cluding multicatheter interstitial
brachytherapy, balloon catheter brachytherapy, 3-di-
mensional conformal radiation therapy, and intraopera-
tive radiotherapy (IORT) have been reported. These
techniques, which are radiobiologically equivalent to
conventional WBI, are capable of accurate delivery of
radiation to the tissue surrounding the lumpectomy cavity.
Despite the absence of long-term data from any large
randomized clinical trial, there have been many prospec-
tive and retrospective studies providing encouraging re-
sults to support the view that APBI is a viable alternative
to WBI.
Among these techniques, multicatheter interstitial brachy-
therapy has been used the longest and most frequently,
but it requires considerable skill to deliver radiation to
the target. Breast brachytherapy using a balloon-based
brachytherapy device has been rapidly incorporated into
clinical practice, especially after it was granted Food and
Drug Administration (FDA) approval [16].
Although intracavitary techniques can achieve accu-
rate anatomic delivery with less of a learning curve for
medical personnel, they are considered by some to incur
the risk of increased toxicity in the skin and the chest
wall because of excessive doses received by those re-
gions, especially in Asian women, who generally have
small breasts [17]. More recently, concerns have been
reported on the use of balloon-based brachytherapy in
APBI. Compared with WBI, balloon-based brachyther-
apy in APBI shows a 2-fold increased risk for subsequent
mastectomy as well as postoperative and radiation-re-
lated complications after 5 years [18].
With regard to the detection of cancer cells and the
lack of necessity for additional surgery for catheter inser-
tion, it might be of benefit for patients to start APBI im-
mediately following lumpectomy with simultaneous
multicatheter insertion during primary surgery after free
margins are confirmed by frozen section analysis. Never-
theless, there is considerable risk of inaccurate radiation
administration because of the change in the lumpectomy
cavity during treatment, and of the side effect of delayed
wound healing. Therefore, the aim of this registry trial
was to report our preliminary findings of an assessment
of the safety and efficacy of APBI.
2. Patients and Methods
2.1. Patients
Eligibility criteria for patient selection included age 40
years, histologically documented breast cancer, unifocal
disease, maximum tumor diameter 3.0 cm on pre-
operative imaging [mammography, ultrasonography, and
breast magnetic resonance imaging (MRI)], negative mar-
gins, and sentinel nodes (SNs) negative for metastases
confirmed by frozen section analysis during surgery.
Eligibility criteria also excluded any prior treatment
including chemotherapy and hormonal therapy. All pa-
tients provided written informed consent, and this registry
study was approved by the institutional review board of
our hospital.
2.2. Treatment Schema
Before surgery, the insertion of applicators and delivery
doses were simulated by computed tomography (CT)
(Figures 1(a) and (b)). Sentinel node biopsy using a blue
dye and a radioisotope as well as lumpectomy with
tumor-free margins of approximately 1 cm were per-
formed. After confirmation of absence of metastases in
SNs by frozen section analysis, patients were enrolled in
the study. The surgical margins of the lumpectomy cavity
were also confirmed as being free by specimen mam-
mography and frozen section analysis, with surgical
hemoclips being placed at the 3, 6, 9, and 12 O’clock
positions. Applicators for the introduction of iridium
wires were inserted according to the preoperative CT-
based simulation (Figure 2).
The lumpectomy cavity was identified on postoperative
CT scans with the help of hemoclips. The clinical target
volume was the estimated tumor volume plus a margin of
10 mm. The planning target volume (PTV) was defined
as the estimated tumor volume plus a 20 mm margin, i.e.,
clipped margin plus 10 mm. Because PTV excluded the
skin, the skin over the tumor was partially removed to a
depth of approximately 5 mm. Dose distribution analysis
was performed on the basis of postoperative CT using
dose-volume histograms (Figure 3). Irradiation plans
were created using the Nucletron PLATO treatment
planning system (Version UPS: 11.3; Nucletron Trading
BV, Veenendaal, The Netherlands). The plans were
made by 2 dosimetrists (A.K. and T.S.) and approved by
a radiation oncologist (M.K.). Patients received high-
dose-rate (HDR) brachytherapy using a 192Ir source.
Radiation coverage of 4 Gy does not reach surround-
ing tissue < 5 mm from the skin surface and the posterior
chest wall, and a radiation dose of 3 Gy does not
directly expose these organs.
APBI was started on the day of primary surgery,
delivering 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
Copyright © 2012 SciRes. JCT
Intraoperative Open-Cavity Implant for Accelerated Partial Breast Irradiation Using High-Dose Rate Multicatheter
Brachytherapy in Japanese Breast Cancer Patients: A Single-Institution Registry Study
Copyright © 2012 SciRes. JCT
824
(a)
(b)
Figure 1. Preoperative simulation using CT scanning for insertion of applicators i n a relative ly small breast (a) and in a rela -
tively large breast (b).
all patients had a predefined schedule including clinical
examination every 3 - 4 months, and mammography and
contrast-enhanced breast MRI every 12 months. Post-
operative complications at each visit were documented
using the National Cancer Institute Common Termi-
nology Criteria for Adverse Events (CTCAE) version 3.0
[19].
The primary endpoint was prevention of damage to the
Intraoperative Open-Cavity Implant for Accelerated Partial Breast Irradiation Using High-Dose Rate Multicatheter
Brachytherapy in Japanese Breast Cancer Patients: A Single-Institution Registry Study
825
(a) (b)(c)
(f) (e)
(d)
Figure 2. Implantation of the multicatheter using the open-cavity method.
Figure 3. Optimization of treatment plans with dose-volume histograms.
conserved breast as assessed by acute and late toxicities:
radiation dermatitis, wound infection, skin breakdown,
and fat necrosis requiring multiple aspirations. Secondary
outcomes were ipsilateral breast recurrence (ILBR) and
cosmesis evaluated by the Harvard/National Surgical
Adjuvant Breast and Bowel Project (NSABP) criteria
[20]. Annual mammography and breast MRI were per-
formed for the detection of locoregional recurrence.
3. Results
3.1. Study Enrolment
A total of 157 consecutive patients with 160 lesions were
treated with BCT using intraoperative open-cavity im-
plantation (IOCI) from October 2008 to July 2012. The
median follow-up time was 918 days (52 - 1424 days).
Patient characteristics and demographics (mean age, 55.0
Copyright © 2012 SciRes. JCT
Intraoperative Open-Cavity Implant for Accelerated Partial Breast Irradiation Using High-Dose Rate Multicatheter
Brachytherapy in Japanese Breast Cancer Patients: A Single-Institution Registry Study
826
years) are listed in Table 1. The most common path-
ological finding was invasive ductal carcinoma. Most
tumors (92.5%) were 2 cm in diameter, whereas 88.1%
were hormone receptor positive. Thirteen patients (8.1%)
required excisional biopsy for a definitive diagnosis.
Most patients lived too far from our institution to permit
frequent follow-up.
Table 1. Patient demographics (n = 157) and tumor charac-
teristics (n = 160).
Characteristics n %
Mean age (range, years) 55.0 (30 - 92)
<40 years 9 5.7
40 - 69 years 133 84.7
>70 years 15 9.6
Pathological tumor stage
pTis 17 10.6
pT1 131 81.9
pT2 12 7.5
Grading (nuclear grade)
Grade I 107 66.9
Grade II 31 19.4
Grade III 1 0.6
NA 21 13.1
Number of lymph node involved
0 135 84.4
1 - 3 17 10.6
>3 8 5.0
Margins at first excision
Free 142 88.7
Suspicious 7 4.4
DCIS only 11 6.9
Hormone receptor status (>10%)
ER+ or PgR+ 141 88.1
ER and PgR 19 11.9
Her2/neu status
+ (IHC 3+ or FISH+) 15 9.4
(IHC 3 and FISH) 128 80.0
NA 17 10.6
Abbreviations: DCIS, ductal carcinoma in situ; ER, estrogen receptor; PgR,
progesterone receptor. Her2/neu, human epidermal growth factor receptor 2;
IHC, immunohistochemistry; FISH, fluorescence in situ hybridization.
Overall, 23 patients (14.6%) did not meet the criteria
because of various factors, including 25 with SNs positive
for metastases, 9 under 40 years of age, and 1 who had
previously received WBI before APBI. 149 patients (94.3%)
underwent adjuvant systemic therapy. 137 patients (86.7%)
received hormonal therapy, 48 (30.4%) received che-
motherapy, and 9 (5.7%) were administered adjuvant tras-
tuzumab. Two patients underwent additional WBI after
APBI because of the high risk of local recurrence.
3.2. Implantation Valuables and Dosimetric
Analyses
The mean number of applicators used was 6.5 (2 - 15)
and the distribution of row for implantation was 1 per 62
lesions (38.8%), 2 for 88 lesions (50.0%), and 3 for 10
lesions (6.2%). Tabular dose-volume histograms were
obtained for all patients. Dose hotspots according to the
volume encompassed by the 150% of isodose surface,
dose homogeneity index, and organs at risk are shown in
Table 2.
3.3. Adverse Events: Acute and Late Toxicities
All acute and late toxicities were generally mild, with no
grade 3 or 4 toxicities, and no patient required secondary
surgery because of toxicity. Table 3 presents an analysis
of variables associated with Grade 0 vs. Grade 1 - 2 skin
toxicity.
The distribution of patients according to late skin tox-
icity score at final follow-up was also analyzed. There
were no cases of Grade 3 or 4 skin toxicity, but 2 patients
developed seroma requiring multiple aspirations because
of fat necrosis, and 10 patients developed wound infec-
Table 2. Dosimetric parameters and doses according to
organs at risk.
PTV V100 V150 DNR
Mean
volume
(cm3)
35.8 29.2 9.6 0.30
Min
volume
(cm3)
6.5 2.6 1.2 0.10
Max
volume
(cm3)
137.1 106.5 59.3 0.56
Breast
(volume, cm3)
Cavity*
(volume, cm3)
Skin
(max dose, Gy)
Lung
(max dose, Gy)
Mean 322.1 18.2 2.0 2.1
Min 47.8 0.3 1.0 0.4
Max 949.4 75.4 12.4 3.5
Abbreviations: PTV, planning target volume; V100/150, volume encompassed
by the 100%/150% isodose surface; DNR, dose nonuniformity ratio
(V150/V100). *clipped margin.
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Intraoperative Open-Cavity Implant for Accelerated Partial Breast Irradiation Using High-Dose Rate Multicatheter
Brachytherapy in Japanese Breast Cancer Patients: A Single-Institution Registry Study
Copyright © 2012 SciRes. JCT
827
registry system and had a relatively short follow-up
period, the number of patients enrolled was larger than
that in previously published reports on Asian populations.
tion followed by wound breakdown. However, most pa-
tients achieved either good or excellent cosmetic out-
come (Figure 4).
HDR multicatheter brachytherapy is the most fre-
quently used method for APBI, and a balloon-type model
is commercially available in the US. After approval of
this device by FDA, there has been a dramatic increase in
the use of the implantable balloon brachytherapy catheter
[21]. Balloon-type brachytherapy may require less of a
learning curve for medical personnel and have high
reproducibility, but is not suitable for most Japanese
3.4. ILBR and Patterns of Failure
At final follow-up, 157 patients remained alive. One
patient died from a nonoriginal breast cancer-related
cause without any local recurrence, and local failure
occurred in 3 patients, including 2 ILBRs (1 tumor bed
failure and 1 distant-site in-breast failure) and 1 lymph
node recurrence without distant metastasis.
One of these ILBRs was regarded as a tumor bed
failure observed adjacent to the initial lumpectomy cavity
12 months after APBI in a patient who had positive
lymph nodes and excised margin involvement. After a
second breast-conserving surgery with WBI, there has
been no sign of recurrence. The other recurrence regarded
as a distant-site in-breast failure was revealed as a tumor
growing approximately 1 cm distant from the lumpectomy
cavity and which had already been observed on contrast-
enhanced MRI before initial surgery. Salvage glandectomy
was performed 24 months after initial surgery.
Table 3. Acute and chronic toxicity after treatment.
Acute Toxicity (CTCAE v3.0[19]) N %
Hemorrhage
Grade 1 2 1.3
Wound infection
Grade 2 1 0.6
Radiation dermatitis
Grade 1 18 11.3
Grade 2 4 2.5
Chronic Toxicity
Seroma requiring multiple aspirations or fat
necrosis 2 1.3
Wound infection with wound breakdown 10 6.3
4. Discussion
This observational study has confirmed that APBI using
multicatheter brachytherapy is safe and represents an
effective alternative to WBI followed by lumpectomy in
Japanese breast cancer patients. Although this was a
single-institution study using a consecutive patient
Figure 4. Patients achieving good or excellent cosmetic outcome after APBI.
Intraoperative Open-Cavity Implant for Accelerated Partial Breast Irradiation Using High-Dose Rate Multicatheter
Brachytherapy in Japanese Breast Cancer Patients: A Single-Institution Registry Study
828
women, who have relatively small breasts. Although the
balloon-type method can deliver a more accurate radi-
ation dose, especially in the area up to 1 cm beyond the
lumpectomy cavity, the actual radiation field would be
restricted by the distance between the skin and chest wall,
especially in patients with small breasts.
Catheter insertion is generally performed on confir-
mation of a definitive pathology report. If margin status
and nodal involvement are examined using frozen section
analysis, catheter insertion can be done during primary
surgery and radiation therapy can start immediately
postoperatively. The aims of IORT are the same as ours
in terms of the management of lumpectomy margins.
This is more convenient for patients, but APBI should be
started without waiting for confirmation of detailed
pathology.
The benefit of this new method is that catheter inser-
tion is based on preoperative CT dosimetric analysis, but
accurate and safe insertion could also be achieved using
an open cavity method. APBI offers more efficacious
tumor control than postoperative WBI because several
reports have found that fluid in the lumpectomy cavity is
conducive to the growth of residual cancer cells [22], and
also that delayed radiation therapy might offer less tumor
control, especially in patients receiving chemotherapy
[23,24]. However, several safety issues must be ad-
dressed: 1) This technique delivers radiation immediately
after surgery, leading to delay in the wound-healing
process. According to IORT data about safety, that delay
might not have to be concerned [25-27]; 2) This study
was conducted in an Asian population and its findings
cannot yet be generalized; 3) Infection is an issue be-
cause of the relatively long length of the catheters used.
In this small cohort, all adverse events were mild and
second surgery was not required in any case. Moreover,
our cohort included 2 patients receiving WBI after APBI
and 1 patient who previously received WBI.
Smith et al. recently reported a double opportunity to
perform mastectomy on patients receiving APBI rather
than on those receiving WBI [18]. However, this report
was based on a retrospective review of a Medicare billing
claims database and did not address the reasons for
mastectomy. In the US, balloon-type APBI is the most
common procedure in brachytherapy-based APBI. The
present report was not based on prospective competitive
trials, and cannot therefore be applied to other APBI
methods. APBI might offer better local control than WBI
because of the direct delivery of radiation exposure to the
lumpectomy cavity. Moreover, APBI can avoid injury to
normal tissues such as the skin, ribs, lung, heart, and
chest wall, i.e., it is a safer procedure than WBI. There
are several reports including randomized clinical trials on
the efficacy of APBI [28-30]. However, we await the
results of a large trial comparing the efficacy of APBI
with WBI, i.e., NSABP B39/Radiation Therapy On-
cology Group 0413 Phase III trial. We did not publish
our data until the median follow-up period had passed
2.5 years, because the median follow-up period of most
reports on APBI-induced late toxicities was longer than
20 months [31-33] and the peak hazard of recurrence is
between 12 and 24 months [34]. Hazard likelihood de-
creases steadily between 2 and 5 years [34].
Our study included 2 cases of ipsilateral breast tumor
recurrence (IBTR) but only 1 of these was a true recur-
rence—the so-called tumor bed recurrence. The other
was located distant to the lumpectomy cavity, which was
evident in contrast breast MRI before the first surgery
(Figure 3). Therefore, it is important to confirm unifocal
disease at the time of the first surgery.
According to the Early Breast Cancer Tria lists Col-
laborative Group database, 1 death from breast cancer
could be avoided for every 4 recurrences, the so-called
“1-in-4 rule” [4,5]. IBTR after APBI should be avoidable.
There are several factors influencing local recurrence,
including patient age, tumor subtype, margin status,
tumor features (size, unicentricity, existence of extensive
intraductal components), nodal status, types of systemic
therapy [35-37]. Before obtaining the results from a large
randomized trial, the correct selection of candidates
would be crucial after consideration of the above factors
[38]. The biological features of the tumor would be also
related to IBTR risk [39-42] and we might have to
consider the use of APBI on the basis of individual
factors. Further research on APBI using the IOCI tech-
nique is needed to establish its clinical efficacy.
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 2010 the American Society of Clini-
cal Oncology-Breast Annual Meeting (poster) and at the
2011 European Breast Cancer Meeting (poster).
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829
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