Sentinel-Node-Driven Personalized Radiation Techniques Ranging from Partial Breast Irradiation to Regional Nodal Radiation after Breast-Conserving Surgery

doi:10.4236/jct.2013.47A008

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Journal of Cancer Therapy, 2013, 4, 49-55

http://dx.doi.org/10.4236/jct.2013.47A008 Published Online August 2013 (http://www.scirp.org/journal/jct)

Sentinel-Node-Driven Personalized Radiation

Techniques Ranging from Partial Breast Irradiation to

Regional Nodal Radiation after Breast-Conserving

Surgery*

Kazuhiko Sato1#, Yoshio Mizuno1, Hiromi Fuchikami1, Masahiro Kato2, Takahiro Shimo2,

Jun Kubota2, Naoko Takeda1,3, Yuko Inoue3, Hiroshi Seto4, Tomohiko Okawa5

1Department of Breast Oncology, Tokyo-West Tokushukai Hospital, Tokyo, Japan; 2Department of Radiation Oncology, Tokyo-

West Tokushukai Hospital, Tokyo, Japan; 3Inoue Ladies Clinic, Tokyo, Japan; 4Seto Hospital, Saitama, Japan; 5Health Evaluation

Center, Utsunomiya Memorial Hospital, Tochigi, Japan.

Email: #[email protected]

Received June 11th, 2013; revised July 10th, 2013; accepted July 17th, 2013

License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly

cited.

ABSTRACT

Background: Breast-conserving surgery (BCS) followed by whole breast irradiation (WBI) has become the standard of

care for treating patients with early-stage breast cancer. Recently, various radiation techniques followed by BCS have

been reported. We have been investigating “personalized radiotherapy after BCS” ranging from accelerated partial

breast irradiation (APBI) to WBI with regional nodal irradiation (RNI) based on the axillary node status. In this study,

we compared different cohorts that received personalized radiotherapy. Method: Of 317 consecutive patients who un-

derwent BCS followed by radiotherapy since November 2007, 187 who received APBI and 122 who received WBI

were analyzed. Results: The local-only recurrence rate was 1.1% in the APBI group and 3.3% in the WBI group, and

the regional-only recurrence rate was 1.1% for APBI and 0.8% for WBI. Conclusions: The clinical efficacy of APBI

for local control after BCS was comparable to that of WBI ± RNI. Although this study was based on a small number of

patients with a short follow-up period, the feasibility of breast-conserving therapy using multicatheter brachytherapy to

achieve acceptable clinical outcomes was demonstrated.

Keywords: Breast Cancer; Personalized Radiotherapy; Sentinel Node; Partial Breast Irradiation; Regional Nodal

Radition

1. Introduction

Breast-conserving surgery (BCS) followed by whole

breast irradiation (WBI) is reportedly as effective as mas-

tectomy and has now become the standard of care for

treating patients with early-stage breast cancer [1,2]. Al-

though the Oxford meta-analysis demonstrated not only a

significant reduction of local recurrence but also an over-

all survival benefit with adjuvant breast radiation therapy

after BCS [3,4], 15% - 30% of patients who undergo

BCS refuse WBI [5-10]. The latter may be caused by po-

tential factors, including severe and long-term adverse

events, such as rib fracture, lung injury, and late cardio-

vascular toxicity, and by long-term daily visits to radia-

tion institutions for at least 5 - 6 weeks. However, no

subset of patients who should forego radiation therapy

after BCS has been identified [11-13] and local recur-

rence after BCS with WBI is most likely to occur in the

vicinity of the lumpectomy site [14-17]. Considering the

above, the efficacy and feasibility of accelerated partial

breast irradiation (APBI) as an alternative to WBI have

been evaluated in many Phases II and III studies [18-22].

In general, these rapid advances in APBI radiation

therapy have been introduced for patients for whom the

absence of positive nodes has been confirmed by senti-

nel-node (SN) biopsy (SNB), and the addition of regional

nodal radiation (RNI) to WBI is recommended for pa-

*This study was not funded by any public or private grant. All authors

declare no conflict of interest.

#Corresponding author.

Sentinel-Node-Driven Personalized Radiation Techniques Ranging from Partial Breast Irradiation to

Regional Nodal Radiation after Breast-Conserving Surgery

tients with ≥4 positive nodes confirmed by axillary

lymph node dissection (ALND). Although the National

Cancer Institute of Canada Clinical Trials Group (NCIC

CTG) MA.20 trial provided evidence that selected pa-

tients with 1 - 3 positive nodes benefit from RNI [23],

the number of positive nodes from ALND could still

provide important information with regard to several dif-

ferent approaches of radiotherapy. Recently, the Ameri-

can College of Surgeons Oncology Group trial (ACOSOG)

Z0011 [24] and the European Organisation for Research

and Treatment of Cancer (EORTC) 10981-22023 After

Mapping of the Axilla: Radiotherapy or Surgery (AMA-

ROS) trial [25] have shown that both ALND and radio-

therapy without ALND provide excellent regional con-

trol for SN-positive patients. However, there are several

issues such as indications for SNB in which ALND may

be omitted and the optimal radiation technique for axilla

and systemic treatment after surgery.

Patients who undergo BCS generally receive WBI at

our institution; however, we have introduced the concept

of “personalized radiation therapy after BCS” to deliver

radiation therapy based on the results of SNB and ALND

that ranges from APBI to WBI with RNI. We initiated a

prospective observational study on APBI with multi-

catheter brachytherapy after BCS. Data regarding the

long-term efficacy of our technique indicated a few in-

stances of local recurrence and a low rate of adverse

events [26,27]. Therefore, APBI, rather than WBI, is

primarily performed in node-negative patients. On the

other hand, an additional RNI is administered to patients

with ≥4 positive nodes.

In this study, we optimized our personalized radiation

therapy ranging from APBI to WBI with RNI for breast-

conserving treatment. First, the ability to select patients

with ≥4 positive nodes as candidates for RNI using

ALND was evaluated to assess the potential of persona-

lized radiotherapy in SN-positive patients without ALND.

Second, we compared different cohorts that received per-

sonalized radiation therapy on the basis of SNB and ALND.

2. Patients and Methods

2.1. Management of the Axilla and Personalized

Radiotherapy after BCS

Before breast surgery, several imaging studies, including

ultrasound (US), magnetic resonance imaging (MRI),

and positron emission tomography/computed tomogram-

phy (CT), were performed to evaluate axillary nodes for

metastasis [28]. When axillary nodes were suspected as

metastatic on the basis of any axillary imaging, US-

guided fine needle aspiration (FNA) was performed to

look for suspicious lymph nodes or axillary ultrasound

was performed to identify the largest visible node. When

axillary FNA revealed any evidence for metastases,

ALND was performed without SNB. Therefore, SNB

was performed in the absence of evidence for positive

axillary nodes. When SNs were revealed to be positive

for metastasis by frozen section analysis, ALND was per-

formed.

Multicatheter brachytherapy is considered to be an al-

ternative to WBI in patients with negative SNs. Patients

with ≥4 positive nodes were administered WBI with RNI

administered to Level III/supraclavicular nodes. Other

key APBI criteria were patient age of ≥40 years and max-

imum tumor diameter of ≤3.0 cm. This APBI registry

study was approved by the institutional review board of

our hospital. In WBI, patients received a total dose of 50

Gy in fractions of 2 Gy to the entire breast. Patients with

risks, such as positive margins and young age, received a

10-Gy boost to the tumor bed. Combined RNI with WBI

after BCS was performed in patients with ≥4 positive

nodes (Figure 1).

2.2. APBI with Multicatheter Brachytherapy

The technique details of multicatheter brachytherapy as

APBI have been previously reported [27,29]. The pro-

cedure involves insertion of applicators and delivery

doses simulated by preoperative CT. Applicators for in-

troduction of iridium wires were inserted according to

preoperative CT-based simulation (Figure 2). The lum-

pectomy cavity was identified on postoperative CT scans

with the help of hemoclips. The planned target volume

was defined as the estimated tumor volume plus a 20-mm

margin. Dose distribution analysis using dose-volume

histograms was performed on the basis of postoperative

CT. APBI was initiated on the day of primary surgery at

a dose of 32 Gy in 8 fractions over 5 - 6 days. Fractions

delivered twice daily were separated by an interval of at

least 6 h.

2.3. Assessment of Outcomes

The prospective follow-up policy was designed so that

Figure 1. Management of axilla and personalized radio-

therapy after breast-conserving surgery.

Sentinel-Node-Driven Personalized Radiation Techniques Ranging from Partial Breast Irradiation to

Regional Nodal Radiation after Breast-Conserving Surgery

Figure 2. Implantation of multicatheters and optimization of treatment regimens.

all patients had a predefined schedule, including clinical

examination every 3 - 4 months and annual mammo-

graphy. Contrast-enhanced breast MRI was also per-

formed every 12 months for the first 5 years of follow-up.

For analysis, ipsilateral breast tumor recurrence (IBTR)

was classified by clinical location in relation to the initial

lumpectomy cavity. Tumor-bed recurrence (true recur-

rence) was defined as recurrence of the treated cancer

within or immediately adjacent to the primary tumor site.

Failure elsewhere was defined as IBTR several centime-

ters from the primary site and was generally considered

to be a new primary cancer.

The chi-square test was used to analyze associations

among categorical variables with treatment groups. Stu-

dent’s unpaired t-test was used to analyze differences

between 2 sample means of continuous variables. A p

value of <0.05 was considered to indicate statistical sig-

nificance. Statview 5.0 (SAS Institute Inc. Cary, NC,

USA) was used to perform statistical analyses.

3. Results

3.1. Personalized Radiotherapy in SN-Positive

Patients without ALND

Between August 2008 and April 2013, SNB using blue

dye and radioisotopes was performed in 371 patients, and

Sentinel-Node-Driven Personalized Radiation Techniques Ranging from Partial Breast Irradiation to

Regional Nodal Radiation after Breast-Conserving Surgery

ALND was performed without SNB in 55 patients with

positive axillary FNA findings. Among the 371 patients

who underwent SNB, ALND was performed in 52

because of positive SNs. For the patients with ≥4 positive

nodes, RNI was combined with WBI for 12 (23.1%)

patients who underwent SNB followed by ALND and for

32 (58.2%) patients who underwent ALND and were

axillary FNA positive, respectively (Table 1). Therefore,

among the ALND patients, those with positive axillary

FNA findings had a significantly higher rate of require-

ment for RNI with WBI than those who underwent SNB

(p < 0.001).

3.2. SN-Driven Personalized Radiation Therapy

after BCS

A total of 317 consecutive patients who underwent BCS

followed by radiotherapy since November 2007 were

analyzed. Patients who received neoadjuvant chemo-

therapy were not enrolled in this study. A prospective

multicatheter brachytherapy study on these patients was

initiated in October 2008. A consort diagram is shown in

Figure 3. Table 2 lists the clinical, pathological, and

treatment-related characteristics of the 2 groups. The

mean age of the interstitial APBI patients (56.0 years)

was significantly higher than that of the WBI patients;

however, the difference was not significant (51.3 years, p <

0.05). APBI patients were more likely to have negative

margins than WBI patients (86.1% vs. 77.9%, respec-

tively; n.s.) and less likely to be node negative (86.6% vs.

Table 1. Potential of personalized radiotherapy in sentinel

node-positive patients without axillary lymph node dissec-

tion (August 2008-April 2013).

371 SNB followed

by ALND

ALND with axillary

FNA-positive status

Patients (n) 52 55

Positive nodes (mean) 2.4 (1 - 15) 8.7 (1 - 31)

Patients with ≥4 positive

nodes (n) 12 32

Patients who required

RNI (%) 23.1% 58.2%

Figure 3. Consort diagram of radiotherapy after breast-con-

serving surgery.

Table 2. Patient demographics and tumor characteristics.

APBI

(2008.10-2013.4)

WBI (+RNI)

(2007.11-2013.4) p-value

Age (mean) 56.0 (30 - 92 y/o) 51.3 (31 - 84 y/o)p < 0.05

<50 68 (36.4%) 58 (47.5%)

50 - 59 46 (24.6%) 38 (31.2%)

≥60 73 (39%) 26 (21.3%)

Follow-up

time (mean) 30.1 months 36.5 months p < 0.05

Pathological

diameter of invasive

tumor (mean)

12.1 mm

(0 - 38 mm)

12.3 mm

(0 - 27 mm) n.s.

Tis 18 (9.6%) 19 (15.6%)

T1 156 (83.4%) 93 (76.2%)

T2 13 (7.0%) 10 (8.2%)

Margin negative161 (86.1%) 95 (77.9%) n.s.

Grades II-III 31 (16.6%) 24 (19.7%) n.s.

ER positive 167 (89.3%) 105 (86.0%) n.s.

HER2 overexpressed17 (9.1%) 17 (13.9%) n.s.

Node negative 162 (86.6%) 93 (76.2%) p < 0.05

Adjuvant

chemotherapy 52 (27.8%) 42 (34.4%) n.s.

76.2%, respectively; n.s.). Further, patients in the APBI

cohort received adjuvant chemotherapy less frequently

than those in the WBI cohort (27.8% vs. 34.4%, respec-

tively; n.s.).

3.3. Recurrence and Survival Rates

The treatment outcomes for the 2 cohort groups are

shown in Table 3. With our follow-up period, locoer-

gional and distant recurrence were similar between the 2

groups. The local-only recurrence rate (IBTR) was 1.1%

in the APBI group and 3.3% in the WBI group. The re-

gional-only recurrence rate was 1.1% in the APBI cohort

and 0.8% in the WBI group. The characteristics of the

patients who experienced disease recurrence are also

described in Table 3. There were 4 patients with distant

recurrence only in the WBI cohort, and 1 death from

other causes among the 2 arms.

4. Discussion

Breast cancer is the most frequently occurring cancer in

Japan [30]. After the introduction of a mammography

program to screen for breast cancer, the ratio of patients

who underwent BCS increased, and this procedure be-

came the most common treatment for breast cancer after

2003 [31,32]. Breast-conserving therapy consisting of

BCS with radiotherapy has become the standard of care

for early-stage breast cancer because of equivalent local

control and survival for both BCT and mastectomy.

Sentinel-Node-Driven Personalized Radiation Techniques Ranging from Partial Breast Irradiation to

Regional Nodal Radiation after Breast-Conserving Surgery

Table 3. Locoregional control and distant recurrence.

APBI (n = 187) WBI (+RNI) (n = 122)

Locoregional Recurrence

Local only (IBTR) 2 (1.1%) 4 (3.3%)

Tumor bed recurrence 1 3

Failure elsewhere 1 1

Regional only 2 (1.1%) 1 (0.8%)

Local + regional 4 (2.1%) 5 (4.1%)

Distant Recurrence

First or concurrent 0 4 (3.3%)

After locoregional 0 0

Moreover, according to a recent report, BCT was associ-

ated with improvement in overall survival and disease-

specific survival regardless of age or hormone receptor

status [33]. Although EBCTCG data demonstrated that

omission of radiotherapy was one of the most relevant

factors associated with local recurrence and the rela-

tionship between effects on local control and breast can-

cer mortality showed that 1 death from breast cancer

could be avoided for every 4 local recurrences prevented

[3,4], 20% of patients who underwent BCS in Japan did

not receive WBI [34] because they had complete patho-

logically negative margins, occasional severe adverse

events because of WBI, and long-term daily visits to ra-

diation institutes.

Therefore, we previously initiated a prospective ob-

servational study of APBI with multicatheter brachy-

therapy as an alternative to WBI after BCS. Data regard-

ing the long-term efficacy of our technique in Japanese

breast cancer patients indicated a few instances of local

recurrence and a low rate of adverse events [25,26].

In this study, we optimized our personalized radiation

therapy ranging from APBI to WBI with RNI for breast-

conserving treatment. The results demonstrated that

clinical efficacy of APBI for local control after BCS was

comparable to that of WBI ± RNI at approximately 2.5

years of follow-up. The limitations of this study were

that it was not randomized, was based on only a small

number of participants, and covered only a short follow-

up period. However, to the best of our knowledge, this is

one of the largest observational studies from Asia to

demonstrate the feasibility of BCT using multicatheter

brachytherapy and with acceptable clinical outcomes.

In terms of “personalized radiotherapy after BCS”,

many other factors other than axillary node status need to

be considered because the risk of recurrence has been

reported to be associated with not only the number of

positive nodes but also various other factors (e.g., tumor

subtype was recently claimed to be a factor relevant to

local recurrence). The recent publication of the results of

the American College of Surgeons Oncology Group trial

Z0011 demonstrated equivalent survival and local con-

trol in patients with 1 - 2 positive SNs who were ran-

domly assigned to SNB alone or SNB followed by

ALND [23]. The EORTC AMAROS trial has also shown

that both ALND and axillary radiotherapy without ALND

provided excellent regional control for SN positive pa-

tients [24]. The number of positive nodes was still im-

portant for the personalization of radiotherapy through

several different approaches, from APBI to WBI with

RNI. However, the number of positive nodes present

cannot be determined if ALND is omitted.

When multi-image analyses and axillary FNA for sus-

picious lymph nodes have been introduced to select can-

didates for SNB, about 80% of SN-positive patients did

not require RNI. On the other hand, if axillary FNA re-

vealed metastatic lymph nodes, approximately 60% need-

ed RNI because they had ≥4 positive nodes. Therefore, to

extend “personalized radiotherapy after BCS”, we may

adopt the following strategy: APBI (or WBI in selected

patients) for SN-negative patients, WBI and ALND (or

APBI and ALND in selected patients) for SN-positive

patients, and WBI and ALND with or without RNI for

axillary FNA-positive patients. Additional research infor-

mation from several institutions is required, and random-

ized clinical trials to confirm the validity of the above

strategy are warranted.

5. Acknowledgements

The authors would like to thank Enago (www.enago.jp)

for the English language review. This study was pre-

sented in part at the 2013 the Japanese Breast Cancer

Society Annual Meeting.

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