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Accelerated Breast Irradiation after Breast-Conserving
Surgery for Early Stage Breast Cancer and Breast
Brachytherapy as Boost with Whole-Breast Irradiation
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Medical Policy
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Title:
Accelerated Breast Irradiation After Breast-Conserving
Surgery for Early Stage Breast Cancer and Breast
Brachytherapy as Boost with Whole-Breast Irradiation
Professional
Original Effective Date: July 1, 2007
Revision Date(s): June 29, 2010;
May 27, 2013; December 11, 2013;
May 28, 2015; January 1, 2016
Current Effective Date: May 28, 2015
Institutional
Original Effective Date: July 1, 2007
Revision Date(s): June 29, 2010;
May 27, 2013; December 11, 2013;
May 28, 2015; January 1, 2016
Current Effective Date: May 28, 2015
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DESCRIPTION
Radiation therapy is the standard care for patients with breast cancer undergoing breastconserving surgery (BCS), as it reduces recurrences and lengthens survival. The conventional
radiation therapy regimen consists of approximately 25 treatments of 2 Gray (Gy; a measure of
absorbed radiation dose) delivered over 5 to 6 weeks. Nonetheless, not all patients undergo
radiation therapy following BCS; the duration and logistics of treatment may be barriers for some
women. Accelerated radiotherapy approaches have been proposed to make the regimen less
burdensome for patients with early-stage breast cancer at low risk of recurrence:
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Surgery for Early Stage Breast Cancer and Breast
Brachytherapy as Boost with Whole-Breast Irradiation
•
•
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Accelerated (also called hypofractionated) whole-breast irradiation (AWBI) reduces the
number of fractions and the duration of treatment to about 3 weeks. This approach has
been commonly used in Canada and Europe.
Accelerated partial-breast irradiation (APBI) irradiates a limited part of the breast in and
close to the tumor cavity. By reducing the area irradiated, fewer treatments are needed,
and the total treatment takes about 1 week. Several approaches can be used to deliver
APBI, including interstitial brachytherapy, balloon brachytherapy, external beam
radiotherapy, or intraoperative radiotherapy (which occurs on only 1 day).
The critical question is whether these three approaches are equivalent in outcomes and adverse
events to the conventional radiation therapy regimen.
Accelerated Whole Breast Irradiation
The overall body of evidence on AWBI compared with conventional whole-breast irradiation
suggests that local recurrence rates with AWBI are not worse than with conventional wholebreast irradiation in patients meeting criteria of the Canadian trial, with a noninferiority margin of
5%. Patient selection is important, and at this point, only patients similar to those in the
Canadian trial should be considered for this therapy. Thus, AWBI may be considered medically
necessary for these patients with clinical characteristics noted in the medically necessary policy
statement. Outcomes could differ in women with other disease characteristics.
Brachytherapy Boost with Whole-Breast Irradiation
For patients treated with whole-breast external-beam radiation and BCS, local boost irradiation
via interstitial or balloon brachytherapy is likely to result in equivalent outcomes compared with
local boost given by external-beam. This is based on results from nonrandomized comparative
studies, a TEC Assessment, and specialty society guidelines. As a result, interstitial or balloon
brachytherapy may be considered medically necessary for these patients when used as local
boost irradiation.
Accelerated Partial Breast Irradiation
Overall, the body of evidence on interstitial accelerated partial-breast irradiation (APBI) compared
with conventional whole-breast irradiation is weak; evidence is extremely weak (ie, no
randomized studies) for balloon brachytherapy. The strongest published evidence is on
intraoperative radiotherapy. Five-year results of one randomized controlled trial (TARGIT-A)
showed increased ipsilateral local recurrence with APBI compared with whole-breast
radiotherapy. In another randomized controlled trial that used a different technology (ELIOT),
recurrence rate with intraoperative radiation therapy was statistically greater than with wholebreast irradiation. It is becoming increasingly clear that each type of APBI should be judged on
its own merits, and studies comparing different APBI techniques to each other, as well as to
whole-breast irradiation, are needed. A number of large RCTs are underway. However, based on
current evidence, APBI is considered investigational for treatment of early stage breast cancer
after BCS, except when interstitial or balloon brachytherapy is used as local boost with wholebreast external-beam radiation after BCS, as described above.
Noninvasive Breast Brachytherapy
Evidence for noninvasive breast brachytherapy using Accuboost® to provide boost radiation to
the tumor bed is very weak; therefore this technique is considered investigational.
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Background
Breast Conservation Therapy
For patients diagnosed with stage 1 or 2 breast tumors, survival after breast-conservation
therapy (BCT) is equivalent to survival after mastectomy. BCT is a multimodality treatment that
initially comprised breast-conserving surgery (BCS) to excise the tumor with adequate margins,
followed by whole-breast external-beam radiation therapy (EBRT) administered as 5 daily
fractions per week over 5 to 6 weeks. Local boost irradiation to the tumor bed often is added to
whole-breast irradiation to provide a higher dose of radiation at the site where recurrence most
frequently occurs. For some patients, BCT also includes axillary lymph node dissection, sentinel
lymph node biopsy, or irradiation of the axilla. A number of randomized controlled trials (RCTs)
have demonstrated that the addition of radiotherapy after BCS reduces recurrences and
mortality. In an expanded update of an individual-level meta-analysis, the Early Breast Cancer
Trialists’ Collaborative Group (EBCTCG) reported that radiotherapy halved the annual recurrence
rate after 10 years for women with node-negative disease (n=7287), from 31.0% for those not
receiving radiotherapy to 15.6% for those receiving it.(1) It also reduced the 15-year risk of
breast cancer death from 20.5% to 17.2% (p=0.005). For women with node-positive disease
(n=1050), radiotherapy reduced the 1-year recurrence risk from 26.0% to 5.1%. Radiotherapy
also reduced the 15-year risk of breast cancer death from 51.3% to 42.8% (p=0.01).
Consequently, radiation therapy is generally recommended following BCS. A potential exception is
for older women at low risk of recurrence. For example, current National Comprehensive Cancer
Network (NCCN) guidelines state that women aged 70 or older may omit radiotherapy if they
have estrogen-receptor positive, T1 tumors, clinically negative lymph nodes, and plans to take
adjuvant endocrine therapy.(2) However, a 2012 study has raised questions about this
recommendation.(3)
Controversy continues on the length of follow-up needed to determine whether APBI is
equivalent to whole-breast irradiation (for more information, see the 2013 TEC Assessment on
Accelerated Radiotherapy after Breast-Conserving Surgery for Early Stage Breast Cancer).(4)
Because recurrences are relatively rare among low risk early breast cancer patients, it may take
considerable time for enough recurrences to occur to provide sufficient power for comparing
recurrence rates across radiotherapy approaches. Additionally, radiation-induced adverse
cardiovascular effects and radiation-induced non-breast cancers tend to occur 10 or more years
after treatment.(5-7) For accelerated whole-breast irradiation (AWBI), some 10-year data are
available. However, for newer approaches, the issue may be resolved by statistical issues rather
than biological ones. For example, in the large NSABP-39/RTOG 0413 trial comparing wholebreast irradiation versus APBI (see Table 2), enrollment has reached the revised target of 4214.
Trial duration (presumably barring early termination) is determined by the occurrence of a
prespecified number (175) of in-breast recurrences. The researchers expect that reaching that
number of recurrences will take approximately 10 years.
Currently, most patients diagnosed with stage 1 or 2 breast cancer are offered a choice of BCT or
modified radical mastectomy, but BCT is selected less often than expected. Studies have shown
that those living furthest from treatment facilities are least likely to select BCT instead of
mastectomy and most likely to forgo radiation therapy after BCS.(8-10) A study using data from
the National Cancer Institute’s Surveillance, Epidemiology, and End Results tumor registries from
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Surgery for Early Stage Breast Cancer and Breast
Brachytherapy as Boost with Whole-Breast Irradiation
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1992 to 2002 examined how many women with early stage (1 or 2) breast cancer received
radiotherapy within 4 months following BCS.(11) After adjusting for age, they found that in 2002,
30.8% of Caucasian women and 44.7% of African-American women had not received
radiotherapy. Furthermore, these rates had increased from 24.7% for Caucasian and 34.0% for
African-American women in 1992.
Given that duration and logistics appear to be barriers to completion of treatment, there has
been interest in developing shorter radiotherapy regimens. Two approaches have been explored.
The first method is to provide the same dose to the whole breast in a shorter time by increasing
the dose provided per treatment (hypofractionation). This approach was initially avoided out of
concern that increasing doses might induce more severe adverse events from radiation exposure,
thus tipping the balance between benefits and harms. More recent research, some of which is
highlighted below, has allayed most of these concerns. AWBI has been adopted widely in Canada
and Europe.
The second approach to reducing radiotherapy treatment time is accelerated partial-breast
irradiation (APBI). It differs from conventional whole-breast irradiation in several ways. First, the
radiation only targets the segment of the breast surrounding the area where the tumor was
removed, rather than the entire breast. This approach was based in part on the finding that
recurrences are more likely to occur close to the tumor site rather than elsewhere in the breast.
Second, the duration of treatment is 4 to 5 days (or 1 day with intraoperative radiotherapy)
rather than 5 to 6 weeks, because radiation is delivered to the tumor bed in fewer fractions at
larger doses per fraction. Third, radiation dose is intrinsically less uniform within the target
volume when APBI uses brachytherapy (ie, the implantation of radioactive material directly in the
breast tissue).
The major types of radiotherapy used after BCS are outlined in Table 1. They differ in their
techniques, instrumentation, dose delivery, and possibly in their outcomes.
Table 1. Major Types of Radiation Therapy Following Breast-Conserving Surgerya
RT Type
Conventional wholebreast irradiation
Accelerated wholebreast irradiation
Interstitial APBIb
Balloon APBIc
External Beam APBId
Intraoperative APBIe
Accelerated?
Whole or
pPrtial
Breast
EBRT or
Brachytherapy
Approximate
Duration of
Treatment
No
Whole
EBRT
5-6 wks
Yes
Whole
EBRT
3 wks
Published
RCTs (length
of follow-up
in yrs)
Multiple; >15
yrs
4; 10 yrs
Yes
Yes
Yes
Yes
Partial
Partial
Partial
Partial
Brachytherapy
Brachytherapy
EBRT
Not applicable
1 wk
1 wk
1 wk
1 day
2; 5.4 yrs
0
0
1; 5 yrs
APBI: accelerated partial breast irradiation; EBRT: external-beam radiation therapy; RCT: randomized controlled trial
a
Noninvasive breast brachytherapy using Accuboost® has been described by the manufacturer as capable of delivering
APBI, but no studies on this indication were found.
b
Interstitial brachytherapy entails placement of multiple hollow needles and catheters to guide placement of the
radioactive material by a remote afterloading device. It is more difficult to perform than other types of brachytherapy
and has a steep learning curve.
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c
Balloon brachytherapy, eg, Mammosite®, entails inserting a balloon into the tumor bed, inflating the balloon,
confirming its position radiographically, and then using a remote afterloader to irradiate the targeted area. Some
brachytherapy systems combine aspects of interstitial and balloon brachytherapy.
d
External-beam APBI is delivered in the same way as conventional or accelerated whole-breast radiotherapy but to a
smaller area. All 3 external-beam regimens can use 3-dimensional conformal radiation therapy or intensity-modulated
radiation therapy.
e
Intraoperative APBI is performed during breast-conserving surgery with a single dose of radiation delivered to the
exposed tumor bed.
To appreciate the differences among radiotherapy techniques, it is useful to understand
attributes of radiation delivery. The goals of cancer radiotherapy are to provide the tumor or
tumor bed with a high dose of homogeneous radiation (i.e., all parts of the tumor cavity receive
close to the targeted dose). Areas adjacent to the tumor may be treated with a lower dose of
radiation (e.g., with whole-breast irradiation) to treat any unobserved cancerous lesions).
Radiation outside the treatment area should be minimal or nonexistent. The goal is to target the
tumor or adjacent areas at risk of harboring unseen cancer with an optimum dose, while avoiding
healthy tissues.
Brachytherapy Boost with Whole-Breast Irradiation
Brachytherapy also can be used as an alternative to EBRT to deliver boost radiation therapy
combined with whole-breast EBRT. Most studies of local boost brachytherapy use temporarily
implanted needles, wires, or seeds after patients have recovered from surgery and completed
whole-breast radiation therapy.
Regulatory Status
The MammoSite® Radiation Therapy System (Proxima Therapeutics; Alpharetta, GA), the first
device specifically designed for breast brachytherapy,(12) was FDA-cleared under a 510(k)
premarket notification in 2002. Its intended use is ‘‘to provide brachytherapy when the physician
chooses to deliver intracavitary radiation to the surgical margins following lumpectomy for breast
cancer.’’(13)
Since 2002, several other devices for breast brachytherapy have been FDA-cleared for marketing
through the 510(k) process as substantially equivalent to predicate devices (e.g., Axxent®
Electronic Brachytherapy System [Xoft; San Jose, CA], Strut-Adjusted Volume Implant [SAVI™]
Applicator Kit [Biolucent (now Cianna Medical); Aliso Viejo, CA], Contura® Multi-Lumen Balloon
Source Applicator for Brachytherapy [SenoRx; Aliso Viejo, CA], ClearPath™ Adjustable MultiCatheter Source Applicator [North American Scientific; Chatsworth, CA], Intrabeam® System [Carl
Zeiss Surgical, GmbH; Oberkochen, Germany]). Each includes an FDA-required warning that the
safety and effectiveness of the device “as a replacement for whole-breast irradiation in the
treatment of breast cancer has not been established.”
Although the Intrabeam® System (discussed further below; see Intraoperative Brachytherapy) is
subject to FDA regulation, it does not fall under the regulatory purview of the U.S. Nuclear
Regulatory Commission. In some states, participation of radiation oncologists in delivering
radiation is not required.
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Brachytherapy as Boost with Whole-Breast Irradiation
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POLICY
When using radiation therapy after breast-conserving surgery for early stage breast
cancer:
A.
Accelerated whole breast irradiation may be considered medically necessary
for patients who meet the following conditions:
1.
2.
3.
Invasive carcinoma of the breast. Exclude disease involving the margins of
excision; tumors >5 cm in diameter; breast width >25 cm at posterior
border of medial and lateral tangential beams.
Negative lymph nodes
Technically clear surgical margins
B.
Accelerated whole breast irradiation is considered experimental /
investigational in all other situations involving treatment of early stage breast
cancer after breast-conserving surgery.
C.
Interstitial or balloon brachytherapy may be considered medically necessary
for patients undergoing initial treatment for stage I or II breast cancer when
used as local boost irradiation in patients who are also treated with breastconserving surgery and whole-breast external-beam radiotherapy.
D.
Accelerated partial breast irradiation (APBI), including interstitial APBI, balloon
APBI, external beam APBI, noninvasive brachytherapy using Accuboost®, and
intra-operative APBI, is considered experimental / investigational.
E.
Noninvasive brachytherapy using Accuboost® for patients undergoing initial
treatment for stage 1 or 2 breast cancer when used as local boost irradiation in
patients who are also treated with BCS and whole-breast external-beam
radiotherapy is considered experimental / investigational.
Policy Guidelines
Electronic brachytherapy is considered a type of balloon brachytherapy that can be used
to deliver APBI.
RATIONALE
The most recent literature search update covered the period through November 3, 2014.(4)
Accelerated Whole-Breast Irradiation
Four randomized controlled trials (RCTs) and 1 nonrandomized study compared accelerated
whole-breast radiotherapy to 5-week whole-breast radiotherapy.(14-19) Two RCTs directly
compared a 5-week to a 3-week regimen.(15,17,18) Both were prospective noninferiority trials
with noninferiority margins of 5 percentage points for local or local-regional recurrence in the
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accelerated group at 5 (1-sided α=0.025(15) or 0.05(17)) or 10 years (1-sided α=0.025[18]).
Although the trials differed in specific fractionation schedules and patient characteristics, they
reported similar ipsilateral local recurrence rates (i.e., cancer recurrence in the same breast)
across treatment arms.
The first RCT (Standardisation of Breast Radiotherapy [START] B; 2008), from the U.K., included
women with stage 1-3 tumors (N=2215).(15) Approximately 75% of the women had negative
lymph nodes, and approximately 42% had a radiation boost to the tumor bed. Randomization
was stratified for hospital, type of surgery (8% underwent mastectomy), and plans for tumor bed
boost. Systemic therapy, primarily tamoxifen, was used by some patients and appeared to be
evenly distributed across treatment groups. Treatment arms compared a total dose of 40 Gy in
15 fractions over 3 weeks to 50 Gy in 25 fractions over 5 weeks. The primary efficacy outcome
was local-regional relapse (relapse in ipsilateral breast or chest wall and or in ipsilateral axilla or
supraclavicular fossa if previously irradiated) at 5 years. At median follow up of 6.0 years
(interquartile range [IQR], 5.0-6.2), estimated 5-year local-regional tumor relapse rate was 2.2%
(95% confidence interval [CI], 1.3 to 3.1) in the 40 Gy group and 3.3% (95% CI, 2.2 to 4.5) in
the 50 Gy group, for an absolute difference of -0.7% (95% CI: -1.7% to 0.9%). Hazard ratios
(HRs) for 40 Gy accelerated whole-breast radiotherapy versus conventional whole-breast
radiotherapy were not statistically significant (using the log-rank test) for local or local-regional
relapse. There were statistically significant differences between the 2 treatment regimens for
distant relapse and overall survival (OS), with relapse less frequent and survival longer for the 40
Gy accelerated whole-breast irradiation (AWBI) group. This unexpected difference between
treatment arms began to appear at about 1 year; trial authors speculated that the difference may
have been due to chance and may have changed with longer follow-up.
Subsequent publications provided additional results for both START trials (i.e., START A, which
compared two 5-week whole breast radiotherapy regimens, and START B). Hopwood et al (2010)
examined patient-reported breast, arm, and shoulder symptoms, as well as body image, over 5
years of follow-up.(20) There was no evidence that providing radiotherapy in fewer, larger
fractions increased the incidence of these adverse events or adversely affected body image.
Haviland et al (2013) reported 10-year relapse, survival, and adverse event outcomes (median
follow-up, 9.9 years [IQR, 7.5-10.1]).(21) Local-regional relapse did not differ significantly
between the 2 treatment groups: 4.3% (95% CI, 3.2 to 5.9) for the AWBI group and 5.5% (95%
CI, 4.2 to 7.2) for the standard whole-breast radiotherapy group (HR=0.77 [95% CI, 0.51 to
1.16]; p=0.21). However, breast shrinkage, telangiectasia, and breast edema were significantly
less common in the AWBI group. These effects were assessed by physician, photographic
comparison with baseline, and patient report. Distant relapse (p=0.014), any breast-cancerrelated event (local, regional, or distant relapse, breast cancer death, contralateral breast cancer)
(p=0.022), and all-cause mortality (p=0.042) were significantly less common in the AWBI group.
The second RCT, from Canada, compared AWBI versus whole-breast irradiation in women with
lymph node-negative stage 1-3 tumors.(17,18) Of 2429 eligible patients, 51% agreed to
participate in the trial. Intention-to-treat (ITT) analysis was used. Treatment arms compared a
total dose of 42.5 Gy in 16 fractions over 3 weeks to 50 Gy in 25 fractions over 5 weeks. Boost
radiation was not used. Five-year local recurrence-free survival was 97.2% in the accelerated
arm and 96.8% in the conventional arm (absolute difference: 0.4% [95% CI, -1.5% to 2.4%).
Ten-year local recurrence was 6.2% for the accelerated arm and 6.7% for the conventional arm
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(absolute difference: -0.5% [95% CI, -2.5% to 3.5%). At 5 or 10 years, local recurrence rates
with AWBI were not worse than conventional WBI, when applying a noninferiority margin of 5%.
In prespecified subgroup analyses, treatment effects were similar by age, tumor size, estrogenreceptor status, and chemotherapy use (48% had no systemic therapy). However, local
recurrence at 10 years for patients with high-grade tumors (post hoc analysis[22]) was 4.7% for
the conventional WBI arm and 15.6% for the AWBI arm. The absolute difference was -10.9
percentage points (95% CI, -19.1 to -2.8; test for interaction, p=0.01).
A 2010 Cochrane review entitled “Fraction Size in Radiation Treatment for Breast Conservation in
Early Breast Cancer”(23) included a systematic review based on the 4 RCTs described above. The
authors concluded:
“We have evidence from four low to medium quality randomised trials that using
unconventional fractionation regimens (greater than 2 Gy per fraction) does not affect
local recurrence, is associated with decreased acute toxicity and does not seem to
affect breast appearance or late toxicity for selected women treated with breast
conserving surgery.”
A large retrospective study compared cardiac toxicity in patients with left-sided, early stage
breast cancer who received conventional versus accelerated whole breast radiation
therapy.(24,25) Chan et al (2014) in Canada reviewed medical database records of 2706 patients
who received conventional (n=2221) or accelerated (n=485) whole breast irradiation. Cardiotoxic
chemotherapy regimens were similar between groups. At median follow-up of 14.2 years, there
was no statistical difference in cardiac hospitalization or cardiac mortality, breast cancer
mortality, or overall mortality. Results were similar for 2628 patients with right-sided tumors. This
study was not designed to capture outcomes of moderate or mild cardiac toxicity.
Several authors have examined AWBI in patients with ductal carcinoma in situ (prospective
cohort studies(26) and retrospective reviews(27,28) [total N=2152]). With median follow-up of 9
years, one retrospective study reported estimated 10-year local recurrence-free survival of 89%
in 638 patients who received AWPI and 86% in 971 patients who received conventional whole
breast irradiation (log rank test, p=0.03).(27) This result requires replication in prospective,
randomized trials before deviation from patient selection criteria derived from the Canadian study
(described above) can be considered.
Section Summary
The overall body of evidence on AWBI compared with conventional whole-breast irradiation
indicates that local recurrence rates with accelerated whole-breast radiotherapy were not worse
than conventional whole-breast irradiation in patients meeting criteria of the Canadian trial, when
applying a noninferiority margin of 5%. Longer follow-up is needed for the U.K. trial. Based on
14-year retrospective data, severe cardiac toxicity with AWBI for left-sided breast cancers may
not be increased compared with conventional WBI.
Patient selection is key, and at this point, only patients similar to those in the Canadian trial
should be considered for this therapy. Outcomes could differ in women with other disease
characteristics. Patients in this trial all had invasive carcinoma of the breast with negative lymph
nodes and surgical margins, and they did not have a radiotherapy boost to the tumor site.
Exclusion criteria included “invasive disease or ductal carcinoma in situ (DCIS) involving the
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margins of excision, tumors that were larger than 5 cm in diameter, and a breast width of more
than 25 cm at the posterior border of the medial and lateral tangential beams, which could
increase the heterogeneity of the radiation dose to the breast.” Lymph node status was
determined by axillary dissection, but subsequent reports suggested that sentinel lymph node
biopsy is likely to be as effective (e.g., see James et al [2010][23]). Despite the fact that 71% of
women were estrogen-receptor positive, only 41% took tamoxifen.
Patients selecting accelerated whole-breast radiotherapy should be told that although
current evidence on this radiotherapy regimen is strong, it is not as strong as that for
conventional whole-breast irradiation. Additional RCTs or longer follow-up could uncover
additional concerns. Some potential adverse events, such as cardiac ischemia, may take
longer to become evident. This accelerated whole-breast regimen has been widely used
outside the United States without substantial reports of major adverse events. Potential
patients should be carefully selected and given full information.
Accelerated Partial-Breast Irradiation
Six RCTs(29-38) and 9 nonrandomized comparative studies(39-50) evaluated interstitial,
external-beam, or intraoperative accelerated partial-breast irradiation (APBI) compared with
conventional whole-breast irradiation. Several of these studies were included in a 2014 metaanalysis by Kong et al that compared APBI (various methods) with whole-breast irradiation.(51)
Literature was searched through June 2012, and 11 comparative studies were included (4 RCTs,
2 retrospective and 5 prospective cohort studies). APBI methods included interstitial
brachytherapy (5 studies), balloon brachytherapy (3 studies), intraoperative radiotherapy (1
study), external beam radiation therapy (1 study), and multiple techniques (1 study). Median
follow-up was 5 years (range, 5 months to 12 years). A small risk of publication bias was
detected. Fixed effects meta-analysis of 10 studies (total N=4995) showed greater odds of local
recurrence in patients who received APBI compared with patients who received whole-breast
irradiation (pooled OR=1.54 [95% CI, 1.15 to 2.06]; p=0.004; I2=0%). Meta-analysis of 5
studies (total N not reported) showed greater odds of axillary failure in patients who received
APBI (pooled OR=2.52 [95% CI, 1.72 to 3.68]; p<0.001; I2 not reported). Meta-analyses of
other outcomes showed no statistical differences in odds of distant metastases, overall survival,
and disease-free survival. Given the heterogeneity of APBI methods, comparative efficacy of
which is currently unknown, and follow-up durations across studies, clinically informative
conclusions that can be drawn from these results are limited.
Interstitial Brachytherapy
For a 2007 RCT, accrual was stopped before reaching the goal specified to evaluate differences in
local recurrence, to allow patients to enroll in another trial.(31,32) The randomization process
was unclear; patients deemed “technically unsuitable” for interstitial brachytherapy were given
EBRT APBI; and patient characteristics and outcomes for each type of APBI were not reported
separately. Finally, the sample size of 126 was relatively small, and longest reported follow-up
was 66 months. Similar local and regional failure rates were found across treatment arms.
Ajkay et al (2014) reported a retrospective study of 5-year adverse events in patients with early
stage breast cancer who were treated at a single U.S. center.(52) Of 417 patients who received
BCS and radiation therapy, 271 received intracavitary brachytherapy (34 Gy in 10 fractions; 90%
MammoSite®, 9% Contura®, 1% strut-adjusted volume implant [SAVI]) and 146 received whole
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breast irradiation using 3-dimensional conformal radiotherapy (3D-CRT; 45-50.4 Gy in 25-28
fractions with 10-16 Gy boost). Median follow-up was 4.8 years in the brachytherapy group and
4.1 years in the whole breast irradiation group. Estimated 5-year overall incidence of any adverse
event was greater in the brachytherapy group compared with the whole breast irradiation group
(72% vs 52%; log rank test for all comparisons, p<0.001). For prespecified adverse events of
interest, estimated 5-year incidence of infectious skin complications, abscess, telangiectasia, and
breast pain was similar between groups. Estimated 5-year incidence of seroma (47% vs 19%,
p<0.001) and fat necrosis (40% vs 24%, p<0.001) was greater in the brachytherapy group.
Intraoperative Brachytherapy
One RCT compared intraoperative radiotherapy (IORT) to whole-breast irradiation in 2232
women.(34,35) Radiotherapy was delivered to the tumor bed using the Intrabeam® device,
which provides a point source of 50 kV energy x-rays at the center of a spherical applicator, for
20 to 45 minutes. It was specifically developed for IORT. The TARGIT-A (Risk-adapted Targeted
Intraoperative Radiotherapy) trial was a noninferiority trial with 28 centers in 9 countries and a
sample size of 3451. (In 2010, the trial was extended for 2 more years to allow accrual in
subprotocols.) An ITT approach was used. Patients were not blinded to treatment choice. As
anticipated in advance, 14% of those in the IORT arm received EBRT as well, because of
unfavorable pathologic features determined after surgery, e.g., lobular carcinoma. The
predefined noninferiority margin was an absolute difference of 2.5% between groups for
pathologically confirmed, ipsilateral local recurrence. The most recent article reported 5-year
results, defined as results for patients with 5-years of follow-up or “if they were seen the year
before database lock.”(35) Median follow-up for all patients was 2 years and 5 months (IQR, 1252 months), and 1222 patients (35%) had a median follow-up of 5 years. Estimated 5-year risks
for ipsilateral local recurrence were 3.3% (95% CI, 2.1 to 5.1) in the TARGIT group and 1.3%
(95% CI, 0.7 to 2.5; p=0.042) in the whole-breast radiotherapy group. Mortality was similar
between the 2 groups (2.6% TARGIT vs 1.9%; p=0.56). However, there were significantly fewer
nonbreast cancer deaths in the TARGIT group than in the whole-breast radiotherapy group
(1.4% [95% CI, 0.8 to 2.5] vs 3.5% [95% CI, 2.3 to 5.2]; p<0.001), with fewer deaths from
cardiovascular causes and other cancers in the TARGIT group. Overall, there were 12 more local
recurrences but 14 fewer deaths in the TARGIT group than in the whole-breast radiotherapy
group. In the group that received IORT plus whole-breast radiotherapy, the mortality rate was
higher at 8% (95% CI, 3.7 to 17.5), but the percentage of women with local recurrences (0.9%;
95% CI, 0.1 to 6.1) was similar to those who received only IORT. Noninferiority was established
for the whole intraoperative cohort and for those who received IORT alone, but not for those
patients who underwent both types of radiotherapy. There was no significant difference between
the IORT and whole-breast radiotherapy groups in predefined 6-month wound-related
complications. However, grade 3 or 4 radiotherapy-related skin complications were more
common in the whole-breast radiotherapy group (13/1730 vs 4/1731; p=0.029). Five- and 10year follow-up for the entire TARGIT-A cohort has yet to be accrued.
A number of reviews and editorials discussed results of the TARGIT-A trial.(5,6,53-59) While
recognizing the potential benefits of intraoperative radiotherapy, including convenience,
“excellent delineation of the tumour bed under visual control, very good dose homogeneity, and
high sparing of normal tissue,”(53) a number of concerns have been expressed. They include the
following:
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• If IORT is performed during the surgery to excise the tumor, definitive pathology is
unavailable when radiotherapy is performed. Therefore, a subset of patients must also
undergo whole-breast EBRT following surgery. In the trial, 14% of patients in the IORT arm
also received whole-breast EBRT. When only those who received IORT during initial surgery
(rather than during repeat surgery to clear positive margins) were considered, 21%
received whole-breast EBRT. Limited data suggest that breast symptoms and pain after
treatment may be greater for patients receiving both IORT and whole-breast external
radiotherapy compared with those receiving IORT alone and that patient satisfaction is
greater with whole-breast external radiotherapy or IORT alone compared with combined
treatment.(60) Therefore, IORT may result in harm for a subset of patients who receive
both IORT and whole-breast external radiotherapy.
• Whether radiation dose and type is actually equivalent to the standard radiation therapy
regimen is unknown. Of particular concern is the rapid drop in dose with distance from the
applicator and whether any residual disease will be eradicated. Some argue that the
TARGIT-A trial alleviates this concern, but others disagree.
• Because 93% of tumors included in the TARGIT trial were estrogen-receptor positive, and
estrogen-receptor positive tumors tend to recur later, longer follow-up is needed. Further,
because cardiovascular adverse events may occur more than 7-10 years after completion of
radiation treatment, 10-year results are needed to assess net health benefit.(5,6)
• Claims that IORT may improve overall survival due to fewer non-breast cancer deaths may
be premature due to short median follow-up (2.4 years) in TARGIT-A. Studies suggest that
the latency period for radiation-induced non-breast cancers is 15-20 years from breast
treatment.(6)
A 2014 Cochrane review on partial breast irradiation for early breast cancer included the 3 RCTs
discussed above plus a fourth RCT that compared conventional (not accelerated) whole breast
irradiation to conventional partial breast irradiation by a variety of techniques.(61) The overall
quality of evidence was considered low to very low, and conclusions could not be reached.
Another form of intraoperative radiotherapy, called electron intraoperative radiotherapy (ELIOT),
uses electrons.(62) The 2013 ELIOT trial compared intraoperative radiotherapy with ELIOT to
whole-breast irradiation.(36) With a sample size of 1305 patients and median follow-up of 5.8
years (IQR, 4.1-7.7), 35 patients in the intraoperative group (4.4%) and 4 patients in the wholebreast irradiation group (0.4%) developed ipsilateral breast tumor recurrences (HR=9.3 [95% CI,
3.3 to 26.3]; log-rank test, p<0.001). There was no statistically significant difference in 5-year
overall survival. For women with data on adverse skin events (intraoperative radiotherapy=464;
whole-breast irradiation=412), there were significantly fewer events among women who received
intraoperative radiotherapy (p<0.001). This was an equivalence trial with a prespecified
equivalence limit for local recurrence in the intraoperative radiotherapy group only of 7.5%.
Therefore, although the criterion for equivalence was satisfied, ipsilateral breast recurrence rate
was significantly higher in the intraoperative radiotherapy group. A subsequent review of the
ELIOT trial noted that, of 69 women who had 4 or more positive lymph nodes, those randomized
to whole breast irradiation (n=38) received concurrent axillary radiation; for those randomized to
ELIOT (n=31), axillary irradiation was delayed 6 to 12 weeks.(7) These reviewers also
characterized ELIOT data as “still early” and noted that long-term results are needed to assess
net health benefit.
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All 8 nonrandomized, comparative studies included in the 2013 TEC Assessment were flawed, due
to potential baseline differences in treatment groups, lack of multivariable analyses to account for
them, inclusion of patients who did not meet eligibility criteria, variations in treatment within
arms, and generally small sample sizes and insufficient follow-up.(39-49)
Other IORT modalities are being researched, e.g., electronic brachytherapy using the Xoft®
Axxent® eBx™ system (NCT01644669; see Ongoing and Unpublished Clinical Trials). Use of the
Xoft® Axxent® eBx™ system is not limited to intraoperative radiotherapy of the breast; it is also
used in breast balloon brachytherapy and to treat other organs. Few studies have evaluated
electronic brachytherapy devices (balloon and radiation source); no comparative studies were
found. The purported advantage of using Axxent® is to eliminate the need for heavy shielding, as
required when using a high-dose rate afterloader unit. (For more information on the Intrabeam®
device and the Xoft® Axxent® eBx™ system, see Cox and Swanson.)(63)
External-Beam APBI
Two RCTs compared EBRT APBI to whole-breast radiotherapy using 3D-CRT. In the first, 102
patients were randomized to either whole-breast irradiation, with or without a boost to the tumor
bed, or APBI.(37) The primary endpoint was local recurrence within 5 years. In this noninferiority
trial, the sample size was calculated to detect a 10% difference between treatment arms, with a
power of 80% and a significance level of 0.05. The APBI group was significantly younger than
the whole-breast irradiation group (mean age [SD], 67.1 [6.1] years vs 70.1 [5.2] years;
p=0.009). After median follow-up of 5 years, there were no recurrences in either group, nor was
there a statistically significant difference in survival. Investigators noted that the sample size may
have been insufficient to detect a true difference in local control. Ninety percent (46/51) APBI
patients had acute skin effects, mostly grade 1; all patients in the whole-breast irradiation group
had acute skin effects, and most were grade 2. Grade 1 and 2 late effects were reported with
some changes in the relative positions of the treatment groups over time.
The second RCT was the multicenter randomized RAPID trial (Randomized Trial of Accelerated
Partial Breast Irradiation).(38) The sample size was 2135, and median follow-up was 3 years.
Most patients were older than 50 years and had estrogen-receptive-positive tumors less than 1.5
cm in diameter. An interim article reported on cosmetic and toxicity results. An accelerated
regimen was used for whole-breast irradiation, and 21% of these patients received a boost to the
tumor bed. APBI patients were more likely than whole-breast irradiation patients to have adverse
cosmesis at 3 years, whether reported by physicians (p<0.001), nurses (p<0.001), or patients
(p<0.05). As for late toxicities, 1.4% of APBI patients had a grade 3 adverse event versus none
of the whole-breast irradiation patients. Telangiectasia and breast induration were more common
among APBI patients (p<0.001).
One RCT was reported in 1990 and 1993, and many changes in the care of patients with breast
cancer have occurred since then.(29,30) The study was weakened by the fact that initial groups
were potentially unbalanced, and nodal status was based on clinical exam, among other factors.
Recurrence was higher for the “limited field” treatment arm (analogous to partial-breast
irradiation) than for the “wide field” arm (analogous to whole-breast irradiation), but some of the
“excess” recurrences in the limited field arm were axillary. This may be accounted for by the fact
that the axillary area was included in the wide field radiotherapy but not in the limited field, and
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initial work-up for nodal involvement was limited. The follow-up was 65 months; and the sample
size was 708.
Smith et al (2012) analyzed Medicare data on 92,735 women, 67 years or older diagnosed with
breast cancer between 2003 and 2007, who underwent lumpectomy followed by radiation
therapy.(64) The mean age (SD) was 74.8 (5.5) years. Use of brachytherapy increased from
3.5% in 2003-2004 to 12.5% in 2007 (p<0.001 for trend). Brachytherapy patients were more
likely to undergo a subsequent mastectomy than matched whole-breast irradiation (WBI)
patients, even after adjusting for imbalanced covariates (HR=1.87 [95% CI, 1.36 to 2.58];
p<0.001). This finding held true when all WBI patients were compared with all brachytherapy
patients using multivariable analysis (HR=2.19 [95% CI, 1.84 to 2.61]; p<0.001). Covariates that
were significantly associated with subsequent mastectomy (besides brachytherapy) included age
75 to 79 (p=0.01), axillary lymph node involvement (p=0.004), and living in the South
(p=0.005). The cause of the mastectomies, eg, recurrence or treatment complications, could not
be determined from the claims data. Breast brachytherapy also was associated with a higher risk
of postoperative complications, both infectious and noninfectious (27.56% [95% CI, 26.51% to
28.63%] vs 16.92% for WBI patients [95% CI, 16.67% to 17.18%], p<0.001).
Czechura et al (2013) evaluated the frequency of APBI versus whole-breast irradiation in the
National Cancer Data Base from 2003 to 2010.(65) The use of brachytherapy accounted for 3.4%
of cases in 2003, 12.8% (p<0.001) in 2008, and 12.4% in 2010. The largest percentage point
increase by type of APBI was for brachytherapy (from 2.0% to 8.9%) followed by 3D-CRT (from
0.8% to 2.2%) and intensity-modulated radiation therapy (IMRT) (from 0.7% to 1.3%). Mean
age was 58.7 years for whole-breast irradiation patients versus 61.6 years for APBI patients.
Patients with managed care were most likely to use APBI (46.3% of all APBI), compared with
12.2% for private payers and 6.9% for Medicare. APBI was used most often in the southeastern
U.S. Considering invasive cancers, 43.6% of APBI patients met the ASTRO (American Society for
Radiation Oncology) “suitable” guidelines; 47.0%, the “cautionary” guidelines; and 9.2%, the
“unsuitable” guidelines.
Section Summary
Overall, the body of evidence on interstitial APBI compared with conventional whole-breast
irradiation is weak; and it is extremely weak (i.e., no randomized studies) for balloon
brachytherapy. One small RCT compared EBRT APBI to whole-breast radiotherapy, and a second
larger RCT reported on cosmesis and toxicity after a median of 3 years. The strongest published
evidence is on intraoperative radiotherapy (the TARGIT trial); 5-year results showed increased
ipsilateral local recurrence with APBI compared with whole-breast radiotherapy, although a
prespecified noninferiority criterion for this outcome was satisfied.
Similarly, 5-year results of the ELIOT trial met a prespecified equivalence criterion; however,
recurrence rate for intraoperative radiotherapy patients was statistically greater than for wholebreast irradiation patients. Furthermore, it is becoming increasingly clear that each type of APBI
should be judged on its own merits, and studies comparing different APBI techniques to each
other, as well as to whole-breast irradiation, are needed. Fortunately, a number of large RCTs are
underway.
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Given the current level of evidence, it is important for patients to be aware of the uncertainty
regarding the outcomes of this approach. This information should include failure rates for specific
devices (e.g., explantation for Mammosite®, incomplete expansion of the catheters for some of
the hybrid devices), as well as the uncertainty regarding their comparative effectiveness. The
intermediate alternative provided by AWBI also should be presented to women who meet criteria
for the Canadian trial, as well as the critical importance of completing radiotherapy for the
majority of patients undergoing BCS.
Use as Local Boost Radiotherapy
A 1996 TEC Assessment concluded that net health outcome with brachytherapy local boost were
equivalent to outcomes with EBRT local boost in women who received BCS plus whole-breast
radiation therapy as initial treatment for stage 1 or stage 2 breast cancer.(66) In 7
nonrandomized comparisons (total N=2022), the 5-year local control rate was 88%-98% for
those who received brachytherapy local boost, compared with 91%-99% for those who received
EBRT local boost.
Accuboost® for image-guided breast irradiation, also called noninvasive breast brachytherapy,
has been used for local boost around the tumor bed. The Accuboost® system provides imageguided radiotherapy before each treatment to ensure that radiation is directed at the treatment
target. The breast is placed between mammography paddles, where images are taken and
radiation is delivered using a distinct applicator. The paddles prevent motion during treatment.
Radiation is delivered from 1 side of the breast to the other or from the top of the breast to the
bottom. This is proposed to reduce radiation exposure to adjacent tissues, including the heart
and lung.(67) No long-term studies are available to confirm this. There is only 1 comparative
study for this use, a matched retrospective study of patients receiving the boost dose using
Accuboost® or electron beams (a type of EBRT).(68) Each of 47 Accuboost® patients was
compared with 2 controls matched on age, stage, chemotherapy use, fractionation, and when
possible, breast size, comorbidities, and smoking status. Main differences between the 2
treatment groups were in radiation dose received and timing of radiotherapy administration. The
percentage of patients with a whole-breast irradiation dose (accompanying the boost dose) of 50
to 50.4 Gy was 68% in the Accuboost® group and 37% in the electron-treated group (p<0.001).
Also, a greater proportion of patients in the electron-treated group received the boost dose after
whole-breast irradiation, rather than during whole-breast irradiation or starting before and ending
during whole-breast irradiation (99% for the electron-treated group vs 6% for the Accuboost®
group). Approximately 60% of patients had stage 1 breast cancer, and approximately one
quarter, DCIS. With median follow-up of 13.6 months, skin/subcutaneous tissue toxicity occurred
less often among patients treated with Accuboost® than among those treated with electron
beam (p=0.046). Local-regional control rates were 99% or greater in both groups. Study
limitations included the between-group differences in whole-breast radiation dose and timing of
boost, as well as selection bias and the study’s retrospective design.
Section Summary
For women undergoing breast-conserving surgery plus whole-breast irradiation as initial
treatment for stage 1 or stage 2 breast cancer, nonrandomized comparative studies have shown
similar outcomes with brachytherapy local boost and with EBRT (external beam radiation
therapy) local boost.
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One matched retrospective study of 141 patients who received noninvasive breast brachytherapy
with Accuboost® or electron beam irradiation (a type of EBRT) to provide boost radiation to the
tumor bed had a median follow-up of 14 months. This evidence is insufficient to form any
conclusion about Accuboost®.
Ongoing and Unpublished Clinical Trials
A search of online site ClinicalTrials.gov found 12 ongoing comparative trials (10 randomized, 2
nonrandomized) of APBI (see Table 2). No comparative trials of accelerated whole breast
irradiation or Accuboost® were identified.
Additionally, GEC-ESTRO (Groupe Européen de Curietherapie-European Society for Therapeutic
Radiology and Oncology) is sponsoring a phase 3 multicenter trial to compare interstitial
brachytherapy alone versus EBRT after BCS in patients with low risk invasive carcinoma or low
risk DCIS.(69) This trial is not listed at ClinicalTrials.gov or the European Union Clinical Trials
Register. Expected enrollment is 1170 patients, and 10-year follow-up is planned.
In 2009, Mannino and Yarnold (note Yarnold is a lead author on the START A and B trials)
reviewed current ongoing APBI trials and raised several concerns regarding cross-trial
variations.(70) The extent of initial BCS can vary substantially across studies, as well as the
definition of the targeted tumor cavity. A larger margin is usually drawn around the tumor cavity
for 3D-CRT, for example, because of the need to allow for variations in set-up and respiratory
motion. Studies of APBI usually distinguish between “same site relapse,” ie, close to the
irradiated area and “elsewhere relapse,” yet it is unclear whether what constitutes the same site
varies across studies. The percentage of relapses occurring “elsewhere” in the ipsilateral breast in
studies of whole-breast radiotherapy following BCS range from 18% to 42%; these studies may
include some patients at higher risk of recurrence. Proponents of APBI have sometimes asserted
that “elsewhere” tumors are rare, that they are mostly new primary tumors (rather than
recurrence), or that earlier studies have shown that radiotherapy is not effective for these tumors
in any case. Mannino and Yarnold challenged each of these points in turn, although they also
concluded that results of trials currently underway will provide level-1 evidence for or against
APBI.
Table 2. Ongoing Comparative Trials of Accelerated Partial Breast Irradiation Listed at
ClinicalTrials.gov
NCT Number
Title
WBI vs APBI ± tumor bed boost in DCIS
NCT00470236
Radiation Doses and Fractionation Schedules
in Non-low Risk Ductal Carcinoma In Situ
(DCIS) of the Breast (TROG)
Intraoperative brachytherapy
NCT01343459
Intra-Operative Electron Boost and
Hypofractionated Whole-Breast Irradiation
During Breast-conserving Treatment (BCT)
(HIOB)
NCT01644669
Safety and Efficacy Study of the Xoft®
Axxent® eBx™ IORT System
Phase
Enrollmenta
Completion
Dateb
3
1600
Nov 2024
3
1000
Mar 2021
4
1000
Dec 2024
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NCT Number
Title
External beam APBI
NCT01185132
Intensity Modulated Radiotherapy (IMRT) vs
3D-conformal Accelerated Partial Breast
Irradiation (APBI) for Early Stage Breast
Cancer After Lumpectomy (2009-APBI)
NCT01247233
Standard or Hypofractionated Radiotherapy
vs Accelerated Partial Breast Irradiation
(APBI) for Breast Cancer (SHARE)
NCT01803958
Breast Cancer With Low Risk Of Local
Recurrence: Partial and Accelerated
Radiation With 3D-Conformal Radiotherapy
(EDCRT) vs Standard Radiotherapy After
Conserving Surgery (Phase III Study) (IRMA)
NCT02104895
Accelerated Partial Breast Irradiation Using
Intensity Modulated Radiotherapy vs Whole
Breast Irradiation
Accelerated partial breast irradiation (multimodality)
NCT00103181
Radiation Therapy (WBI vs PBIc) in
Treatment Women Who Have Undergone
Surgery For Ductal Carcinoma In Situ or
Stage I or Stage II Breast Cancer (RTOG
0413/NSABP B39)
NCT00282035
Randomized Trial of Accelerated Partial
Breast Irradiationd (RAPID)
NCT00892814
Partial Breaste vs Whole Breast Irradiation in
Elderly Women Operated on for Early Breast
Cancer
NCT00185744
Accelerated Partial Breast Irradiationf
Following Lumpectomy for Breast Cancerg
NCT01185145
Accelerated Partial Breast Radiotherapy With
Either Mammosite or Intensity Modulated
Radiotherapy (APBI)g
Page 16 of 27
Phase
Enrollmenta
Completion
Dateb
3
660
Jul 2028
3
2796
Oct 2024
NR
3302
Dec 2017
3
520
Feb 2014
3
4216
June 2016
3
2128
Dec 2020
2
628
May 2022
NR
400
Dec 2015
2
291
Aug 2024
DCIS: ductal carcinoma in situ; NR: not reported; PBI: partial breast irradiation; WBI: whole breast irradiation
a
Expected.
b
Estimated.
c
Accelerated interstitial or balloon PBI, or 3-dimensional conformal accelerated PBI.
d
3-dimensional conformal accelerated PBI.
e
PBI mode of delivery unspecified.
f
Intraoperative radiotherapy, balloon APBI, or stereotactic APBI.
g
Nonrandomized.
Clinical Input Received From Physician Specialty Societies and Academic Medical
Centers
While the various physician specialty societies and academic medical centers may collaborate
with and make recommendations during this process through the provision of appropriate
reviewers, input received does not represent an endorsement or position statement by the
physician specialty societies or academic medical centers, unless otherwise noted.
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2011 Input
In response to requests, input was received from 1 physician specialty society and 4 academic
medical centers while this policy was under review in 2011. There was near-unanimous support
for the policy statement regarding AWBI. The input was mixed regarding APBI; those agreeing
with the conclusion noted the need to define the risks and benefits of this approach in patient
subgroups and noted that current data are inconclusive concerning the effectiveness of APBI
compared with whole-breast irradiation.
Summary
Accelerated Whole Breast Irradiation
The overall body of evidence on AWBI compared with conventional whole-breast irradiation
suggests that local recurrence rates with AWBI are not worse than with conventional wholebreast irradiation in patients meeting criteria of the Canadian trial, with a noninferiority margin of
5%. Patient selection is important, and at this point, only patients similar to those in the
Canadian trial should be considered for this therapy. Thus, AWBI may be considered medically
necessary for these patients with clinical characteristics noted in the medically necessary policy
statement. Outcomes could differ in women with other disease characteristics.
Brachytherapy Boost With Whole-Breast Irradiation
For patients treated with whole-breast EBRT and BCS, local boost irradiation via interstitial or
balloon brachytherapy is likely to result in equivalent outcomes compared with local boost given
by EBRT. This is based on results from nonrandomized comparative studies, a TEC Assessment,
and specialty society guidelines. As a result, interstitial or balloon brachytherapy may be
considered medically necessary for these patients when used as local boost irradiation.
Accelerated Partial Breast Irradiation
Overall, the body of evidence on interstitial accelerated partial-breast irradiation (APBI) compared
with conventional whole-breast irradiation is weak; evidence is extremely weak (ie, no
randomized studies) for balloon brachytherapy. The strongest published evidence is on
intraoperative radiotherapy. Five-year results of one randomized controlled trial (TARGIT-A)
showed increased ipsilateral local recurrence with APBI compared with whole-breast
radiotherapy. In another randomized controlled trial that used a different technology (ELIOT),
recurrence rate with intraoperative radiation therapy was statistically greater than with wholebreast irradiation. It is becoming increasingly clear that each type of APBI should be judged on
its own merits, and studies comparing different APBI techniques to each other, as well as to
whole-breast irradiation, are needed. A number of large RCTs are underway. However, based on
current evidence, APBI is considered investigational for treatment of early stage breast cancer
after BCS, except when interstitial or balloon brachytherapy is used as local boost with wholebreast external-beam radiation after BCS, as described above.
Noninvasive Breast Brachytherapy
Evidence for noninvasive breast brachytherapy using Accuboost® to provide boost radiation to
the tumor bed is very weak; therefore this technique is considered investigational.
Practice Guidelines and Position Statements
According to current National Comprehensive Cancer Network (NCCN) guidelines (version
3.2014),(2) “Preliminary studies of APBI suggest rates of local control in selected patients with
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early stage breast cancer may be comparable to those treated with standard whole breast RT
[radiotherapy]. However, compared with standard whole breast radiation, several recent studies
documented an inferior cosmetic outcome with APBI. Follow-up is limited and studies are
ongoing. Patients are encouraged to participate in clinical trials. If not trial eligible, per the
consensus statement from the American Society for Radiation Oncology (ASTRO), patients who
may be suitable are…[see ASTRO Criteria: Suitable in Table 3]” For whole-breast radiotherapy,
NCCN recommends either a conventional whole-breast irradiation regimen or a total dose of 42.5
Gy with 2.66 Gy per fraction, which equals 16 fractions. Although NCCN guidelines do not specify
the duration of treatment, the latter is presumably an AWBI regimen. A boost to the tumor bed is
recommended for higher risk patients receiving whole-breast radiotherapy, ie, those who are
younger than 50 years old with high-grade disease.The American College of Radiology has ACR
Appropriateness Criteria® for conservative surgery and radiation for stage 1 and 2 breast
carcinoma, last reviewed in 2011. The document provides appropriateness criteria for the use of
radiotherapy after breast conserving surgery for specific cases.
The American Society of Breast Surgeons (ASBS), ASTRO, and the American Brachytherapy
Society (ABS) have issued consensus statements for the selection of patients for APBI
(summarized in Table 2). According to statement authors, the impetus for the publications was
the increased use of APBI outside of clinical trials, even as results of those trials were awaited.
The authors estimated that more than 32,000 women have already been treated with
MammoSite®, a mechanism for delivering APBI. The statements are based on systematic
reviews, which are not described in detail, and expert opinion. Several authors have questioned
the validity of ASTRO consensus statement categories based on retrospective studies that
showed inconsistent associations between ASTRO category and recurrence rates and no
association between ASTRO category and survival outcomes.(50,71-73)
Table 3. Professional Medical Society Criteria for Performing APBI(74-77)
Factor
Patient factors
Age
ASTRO
"Suitable"
ASTRO
"Cautionary"
ASTRO
"Unsuitable"
≥60 y
50-59 y
< 50 y
BRCA ½
Mutation
Pathologic factors
Not present
NR
Tumor size
≤ 2 cm
Tumor stage
Margins
T1
Negative ≥ 2 mm
Grade
LVSI
ASBS
ABS
≥ 50 y
Present
≥ 45 y
≥ 50 y for
DCIS
NR
2.1-3.0 cm
> 3 cm
≤ 3 cm
≤ 3 cm
T0 or T2
Close (<2 mm)
T3-4
Positive
Negative
Any
NR
NR
NR
Microscopically
negative
NR
No
Limited/focal
Extensive
NR
NR
NR
NR
Present
Clinically multifocal
or microscopically
multifocal, total
size ≥ 3 cm
NR
NR
Positive or
negative
NR
NR
a
ER status
Positive
Negative
Multicentricity
Multifocality
Unicentric
Clinically unifocal,
total size ≤ 2.0 cm
NR
Clinically unifocal,
total size: 2.1-3.0
cm
NR
NR
Current Procedural Terminology © American Medical Association. All Rights Reserved.
Contains Public Information
Accelerated Breast Irradiation after Breast-Conserving
Surgery for Early Stage Breast Cancer and Breast
Brachytherapy as Boost with Whole-Breast Irradiation
Factor
Histology
ASTRO
"Suitable"
Invasive ductal or
other favorable
subtypes
ASTRO
"Cautionary"
Invasive lobular
Page 19 of 27
ASTRO
"Unsuitable"
NR
ASBS
Invasive
ductal
carcinoma or
DCIS
≤ 3 cm
NR
NR
ABS
All invasive
subtypes
and DCIS
Pure DCIS
Not allowed
≤ 3 cm
> 3 cm
≤ 3 cm
EIC
Not allowed
≤ 3 cm
>3 cm
NR
Associated LCIS
Allowed
NR
NR
NR
Nodal factors
Nodal stage
pNO (i-, i+)
NR
pN1, pN2, pN3
SN pNO
pNOb
Nodal surgery
SN Bx, ALND
NR
None performed
NR
NR
Treatment factors
Neoadjuvant therapy Not allowed
NR
If used
NR
NR
ABS: American Brachytherapy Society; ALND: axillary lymph node dissection; ASTRO: American Society for Radiation
Oncology; ASBS: American Society of Breast Surgeons; DCIS: ductal carcinoma in situ; EIC: extensive intraductal
component; ER status: estrogen receptor status; LCIS: lobular carcinoma in situ; LVSI: lymphovascular space invasion;
NR: not reported; SN: sentinel node
a
Strongly encouraged to enroll in NSABP B-39/RTOG 04-13 trial.
b
Lymphovascular space invasion is considered a contraindication for APBI.
ASTRO released guidelines on fractionation for whole-breast irradiation in 2010.(78) Guidelines
are based on the Canadian trial,(17,18) START A(16) and START B(15), and a third RCT.(14,19)
Guideline authors concluded that “Data are sufficient to support the use of HF-WBI
[hypofractionated or accelerated, whole breast irradiation] for patients with early breast cancer
who meet all of the aforementioned criteria,” including age 50 years or older, disease stage pT12 pN0, no chemotherapy, and treatment with radiation dose homogeneity within ±7% in the
central axis plane. The task force did not agree on whether HF-WBI is recommended for tumor
boost.
U.S. Preventive Services Task Force Recommendations
Not applicable.
CODING
The following codes for treatment and procedures applicable to this policy are included below
for informational purposes. Inclusion or exclusion of a procedure, diagnosis or device code(s)
does not constitute or imply member coverage or provider reimbursement. Please refer to the
member's contract benefits in effect at the time of service to determine coverage or noncoverage of these services as it applies to an individual member.
CPT
19296
19297
Placement of radiotherapy afterloading expandable catheter (single or multichannel)
into the breast for interstitial radioelement application following partial mastectomy,
includes imaging guidance; on date separate from partial mastectomy
Placement of radiotherapy afterloading expandable catheter(single or multichannel)
into the breast for interstitial radioelement application following partial mastectomy,
includes imaging guidance; concurrent with partial mastectomy (List separately in
addition to code for primary procedure)
Current Procedural Terminology © American Medical Association. All Rights Reserved.
Contains Public Information
Accelerated Breast Irradiation after Breast-Conserving
Surgery for Early Stage Breast Cancer and Breast
Brachytherapy as Boost with Whole-Breast Irradiation
19298
77770
77771
77772
0395T
Page 20 of 27
Placement of radiotherapy afterloading brachytherapy catheters (multiple tube and
button type) into the breast for interstitial radioelement application following (at the
time of or subsequent to) partial mastectomy, includes imaging guidance
Remote afterloading high dose rate radionuclide interstitial or intracavitary
brachytherapy, includes basic dosimetry, when performed; 1 channel
Remote afterloading high dose rate radionuclide interstitial or intracavitary
brachytherapy, includes basic dosimetry, when performed; 2-12 channels
Remote afterloading high dose rate radionuclide interstitial or intracavitary
brachytherapy, includes basic dosimetry, when performed; over 12 channels
High dose rate electronic brachytherapy, interstitial or intracavitary treatment, per
fraction, includes basic dosimetry, when performed
ICD-9 Diagnoses
These diagnoses are otherwise subject to medical policy as stated above
174.0
Malignant neoplasm of female breast; Nipple and areola
174.1
Malignant neoplasm of female breast; Central portion
174.2
Malignant neoplasm of female breast; Upper-inner quadrant
174.3
Malignant neoplasm of female breast; Lower-inner quadrant
174.4
Malignant neoplasm of female breast; Upper-outer quadrant
174.5
Malignant neoplasm of female breast; Lower-outer quadrant
174.6
Malignant neoplasm of female breast; Axillary tail
174.8
Malignant neoplasm of female breast; Other specified sites of female breast
ICD-10 Diagnoses (Effective October 1, 2015)
C50.011
C50.012
C50.111
C50.112
C50.211
C50.212
C50.311
C50.312
C50.411
C50.412
C50.511
C50.512
C50.611
C50.612
C50.811
C50.812
Malignant
Malignant
Malignant
Malignant
Malignant
Malignant
Malignant
Malignant
Malignant
Malignant
Malignant
Malignant
Malignant
Malignant
Malignant
Malignant
neoplasm of
neoplasm of
neoplasm of
neoplasm of
neoplasm of
neoplasm of
neoplasm of
neoplasm of
neoplasm of
neoplasm of
neoplasm of
neoplasm of
neoplasm of
neoplasm of
neoplasm of
neoplasm of
nipple and areola, right female breast
nipple and areola, left female breast
central portion of right female breast
central portion of left female breast
upper-inner quadrant of right female breast
upper-inner quadrant of left female breast
lower-inner quadrant of right female breast
lower-inner quadrant of left female breast
upper-outer quadrant of right female breast
upper-outer quadrant of left female breast
lower-outer quadrant of right female breast
lower-outer quadrant of left female breast
axillary tail of right female breast
axillary tail of left female breast
overlapping sites of right female breast
overlapping sites of left female breast
REVISIONS
06-29-2010
05-27-2013
In


In
Coding Section:
Updated wording for the following CPT Codes: 19296, 19297.
Added CPT Codes: 77785, 77786, 77787 (effective 01/01/09).
the Medical Policy Title section:
Current Procedural Terminology © American Medical Association. All Rights Reserved.
Contains Public Information
Accelerated Breast Irradiation after Breast-Conserving
Surgery for Early Stage Breast Cancer and Breast
Brachytherapy as Boost with Whole-Breast Irradiation
12-11-2013
05-28-2015
01-01-2016
Page 21 of 27
Revised the following medical policy title:
"High Dose Rate (HCR) Breast Brachytherapy with HDR Radioactive Source via MammoSite
Catheter".
Updated the Description section.
In the Policy section:
Revised the following medical policy language:
"A. Brachytherapy used as accelerated partial breast irradiation (local boost irradiation) is a
medically appropriate treatment option in women with stage 0, I, or II breast cancer who
are also treated with breast conserving surgery and whole breast radiation therapy.
B. Brachytherapy as the sole form of breast irradiation after breast-conserving surgery for
early stage breast cancer (Stage 0, I, or II – based on size only – over 2 cm) is considered
investigational. It may be considered as a medically appropriate treatment option in limited
circumstances for patients in whom whole breast external beam irradiation is not feasible,
although this is not the current standard of care. These patients fall into one of the two
categories:
1. Patients with anatomic difficulties (e.g. large, pendulous breasts) that prevent
delivery of traditional whole breast external beam radiation without compromising
large sections of the lung; or
2. Patients with infirmities (e.g. arthritis, severe pulmonary disease, multiple medical
problems) that make the tolerance of a 6-7 week course of radiotherapy difficult or
impossible."
Updated the Rationale section.
Updated the Reference section.
In Coding section:
 Added ICD-10 Diagnosis (Effective October 1, 2014)
Updated Description section.
In Policy section:
 In Item B, added "involving treatment of early stage breast cancer after breastconserving surgery," to read "Accelerated whole breast irradiation is considered
experimental/investigational in all other situations involving treatment of early stage
breast cancer after breast-conserving surgery."
 In Item D, added "balloon APBI" and "noninvasive brachytherapy using Accuboost®," to
read, "Accelerated partial breast irradiation (APBI), including interstitial APBI, balloon
APBI, external beam APBI, noninvasive brachytherapy using Accuboost®, and intraoperative APBI, is considered experimental/investigational."
 Added Item E, "Noninvasive brachytherapy using Accuboost® for patients undergoing
initial treatment for stage 1 or 2 breast cancer when used as local boost irradiation in
patients who are also treated with BCS and whole-breast external-beam radiotherapy is
considered experimental/investigational."
 Added Policy Guidelines, "Electronic brachytherapy is considered a type of balloon
brachytherapy that can be used to deliver APBI."
Updated Rationale section.
In Coding section:
 Added HCPCS code 0182T.
 Updated ICD-10 effective date to October 1, 2015.
Updated References section.
In Coding section:
 Added CPT codes 77770, 77771, 77772, and 0395T.
 Removed CPT codes 77785, 77786, 77787, 0182T.
Current Procedural Terminology © American Medical Association. All Rights Reserved.
Contains Public Information
Accelerated Breast Irradiation after Breast-Conserving
Surgery for Early Stage Breast Cancer and Breast
Brachytherapy as Boost with Whole-Breast Irradiation
Page 22 of 27
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Surgery for Early Stage Breast Cancer and Breast
Brachytherapy as Boost with Whole-Breast Irradiation
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Blue Cross and Blue Shield of Kansas Newsletter, Blue Shield Report. MAC-01-07); January
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Current Procedural Terminology © American Medical Association. All Rights Reserved.
Contains Public Information