Accelerated Breast Irradiation and Brachytherapy Boost After Breast-Conserving Surgery for Early-Stage Breast Cancer - CAM 80113

Description: 
Radiotherapy is the standard of care for patients with breast cancer undergoing breast-conserving surgery (BCS) because it reduces recurrences and lengthens survival. The conventional radiotherapy regimen consists of approximately 25 treatments of 2 gray (a measure of absorbed radiation dose) delivered over 5 to 6 weeks. Nonetheless, not all patients undergo radiotherapy 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 a low-risk of recurrence. Accelerated (also called hypofractionated) whole-breast irradiation (AWBI) reduces the number of fractions and the duration of treatment to about three weeks. Accelerated partial-breast irradiation (APBI) targets 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 one week.

Accelerated Whole-Breast Irradiation
For individuals who have node-negative, early-stage breast cancer with clear surgical margins who receive AWBI after BCS, the evidence includes randomized controlled trials (RCTs) and systematic reviews. The relevant outcomes are overall survival (OS), disease-specific survival, change in disease status, and treatment-related morbidity. Two randomized noninferiority trials both reported ten-year follow-up data on local recurrence. Both trials found that local recurrence rates with AWBI were no worse than conventional whole-breast irradiation (WBI) when applying a noninferiority margin of 5%. Conclusions apply to patients meeting eligibility criteria of the RCTs trials, including having early-stage invasive breast cancer, clear surgical margins, and negative lymph nodes. In addition, consistent with national guidelines, these conclusions apply to tumors less than or equal to 5 cm in diameter and women at least 50 years old. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

Input obtained in 2017 and in 2011 supported the use of AWBI.

Accelerated Partial-Breast Irradiation
For individuals who have early-stage breast cancer who receive interstitial brachytherapy, the evidence includes an RCT. The relevant outcomes are OS, disease-specific survival, change in disease status, and treatment-related morbidity. The RCT reported five-year follow-up data and found that interstitial brachytherapy was noninferior to WBI for rates of local breast cancer recurrence when applying a noninferiority margin of 3%. Ten-year follow-up data are needed on local recurrence as well as at least one additional trial confirming these findings.  

For individuals who have early-stage breast cancer who receive intraoperative brachytherapy, the evidence includes RCTs. The relevant outcomes are OS, disease-specific survival, change in disease status, and treatment-related morbidity. Several RCTs have been published but collectively they have not demonstrated that outcomes after intraoperative brachytherapy are noninferior to WBI. Results of two RCTs (TARGIT-A, ELIOT) comparing intraoperative brachytherapy with WBI found higher rates of local recurrence with intraoperative brachytherapy than with WBI. The evidence is insufficient to determine the effects of the technology on health outcomes.

For individuals who have early-stage breast cancer who receive external-beam APBI, the evidence includes RCTs. The relevant outcomes are OS, disease-specific survival, change in disease status, and treatment-related morbidity. The RCTs have reported outcomes out to three to five years, and ten-year data are required to draw conclusions about the impact of the technology on health outcomes. One trial reported higher rates of adverse cosmesis and grade 3 toxicities in the external-beam APBI group compared with the WBI group. The evidence is insufficient to determine the effects of the technology on health outcomes.

Input obtained in 2011 was mixed in its support of APBI.

Local Boost Brachytherapy with Whole-Breast Irradiation
For individuals who have early-stage breast cancer who receive local boost brachytherapy with WBI, the evidence includes nonrandomized studies and a systematic review. The relevant outcomes are OS, disease-specific survival, change in disease status, and treatment-related morbidity. A TEC Assessment concluded that, for women undergoing BCS plus WBI as initial treatment for stage I or II breast cancer, nonrandomized comparative studies have shown similar outcomes with brachytherapy local boost and with external-beam radiotherapy local boost. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

Noninvasive Breast Brachytherapy
For individuals who have early-stage breast cancer who receive noninvasive breast brachytherapy, the evidence includes a retrospective comparative study. The relevant outcomes are OS, disease-specific survival, change in disease status, and treatment-related morbidity. The retrospective study was a matched comparison of noninvasive breast brachytherapy or electron beam radiotherapy to provide boost radiation to the tumor bed. The study was subject to selection bias, relatively short follow-up, and use of a retrospective design. The evidence is insufficient to determine the effects of the technology on health outcomes.

Background 
Breast Cancer
Current estimates suggest that 276,480 new cases of breast cancer of any stage will occur in the U.S. in 2020. Based on adjusted data from 2013 to 2017, among women, the number of new cases is 128.5 per 100,000 and the number of deaths 20.3 per 100,000.2

Breast Conservation Therapy
For patients diagnosed with stage I or II breast tumors, survival after breast conservation therapy (BCT) is equivalent to survival after mastectomy. BCT is a multimodality treatment that initially comprises breast-conserving surgery (BCS) to excise the tumor with adequate margins, followed by whole-breast external-beam radiotherapy (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 (WBI) 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 patient data meta-analysis, the Early Breast Cancer Trialists' Collaborative Group (2011) reported that radiotherapy halved the annual recurrence rate after 10 years for women with a node-negative disease (n = 7287), from 31.0% for those not receiving radiotherapy to 15.6% for those receiving radiotherapy.3 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, radiotherapy 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 ages 70 or older may omit radiotherapy if they are estrogen receptor-positive, have T1 tumors, have clinically negative lymph nodes, and plan to take adjuvant endocrine therapy.4 However, the agreement is not universal.5

Controversy continues on the length of follow-up needed to determine whether accelerated partial-breast irradiation (APBI) is equivalent to WBI (see the TEC Assessment [2013] on accelerated radiotherapy after BCS for early-stage breast cancer for details.6 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.7-9 For accelerated WBI, some 10-year data are available. However, for newer approaches, the issue may be resolved by statistical issues rather than biologic ones.

Currently, most patients diagnosed with stage I or II breast cancer are offered a choice between BCT and mastectomy but BCT is selected less often than expected. Studies have shown that those living farthest from treatment facilities are least likely to select BCT instead of mastectomy and most likely to forgo radiotherapy after BCS.10-12

Approaches to Radiotherapy Following Breast-Conservation Treatment
The goals of cancer radiotherapy are to deliver a high dose of homogeneous radiation (ie, all parts of the tumor cavity receive close to the targeted dose) to the tumor or tumor bed. Areas adjacent to the tumor may be given a lower dose of radiation (eg, with WBI) 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.

Table 1 outlines the major types of radiotherapy used after BCS. They differ by technique, instrumentation, dose delivery, and possible outcomes. 

Table 1. Major Types of Radiotherapy Following Breast-Conserving Surgerya

Radiation Type

Accelerated?

Whole or Partial Breast

EBRT or Brachytherapy

Treatment Duration

Published RCTs

Length of Follow-Up

Conventional WBI

No

Whole

EBRT

5-6 wk

Multiple

>15 y

Accelerated WBI

Yes

Whole

EBRT

3 wk

4

10 y

Interstitial APBIb

Yes

Partial

Brachytherapy

1 wk

2

5.4 y

Balloon APBIc

Yes

Partial

Brachytherapy

1 wk

0

0

EBRT APBId

Yes

Partial

EBRT

1 wk

3

0

Intraoperative APBIe

Yes

Partial

Not applicable

1 d

1

5 y

APBI: accelerated partial-breast irradiation; EBRT: external-beam radiotherapy; RCT: randomized controlled trial; WBI: whole-breast irradiation.
a Noninvasive breast brachytherapy using AccuBoost has been described by the manufacturer as capable of delivering APBI but no studies for 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.
c Balloon brachytherapy (e.g., 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 three external-beam regimens can use 3-dimensional conformal radiotherapy or intensity-modulated radiotherapy.
e Intraoperative APBI is performed during breast-conserving surgery with a single dose of radiation delivered to the exposed tumor bed.

Regulatory Status
In 2002, the MammoSite® Radiation Therapy System (Proxima Therapeutics), the first device specifically designed for breast brachytherapy,12 was cleared for marketing by the U.S. Food and Drug Administration (FDA) through the 510(k) process. 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 cleared for marketing by FDA through the 510(k) process. FDA determined that several devices (e.g., Axxent® Electronic Brachytherapy System [Xoft], Strut-Adjusted Volume Implant [SAVI™] Applicator Kit [Biolucent (now Cianna Medical)], Contura® Multi-Lumen Balloon Source Applicator for Brachytherapy [SenoRx], ClearPath™ Adjustable Multi-Catheter Source Applicator [North American Scientific], Intrabeam® System [Carl Zeiss Surgical]) were substantially equivalent to predicate devices. 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 in the Intraoperative Brachytherapy subsection) is subject to FDA regulation, it does not fall under the regulatory purview of the U.S. Nuclear Regulatory Commission. In some states, the participation of radiation oncologists in delivering radiation is not required. 

Policy: 
When using radiotherapy after breast-conserving surgery (BCS) for early-stage breast cancer:

Accelerated whole-breast irradiation (AWBI) may be considered MEDICALLY NECESSARY for patients who meet the following conditions:

  • Invasive carcinoma of the breast

  • tumors ≤ 5 cm in diameter

  • negative lymph nodes

  • technically clear surgical margins, i.e., no ink on tumor on invasive carcinoma or ductal carcinoma in situ

AWBI is investigational and/or unproven and therefore considered NOT MEDICALLY NECESSARY in all other situations involving treatment of early-stage breast cancer after BCS.

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 those who are also treated with BCS and whole-breast external-beam radiotherapy.  

Accelerated partial breast irradiation may be considered MEDICALLY NECESSARY following breast conserving surgery for patients who meet the following conditions.   

  • Invasive carcinoma of the breast or ductal carcinoma < 3 cm in diameter
  • Unifocal tumors
  • Negative lymph nodes
  • Negative margin defined as no tumor on ink for invasive carcinoma of the breast (2mm margin on DCIS as this is the current guideline for whole breast irradiation) 

Noninvasive brachytherapy using AccuBoost® for patients undergoing initial treatment for stage I or II breast cancer when used as local boost irradiation in those who are also treated with BCS and whole-breast external-beam radiotherapy is investigational and/or unproven and therefore considered NOT MEDICALLY NECESSARY.

Policy Guidelines 
Electronic brachytherapy is considered a type of balloon brachytherapy that can be used to deliver accelerated partial-breast irradiation (APBI).

As recommended by the Society of Surgical Oncology and the American Society for Radiation Oncology (ASTRO), technically clear surgical margins can be defined as no ink on tumor of invasive carcinoma or ductal carcinoma in situ.1

As part of the clinical input process, ASTRO recommended additional criteria that should be satisfied for patients undergoing AWBI: 

  1. Pathologic stage is T1-2N0 and the patient has been treated with breast-conserving surgery.

  2. Patient has not been treated with systemic chemotherapy.

  3. Within the breast along the central axis, the minimum dose is no less than 93% and maximum dose is no greater than 107% of the prescription dose (± 7%) (as calculated with 2-dimensional treatment planning without heterogeneity corrections).

CODING
Please see the Codes table for details.

Benefit Application
BlueCard/National Account Issues
State or federal mandates (e.g., FEP) may dictate that all devices approved by the U.S. Food and Drug Administration (FDA) may not be considered investigational. Therefore, FDA-approved devices may only be assessed on the basis of their medical necessity.

Rationale   

This review was informed by several TEC Assessments, the most recent of which was released in 2013, on accelerated breast irradiation following breast-conserving surgery for early-stage breast cancer.6

Evidence reviews assess the clinical evidence to determine whether the use of a technology improves the net health outcome. Broadly defined, health outcomes are the length of life, quality of life, and ability to function-including benefits and harms. Every clinical condition has specific outcomes that are important to patients and managing the course of that condition. Validated outcome measures are necessary to ascertain whether a condition improves or worsens; and whether the magnitude of that change is clinically significant. The net health outcome is a balance of benefits and harms.

To assess whether the evidence is sufficient to draw conclusions about the net health outcome of technology, 2 domains are examined: the relevance, and quality and credibility. To be relevant, studies must represent 1 or more intended clinical use of the technology in the intended population and compare an effective and appropriate alternative at a comparable intensity. For some conditions, the alternative will be supportive care or surveillance. The quality and credibility of the evidence depend on study design and conduct, minimizing bias and confounding that can generate incorrect findings. The randomized controlled trial (RCT) is preferred to assess efficacy; however, in some circumstances, nonrandomized studies may be adequate. RCTs are rarely large enough or long enough to capture less common adverse events and long-term effects. Other types of studies can be used for these purposes and to assess generalizability to broader clinical populations and settings of clinical practice.

Accelerated Whole-Breast Irradiation
Clinical Context and Therapy Purpose

The purpose of accelerated whole-breast irradiation (AWBI) after breast-conserving surgery in patients who have node-negative, early-stage breast cancer with clear surgical margins is to provide a treatment option that is an alternative to or an improvement on existing therapies.

The question addressed in this evidence review is: Does AWBI after breast-conserving surgery improve the net health outcome in patients who have node-negative, early-stage breast cancer with clear surgical margins?

The following PICO was used to select literature to inform this review.

Populations
The relevant population of interest is patients who have node-negative, early-stage breast cancer with clear surgical margins.

Interventions
The therapy being considered is AWBI after breast-conserving surgery. Accelerated whole-breast irradiation provides the same dose to the whole breast in a shorter time than whole-breast irradiation (WBI) 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 has allayed most of these concerns. Accelerated whole-breast irradiation has been adopted widely in Canada and Europe.

Comparators
The following therapy is currently being used to make decisions: standard WBI.

Outcomes
The general outcomes of interest are overall survival (OS), disease-related survival, local recurrence, and treatment-related adverse events.

Patients with early-stage breast cancer should be followed for 10 years to evaluate OS and disease-related survival.

Study Selection Criteria
Methodologically credible studies were selected using the following principles:

  • To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs and systematic reviews of RCTs.

  • In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.

  • To assess long-term outcomes and adverse effects, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.

Review of Evidence
Systematic Reviews

Systematic reviews of RCTs have compared AWBI (also referred to as accelerated whole-breast radiotherapy) with conventional 5-week WBI. A systematic review and meta-analysis by Valle et al. (2017) included 13 trials (N = 8,189 patients) published prior to October 2014 that compared AWBI with standard fractionation.15 No differences were observed in local recurrence (7 trials; relative risk [RR], 0.97; 95% confidence interval [CI], 0.78 to 1.19), locoregional failure (8 trials; RR, 0.86; 95% CI, 0.63 to 1.16), or survival (4 trials; RR, 1.00; 95% CI, 0.85 to 1.17). There was less acute toxicity with AWBI (5 trials; RR, 0.36; 95% CI, 0.21 to 0.62), and no difference in late cosmesis (RR, 0.95; 95% CI, 0.81 to 1.12). The largest trials included in the meta-analysis were the Standardisation of Breast Radiotherapy (START) A, START B, and NCIC (detailed below).16,17,18

Randomized Controlled Trials
Two of the RCTs included in the systematic review were noninferiority trials that directly compared a 5-week with a 3-week regimen.16,17,18 Both trials used noninferiority margins of 5 percentage points for local or locoregional recurrence in the accelerated group at 5 years (1-sided α = .02516 or .0517) or 10 years (1-sided α = .02518). Although the trials differed in specific fractionation schedules and patient characteristics, they reported similar ipsilateral local recurrence rates (ie, cancer recurrence in the same breast) across treatment arms.

The first RCT evaluating an accelerated whole-breast radiotherapy regimen START B (2008), from the U.K., included women with stage I, II or III tumors (N = 2,215) who had clear tumor margins (≥ 1 mm).16 Approximately 75% of the women had negative lymph nodes, and approximately 42% had a radiation boost to the tumor bed. Randomization was stratified for the hospital, type of surgery (8% underwent mastectomy), and plans for a 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 gray (Gy) in 15 fractions over 3 weeks with 50 Gy in 25 fractions over 5 weeks. The primary efficacy outcome was locoregional relapse (relapse in ipsilateral breast or chest wall or in the ipsilateral axilla or supraclavicular fossa if previously irradiated) at 5 years. At median follow-up of 6.0 years (interquartile range, 5.0 to 6.2), estimated 5-year locoregional tumor relapse rate was 2.2% (95% 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 for 40 Gy AWBI versus conventional WBI were not statistically significant for local or locoregional relapse. There were statistically significant differences between the 2 treatment regimens for distant relapse and OS, with relapse less frequent and survival longer for the 40 Gy AWBI group. This unexpected difference between treatment arms began to appear at about 1 year; trialists speculated that the difference might have been due to chance and might change over 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 the patient-reported breast, arm, and shoulder symptoms, as well as body image, over 5 years of follow-up.19 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).20 Locoregional recurrence did not differ significantly between the 2 treatment groups: 4.3% for the AWBI group and 5.5% for the standard WBI group. However, breast shrinkage, telangiectasia, and breast edema were significantly less common in the AWBI group. These effects were assessed by a physician, photographic comparison with baseline, and patient report.

The second RCT assessing a 5- and a 3-week radiotherapy regimen compared AWBI with WBI in women who had lymph node-negative stage I, II, or III tumors.17,18 Treatment arms included a hypofractionated-radiation group (n = 622), who were treated with a total dose of 42.5 Gy in 16 fractions over 3 weeks, and a standard irradiation group (n = 612), who were treated with 50 Gy in 25 fractions over 5 weeks. Five-year local recurrence-free survival was 97.2% in the accelerated arm and 96.8% in the conventional arm (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 (difference, -0.5%; 95% CI, -2.5% to 3.5%). At 5 or 10 years, local recurrence rates with AWBI were no worse than with conventional WBI, when applying a noninferiority margin of 5%. In prespecified subgroup analyses, treatment effects were similar by age, tumor size, estrogen receptor status, and chemotherapy use (48% had no systemic therapy).

An RCT by Shaitelman et al. (2015), not included in the Valle et al. (2017) systematic review, focused on acute and short-term toxicity for conventional WBI versus AWBI.21, This unblinded trial included 287 patients with stage 0 to III breast cancer treated with breast-conserving therapy who had negative tumor margins. Patients were randomized to conventional radiotherapy at 50 Gy in 25 fractions (n=149) or AWBI at 42 Gy in 16 fractions (n=138). The rate of grade 2 or higher acute toxic events was 47% in the AWBI group and 78% in the conventional WBI group (p<.001). A total of 271 (94%) of 287 patients were available for an assessment at 6 months. There were no significant between-group differences in toxic effects at 6 months except that the rate of fatigue (grade ≥2) was significantly lower in the accelerated radiotherapy group (0%) than in the conventional radiotherapy group (6%; p=.01).

In 2020, Brunt et al. published 10 year results of the FASTer radiotherapy for breast radiotherapy (FAST) trial.22, This multicenter, phase III, RCT enrolled 915 women ≥50 years of age with low-risk invasive breast carcinoma who had undergone breast-conserving surgery with complete microscopic resection and randomly assigned them to 50 Gy in 25 fractions of 2 Gy, 30 Gy in 5 once weekly fractions of 6 Gy, or 28.5 Gy in 5 once weekly fractions of 5.7 Gy. At the time of this analysis, median follow-up was 9.9 years (interquartile range: 8.3 to 10.1 years). Results revealed that the odds ratios for any moderate/marked physician-assessed breast normal tissue effects (ie, shrinkage, induration, telangiectasia, edema) were significantly higher for the 30 Gy versus 50 Gy group (2.12; 95% CI, 1.55 to 2.89; p<.001), but not significantly different for the 28.5 Gy versus 50 Gy group (1.22; 95% CI, 0.87 to 1.72; p=.248). Additionally, 11 ipsilateral breast cancer events (50 Gy: 3; 30 Gy: 4; 28.5 Gy: 4) and 96 deaths (50 Gy: 30; 30 Gy: 33; 28.5 Gy: 33) were reported at 10 years of follow-up. These results appear to confirm that a 5-fraction schedule (28.5 Gy in 5 once weekly fractions) is radiobiologically equivalent to the standard 25-fraction schedule with regard to late normal tissue effects.

Brunt et al. (2020) also published results from the multicenter, noninferiority, randomized, FAST-Forward trial.23, This study enrolled 4096 adults with invasive breast carcinoma following complete microscopic excision of the primary tumor by breast-conserving surgery or mastectomy who were randomly assigned to 3 groups of hypofractionated radiotherapy: 40 Gy in 15 fractions over 3 weeks, 27 Gy in 5 fractions over 1 week, or 26 Gy in 5 fractions over 1 week. At a median follow-up of 71.5 months (interquartile range: 71.3 to 71.7 months), ipsilateral breast tumor relapse occurred in a total of 79 patients (40 Gy: 31; 27 Gy: 27; 26 Gy: 21); the hazard ratio for 27 Gy versus 40 Gy was 0.86 (95% CI, 0.51 to 1.44) and for 26 Gy versus 40 Gy was 0.67 (95% CI, 0.38 to 1.16). The estimated cumulative incidence of ipsilateral breast tumor relapse up to 5 years was 2.1% (95% CI, 1.4 to 3.1) for 40 Gy; 1.7% (95% CI, 1.2 to 2.6) for 27 Gy; and 1.4% (95% CI, 0.9 to 2.2) for 26 Gy. Estimated absolute differences in this outcome were -0.3% (95% CI, -1.0 to 0.9) for 27 Gy versus 40 Gy and -0.7% (95% CI, -1.3 to 0.3) for 26 Gy versus 40 Gy. Moderate or marked physician-assessed normal tissue effects in the breast or chest wall were seen in 9.9% of 40 Gy patients, 15.4% of 27 Gy patients, and 11.9% of 26 Gy patients at 5 years; a significant difference between 40 and 27 Gy (p=.0003) but not between 40 and 26 Gy (p=.17) was observed. These results show that a 1-week course of adjuvant breast radiotherapy delivered in 5 fractions is non-inferior to the standard 3-week schedule, with the 26 Gy dose level being similar to 40 Gy in terms of local tumor control and normal tissue effects for up to 5 years.

Observational Studies
Toxicity was evaluated in a large retrospective study of patients with left-sided early-stage breast cancer published by Chan et al. (2014, 2015).24,25, The study included 2706 patients who received conventional WBI (n=2221) or AWBI (n=485). Cardiotoxic chemotherapy regimens were similar between groups. At a median follow-up of 14.2 years, there were no statistical differences 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.

Section Summary: Accelerated Whole-Breast Irradiation
The overall body of evidence on AWBI compared with conventional WBI has indicated that local recurrence rates with AWBI are no worse than conventional WBI when applying a noninferiority margin of 5%. Canadian and U.K. noninferiority trials have reported 10-year follow-up data. Thus, conclusions apply to patients meeting eligibility criteria of these trials, including having early-stage invasive breast cancer, clear surgical margins, and negative lymph nodes. In addition, consistent with national guidelines, these conclusions apply to tumors less than or equal to 5 cm in diameter and women at least 50 years old. Based on 14-year retrospective data, severe cardiac toxicity with AWBI for left-sided breast cancers may not be increased compared with conventional WBI. Additionally, recent data imply that even more accelerated WBI scheduling may be non-inferior to standard 3- or 5-week schedules.

Accelerated Partial-Breast Irradiation
Clinical Context and Therapy Purpose

The purpose of APBI in patients who have early-stage breast cancer is to provide a treatment option that is an alternative to or an improvement on existing therapies.

The question addressed in this evidence review is: Does APBI improve the net health outcome in patients who have early-stage breast cancer?

The following PICO was used to select literature to inform this review.

Populations
The relevant population of interest is patients who have early-stage breast cancer.

Interventions
The therapies being considered are interstitial brachytherapy alone, intraoperative brachytherapy alone, and external-beam APBI. APBI differs from conventional WBI 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 [IORT]) rather than 5 to 6 weeks, because radiation is delivered to the tumor bed in fewer fractions at larger doses per fraction. Third, the 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).

Comparators
The following therapy is currently being used to make decisions about early-stage breast cancer: standard WBI.

Outcomes
The general outcomes of interest are OS, disease-related survival, local recurrence, and treatment-related adverse events.

Patients with early-stage breast cancer should be followed for 10 years to evaluate OS and disease-related survival.

Study Selection Criteria
Methodologically credible studies were selected using the following principles:

  • To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs and systematic reviews of RCTs.

  • In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.

  • To assess long-term outcomes and adverse effects, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.

Review of Evidence
Systematic Reviews

A number of RCTs and nonrandomized comparative studies have evaluated interstitial, external-beam, or intraoperative APBI compared with conventional WBI. Several meta-analyses of these studies have evaluated evidence on APBI compared to WBI, with various methods grouped in the same review.26,27,28,29,30,31,32,33, Conclusions cannot be drawn from these meta-analyses because analyses of the methods varied and methods were not evaluated individually. The review authors were generally consistent in concluding that additional data from RCTs are needed. In 2020, Viani et al. published a systematic review and updated meta-analysis of partial- versus WBI for early breast cancer that included a subgroup analysis assessing the potential effectiveness of APBI technique - IORT , brachytherapy, or external beam radiotherapy (EBRT).34, Results revealed no significant difference in local recurrence with APBI and WBI when using brachytherapy (p=.051), EBRT (p=.25), or mixed techniques (p=.89) at 5 years; however, a significant increase in local recurrence was noted with IORT use (p=.014). At 7 and 10 years follow-up, the difference in local recurrence within the IORT subgroup disappeared. Additionally, an analysis of overall mortality revealed no difference at 5, 7, and 10 years of follow-up for any subgroup. Korzets et al. (2019) revealed similar results from a subgroup analysis of APBI modality within a systematic review and meta-analysis that evaluated toxicity and clinical outcomes of partial- versus WBI for early-stage breast cancer.35, These authors concluded that the highest risk of local recurrence was seen with IORT, whereas when EBRT was used the odds for local recurrence were equivalent to WBI. The IORT studies included a larger number of patients with high-grade disease and nodal involvement, which may partially explain the increased local recurrence rate with this modality.

Interstitial Brachytherapy
Randomized Controlled Trials

GEC-ESTRO was a European multicenter noninferiority RCT with 5-year results (Table 2). Primary results were published in 2016, late-side effects in 2017, and quality of life in 2018.36,37,38, The primary study endpoint was the first incidence of local ipsilateral breast cancer recurrence within the 5-year observation period and the noninferiority margin was a 3% difference. At 5 years, the associated cumulative incidence of local recurrence was 0.92% (95% CI, 0.12% to 1.73%) in the conventional WBI group and 1.44% (95% CI, 0.51% to 2.38%) in the APBI group (Table 3). The difference between groups was within the noninferiority margin. There was no grade 4 skin toxicity. Grade 2 and 3 skin toxicity was 10.7% with WBI and 6.9% with APBI (p=.02).

Table 2. Summary of Key RCT Characteristics

Study; Trial Countries Sites Dates Participants Interventions
          Active Comparator
GEC-ESTRO36,37,38 EU 16 2004 – 2009 1328 patients ≥ 40 y with BCS for stage 0-IIa breast cancer, lesions ≤ 3 cm in diameter, clear margins ≥ 2 mm in any direction, and no lymph or blood vessel invasion 655 patients given APBI using interstitial brachytherapy 673 patients given WBI at 50 Gy in daily fractions of 1.8 to 2.0 Gy over 5 wk

APBI: accelerated partial breast irradiation; EU: European Union; Gy: gray; RCT: randomized controlled trial; WBI: whole-breast irradiation.

Table 3. Summary of Key RCT Results 

Study

Local Recurrence, n (%)

Overall Survival

Grade 2 to 3 Late Skin Toxicity

Excellent-to-Good Cosmetic Results, n (%)

Global Health Status (SD)

GEC-ESTRO36,37,38

 

 

 

 

 

n

1184

1184

1184

1007

537

WBI

5 (0.92)

95.5%

5.7%

408 (90)

66.0 (21.8)

APBI

9 (1.44)

97.27%

3.2%

503 (93)

66.2 (22.2)

Diff (95% CI)

0.52%
(-0.72% to 1.75%)

1.72%
(-0.44% to 3.88%)

 

 

-0.2
(-4.0 to 3.6)

p

NS

.11

.080

.12

.94

APBI: accelerated partial breast irradiation; CI: confidence interval; Diff: difference; NS: nonsignificant; RCT: randomized controlled trial; WBI: whole-breast irradiation; SD: standard deviation.

Major limitations in relevance and design and conduct are shown in Tables 4 and 5, respectively. This information is synthesized as a summary of the body of evidence following each table and provides the conclusions on the sufficiency of the evidence supporting the position statement.

Table 4. Study Relevance Limitations 

Study

Populationa

Interventionb

Comparatorc

Outcomesd

Follow-Upe

GEC-ESTRO36,37,38

 

 

 

1. Overall survival was not a primary outcome

1. Only followed for 5 y

The study limitations stated in this table are those notable in the current review; this is not a comprehensive gaps assessment.
a Population key: 1. Intended use population unclear; 2. Clinical context is unclear; 3. Study population is unclear; 4. Study population not representative of intended use.
b Intervention key: 1. Not clearly defined; 2. Version used unclear; 3. Delivery not similar intensity as comparator; 4. Not the intervention of interest.
c Comparator key: 1. Not clearly defined; 2. Not standard or optimal; 3. Delivery not similar intensity as intervention; 4. Not delivered effectively.
d Outcomes key: 1. Key health outcomes not addressed; 2. Physiologic measures, not validated surrogates; 3. No CONSORT reporting of harms; 4. Not establish and validated measurements; 5. Clinical significant difference not prespecified; 6. Clinical significant difference not supported.
e Follow-Up key: 1. Not sufficient duration for benefit; 2. Not sufficient duration for harms.

Table 5. Study Design and Conduct Limitations 

Study

Allocationa

Blindingb

Selective Reportingc

Data Completenessd

Powere

Statisticalf

GEC-ESTRO36,37,38

 

1 – 3. Not blinded

 

 

 

1. No prespecified noninferiority analysis on survival outcomes

The study limitations stated in this table are those notable in the current review; this is not a comprehensive gaps assessment.
a Allocation key: 1. Participants not randomly allocated; 2. Allocation not concealed; 3. Allocation concealment unclear; 4. Inadequate control for selection bias.
b Blinding key: 1. Not blinded to treatment assignment; 2. Not blinded outcome assessment; 3. Outcome assessed by treating physician.
c Selective Reporting key: 1. Not registered; 2. Evidence of selective reporting; 3. Evidence of selective publication.
d Data Completeness key: 1. High loss to follow-up or missing data; 2. Inadequate handling of missing data; 3. High number of crossovers; 4. Inadequate handling of crossovers; 5. Inappropriate exclusions; 6. Not intent to treat analysis (per protocol for noninferiority trials).
e Power key: 1. Power calculations not reported; 2. Power not calculated for primary outcome; 3. Power not based on clinically important difference.
f Statistical key: 1. Analysis is not appropriate for outcome type: (a) continuous; (b) binary; (c) time to event; 2. Analysis is not appropriate for multiple observations per patient; 3. Confidence intervals and/or p values not reported; 4.Comparative treatment effects not calculated.

Nonrandomized Studies
Ajkay et al. (2015) reported retrospectively on 5-year adverse events in patients with early-stage breast cancer treated at a single-center.39 Of 417 patients who received breast-conserving surgery and radiotherapy, 271 received brachytherapy (34 Gy in 10 fractions; 90% MammoSite, 9% Contura, 1% strut-adjusted volume implant) and 146 received WBI using 3-dimensional conformal radiotherapy (45 to 50.4 Gy in 25 to 28 fractions with 10 to 16 Gy boost). Median follow-up was 4.8 years in the brachytherapy group and 4.1 years in the WBI group. The estimated 5-year overall incidence of any adverse event was greater in the brachytherapy group (72%) than in the WBI group (52%; p < .001). For prespecified adverse events of interest, estimated 5-year incidences of infectious skin complications, abscess, telangiectasia, and breast pain were similar between groups. Estimated 5-year incidences of seroma (47% vs. 19%, p < .001) and fat necrosis (40% vs. 24%, p < .001) were greater in the brachytherapy group, respectively.

Section Summary: Interstitial Brachytherapy
The 2015 GEC-ESTRO RCT reported 5-year follow-up data and found that interstitial brachytherapy was noninferior to WBI on rates of local breast cancer recurrence when applying a 3% noninferiority margin. The number of events at 5 years was small. Ten-year follow-up data and at least 1 additional trial confirming these findings are needed.

Intraoperative Brachytherapy
Randomized Controlled Trials

One RCT, reported by Vaidya et al. (2010, 2014) compared IORT with WBI in 2,232 women.40,41 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 Risk-adapted Targeted Intraoperative Radiotherapy (TARGIT-A) trial was a noninferiority study at 28 centers in 9 countries with a sample size of 3,451. (In 2010, the trial was extended for 2 more years to allow accrual in subprotocols.) An intention-to-treat approach was used. Patients were not blinded to treatment choice. As anticipated, 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. In 2013, a study report provided 5-year results, defined as results for patients with 5 years of follow-up or "if they were seen the year before database lock."41 Median follow-up for all patients was 2 years and 5 months (interquartile range, 12 to 52 months), and 1,222 (35%) patients 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 = .042) in the WBI group. Mortality was similar between the 2 groups (2.6% with TARGIT vs 1.9% with WBI; p = .56). However, there were significantly fewer non-breast cancer deaths in the TARGIT group (1.4%; 95% CI, 0.8% to 2.5%) than in the WBI group (3.5%; 95% CI, 2.3% to 5.2%; p < .001), with fewer deaths from cardiovascular causes and other cancers in the TARGIT group. In the group that received IORT plus WBI, 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 for those who only received IORT. Noninferiority was established for the whole intraoperative cohort and for those who received IORT alone but not for patients who underwent both types of radiotherapy. There was no significant difference between the IORT and WBI groups in predefined 6-month wound-related complications. However, grade 3 or 4 radiotherapy-related skin complications were more common in the WBI group (13/1730 vs 4/1731; p = .029). In 2016, the full final report of the TARGIT-A trial was published concluding that "for patients with breast cancer (women who are aged ≥ 45 years with hormone-sensitive invasive ductal carcinoma that is up to 3.5 cm in size), targeted IORT concurrent with lumpectomy within a risk-adapted approach is as effective as, safer than, and less expensive than postoperative EBRT."42

In a parallel study to TARGIT-A, Vaidya and colleagues (2020) randomly assigned 1153 patients who had undergone breast cancer excision to either conventional fractionated whole breast EBRT over 3 to 6 weeks or to undergo a further operation to deliver delayed radiotherapy (as a single dose via Intrabeam) to the wound by reopening the original incision.43 Results at 5 years revealed local recurrence rates of 3.96% for delayed IORT versus 1.05% for EBRT; a difference of 2.9% with an upper 90% CI of 4.4, which crossed the noninferiority margin of 2.5%. Of note, at a median follow-up of 9 years, there no significant differences between the 2 treatment approaches with regard to local recurrence-free survival, invasive local recurrence-free survival, mastectomy-free survival, distant disease-free survival, breast cancer mortality, and overall survival. The authors concluded that the results of this trial clearly show that the preferred timing of IORT use is during the initial surgical excision of breast cancer setting, not in the delayed setting; however, if immediate IORT is not possible the data from this trial may assist clinicians and patients who want to avoid a prolonged postoperative EBRT course.

Another form of IORT, called electron intraoperative radiotherapy (ELIOT), uses electrons.44 The ELIOT trial, reported by Veronesi et al. (2013), compared IORT plus ELIOT with WBI.45 With a sample size of 1305 patients and median follow-up of 5.8 years (interquartile range, 4.1 to 7.7 years), 35 (4.4%) patients in the intraoperative group and 4 (0.4%) patients in the WBI group developed ipsilateral breast tumor recurrences (hazard ratio, 9.3; 95% CI, 3.3 to 26.3; p < .001). There was no statistically significant difference in 5-year OS. For women with data on adverse skin events (IORT = 464, WBI = 412), there were significantly fewer events among women who received IORT (p < .001). This was an equivalence trial with a prespecified limit of 7.5% for local recurrence in the IORT group only. Therefore, although the criterion for equivalence was satisfied, the ipsilateral breast recurrence rate was significantly higher in the IORT group. A subsequent review of ELIOT trial data by Silverstein et al. (2014) noted that, of 69 women who had 4 or more positive lymph nodes, those randomized to WBI (n = 38) received concurrent axillary radiation; for those randomized to ELIOT (n = 31), axillary irradiation was delayed 6 to 12 weeks.8 These reviewers also characterized ELIOT data as premature and noted that long-term results are needed to assess net health benefit. Orrechia et al. (2021) reported 15-year results of the ELIOT trial that confirmed the 5-year findings.46 After a median follow-up of 12.4 years (interquartile range, 9.7 to 14.7 years), ipsilateral breast tumor recurrence had occurred in 70 patients (11%) in the IORT group 16 patients (2%) in the WBI group (hazard ratio, 4.62; 95% CI, 2.68 to 7.95; p < .0001). Fifteen-year OS was 83.4% in the IORT group and 82.4% in the WBI group. The authors concluded that low risk patients may be appropriate for IORT since the higher rate of ipsilateral breast cancer recurrence in the ELIOT trial did not lead to an increase in OS.

Section Summary: Intraoperative Brachytherapy
Randomized controlled trials have not demonstrated that outcomes after intraoperative brachytherapy are noninferior to WBI. Five-year results from the TARGIT-A RCT showed increased ipsilateral local recurrence with APBI compared with WBI. In a parallel study to TARGIT-A, delayed IORT was also associated with an increase in local recurrence rates at 5 years as compared to EBRT. In another RCT that used a related but different technology (ELIOT), the recurrence rate with IORT was statistically greater than that with WBI.

External-Beam Accelerated Partial-Breast Irradiation
Randomized Controlled Trials

Rodriguez et al. (2013) reported on 102 patients randomized to WBI, with or without a boost to the tumor bed, or APBI.47 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% at a significance level of 0.05. The APBI group was significantly younger than the WBI group (mean age, 67.1 years vs 70.1 years; p = .009). After a 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 might have been insufficient to detect a true difference in local control. Ninety percent (46/51) of APBI patients had acute skin effects, mostly grade 1; all patients in the WBI 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. Li et al. (2021) reported long-term results of this trial (median, 10.3 years).48 Rates of recurrence (4%) and disease-free survival (84%) were the same in both groups. Estimated 12-year OS was also similar between groups (81.8 ± 7.4% APBI vs 89.9 ± 4.3% WBI; p > .05). Grade 1 and 2 fibrosis was numerically more common the ABPI group (n = 10) than the WBI group (n = 4; p = .18).

Olivotto et al. (2013) reported interim results of the multicenter Randomized Trial of Accelerated Partial Breast Irradiation (RAPID) trial.49 The sample size was 2135, and the median follow-up was 3 years. Most patients were older than 50 years and had estrogen receptor-positive tumors less than 1.5 cm in diameter. This interim report provided cosmetic and toxicity results. An accelerated regimen was used for WBI, and 21% of these patients received a boost to the tumor bed. APBI patients were more likely than WBI patients to have adverse cosmesis at 3 years, whether reported by physicians (p < .001), nurses (p < .001), or patients (p < .05). As for late toxicities, 1.4% of APBI patients had a grade 3 adverse event versus none of the WBI patients. Telangiectasia and breast induration were more common among APBI patients (p < .001). Although the primary outcome was ipsilateral local breast tumor recurrence, there were too few events to trigger an efficacy analysis. In 2019, Whelan et al. (2019) published longer term results from RAPID.50 Results from this analysis revealed similar ipsilateral breast tumor recurrence rates at 8 year between the groups (hazard ratio, 1.27; 90% CI, 0.84 to 1.91) and no difference in OS (hazard ratio, 1.18; 95% CI, 0.84 to 1.64).

In Livi et al. (2015), 520 patients with early breast cancer were randomized to APBI using intensity-modulated radiotherapy or WBI.51 The local recurrence rate at 5 years was 1.5% (3 cases) in the APBI group. There were 7 deaths in the WBI group and 1 in the APBI group (p = .057). The 5-year OS was 96.6% for the WBI group and 99.4% for the APBI group. Long-term results (mean, 10.5 years; range, 1.4 to 14.8 years) were published by Meattini et al. (2020).52 The 10-year cumulative ipsilateral breast tumor recurrence rate was 2.5% with APBI and 3.7% with WBI (hazard ratio, 1.56; 95% CI, 0.55 to 4.37; p = .40). A similar number of deaths occurred in both groups (24 ABPI vs 25 WBI) and the 10-year point estimate for OS was the same in both groups (91.9%; hazard ratio, 0.95; 95% CI, 0.50 to 1.79; p = .86).

Vicini et al. (2019) completed a phase 3, equivalence, multicenter, RCT comparing APBI to WBI after breast-conserving surgery for early-stage breast cancer that enrolled the largest number of patients (N = 4,216) and provided the longest follow-up reported to date.53 Results revealed that, at a median follow-up of 10.2 years, ABPI did not meet the criteria for equivalence to WBI with regard to controlling ipsilateral breast tumor recurrence (hazard ratio, 1.22; 90% CI, 0.94 to 1.58); however, the absolute difference in the 10-year cumulative incidence of ipsilateral recurrence was < 1% (4.6% APBI vs 3.9% WBI). Significantly more evaluable patients in the APBI group had recurrence-free interval events than patients in the WBI group (hazard ratio, 1.33; 95% CI, 1.04 to 1.69; p = .02); distant disease-free survival, OS, and disease-free survival were not different between the groups. The trial had broad eligibility criteria, but was not designed to test equivalence in patient subgroups or outcomes from varying APBI techniques. Tables 6 and 7 detail key characteristics and results of the RCTs in this section.

Polgar et al. (2021) reported 20-year results of an RCT that compared APBI with either EBRT or high-dose interstitial brachytherapy (n = 128) and WBI (n = 130) in patients with early-stage breast cancer who had undergone breast-conserving surgery.54 Patient accrual was stopped early and the study did not have sufficient power for the difference that was seen in the primary outcome (ipsilateral breast tumor recurrence). Median follow-up was 17 years (range, 1.5 to 21.2 years). Tumor recurrence rates were similar with APBI and WBI (9.6% vs 7.9%, respectively; p = .59). Overall survival at 20 years was also similar between groups (59.5% vs 59.7%, respectively; p = .90). Similar rates of grade 2 to 3 skin toxicity (p = .32) and fibrosis (p = .16) were reported in both groups.

Table 6. Summary of Key RCT Characteristics-External Beam APBI Versus WBI

Trial Countries Sites Dates Participants Interventions
Polgar et al. (2021)54 Hungary 1 1998 – 2004 Low risk invasive breast carcinoma with negative margins after breast-conserving therapy APBI: 5.2 Gy fractions given twice daily for 7 fractions with brachytherapy or 50 Gy total dose fractions over 5 weeks with EBRT
N = 128
WBI: 50 Gy given in 25 fractions over 5 weeks
N = 130
Vicini et al. (2019)53 U.S., Canada, Ireland, Israel 154 2005 – 2013 Over age 18, lumpectomy for stage 0 cancer or stage I or II invasive adenocarcinoma of the breast with no distant metastases, life expectancy of at least 10 y; surgical resection margins needed to be cancer free APBI: 34 Gy with brachytherapy or 38.5 Gy with EBRT in 10 fractions given twice daily, at least 6 hours apart, on 5 treatment days within an 8-day period
N = 2107
WBI: 50 Gy per day in 25 total fractions spread over 5 weeks
N = 2109
Livi it al. (2015)51; Meattini et al. (2020)52 Italy 1 2005 – 2013 Over age 40, maximum tumor size 25mm APBI: 30 Gy to the tumour bed in 5 daily fractions
N = 260
WBI: 50 Gy in 25 fractions, followed by a boost on the tumour bed of 10 Gy in 5 fractions
N = 260
Olivotto et al. (2013)49; Whelan et al. (2019)50 Canada, Australia, New Zealand 33 2006 – 2011 Invasive ductal carcinoma or DCIS treated with breast-conserving therapy with microscopically clear margins and negative axillary nodes by sentinel node biopsy, or axillary dissection for those with invasive disease, or by clinical examination for those with DCIS alone APBI: 38.5 Gy in 10 fractions
treated twice daily over 5 to 8 days with a minimum interfraction interval of 6 hours
N = 1,070
WBI: 42.5 Gy in 16 fractions or 50 Gy in 25 fractions. Boost irradiation of 10 Gy in 4 to 5 daily fractions after WBI was based on criteria such as young age or close margins
N = 1,065
Rodriguez et al. (2013)47; Li et al. (2021)48 Spain 1 NR Invasive ductal carcinoma; age 60 or older; unifocal tumor; primary tumor size 30 mm 37.5 Gy in 3.75 Gy per fraction
delivered twice daily
N = 51
WBI: 48 Gy in daily fractions of 2 Gy, with or without additional 10 Gy to the tumor bed
N = 51

APBI: accelerated partial breast irradiation; DCIS: ductal carcinoma in situ; EBRT: external beam radiotherapy; Gy: gray; N: sample size; NR: not reported; RCT: randomized controlled trial; WBI: whole breast irradiation.

Table 7. Summary of Key RCT Results-External Beam APBI versus WBI

Study Local Recurrence Overall Survival Toxicity
Polgar et al. (2021)54 Ipsilateral tumor recurrence at 20 years 20-year OS Grade 2-3 late toxicity
N 258    
APBI 9.6% 59.5% Skin: 13.6%
Fibrosis: 14.4%
WBI 7.9% 59.7% Skin: 11.8%
Fibrosis: 9.4%
Vicini et al. (2019)53 Ipsilateral tumor recurrence (first recurrence) 10-year point-estimate CTCAE toxicity grade
N 4025   4109
ABPI 4% 90.6% Grade 1: 40%
Grade 2: 44%
Grade 3: 10%
WBI 3% 91.3% Grade 1: 31%
Grade 2: 59%
Grade 3: 7%
Livi it al (2015)51; Meattini et al. (2020)52 Ipsilateral tumor recurrence at 10 years Number of deaths at 10 years Acute skin toxicity (> grade 2) at 10 years
N 520   520
APBI 2.7% 24 0%
WBI 3.5% 25 2.7%
Olivotto et al. (2013)49; Whelan et al. (2019)50 Ipsilateral tumor recurrence at 8 years Deaths Grade 2 or 3 toxicity at 3 years
N -- 140 1070
APBI 3% 76 1.4%
WBI 2.8% 64 0%
Rodriguez et al. (2013)47; Li et al. (2021)48   12-year OS Acute and late toxicity
N 102 102 Acute: 102; 4 years: 70
APBI 4% 81.8% Acute: 46/51 (90.2%); 4 years: 16%, all grade 1
WBI 4% 89.9% Acute: 51/51 (100%); 4 years: 11%, all grade 1

APBI: accelerated partial breast irradiation; CTCAE: Common Terminology Criteria for Adverse Events; N: sample size; RCT: randomized controlled trial; WBI: whole breast irradiation.

Relevance and study design limitations are summarized in Tables 8 and 9, respectively.

Table 8. Study Relevance Limitations-External Beam APBI versus WBI

Study Populationa Interventionb Comparatorc Outcomesd Follow-Upe
Polgar et al. (2021)54   3. 69% of patients received high-dose brachytherapy, 33% of patients received EBRT   3. Not reported  
Vicini et al. (2019)53 4. Absence of HER2 data for enrolled patients with invasive breast cancer 3. 73% of patients had 3DCRT as their APBI technique; 27% underwent brachytherapy as the ABPI technique (either single-entry or multi-catheter)      
Livi et al. (2015)51; Meattini et al. (2020)52       1. Overall survival NR  
Olivotto et al. (2013)49; Whelan et al. (2019)50       1. Too few events for efficacy analysis of the primary outcome (local recurrence)  
Rodriguez et al. (2013)47; Li et al. (2021)48        

APBI: accelerated partial breast irradiation; HER2: human epidermal growth factor receptor 2; NR: not reported; WBI: whole breast irradiation.
The study limitations stated in this table are those notable in the current review; this is not a comprehensive gaps assessment.
a Population key: 1. Intended use population unclear; 2. Clinical context is unclear; 3. Study population is unclear; 4. Study population not representative of intended use.
b Intervention key: 1. Not clearly defined; 2. Version used unclear; 3. Delivery not similar intensity as comparator; 4.Not the intervention of interest.
c Comparator key: 1. Not clearly defined; 2. Not standard or optimal; 3. Delivery not similar intensity as intervention; 4. Not delivered effectively.
d Outcomes key: 1. Key health outcomes not addressed; 2. Physiologic measures, not validated surrogates; 3. No CONSORT reporting of harms; 4. Not establish and validated measurements; 5. Clinical significant difference not prespecified; 6. Clinical significant difference not supported.
e Follow-Up key: 1. Not sufficient duration for benefit; 2. Not sufficient duration for harms.

Table 9. Study Design and Conduct Limitations-External Beam APBI Versus WBI

Study

Allocationa

Blindingb

Selective Reportingc

Data Completenessd

Powere

Statisticalf

Polgar et al. (2021)54

 

1, 2

1. Protocol not registered

 

 

 

Vicini et al. (2019)53

 

1, 2

 

 

 

 

Livi it al (2015)51; Meattini et al. (2020)52

 

 

 

 

 

 

Olivotto et al. (2013)49; Whelan et al. (2019) 50

 

1

 

1. 335/2135 (15.7%) completed 5-year assessment

 

 

Rodriguez et al. (2013)47; Li et al. (2021)48

 

 

1. Protocol not registered

1. Toxicity outcomes reported in 70/102 patients (68.6%)

3. May have been underpowered to detect difference in local recurrence rates

Trial terminated early due to cosmesis benefit

APBI: accelerated partial breast irradiation; WBI: whole breast irradiation.
The study limitations stated in this table are those notable in the current review; this is not a comprehensive gaps assessment.
a Allocation key: 1. Participants not randomly allocated; 2. Allocation not concealed; 3. Allocation concealment unclear; 4. Inadequate control for selection bias.
b Blinding key: 1. Not blinded to treatment assignment; 2. Not blinded outcome assessment; 3. Outcome assessed by treating physician.
c Selective Reporting key: 1. Not registered; 2. Evidence of selective reporting; 3. Evidence of selective publication.
d Data Completeness key: 1. High loss to follow-up or missing data; 2. Inadequate handling of missing data; 3. High number of crossovers; 4. Inadequate handling of crossovers; 5. Inappropriate exclusions; 6. Not intent to treat analysis (per protocol for noninferiority trials).
e Power key: 1. Power calculations not reported; 2. Power not calculated for primary outcome; 3. Power not based on clinically important difference.
f Statistical key: 1. Analysis is not appropriate for outcome type: (a) continuous; (b) binary; (c) time to event; 2. Analysis is not appropriate for multiple observations per patient; 3. Confidence intervals and/or p values not reported; 4. Comparative treatment effects not calculated.

Section Summary: External-Beam Accelerated Partial-Breast Irradiation
Randomized controlled trials have reported outcomes from 5 to 20 years. Results from the trial with the largest number of patients reveal that external-beam APBI did not meet the criteria for equivalence to WBI with regard to controlling tumor recurrence; however, the the absolute difference in the 10-year cumulative incidence of ipsilateral recurrence was low and survival was not different between groups. Other RCTs found no significant differences between external beam ABPI and WBI regarding local recurrence or survival, including the trial with the longest follow-up (20 years). Moreover, 1 of the trials reported higher rates of adverse cosmetic outcomes and grade 3 toxicities in the external-beam APBI group than in the WBI group.

Local Boost Brachytherapy
Clinical Context and Therapy Purpose

The purpose of local boost brachytherapy with WBI in patients who have early-stage breast cancer is to provide a treatment option that is an alternative to or an improvement on existing therapies.

The question addressed in this evidence review is: Does local boost brachytherapy with WBI improve the net health outcome in patients who have early-stage breast cancer?

The following PICO was used to select literature to inform this review.

Populations
The relevant population of interest is patients who have early-stage breast cancer.

Interventions
The therapy being considered is local boost brachytherapy with WBI. Brachytherapy can be used as an alternative to EBRT to deliver boost radiotherapy combined with whole-breast irradiation. Most studies of local boost brachytherapy use temporarily implanted needles, wires, or seeds after patients have recovered from surgery and completed whole-breast radiotherapy.

Comparators
The following therapy is currently being used to make decisions about early-stage breast cancer: standard WBI with or without an external-beam boost to the tumor bed.

Outcomes
The general outcomes of interest are OS, disease-related survival, local recurrence, and treatment-related adverse events.

Patients with early-stage breast cancer should be followed for 10 years to evaluate OS and disease-related survival.

Study Selection Criteria
Methodologically credible studies were selected using the following principles:

  • To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs and systematic reviews of RCTs.
  • In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.
  • To assess long-term outcomes and adverse effects, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.

Review of Evidence
Systematic Reviews

A TEC Assessment (1996) concluded that net health outcomes with a local boost using brachytherapy were equivalent to outcomes of local boost using EBRT in women who received breast-conserving surgery plus WBI as initial treatment for stage I or II breast cancer.55 No RCTs were identified. However, there were 7 nonrandomized studies comparing 2 types of local boost radiotherapy: brachytherapy (n = 2,033) and EBRT (n = 1,557); all patients also received breast-conserving surgery and WBI. The combination of brachytherapy with local boost, breast-conserving surgery, and WBI prevented local tumor recurrence and salvage mastectomy in 95% to 97% of patients at 5 years and 88% to 92% of patients at 10 years. Five-year survival in the 5 studies reporting this outcome ranged from 83% to 96%. Data from uncontrolled studies reported similar rates of local control and 5-year survival.

Section Summary: Local Boost Brachytherapy
For women undergoing breast-conserving surgery plus WBI as initial treatment for stage I or II breast cancer, nonrandomized comparative studies have shown similar outcomes with local boost using brachytherapy and local boost using EBRT.

Noninvasive Breast Brachytherapy
Clinical Context and Therapy Purpose

The purpose of noninvasive breast brachytherapy in patients who have early-stage breast cancer is to provide a treatment option that is an alternative to or an improvement on existing therapies.

The question addressed in this evidence review is: Does noninvasive breast brachytherapy improve the net health outcome in patients who have early-stage breast cancer?

The following PICO was used to select literature to inform this review.

Populations
The relevant population of interest is patients who have early-stage breast cancer.

Interventions
The therapy being considered is noninvasive breast brachytherapy. 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 image-guided 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.56 No long-term studies are available to confirm this potential benefit.

Comparators
The following therapy is currently being used to make decisions about early-stage breast cancer: standard WBI.

Outcomes
The general outcomes of interest are OS, disease-related survival, local recurrence, and treatment-related adverse events.

Patients with early-stage breast cancer should be followed for 10 years to evaluate OS and disease-related survival.

Study Selection Criteria
Methodologically credible studies were selected using the following principles:

  • To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs and systematic reviews of RCTs.
  • In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.
  • To assess long-term outcomes and adverse effects, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.

Review of Evidence
No systematic reviews or RCTs of noninvasive breast brachytherapy for patients with early-stage breast cancer were identified.

Nonrandomized Studies
One comparative study on noninvasive breast brachytherapy was identified. This matched retrospective study by Leonard et al. (2013) assessed patients receiving the boost dose using AccuBoost or electron beams (a type of EBRT).57 Each of the 47 AccuBoost patients was compared with 2 controls matched on age, stage, chemotherapy use, fractionation, and when possible, breast size, comorbidities, and smoking status. The main differences between the 2 treatment groups were in radiation doses received and the timing of radiotherapy administration. The percentage of patients with a WBI 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 < .001). Also, a greater proportion of patients in the electron-treated group received the boost dose after WBI, rather than during WBI or starting before and ending during WBI (99% for the electron-treated group vs 6% for the AccuBoost group). Approximately 60% of patients had stage I breast cancer, and approximately 25%, ductal carcinoma in situ. With a median follow-up of 13.6 months, skin and subcutaneous tissue toxicity incidence occurred less often among patients treated with AccuBoost than among those treated with an electron beam (p = .046). Locoregional control rates were 99% or greater in both groups. Study limitations included the between-group differences in dose and timing of boost, as well as selection bias and the study's retrospective design.

Section Summary: Noninvasive Breast Brachytherapy
One nonrandomized comparative study was identified. The comparative study was a retrospective matched comparison of noninvasive breast brachytherapy or EBRT to provide boost radiation to the tumor bed. The study was subject to selection bias, relatively short follow-up, and use of a retrospective design.

Summary of Evidence
For individuals who have node-negative, early-stage breast cancer with clear surgical margins who receive AWBI after breast-conserving surgery, the evidence includes RCTs and systematic reviews. Relevant outcomes are OS , disease-specific survival, change in disease status, and treatment-related morbidity. Two randomized noninferiority trials both reported 10-year follow-up data on local recurrence. Both trials found that local recurrence rates with AWBI were no worse than conventional WBI when applying a noninferiority margin of 5%. Conclusions apply to patients meeting eligibility criteria of the RCTs, including having early-stage invasive breast cancer, clear surgical margins, and negative lymph nodes. In addition, consistent with national guidelines, these conclusions apply to tumors less than or equal to 5 cm in diameter and women at least 50 years old. The evidence is sufficient to determine that the technology results in an improvement in the net health outcome.

For individuals who have early-stage breast cancer who receive interstitial brachytherapy, the evidence includes an RCT. Relevant outcomes are OS, disease-specific survival, change in disease status, and treatment-related morbidity. The RCT reported 5-year follow-up data and found that interstitial brachytherapy was noninferior to WBI for rates of local breast cancer recurrence when applying a noninferiority margin of 3%. Ten-year follow-up data are needed on local recurrence as well as at least 1 additional trial confirming these findings. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

For individuals who have early-stage breast cancer who receive intraoperative brachytherapy, the evidence includes RCTs. Relevant outcomes are OS, disease-specific survival, change in disease status, and treatment-related morbidity. Several RCTs have been published but collectively results have not demonstrated that outcomes after intraoperative brachytherapy are noninferior to WBI. Results of 2 RCTs (TARGIT-A, ELIOT) comparing intraoperative brachytherapy with WBI found higher rates of local recurrence with intraoperative brachytherapy than with WBI. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

For individuals who have early-stage breast cancer who receive external-beam APBI, the evidence includes RCTs. Relevant outcomes are OS, disease-specific survival, change in disease status, and treatment-related morbidity. RCTs have reported outcomes from 5 to 20 years. Results from the trial with the largest number of patients reveal that external-beam APBI did not meet the criteria for equivalence to WBI with regard to controlling tumor recurrence; however, the the absolute difference in the 10-year cumulative incidence of ipsilateral recurrence was low and survival was not different between groups. Other RCTs found no significant differences between external beam ABPI and WBI regarding local recurrence or survival, including the trial with the longest follow-up (20 years). Moreover, 1 of the trials reported higher rates of adverse cosmetic outcomes and grade 3 toxicities in the external-beam APBI group than in the WBI group. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

For individuals who have early-stage breast cancer who receive local boost brachytherapy with WBI, the evidence includes nonrandomized studies and a systematic review. Relevant outcomes are OS, disease-specific survival, change in disease status, and treatment-related morbidity. A TEC Assessment concluded that, for women undergoing BCS plus WBI as initial treatment for stage I or II breast cancer, nonrandomized comparative studies have shown similar outcomes with brachytherapy local boost and with external-beam radiotherapy local boost. The evidence is sufficient to determine that the technology results in an improvement in the net health outcome.

For individuals who have early-stage breast cancer who receive noninvasive breast brachytherapy, the evidence includes a retrospective comparative study. Relevant outcomes are OS, disease-specific survival, change in disease status, and treatment-related morbidity. The retrospective study was a matched comparison of noninvasive breast brachytherapy or electron beam radiotherapy to provide boost radiation to the tumor bed. The study was subject to selection bias, relatively short follow-up, and use of a retrospective design. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

The purpose of the following information is to provide reference material. Inclusion does not imply endorsement or alignment with the evidence review conclusions.

Clinical Input 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.

2017 Input
Clinical input was sought to help determine whether the use of accelerated whole breast irradiation (AWBI) for individuals with node-negative, early-stage breast cancer with clear surgical margins would provide a clinically meaningful improvement in net health outcome and whether the use is consistent with generally accepted medical practice. In response to requests, clinical input was received from 5 respondents, including 1 physician-level responses identified through a specialty society and 4 physician-level responses identified through an academic medical center.

For individuals who have node-negative, early-stage breast cancer with clear surgical margins who receive AWBI, clinical input supports this use provides a clinically meaningful improvement in net health outcome and indicates this use is consistent with generally accepted medical practice. Input was limited to the policy statement on AWBI. Three of 4 academic medical centers and the physician specialty society agreed with the statement as a whole. Reviewers suggested other eligibility criteria but there was no consensus on specific criteria.

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 on accelerated whole-breast irradiation. Input was mixed on accelerated partial-breast irradiation; 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 on the effectiveness of accelerated partial-breast irradiation compared with whole-breast irradiation.

Practice Guidelines and Position Statements
Guidelines or position statements will be considered for inclusion in Supplemental Information if they were issued by, or jointly by, a U.S. professional society, an international society with U.S. representation, or National Institute for Health and Care Excellence (NICE). Priority will be given to guidelines that are informed by a systematic review, include strength of evidence ratings, and include a description of management of conflict of interest.

National Comprehensive Cancer Network
Current National Comprehensive Cancer Network (NCCN) guidelines (v.4.202 1) on breast cancer state4:

"Studies of APBI [accelerated partial-breast irradiation] suggest that rates of local control in selected low-risk patients with early-stage breast cancer may be comparable to those treated with standard whole breast RT [radiotherapy]. However, compared to standard whole breast radiation, several studies document an inferior cosmetic outcome with external beam delivery methods of APBI. Follow-up is limited and studies are ongoing. Patients are encouraged to participate in clinical trials. The NCCN panel accepts the updated version of the ASTRO [American Society for Radiation Oncology] APBI guideline consensus statement" (see Table 10 below).
For whole-breast radiotherapy, the NCCN recommends a dose of 46 to 50 gray in 23 to 25 fractions or 40 to 42.5 gray in 15 to 16 fractions. Based on convenience and the data from the START trials, the short course of radiation therapy is the NCCN preferred option in patients given radiation treatment to the breast only. A boost to the tumor bed is recommended for higher-risk patients receiving whole-breast radiotherapy (i.e., those who are < 50 years old, high-grade disease, or patients with focally positive margins) in order to reduce local relapse.

American Society for Radiation Oncology et al.
The American Society for Radiation Oncology (ASTRO, 2017), American Society of Breast Surgeons (2018), and the American Brachytherapy Society (2018) have issued various consensus statements for the selection of patients for APBI (summarized in Table 10).58,59,60 Recommendations were based on systematic reviews, which are not described in detail, and expert opinion.

Table 10. Professional Medical Society Criteria for Performing APBI

Factor

ASTRO "Suitable"

ASTRO "Cautionary"

ASTRO "Unsuitable"

ASBS

ABS

Patient factors

 

 

 

 

 

Age

≥ 50 y

40 – 49 y; ≥ 50 y if patient has at least 1 of the pathologic factors and does not have any "unsuitable" factors

< 40 y; 40 to 49 y and do not meet the criteria for cautionary

≥ 45 y for all tumor types

≥ 45 y

BRCA1 and BRCA2 variants

Not present

NR

Present

Patients should not be treated if they have a BRCA genetic mutation

NR

Pathologic factors

 

 

 

 

Tumor size

≤ 2 cm

2.1 – 3.0 cm

> 3 cm

≤ 3 cm

≤ 3 cm

Tumor stage

Tis or T1

T0 or T2

T3 – 4

Tis, T1, T2 (≤3 cm)

 

Margins

Negative ≥ 2 mm

Close (< 2 mm)

Positive

No tumor on ink for invasive tumors or tumors involved with DCIS; ≥ 2 mm for DCIS

Negative (no tumor on ink for invasive ≥ 2 mm for DCIS)

Grade

Any

NR

NR

NR

NR

LVSI

No

Limited/focal

Extensive

Allowed as long as it is focal

Not present

ER status

Positive

Negative

NR

Positive or negative

Positive or negative

Multicentricity

Unicentric

NR

Present

NR

NR

Multifocality

Clinically unifocal; total size, ≤ 2.0 cm

Clinically unifocal; size, 2.1 – 3.0 cm

Clinically multifocal or microscopically multifocal; size, ≥ 3 cm

Multifocal disease is allowed as long as the combined area of tumor is ≤ 3 cm

NR

Histology

Invasive ductal or other favorable subtypes

Invasive lobular

NR

All invasive subtypes; DCIS

All invasive subtypes and DCIS

Pure DCIS

Not alloweda

≤ 3 cm if "suitable" criteria not fully met

> 3 cm

≤ 3 cm

≤ 3 cm

EIC

Not allowed

≤ 3 cm

> 3 cm

NR

NR

Associated LCIS

Allowed

NR

NR

NR

NR

Nodal factors

 

 

 

 

 

Nodal stage/status

pN0 (i-, i+)

NR

pN1, pN2, pN3

Negative

Negative

Nodal surgery

SNB, 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; APBI: accelerated partial-breast irradiation; ASBS: American Society of Breast Surgeons; ASTRO: American Society for Radiation Oncology; DCIS: ductal carcinoma in situ; EIC: extensive intraductal component; ER: estrogen receptor; LCIS: lobular carcinoma in situ; LVSI: lymphovascular space invasion; NR: not reported; SN: sentinel node; SNB sentinel node biopsy. 

a Allowed if screen-detected, low to intermediate nuclear grade, ≤ 2.5 cm size, and resected with margins negative at ≥ 3 mm. 

The ASTRO (2018) updated its guidelines on fractionation for whole-breast irradiation.61 The consensus-based guidelines conclude that accelerated whole-breast irradiation may be used for any age and any stage provided the intent is to treat the whole breast without any additional field, and with any chemotherapy.

U.S. Preventive Services Task Force Recommendations
Not applicable

Ongoing and Unpublished Clinical Trials
Some currently unpublished trials that might influence this review are listed in Table 11.

Table 11. Summary of Key Trials

NCT No.

Trial Name

Planned Enrollment

Completion Date

Ongoing

 

 

 

WBI vs APBI with or without tumor bed boost

 

 

NCT04669873

Clinical Trial, Randomized, Open Label, With an Active Comparator to Assess the Efficacy and Safety of Using Accelerated Partial Irradiation Versus Standard or Hypofractionated Irradiation of the Entire Breast in Patients With Initial Breast Cancer After Conservative Surgery

36

Dec 2026

NCT00470236

Radiation Doses and Fractionation Schedules in Non-low Risk Ductal Carcinoma In Situ (DCIS) of the Breast (TROG)

1608

Jun 2024

Intraoperative brachytherapy

 

 

NCT01343459

Intra-Operative Electron Boost and Hypofractionated Whole-Breast Irradiation During Breast-conserving Treatment (BCT) (HIOB)

1300

May 2022

NCT01644669

Safety and Efficacy Study of the Xoft® Axxent® eBx™ IORT System

1200

Dec 2029

External-beam APBI

 

 

NCT01247233

Standard or Hypofractionated Radiotherapy Versus Accelerated Partial Breast Irradiation (APBI) for Breast Cancer (SHARE)

1006

Oct 2025

NCT01185132

Intensity Modulated Radiotherapy (IMRT) vs 3D-conformal Accelerated Partial Breast Irradiation (APBI) for Early Stage Breast Cancer After Lumpectomy (2009-APBI)

660

Jul 2028

APBI (multimodality)

 

 

NCT00892814

Partial Breast Versus Whole Breast Irradiation in Elderly Women Operated on for Early Breast Cancer

882

March 2026

NCT01185145

Accelerated Partial Breast Radiotherapy With Either Mammosite or Intensity Modulated Radiotherapy (APBI)

291

Aug 2024

Unpublished

 

 

 

External-beam APBI

NCT01803958

Breast Cancer With Low Risk Of Local Recurrence: Partial and Accelerated Radiation With Three-Dimensional Conformal Radiotherapy (3DCRT) vs Standard Radiotherapy After Conserving Surgery (Phase III Study) (IRMA)

3302

Jan 2019

APBI: accelerated partial-breast irradiation; DCIS: ductal carcinoma in situ; NCT: national clinical trial; WBI: whole-breast irradiation.

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  59. American Society of Breast Surgeons. Consensus statements: accelerated partial breast irradiation. Revised. 2018 https://www.breastsurgeons.org/about/statements/. Accessed June 5, 2021

  60. Shah C, Vicini F, Shaitelman SF, et al. The American Brachytherapy Society consensus statement for accelerated partial-breast irradiation. Brachytherapy. Jan 2018; 17(1): 154-170. PMID 29074088

  61. Smith BD, Bellon JR, Blitzblau R, et al. Radiation therapy for the whole breast: Executive summary of an American Society for Radiation Oncology (ASTRO) evidence-based guideline. Pract Radiat Oncol. May 2018; 8(3): 145-152. PMID 29545124

Coding Section

Codes

Number

Description

CPT

19296

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 (code language revised effective 01/01/09 to include multichannel catheters)

 

19297

concurrent with partial mastectomy (List separately in addition to code for primary procedure)

 

19298

Placement of radiotherapy afterloading brachytherapy catheters (multiple tube and button type) into the breast for interstitial radioelement application following (at the time or subsequent to)  partial mastectomy, includes imaging guidance

 

77261-77263

Therapeutic radiology treatment planning code range

 

77280-77295

Therapeutic radiology simulation-aided field-setting code range

 

77326

Brachytherapy isodose calculation; simple (calculation made from single plane, 1 to 4 sources/ribbon application, remote afterloading brachytherapy, 1 to 8 sources)

 

77327 

; intermediate (multiplane dosage calculations, application involving 5 to 10 sources/ribbons, remote afterloading brachytherapy, 9 to 12 sources) 

 

77328

; complex (multiplane isodose plan, volume implant calculations, over 10 sources/ribbons used, special spatial reconstruction, remote afterloading brachytherapy, over 12 sources) 

 

77776-77778

Interstitial radiation source application code range 

 

77785-77787 

Remote afterloading high dose rate radionuclide brachytherapy code range  

 

0182T 

High dose rate electronic brachytherapy, per fraction 

ICD-9 Procedure 

85.0 

Mastotomy 

 

92.27 

Implantation or insertion of radioactive elements 

ICD-9 Diagnosis 

174.0-174.9 

Primary malignant neoplasm of breast, female 

 

175.0-175.9 

Primary malignant neoplasm of breast, male 

 

198.81 

Secondary malignant neoplasm of breast (male/female) 

HCPCS 

C1717 

Placement and removal (if performed) of applicator into breast for radiation therapy 

 

C9726 

Radioelements for brachytherapy, any type, each 

 

Q3001 

Malignant neoplasm male and female breast code range 

ICD-10-CM (effective 10/01/15)

C50.011-C50.929 

Secondary malignant neoplasm of breast 

 

C79.81 

ICD-10-PCS codes are only used for inpatient services. There is no specific ICD-10-PCS code for this procedure. 

ICD-10-PCS (effective 10/01/15)

DM1097Z, DM1098Z, DM1099Z, DM109BZ, DM109CZ, DM109YZ, DM10B7Z, DM10B8Z, DM10B9Z, DM10BBZ, DM10BCZ, DM10BYZ, DM1197Z, DM1198Z, DM1199Z, DM119BZ, DM119CZ, DM119YZ, DM11B7Z, DM11B8Z, DM11B9Z, DM11BBZ, DM11BCZ, DM11BYZ 

Radiation oncology, breast, brachytherapy, code by body part (right or left), modality qualifier (high dose rate or low dose rate), and isotope (Cesium 137, Iridium 192, Iodine 125, Palladium 103, Californium 252, or other isotope) 

 

0HHT01Z, 0HHT31Z, 0HHT71Z, 0HHT81Z, 0HHTX1Z, 0HHU01Z, 0HHU31Z, 0HHU71Z, 0HHU81Z, 0HHUX1Z, 0HHV01Z, 0HHV31Z, 0HHV71Z, 0HHV81Z, 0HHVX1Z 

Surgical, skin & breast, insertion, radioactive element, code by body part (right, left or bilateral), and approach (open, percutaneous, via natural or artificial opening, via natural or artificial opening endoscopic, or external)

 

 

0HCT0ZZ, 0HCT3ZZ, 0HCU0ZZ, 0HCU3ZZ, 0HCV0ZZ, 0HCV3ZZ 

Surgical, skin & breast, extirpation, breast, code by body part (right, left or bilateral) and approach (open or percutaneous) 

Type of Service

Radiotherapy 

 

Place of Service 

Inpatient

 

Procedure and diagnosis codes on Medical Policy documents are included only as a general reference tool for each policy. They may not be all-inclusive. 

This medical policy was developed through consideration of peer-reviewed medical literature generally recognized by the relevant medical community, U.S. FDA approval status, nationally accepted standards of medical practice and accepted standards of medical practice in this community, Blue Cross Blue Shield Association technology assessment program (TEC) and other nonaffiliated technology evaluation centers, reference to federal regulations, other plan medical policies, and accredited national guidelines.

"Current Procedural Terminology © American Medical Association. All Rights Reserved" 

History From 2014 Forward     

07/13/2022

Annual review, no change to policy intent. Updating rationale and references.

04/28/2022 

Interim review to add medical necessity criteria for accelerated partial breast irradiation based on NCCN guidelines. No other changes.

01/31/2022 

Correcting language in policy. No change to policy intent

07/01/2021 

Annual review, no change to policy intent. Updating background, guidelines, rationale and references. 

07/28/2020 

Annual review, no change to policy intent. Updating background, description, rationale and references. 

12/04/2019 

Interim review to remove the age restriction of >than 50 in relation to the ASTRO recommendations. No other changes. 

07/01/2019 

Annual review, no change to policy intent. Updating background, description, rationale and references. 

08/03/2018 

Annual review, no change to policy intent. Updating rationale and references. 

07/28/2017 

Annual review, policy verbiage updated: breast width criterion removed from first policy statement, a bullet point on age of at least 50 years added to the AWBI statement, clarification of technically clear surgical margins for AWBI made. Also updating title, background, description, guidelines, rationale and references. 

09/28/2016 

Updated the word guideline to policy. when applicable. No change to policy intent. 

07/01/2016 

Annual review, no change in policy intent. 

07/30/2015 

Annual review, no change to policy statement. Updating background, description, regulatory status, rationale and references. Adding guidelines and coding.

07/08/2014

Annual review. Added "Noninvasive brachytherapy using Accuboost® 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 BCS and whole-breast external-beam radiotherapy is considered investigational." to policy verbiage. Updated background, regulatory status, rationale and references.

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