trials differed in certain technical aspects of treatment, they both showed a lower risk of locoregional recurrence and
metastatic breast cancer with the use of extended RT (DFS, 82.0%
vs. 77.0% and 72.1% vs. 69.1% in the MA.20 and EORTC
studies, respectively). However, no improvement was seen in OS in
either trial. In addition, the toxicity analysis showed an increased
incidence of epithelitis, lymphedema, and pneumonitis (1.2% vs.
0.2% and 4.4% vs. 1.7% in the MA.20 and EORTC studies,
respectively) in patients who had undergone nodal RT than in those
who had not.
Nomograms, such as the one from the Memorial Sloan Kettering
Cancer Center, are available to help predict the risk of residual
positive axillary involvement after SNB.31 However, it is not easy to
translate these data to the risk of DFS. Also, the need for lymph
node RT has been studied in the context of patients who had undergone surgery with ALND. Thus, no clear answer is available for
patients with positive SNB ndings but without ALND regarding
the suitability of irradiating the nodal areas. It would seem logical
that if nodal RT benets patients with node-positive disease who
have undergone surgery of the axillary lymph nodes, it would be still
more benecial for those with nodal involvement demonstrated by
SNB who did not subsequently undergo surgery. It is possible,
however, that this represents the case of a selected group of patients
with a low tumor burden in the axilla and that local RT and systemic treatment (an essential prerequisite that breast RT with
tangential elds be administered with the patient in a supine

Ana Manterola et al
Table 2 Early Breast Cancer Trialists Collaborative Group Study Dataa
10-years Risk of LRR (%)
Stage
pN0
P value
pN
P value
pN1-N3
P value
pN4
P value

RT
3

No RT

22.4

26

51.9

20.3

<.00001

34.2
66.3
<.00001

RT
28.8

62.5

58.3

No RT
26.6

>.1
66.4

.00001
45.7

<.00006
32.1

20-years Risk of BC Mortality (%)

21.4

<.00001

<.00001
13

No RT

>.1

<.00001
3.8

RT

16

>.1
8.1

10-years Risk of Any Recurrence (%)

42.3

50.2

.01
75.1

70.7

80

.04

Abbreviations: BC breast cancer; pN0 pathologically node-negative; pN pathologically node-positive; pN1-N3 1 to 3 pathologically positive nodes; pN4 > 4 pathologically positive
nodes; RT radiotherapy.
a
Effect of RT after mastectomy and axillary dissection on 10-year risk of locoregional and overall recurrence and 20-year risk of BC mortality in pN0, pN, pN1-N3, and pN4.

position and include at least a part of the lower axillary levels) is

sufcient for a good regional disease control.
The Clinical Research in Radiation Oncology Group has launched
a multicenter, randomized study (OPTIMAL: Optimizing Irradiation through Molecular Assessment of Lymph node) whose main
objective is to analyze whether a difference exists in DFS at 5 years
among patients with SNB-positive ndings and no ALND, with a low
tumor load, and conservative treatment of the breast, regardless of
whether they undergo RT to the regional areas. As we await the results
of this and other similar studies, the recommendation of experts is that
no regional RT is necessary for SNB ndings of ITCs or micrometastasis and that regional RT is necessary for SNB ndings showing
multiple involvement with macrometastases (Timothy Whelan,
Presidential Symposium, ASTRO 2014, oral presentation). Also, in
those patients with 1 positive lymph node, other factors should be
considered including patient age, size of the primary lymph node,
estrogen receptor status, tumor grade, and LVI.

Management of Axillary Lymph Nodes After Neoadjuvant

Systemic Therapy
All the studies and recommendations we have discussed have
reported on patients who had undergone primary surgical intervention (ie, without neoadjuvant chemotherapy [NAC]).
Multiple prospective studies have compared NAC with adjuvant
chemotherapy. Despite failing to demonstrate benets in DFS or
OS,32 NAC offers a distinct advantage in routine clinical practice
for breast conservation treatment in patients with tumors that,
because of size, are not indicated for breast conservation surgery. In
the context of research, it allows physicians to know the response to
these drugs earlier in the disease course and permits the differentiation between patients with a PCR, who will have better DFS and
OS, and those without a PCR.33 Thus, research strategies can be
designed to adapt the CT regimen to each patient in a more individualized fashion. Also, examining the different subtypes of breast
cancer has shown that patients with a greater percentage of PCR are
those with triple-negative and HER-2 positive disease34; thus, they
are also those who will most benet from NAC.
As stated, CT will allow reduction of the tumor volume before
surgery, resulting in increased breast conservation and a decrease in

the percentage of positive axillary lymph nodes after surgery. In the

NSABPB-18 study, performance of tumorectomy increased from
60% to 68% (P .0002) and node-negative disease increased from
41% to 57%.35
In a published review of patients treated at the MD Anderson
Cancer Center, those with stage T2 and T3 who underwent NAC, the
resection volume decreased. In contrast, the rate of repeat excision did
not increase (14% in both groups). No differences were found for
patients with T1 tumors. Nor were differences found in the recurrence
rates during a 33-month follow-up period. Thus, because the size of
the excision could be reduced, the cosmetic aspect was improved
without compromising the oncologic outcome.36 More recent studies
with better follow-up data have also not found differences in DFS at 5
and 10 years.37
Regarding the management of the axillary lymph nodes and
possibility of SNB, the advantages of performing SNB before NAC
are that the results obtained can be adapted to the classic TNM
stage, the numbers of false-negative (FN) results are clearly established, and CT will not interfere with axillary staging. The advantages of performing SNB after NAC are that the surgical procedure
is performed in 1 stage, the possibility exists of less-extensive ALND
because of the lower rate of pN, and that knowledge of the
response to NAC in the axillary lymph nodes offers prognostic information. However, in this context, it is unclear which patients
should receive regional RT.
Two meta-analyses studied the results of SNB after NAC in
patients with a diagnosis of clinically negative axillae. They reported
a lymph node identication rate of 90% and FN rate of 12% and
8.4%.38,39 The ASCO guideline has modied its recommendation
on this issue. In 2005, it did not recommend SNB after NAC, but
the 2014 update has recommended SNB. However, the recommendation was moderate, with an intermediate level of evidence in
the absence of clinical axillary involvement.16,17
More problematic is the management of the axilla in patients
with clinically positive axillary lymph nodes, in whom, after NAC,
the SNB produces negative ndings. Studies such as the Canadian
Sentinel Node Biopsy Following NeoAdjuvant Chemotherapy in
Biopsy Proven Node Positive Breast Cancer (SN FNAC)40 and
German SENTINA trial41 analyzed this issue. The SN FNAC trial

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Current Status of Radiotherapy for Regional Nodes

included patients with positive ndings from lymph node biopsy.

The second trial included patients with a positive axillary lymph
node on ultrasound scan. In the Canadian study, the identication
rate was 87%, provided that pN0i was included as positive; the
FN rate was 9.6%. If the number of lymph nodes removed were

2, the FN rate decreased to 4.5%. In the German study, the FN rate
was 14.2%, which decreased to 9.6% when cases with only 1 SLN
resected were excluded, and to 0% to 7% if
3 SLNs were
examined.
The percentage of FN in the ACOSOG Z1071 study42 was
12.6%. If only radiocolloid or blue dye alone were used for identication, the rate was 20% to 22%. If both were used, it decreased
further, to 10.8%. Moreover, if only 2 nodes were examined, the
rate was 21%, with
3 lymph nodes examined, it decreased to 9%
to 11%. It also reduced the risk of FN results by placing clips in
clinically suspicious lymph nodes at the initial biopsy (7.4% of FN
results in this group), although these clips were only found in 56%
of the cases at SNB.
It would, therefore, be advisable to ensure, as far as possible, that
FN ndings do not result by ensuring double labeling of the ganglion
and by obtaining
2 nodes. Additionally, repeat section of any
palpable nodes, and, if this is not possible or the SNB ndings are
positive, ALND should be performed. Placing clips on suspicious
nodes at of biopsy, before NAC, is also recommended. Finally, if the
SNB ndings after NAC are positive, ALND should be performed.
The AO11202 ALLIANCE (NCTO 1901094) study investigated the need for ALND owing to positive SNB ndings after
NAC in patients with cT1-T3N1. It randomized patients with
positive SNB ndings to enhance locoregional RT and ALND or
regional treatment with RT alone. Knowing whether regional RT
after NAC is indicated is a problematic issue for radiation oncologists, owing to the scant evidence available.
In retrospective analyses of prospective studies at MD Anderson
Cancer Center, patients with stage T3-T4 and N2-N3 who underwent RT achieved better DFS and cause-specic survival (CSS)
compared with those who did not undergo RT. Although the use of
RT was not randomized, it is likely that the patients who received
RT had demonstrated a worse response to NAC, reinforcing the
indication for RT in such cases.
Less clear is the indication for the application of RT in the early
stages. In the combined analysis of the NSABP B-18 and NSABP B27 studies,43 patients did not receive RT, except in cases of breastconserving surgery. The greatest risk of locoregional relapse (LRR)
has been found in young patients in the conservation group and in
tumors > 5 cm after mastectomy. In both cases, residual nodal
disease and residual disease in the breast were risk factors.
The meta-analysis of Collaborative Trials in Neoadjuvant Breast
Cancer44 (which excluded the cited NSABP studies because of an
unknown tumor subtype) found similar results regarding an increased
risk of LRR if residual disease was present after NAC. Regarding the
risk according to subtype: luminal A and B disease types had a lower
risk of LRR than did triple-negative and HER-2epositive disease.
However, one half of the HER-2 patients had not received trastuzumab precisely because the meta-analysis included studies in which the
drugs were randomized to analyze their effectiveness. Patients with
triple-negative tumors and residual disease had a 20% greater risk of
LRR. It should be emphasized that the meta-analysis did not

Clinical Breast Cancer February 2016

randomized the use of RT; thus, the effect of locoregional RT on DFS

and CSS after NAC is unclear.
It seems clear that patients with clinical regional involvement
who present with lymph node involvement after NAC will benet
from locoregional RT. However, the benet is less clear for those
with stage pN0 after NAC, because their risk of LRR is low.
The ongoing NSABPB-51/Radiation Therapy Oncology Group
1304 (NRG 9353) study is designed to answer this question. The
study included patients with cT1-T3cN, with nodal positivity
conrmed by biopsy or FNA. After NAC, the study randomized those
with pN0 (after SNB or ALND) to receive or not receive regional RT.
All patients who received conservative surgery underwent local
RT, and all who had undergone mastectomy only received local RT
(locoregional) if they were in the regional RT group.

Conclusion
As we await the results of ongoing studies, the recommendations
of experts include the following. First, patients with SNB ndings
showing ITCs or micrometastasis do not require regional RT.
However, patients with SNB ndings showing multiple macrometastases should undergo regional RT. For patients with 1 positive
node, other factors, such as age, size of primary node, estrogen receptor status, tumor grade, and LVI, should be considered. Finally,
for patients who undergo NAC, those with advanced disease stages
(T3-T4N2-N3) should receive RT after an independent NAC
response. In early disease stages, it would be reasonable for patients
to undergo RT if residual disease is present. If doubts exist in the
case of a PCR, such patients should be assessed individually.

Disclosure
The authors have stated that they have no conicts of interest.

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