| Coverage Policy Manual | |
| Policy #: | 2002011 |
| Category: | Radiology |
| Initiated: | July 2002 |
| Last Review: | December 2023 |
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| Breast Brachytherapy and Accelerated Breast Irradiation | |
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| Description: |
Radiotherapy is the standard of care for patients with breast cancer undergoing breast-conserving surgery because it reduces recurrences and lengthens survival. A 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 breast-conserving surgery; 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 3 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 1 week.
Breast Cancer
Current estimates suggest that 287,850 new cases of breast cancer of any stage will occur in the U.S. in 2022. Based on adjusted data from 2015-2019, among women, the number of new cases is 128.3 per 100,000 women per year and the number of deaths is 19.9 per 100,000 women per year (NCI SEER, 2022).
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 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 breast-conserving surgery 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 (Darby, 2011).,It also reduced the 15-year risk of breast cancer death from 20.5% to 17.2% (p=.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=.01).
Consequently, radiotherapy is generally recommended following breast-conserving surgery. 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 (NCCN, 2022). However, the agreement is not universal (Albert, 2012).
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 breast-conserving surgery for early-stage breast cancer for details) (BCBS Association TEC, 2013).,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 (Kaidar-Person, 2014; Silverstein, 2014; Silverstein, 2014). 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 breast-conserving surgery,,and have recommended the use of multidisciplinary management strategies to eliminate known disparities in rural, minority, and uninsured populations (Athas, 2000; Farrow, 1992; Nattinger, 2001; Dragun, 2011).
Approaches to Radiotherapy Following Breast-Conservation Treatment
The goals of cancer radiotherapy are to deliver a high dose of homogeneous radiation (i.e., 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 (e.g., 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.
Below outlines the major types of radiotherapy used after breast-conserving surgery. They differ by technique, instrumentation, dose delivery, and possible outcomes.
Comparison of the Major Types of Radiotherapy Following Breast-Conserving Surgery: (Type. Accelerated?, Whole or Partial Breast? EBRT or Brachytherapy? Treatment Duration.):
Conventional WBI Not accelerated Whole Breast EBRT 5-6 weeks
Accelerated WBI Accelerated Whole Breast EBRT 3 weeks
Interstitial APBI Accelerated Partial Breast Brachytherapy 1 week
Balloon APBI Accelerated Partial Breast Brachytherapy 1 week
EBRT APBI Accelerated Partial Breast EBRT 1 week
Intraoperative APBI Accelerated Partial Breast Not applicable 1 day
Regulatory Status
In 2002, the MammoSite® Radiation Therapy System (Proxima Therapeutics), the first device specifically designed for breast brachytherapy, was cleared for marketing by the U.S. Food and Drug Administration (FDA) through the 510(k) process (Berliner, 2014). Its intended use is ‘‘to provide brachytherapy when the physician chooses to deliver intracavitary radiation to the surgical margins following lumpectomy for breast cancer'' (FDA, 2002).
Since 2002, several other devices for breast brachytherapy have been cleared for marketing by the FDA through the 510(k) process. The 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 is subject to the 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.
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Policy/ Coverage: |
Effective August 1, 2021, for members of plans that utilize a radiation oncology benefits management program, Prior Approval is required for this service and is managed through the radiation oncology benefits management program.
Effective November 10, 2022
Brachytherapy
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
Brachytherapy meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes for breast cancer when used to deliver ANY one of the following:
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
Brachytherapy for breast cancer is not covered based on benefit certificate primary coverage criteria that there be scientific evidence of effectiveness:
For members with contracts without primary coverage criteria, Brachytherapy for breast cancer is considered investigational and is not covered:
Investigational services are specific contract exclusions in most member benefit certificates of coverage.
Whole Breast Irradiation
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
Whole breast irradiation (WBI) – 17 to 28 fractions of WBI meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes only for individuals who meet ANY one of the following criteria:
For individuals not meeting one of these criteria, up to 16 fractions of WBI will be allowed.
Breast boost irradiation
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
Whole breast irradiation (WBI) and Boost Irradiation for breast cancer is not covered based on benefit certificate primary coverage criteria that there be scientific evidence of effectiveness:
For members with contracts without primary coverage criteria, Whole breast irradiation (WBI) and Boost Irradiation for breast cancer is considered investigational and is not covered:
Investigational services are specific contract exclusions in most member benefit certificates of coverage.
Effective Prior to November 10, 2022
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
Brachytherapy meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes for breast cancer when used to deliver ANY one of the following:
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
Brachytherapy for breast cancer is not covered based on benefit certificate primary coverage criteria that there be scientific evidence of effectiveness:
For members with contracts without primary coverage criteria, Brachytherapy for breast cancer is considered investigational and is not covered:
Investigational services are specific contract exclusions in most member benefit certificates of coverage.
Coverage effective Prior to July 15, 2021
Brachytherapy meets primary coverage criteria for effectiveness and is covered 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 breast-conserving surgery and whole breast external beam radiotherapy.
Brachytherapy, when used in patients with stage I or II disease as the sole form of radiotherapy after surgical excision, or for local boost irradiation when combined with whole breast radiotherapy but without surgical excision, does not meet member benefit certificate Primary Coverage Criteria for effectiveness, as this treatment is being studied in phase III trials.
For contracts without primary coverage criteria, brachytherapy when used in patients with stage I or II disease as the sole form of radiotherapy after surgical excision, or for local boost irradiation when combined with whole breast radiotherapy but without surgical excision is considered investigational. Investigational services are an exclusion in the member certificate of coverage.
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| Rationale: |
This policy was developed based on an Arkansas Blue Cross Blue Shield initial evaluation, 1996: Technology Assessment in 2002.
Brachytherapy as “boost” therapy following whole breast radiation therapy
There are no randomized studies comparing brachytherapy to external beam radiation therapy as a local boost, analysis of 7 nonrandomized retrospective studies that included 2,022 patients indicate that net health outcomes after brachytherapy for local boost are equivalent to those after external beam radiation therapy for local boost in women given breast-conserving surgery and whole breast radiation therapy as initial treatment for stage I or stage II breast cancer. Specifically, the rate of local control at 5 years after treatment was 88%–98% for those given brachytherapy for local boost compared to 91%–99% for those given external beam radiation therapy.
Brachytherapy as the sole form of radiation therapy in patients given breast-conserving surgery for stage I or stage II breast cancer
Literature published from 1996 thru 2002 does not change the above conclusions regarding brachytherapy as the sole form of radiation therapy, although there has been growing research interest, both as a technique to shorten the treatment time compared to whole breast radiation therapy and as a technique to improve cosmesis. For example, Vicini and colleagues reported on a series of 174 patients with stage I or II breast cancer who were treated with breast conserving surgery followed by brachytherapy alone to the tumor bed. To perform a matched pair analysis, each brachytherapy patient was matched for age, tumor size, nodal status, estrogen receptor status, and use of adjuvant modalities with a patient treated with external beam radiation therapy. After a median follow-up of 3 years, there was no significant difference in ipsilateral treatment failure or local treatment failure between the 2 groups. Smaller studies have reported similar results with the authors reporting the importance of detailed patient selection criteria to select patients at low risk of multicentric disease. Studies that have reported conflicting results may have used less rigid patient selection criteria. For example in the Guy’s London trial, 27 patients received an iridium implant to the primary tumor bed as sole radiation treatment. After a 6-year median follow-up, the recurrence rate was 32%. However, 37% of the patients had positive tumor margins, which may have contributed to the high recurrence rate.
While there are some promising results regarding brachytherapy as the sole form of radiation therapy, larger studies with longer follow-up will be needed to determine if radiation to the whole breast can be safely withheld. In February 2001, recommendations issued by the American Brachytherapy Society stated that “… the use of brachytherapy as a sole [radiation] modality should be considered investigational and should be performed in the context of a controlled clinical trial.” the above discussion.
Results of preliminary trials have been promising and the use of brachytherapy continues to be evaluated in ongoing studies comparing it to other methods of radiotherapy for breast cancer.
2004-2006 Update
A 2004 literature search identified 1 new report each from uncontrolled phase II trials of interstitial and balloon brachytherapy to deliver accelerated partial-breast irradiation. However, there were no published reports from controlled studies comparing long-term rates of in-breast recurrence after whole-breast versus accelerated partial-breast radiotherapy.
A subsequent search in November 2005 identified an update with nearly 7 years’ follow-up from a nonrandomized direct comparison of interstitial accelerated partial-breast irradiation (APBI) versus whole-breast radiotherapy (WBRT). Differences in actuarial rates of ipsilateral breast recurrence at 5 and 7 years were not statistically significant. However, the study was not designed to test noninferiority, and the lack of a significant difference is inconclusive since the sample size was small (n=45 given APBI, 80 given WBRT) and few in-breast failures occurred in either arm (3 and 8, respectively). There were an additional 3 reports from single-arm studies on interstitial APBI and 4 reports from single-arm studies on balloon APBI. Follow-up in these uncontrolled reports was insufficient for analysis of outcomes other than acute toxicity and cosmesis.
An updated search in September 2006 found 2 uncontrolled series and a non-randomized comparison (15, 16) on interstitial brachytherapy as APBI. One of the series included few patients (n=7); the other (n=99) followed patients for a median 2.7 years. The nonrandomized comparison (5.4 years median follow-up) reported similar actuarial rates of local recurrence at 5 years for 199 patients given partial breast irradiation between 1993 and 2001 (1%; 95% CI: 0, 2.8%) and a matched group of 199 historical controls (1%; 95% CI: 0, 2.4%) given WBRT between 1980 and 1997. Investigators did not report estimated recurrence rates at times after 5 years. In addition, significantly more patients given partial breast irradiation received adjuvant chemotherapy, were re-excised to achieve tumor-free margins >=2 mm on all sides, and significantly fewer had contralateral breast cancer at 5 years (suggesting different recurrence risks despite matching). These differences may have biased the comparison in favor of partial breast irradiation, and underscore the uncertainties associated with using historical controls to compare partial and whole-breast radiation after breast-conserving surgery. A more recent report on the 199 patients given APBI included a median 6.4 years follow-up, but only reported cosmetic outcomes and treatment-related toxicities.
Five new uncontrolled series reported on patients managed with balloon APBI. Sample sizes ranged from 16 to 169 patients, but duration of follow-up was only 7.35 to 20 months. One study reported that intraoperative placement of the balloon catheter was associated with a high rate (76%) of clinically detectable seroma, with greater than 6 months’ persistence in 68% and at least modest discomfort in 46% of 38 implanted patients. The new uncontrolled studies lack adequate follow-up to resolve current uncertainties on whether long-term recurrence rates after APBI with either interstitial or balloon brachytherapy are equivalent to those of whole-breast radiation therapy.
Another concern is the proportion of implanted balloon catheters that for technical reasons must be explanted without delivering radiation therapy. Reasons include balloon rupture, inadequate skin spacing, poor balloon conformance to the surgical cavity, or if eligibility assessment changes after intra-operative catheter placement based on pathology results. Most such patients undergo WBRT after the balloon is explanted. A recent review summarized data from 4 studies (total n=204; range 23-92). The pooled frequency of explanted balloons was 15% (range, 9% to 20%). Explantation may be less frequent with postoperative placement (9%; n=78) than with intra-operative placement (19%; n=126). A registry report (n=1403) summarized data from 223 investigators at 87 centers; 9% of patients had balloon catheters explanted without being irradiated.
A randomized intergroup trial comparing WBRT and APBI sponsored by the U.S. National Cancer Institute and led by National Surgical Adjuvant Breast and Bowel Project and the Radiation Therapy Oncology Group opened in early 2005 (NSABP B-39/RTOG-0413). The trial is randomizing 3,000 patients to WBRT or APBI after lumpectomy with tumor-free margins verified by histologic examination. Eligible patients for the trial include patients with Stage 0, I, or II breast cancer resected with a lumpectomy. In addition, the tumor must be less than or equal to 3.0 cm, and there must be no more than 3 positive axillary nodes. The primary objective is to compare in-breast tumor control (i.e., recurrence rates) for whole-breast versus partial-breast irradiation. Investigators anticipate accrual will be completed by 29 months from the trial‘s start date. As of September 2006, the trial remains active and continues to accrue new patients.
2007 Update
In February 2007, an updated TEC Assessment reviewed evidence published through December 2006 on APBI as sole radiotherapy after breast-conserving surgery for early stage breast cancer. Included in the Assessment were studies on initial treatment of stage I or II breast cancer if they reported outcomes on 25 or more patients with a mean or median follow-up of at least 5 years to evaluate if APBI is at least as good as WBRT in improving the patients’ net health outcomes, i.e., reduced recurrences and decreased mortality.
In general, patients selected for treatment with APBI have small, usually unifocal tumors, with margins free of malignant cells and minimal extension to lymph nodes. Variation occurs, however, in patient selection criteria such as tumor dimension (from <=2 to 4 cm), width of tumor-free margins (>=2 or 1 mm to unspecified), and nodal status (from negative to as many as 3 positive nodes). Current evidence is not sufficient to reliably determine who should or should not be candidates for APBI using brachytherapy. Moreover, the technique of interstitial brachytherapy has a steep learning curve for practitioners, and findings from these studies cannot be automatically extrapolated to other types of APBI.
The literature search identified 6 controlled studies, 2 uncontrolled studies with at least 5 years of follow-up, and one randomized controlled trial with only 30 months of follow-up. An additional 21 uncontrolled studies were excluded because they did not meet the selection criteria.
The one randomized controlled trial is a prospective evaluation in which 46 women (73%) were treated with APBI using brachytherapy after breast-conserving surgery and 17 (27%) received APBI using wide-field external-beam radiation therapy. The control group (n=63) was treated with WBRT and no local boost. The mean 30-month follow-up is inadequate to permit conclusions regarding frequencies of ipsilateral tumor recurrence.
The 5 controlled trials also offer problems with analysis. One study compares retrospective matched pairs; 199 patients who received brachytherapy have 60 months of follow-up, while the 199 matched controls have 107 months of follow-up. The follow-up is insufficient to estimate recurrence rates after 5 years. Also, the brachytherapy patients were more likely than the control patients to receive adjuvant chemotherapy, to have re-excision surgery to achieve tumor-free margins, and they were less likely to have contralateral breast cancer at 5 years. These differences might bias the comparison in favor of APBI.
Another of the controlled trials compares APBI in 45 patients with WBRT in 90 controls. Follow-up is nearly 7 years, and differences in rates of recurrence are not statistically significant. However, the trial is not designed to test noninferiority, and the lack of a significant difference is inconclusive because of the small sample size. In a third controlled trial, outcomes are compared in 50 patients receiving APBI and 94 who met the same criteria but are treated with WBRT. There is no matching for prognostic factors known to affect the likelihood of relapse, and patient selection bias may confound the results. A fourth trial compares 33 patients undergoing APBI with 30 having WBRT with an external beam boost and 22 having WBRT with an interstitial brachytherapy boost. Median follow-up ranges from 35 to 38 months, and no information is given on recurrence or mortality. The fifth controlled trial dates from the early 1990s and includes patients who currently are not likely to be candidates for APBI and who are not matched to the controls.
One of the 2 uncontrolled studies falls just 3 months short of the 5-year follow-up; there was 1 recurrence at the excision site, and other ipsilateral failures occurred in 4% to 10% of patients. The other trial includes node-positive patients and demonstrates a high rate of nodal failure (13% vs. 5% in Polgar et al). Results of these trials may be confounded by patient selection bias.
The FDA approved the Axxent electronic brachytherapy device in December 2005 via 510(k) as substantially equivalent to the Mammosite and other brachytherapy systems. As with Mammosite, however, the FDA required a warning in a black box stating that “The safety and effectiveness of the Axxent Electronic Brachytherapy System as a replacement for whole breast irradiation in the treatment of breast cancer has not been established.” No clinical studies are currently available on the clinical impact of using the Axxent electronic radiotherapy device.
No new studies were found that would alter the conclusions of the policy statement related to the use of APBI as sole radiotherapy after breast-conserving surgery for early stage breast cancer.
Additional Information
Both the American Society of Breast Surgeons (ASBS) and the American Brachytherapy Society (ABS) have issued position statements on partial breast irradiation, advocating it as an accepted technique for women with small tumors and negative axillary nodes. The 2002 updated report from the ABS consists of a literature review of data on local recurrences of breast cancer after APBI using brachytherapy. The authors concluded that the majority of breast cancers recur at the site of the tumor bed. While the ABS recommendations are based on these data, the same observations served as the impetus to further study of long-term outcomes in the randomized intergroup (NSABP/RTOG) trial. The consensus statement from the ASBS is unreferenced.
Criteria recommended by the American Society of Breast Surgeons (dated December 8, 2005) to select patients for partial breast irradiation are:
Of note, both the ABS and the ASBS suggest that APBI should be limited to patients with node-negative breast cancer. In contrast, the randomized study will accept patients with up to 3 positive axillary nodes. Advocates of breast brachytherapy may have adopted the ABS or ASBS patient selection criteria for ongoing use of breast brachytherapy outside of a clinical trial. Therefore, it is possible that recruitment to the randomized study may focus on those patients with positive axillary nodes, not meeting the existing ABS or ASBS guidelines.
In their updated guideline (version 1.2007), the National Comprehensive Cancer Network (NCCN) recommends radiation therapy to the whole breast with boost for patients with clinical stages I, II, and T2N1M0 breast cancer undergoing lumpectomy (additional radiation and chemotherapy are also discussed). In a footnote, they amplify as follows: "Whole breast irradiation with boost (by photons, brachytherapy or electron beam) to tumor bed. Boost to tumor bed is especially encouraged in those 50 y of age or younger. Partial breast irradiation should be performed only as part of a high quality prospective clinical trial."
2008 Update
Longer follow-up data are now available for 2 of the controlled studies of interstitial brachytherapy described above (Vicini, 2003; Vicini, 2001; Polgar, 2002). Polgar and colleagues (2007) report on 258 patients randomized to WBRT or partial breast irradiation (69% received multicatheter brachytherapy with an accelerated protocol; 31% received electron beam irradiation with the same fractionation schedule as WBRT). With a median follow-up of 66 months, the actuarial rate of local recurrence was not statistically different in the WBRT arm (3.4%) versus the PBI arm (4.7%; p=0.50). Accrual was stopped early in June 2004 when eligible patients were referred to the GEC-ESTRO Phase III APBI trial. The authors stated, “We could not exclude that the PBI arm was inferior (or superior) from our sample of 258. Thus, our results should be confirmed by ongoing multicenter Phase III trials with larger sample size to rule out inferiority of PBI compared with standard WBI.” In addition, results for the 2 types of partial breast irradiation (PBI) were not reported separately. Previous studies which compared outcomes from different types of partial breast irradiation were historical control comparisons, which may or may not be accurate.
Vicini and colleagues (2007) reported on 199 patients treated prospectively at their institution with interstitial brachytherapy and followed for a median of 8 years. Six ipsilateral breast tumor recurrences occurred, as well as 3 regional nodal failures and 5 contralateral breast cancers. The 5-year actuarial rate of ipsilateral recurrence was 1.6%. Three of the ipsilateral recurrences occurred several centimeters from the primary tumor site. Five of the 6 ipsilateral recurrences were clonally related to the original tumor, while one was a new primary tumor. Axillary recurrences may also be important because of a concern that the lower axilla is not included in the standard radiotherapy target volume with APBI, while it is in many cases with WBRT. The authors conclude that the failure rate for APBI is similar to previously reported rates for WBRT, but note the utility of ongoing randomized controlled trials (RCTs) for validating single-institution results. Another uncontrolled study of interstitial therapy in 32 patients reported an actuarial local recurrence rate of 6.1% at 5 years. (Kaufman, 2007)
Data continue to accrue from uncontrolled studies on the use of Mammosite balloon brachytherapy (e.g., Chao, 2007; Chen, 2007). The longest follow-up found was 5 years in a study of 36 patients; no local recurrences were reported. (Benitez, 2007) However, this study began with 70 patients: 16 did not have the catheter implanted, 11 had the catheter explanted, and 7 were discontinued from follow-up. Given the development of recurrences beyond 5 years (23% of local failures in the NSABP B-06 trial [Kaufman, 2007]), longer follow-up is needed, as well as controlled trials.
Several randomized controlled trials are currently underway, including the NSABP B-39/RTOG-0413 trial mentioned above. As of January 15, 2007, 2,547 patients had been accrued, with the accrual goal increased to 4,300 to increase statistical power. (Swanson, 2007) In addition, the Ontario Clinical Oncology Group is conducting an RCT of WBRT vs. 3D-CRT APBI (www.clinicaltrials.gov/ct/show/NCT00282035), and the European Brachytherapy Breast Cancer Working Group of GEC-ESTRO is in the middle of a randomized trial of interstitial brachytherapy vs. WBRT (http://www.clinicaltrials.gov/ct2/show/NCT00402519?term=breast+brachytherapy&rank=5). Additional studies on APBI are listed at clinicaltrials.gov. The results of these trials, when they become available, should provide much stronger evidence on the comparability of WBRT and the various forms of APBI. The impact of each type of APBI on mammographic architecture and therefore on the ability to detect recurrences or new malignancies also requires further investigation. (Dragun, 2007)
Accelerated whole breast irradiation provides an alternative treatment strategy that would reduce treatment time while providing broader treatment of the breast, although the potential long-term toxicities, e.g., to the heart and lungs, remain to be determined through longer follow-up of study cohorts (for a succinct discussion of APBI vs. accelerated WBRT, Munshi, 2007).
As noted above, partial breast irradiation as sole source therapy is being studied in several phase III randomized controlled trials to determine effectiveness. Arkansas BCBS member benefit contracts exclude coverage for services that are being studied in phase I, II, or III trials or are otherwise under study to determine effectiveness. The FDA continues to state that the effectiveness of partial breast irradiation as sole source irradiation for breast cancer is unproven.
Given the above evidence, the policy statements are unchanged at this time.
2011 Update
The optimal set of selection criteria for APBI is not clearly defined. The American Society of Therapeutic Radiology and Oncology (ASTRO) Health Services Research Committee convened a Task Force of breast cancer experts from various oncologic specialties to develop a consensus statement addressing patient selection criteria and best practices for the application of APBI outside of clinical trials (Smith, 2009). The recommendations were based on the results of a systematic literature review of APBI data and supplemented by the expert opinions of the members of the Task Force.
Vicini and colleagues prospectively treated 199 patients with APBI and 199 patients with WBI (Vicini, 2010). All patients had StageI/II breast cancer. The patients were categorized according to the ASTRO CP guidelines for APBI and analyzed for the ability of these criteria to predict differences in clinical outcome compared with traditional clinical, pathologic, and treatment-related variables.
The guidelines developed by the ASTRO CP were unable to differentiate cases that may be more appropriately treated with WBI. According to the authors, “These results await validation from other large APBI databases and suggest that further refinements of these ASTRO CP grouping may be needed. These findings also support the continued enrollment of high-risk patients treated with APBI in Phase III clinical trials and emphasize the importance of the completion of these trials so that, in the future, treatment decisions can be made on existing outcome data.”
Abbott and colleagues, 2011, published results of a retrospective analysis of patients who received whole breast radiotherapy (WBRT) or implantable accelerated partial breast irradiation (IAPBI) from 2000-2007. The proportion of women receiving IAPBI rose 1600% and the rise was greater than 2100% for older women, ages 70 - 79 years. They concluded “The rapid and widespread adoption of IAPBI is concerning, because larger multicenter randomized controlled trials have not yet demonstrated the long-term effectiveness of IAPBI compared with WBRT.”
2012 Update
A review of the available evidence as well as clinical guidelines and ongoing clinical trials is summarized as follows:
There are three RCTs on interstitial, external-beam, or intraoperative accelerated partial-breast irradiation (APBI) compared to conventional whole-breast irradiation, as well as 7 nonrandomized comparative studies. These studies evaluated interstitial, external, or intraoperative brachytherapy; no published comparative studies were found that assessed balloon brachytherapy. For the first, accrual was stopped before reaching the goal specified to evaluate differences in local recurrence, to allow patients to participate in another trial (Polgar, 2001) (Lovey, 2007) (Polgar, 2007). The randomization process was unclear, patients deemed “technically unsuitable” for interstitial brachytherapy were given external-beam APBI; and the patient characteristics and outcomes for each type of APBI were not reported separately. Finally, the sample size of 126 was relatively small, and longest follow-up reported was 66 months. Similar local and regional failure rates were found in the treatment arms.
The second RCT on APBI was reported in 1990 and 1993, and many changes in the care of breast cancer have occurred since (Ribeiro, 1990) (Riberio, 1993). The study was weakened by the fact that the 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 the initial work-up for nodal involvement was limited. The follow-up was 65 months; and the sample size, 708.
The third randomized trial compared intraoperative to external-beam accelerated partial-breast irradiation (Vaidya, 2010). It is a noninferiority trial with 28 centers in 9 countries and a sample size of 2,232. An ITT approach was used; 89% of the intraoperative group and 92% of the external radiotherapy group completed treatment. Patients were not blinded to treatment choice. As anticipated in advance, 14% of those in the intraoperative arm received external beam radiotherapy as well, because of unfavorable pathologic features determined after surgery, e.g., lobular carcinoma. The pre-defined noninferiority margin was an absolute difference of 2.5% between groups for pathologically confirmed, ipsilateral local recurrence. After 4 years, wound seroma needing more than three aspirations was significantly more common in the intraoperative group than in the external radiotherapy group (2.1% vs. 0.8%,respectively; p=0.012). Conversely, Radiation Therapy Oncology Group (RTOG) toxicity grade of 3 or 4 was more common in the external radiotherapy group than in the intraoperative group (2.1% vs. 0.5%, respectively; p=0.002). The 4-year local recurrence rates in the ipsilateral breast were 1.20% (95% CI: 0.53%, 2.71%) in the intraoperative radiotherapy arm vs. 0.95% (95% CI: 0.39%, 2.31%) in the external radiotherapy arm (difference between groups=0.25%, 95% CI: -1.04%, 1.54%; log-rank test, p=0.41). Local recurrence rates after 4 years with intraoperative radiotherapy were not worse than with external irradiation, when applying a noninferiority margin of 2.5%. Fortunately for the patients, the recurrence rates are low: 6 in the intraoperative group versus 5 in the external radiotherapy group. But these small numbers make it more difficult to detect real differences between arms, if they exist. Also, while the results are interesting, the follow-up of 4 years is insufficient to reach a conclusion on the comparative benefits and adverse events of these two treatments.
The other 7 nonrandomized, comparative studies were all 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 (Antonucci,, 2009) (Fentiman,, 1995) (Fentiman,, 1991) (King, 2000) (Ott, 2005) (Polgar, 2004) (Vicini, 2001) (Vicini, 2003) (Wadasadawala, 2009) .
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 the 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 should also be presented to women who meet the criteria for the Canadian trial, as well as the critical importance of completing radiotherapy for the majority of patients undergoing BCS.
A large, multicenter RCT of APBI versus whole-breast irradiation was initiated in 2005 to compare APBI to whole-breast irradiation. It is led by the National Surgical Adjuvant Breast and Bowel Project and the Radiation Therapy Oncology Group and referred to as NSABP B-39/RTOG 0413 (available online at: www.rtog.org). Patients are randomized to whole-breast irradiation (total dose: 60-66.6 Gy) or APBI (total dose: 34-38.5 Gy). Within the APBI group, the participant’s physician may choose whether to use interstitial brachytherapy, Mammosite balloon brachytherapy, or external beam radiotherapy using 3-dimensional, conformal radiation therapy (3D-CRT). The initial target sample size of 3,000 was increased to 4,300 in 2007. The accrual targets for the women with a lower risk of recurrence were met by the end of 2006; only women in the higher risk groups are still being recruited. As of Sept 2008, 3,236 patients had been accrued, of whom 2,948 were White, 204 Black/African American, and 110 Latino/Hispanic. Final data collection for the primary outcome measure is scheduled for June 2015. There are another 6 RCTs on the use of APBI versus whole breast irradiation underway, as well as two trials comparing two forms of APBI (available online at: www.clinicaltrials.gov). There is also a study on using ABI as a boost with whole breast irradiation and 3 randomized trials comparing standard whole breast irradiation and AWBI. It appears that the first randomized trial that compares recurrence for APBI and whole breast irradiation will be completed in November 2014. The study is being conducted by the University of Erlangen-Nurnberg Medical School and has 1,300 participants.
In a review of the APBI trials currently underway, Mannino and Yarnold (note Yarnold is a lead author on the START A and B trials) raise several concerns regarding variations across the trials (Maninn0, 2009). The extent of the 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 respiration motion. Studies of APBI usually distinguish between “same site relapse,” i.e., 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 a recurrence), or that earlier studies have shown that radiotherapy is not effective on these tumors in any case. Mannino and Yarnold challenge each of these points in turn, although they also conclude that the results of the trials currently underway will provide level-1 evidence for or against APBI.
The following is a summary of the identified clinical guidelines:
NCCN: According to the National Comprehensive Cancer Network (NCCN) guidelines, (V.2.2011) “Preliminary studies of APBI suggest rates of local control in selected patients with early stage breast cancer may be comparable to those treated with standard whole breast RT. Follow-up, however, is limited and studies are on-going. Patients are encouraged to participate in clinical trials. Intraoperative radiotherapy with a single dose can be performed at those institutions with the expertise and experience.
ASTRO: The American Society of Breast Surgeons and the American Society for Radiation Oncology (ASTRO) have issued guidelines for the selection of patients for APBI (Smith, 2009). According to the authors, the impetus for this guideline was the increased use of APBI outside of clinical trials, even as the results of those trials are awaited. The authors cite estimates that more than 32,000 women have already been treated with the MammoSite,® a mechanism for delivering APBI. The statement says that the guidelines are based on the results of a systematic review, which is not described in much detail, and expert opinion.
Several studies have tried to assess the validity of these recommendations, by comparing recurrence rates retrospectively for patients that meet the criteria for one or more of these categories. Beitsch et al. used data from the American Society of Breast Surgeons MammoSite® Registry (Beitsch, 2010). The database does not contain data on all of the elements in the recommendations (multifocality, multicentrality, presence of lymph-vascular space invasion, histology of invasive cancer, BRCA 1 or 2 mutation, and type of nodal surgery performed). Of the total of 1,449 patients in the Registry study, 1,025 (70.7%) could be grouped into the Consensus Statement categories. Of these, 176 fell in the unsuitable category (73.9% were under 50 years-old; 21.6% had positive nodes; 10.2% had more than 2 characteristics that put them in this category; 7.4% had positive margins; 5.1% had extensive intraductal component greater than 3 cm; and 3.4% had tumors greater than 3 cm). The 5-year actuarial rate of ipsilateral breast tumor recurrence was 5.25% in this group (7 patients; 2 at lumpectomy site and 5 elsewhere); 4.04% in the suitable or cautionary categories (24 of 849 patients; 8 recurrences at the lumpectomy site and 16 elsewhere). This difference was not statistically significant (p=0.3223). There were no other statistically significant differences between these two groups for any of the other outcomes reported either: regional nodal failure, distant metastases, disease-free survival, cause-specific survival, and overall survival. Another study that appears to be using the data on the same patients but was able to assign them to all three consensus statement categories (suitable, cautionary, and unsuitable) reached the similar conclusions (Shaitelman, 2010). A third study compared 199 patients at a single institution who underwent APBI with 199 matched controls who received whole breast irradiation (Vicini, 2011). When each group was stratified into the three categories in the ASTRO consensus statement, there was no statistically significant difference in the 10-year, ipsilateral breast recurrence rates across categories. There did appear to be a statistically significant difference across the categories for the patients treated with APBI, with no patients in the suitable group having distant metastases at 10 years versus 7.1% of the cautionary group and 11.2% of the unsuitable group (p=0.018); this statistically significant trend was not repeated in the patients receiving whole breast irradiation. Similarly, a statistically significant difference in regional nodal failure at 10 years was evident among all patients (0% for the suitable group; 0.7% for the cautionary group; and 4.0% for the unsuitable group); but not for either the APBI or whole breast irradiation group. The authors state that little evidence was available for the consensus panel in deciding which patients were not suitable and called for further research. The generalizability of the findings is open to question, however, because of the small number of events upon which these calculations are based, as well as missing data elements in the MammoSite® registry that are included in the consensus statement categorization. One researcher was an author on all three articles.
Overall, the body of evidence on interstitial APBI compared to conventional whole-breast irradiation is weak; and it is extremely weak (i.e., no comparative studies) for balloon brachytherapy and external-beam APBI. The strongest published evidence is on intraoperative radiotherapy, but the follow-up is insufficient at this time. 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. Therefore, the policy statement is unchanged.
2016 Update
A literature search conducted through November 2016 did not reveal any new information that would prompt a change in the coverage statement. The key identified literature is summarized below.
According to the National Cancer Institute website, 19 the most common grading system for breast cancer is the Nottingham grading system. High-grade tumors are those with a score of 8 to 9, which is comprised of the sum of three 3-point scales rating normality of tubule formation, nuclear grade, and mitotic rate.)
At least 2 systematic reviews of RCTs on AWBI that include the 4 RCTs discussed above have been published. Budach and colleagues stated that the ipsilateral recurrence rates at 10 years ranged from 3.8% to 14.8% after hypo-fractionated radiotherapy and from 5.2% to 12.1% for conventionally fractionated radiotherapy (Budach, 2015). The pooled 10-year recurrence rate was 8.4% in the hypo-fractionated radiotherapy group and 8.5% in the conventionally fractionated group (p=0.96). A 2010 Cochrane review by James and colleagues, rated the studies as low to medium quality. The authors did not pool study findings, but concluded that unconventional fractional regimens are associated with decreased acute toxicity but not local recurrence or breast appearance (James, 2011)
Two additional RCTs were published in 2015 (Hou, 2015; Shaitelman, 2015). In a single-blind trial, Hou and colleagues reported on 80 patients with stage 1 breast cancer treated with BCS (Hou, 2015). Patients were randomized to AWBI (43.2 Gy in 18 fractions over 24 days, n=40) or conventional WBI (45 Gy in 25 fractions over 44 days, n=40). Both groups received tumor bed boosts, 50.4 Gy in the accelerated group and 59 Gy in the conventional group. Primary endpoints were overall survival and loco-regional recurrence. The 2-year survival rate was 100% in both groups and there was no loco-regional recurrence. Moreover, there were no statistically significant differences in adverse events in the 2 groups.
The other newer RCT, published in 2015 by Shaitelman and colleagues focused on acute and short-term toxicity conventional versus accelerated whole-breast radiotherapy (Shaitrelman, 2015). This un-blinded trial included 287 patients with stage 0 to 3 breast cancer treated with breast-conserving therapy who had negative tumor margins. Patients were randomized to treatment with conventional radiotherapy at 50 Gy in 25 fractions (n=149) or accelerated radiotherapy at 42 Gy in 16 fractions (n=138). The rate of grade 2 or higher acute toxic effects was 47% in the accelerated radiotherapy group and 78% in the conventional radiotherapy group (p<0.001). A total of 271 (94%) of 287 patients were available for an assessment of 6-month toxic effects. There were no significant between-group differences in toxic effects at 6 months except the rate of grade 2 or higher fatigue was significantly lower in the accelerated radiotherapy group (0%) compared with the conventional radiotherapy group (6%; p=0.01).
Interstitial Brachytherapy
In 2015, Strnad and colleagues published findings of the GEC-ESTRO multicenter non-inferiority RCT (Strnad, 2016). The study included patients age 40 and older with stage 0 to 2 breast cancer with lesions of 3 cm or less in diameter. Patients had undergone BCS with clear margins of at least 2 mm in any direction and no lymph or blood vessel invasion. Patients were randomized to conventional WBI at 50 Gy in daily fractions of 1.8 to 2.0 Gy over 5 weeks (n=551) or APBI using interstitial brachytherapy (n=633). The primary study end point was the first event of local ipsilateral breast cancer recurrence within the 5-year observation period and the non-inferiority margin was a difference of 3%. At 5 years, 5 of 551 women in the conventional WBI group and 9 of 633 women in the APBI group had a local recurrence. 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 (risk difference, 0.52%’ 95% CI, -0.72 to 1.75). The difference between groups was within the non-inferiority margin. Overall survival was not a primary end point and there was no pre-specified non-inferiority analysis on survival outcomes. However, the authors reported that, at the time of data analysis, 32 (6%) of 551 patients in the conventional WBI group and 27 (4%) of 633 in the APBI group had died. Limitations of the study include that data were only available up to 5 years, that survival was not a primary end point and that the absolute number of women with local recurrences was small.
Section Summary: Accelerated Partial-Breast Irradiation
The 2015 GEC-ESTRO RCT reported 5-year follow-up data and found that interstitial brachytherapy was non-inferior to WBI regarding rates of local breast cancer recurrence, when applying a non-inferiority margin of 3%. Ten-year follow-up data are needed as well as at least 1 additional trial confirming these findings. The evidence is insufficient to determine the effects of the technology on health outcomes.
Section Summary: Intraoperative Brachytherapy
Several RCTs have been published, but they have not demonstrated that outcomes after intraoperative brachytherapy are non-inferior to WBI. Five-year results of 1 RCT (TARGIT-A) showed increased ipsilateral local recurrence with APBI compared with whole-breast radiotherapy. In another RCT that used a different technology (ELIOT), recurrence rate with intraoperative radiotherapy was statistically greater than with WBI.
2018 Update
A literature search was conducted through November 2018. There was no new information identified that would prompt a change in the coverage statement. The key identified literature is summarized below.
Systematic Reviews
A number of RCTs and systematic reviews of RCTs have compared AWBI (also referred to as accelerated whole-breast radiotherapy) with conventional 5-week WBI. A systematic review and metaanalysis by Valle et al included 13 trials (total N=8189 patients) published prior to October 2014 that compared AWBI with standard fractionation (Valle, 2017). 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).
American Society for Radiation Oncology et al
ASTRO, American Society of Breast Surgeons, and the American Brachytherapy Society have issued various consensus statements for the selection of patients for APBI (ASTRO, 2017; ABS, 2018). Recommendations were based on systematic reviews, which are not described in detail, and expert opinion.
ASTRO updated its guidelines on fractionation for whole-breast irradiation (ASTRO, 2018). 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.
2019 Update
Annual policy review completed with a literature search using the MEDLINE database through November 2019. No new literature was identified that would prompt a change in the coverage statement.
2020 Update
Annual policy review completed with a literature search using the MEDLINE database through November 2020. No new literature was identified that would prompt a change in the coverage statement. The key identified literature is summarized below.
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 (NCI, 2020).
In 2020, Brunt et al published 10-year results of the FASTer radiotherapy for breast radiotherapy (FAST) trial (Brunt, 2020). This multicenter, phase III, RCT enrolled 915 women ≥50 years of age with low-risk invasive breast carcinoma who had undergone BCS 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<0.001), but not significantly different for the 28.5 Gy versus 50 Gy group (1.22; 95% CI, 0.87 to 1.72; p=0.248). 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 also published results from the multicenter, non-inferiority, randomized, FAST-Forward trial (Murray, 2020). This study enrolled 4,096 adults with invasive breast carcinoma following complete microscopic excision of the primary tumor by BCS 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=0.0003) but not between 40 and 26 Gy (p=0.17) 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.
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 (Kong, 2014; Marta, 2015; Lv, 2019; Hickey, 2016; Liu, 2020). 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 update meta-analysis of partial- versus whole-breast radiotherapy for early breast cancer that included a subgroup analysis assessing the potential effectiveness of APBI technique - intraoperative radiotherapy (IORT), brachytherapy, or EBRT (Viani, 2020). Results revealed no significant difference in local recurrence with APBI and WBI when using brachytherapy (p=0.051), EBRT (p=0.25), or mixed techniques (p=0.89) at 5 years; however, a significant increase in local recurrence was noted with IORT use (p=0.014). 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 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 (Korzets, 2019). 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.
In a parallel study to TARGIT-A, Vaidya and colleagues randomly assigned 1,153 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 (Vaidya, 2020). 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.
In 2019, Whelan et al published longer term results from RAPID (Whelan, 2019). 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).
Vicini et al 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 (Vicini, 2019). 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 versus 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=0.02); 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.
Current NCCN guidelines (v.4.2020) on breast cancer state (NCCN, 2020):
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 (ie, those who are <50 years old, high-grade disease, or patients with focally positive margins) in order to reduce local relapse.
The American Society for Radiation Oncology, American Society of Breast Surgeons, and the American Brachytherapy Society have issued various consensus statements for the selection of patients for APBI. Recommendations were based on systematic reviews, which are not described in detail, and expert opinion. American Society of Breast Surgeons criteria includes the following (ASBS, 2018): Age of > 45 years for all tumor types; Patients should not be treated if they have a BRCA genetic mutation; Tumor size < 3 cm; Tumor stage Tis, T1, T2 (≤3 cm); Margins No tumor on ink for invasive tumors or tumors involved with DCIS; ≥2 mm for DCIS; LVSI Allowed as long as it is focal; ER status Positive or negative; Multifocality Multifocal disease is allowed as long as the combined area of tumor is ≤ 3 cm; Histology All invasive subtypes; DCIS; Pure DCIS ≤3 cm; Nodal stage/status Negative.
2021 Update
Annual policy review completed with a literature search using the MEDLINE database through November 2021. No new literature was identified that would prompt a change in the coverage statement. The key identified literature is summarized below.
As mentioned previously, a number of RCTs and nonrandomized comparative studies have evaluated interstitial, external-beam, or intraoperative APBI compared with conventional WBI. Three additional meta-analyses of these studies evaluated evidence on APBI compared to WBI, with various methods grouped in the same review (Haussmann, 2020; Xiang, 2021; Shah, 2021). 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.
Orrechia et al reported 15-year results of the ELIOT trial that confirmed the 5-year findings (Orrechia, 2021). 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.
Rodriguez et al reported on 102 patients randomized to WBI, with or without a boost to the tumor bed, or APBI (Rodriguez, 2013). 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 reported long-term results of this trial (median, 10.3 years) (Li, 2021). 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).
In Livi et al, 520 patients with early breast cancer were randomized to APBI using intensity-modulated radiotherapy or WBI (Livi, 2015). 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 (Meattini, 2020). 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).
Polgar et al 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 (Polgar, 2021). 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.
2022 Update
Annual policy review completed with a literature search using the MEDLINE database through November 2022. No new literature was identified that would prompt a change in the coverage statement. The key identified literature is summarized below.
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 (Kong, 2014; Marta, 2015; Lv, 2019; Liu, 2020; Haussmann, 2020; Xiang, 2021; Shah, 2021; Hickey, 2021). 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 .
Wang et al conducted a systematic review and meta-analysis to compare the efficacy and safety of IORT to WBI in patients with early-stage breast cancer receiving breast-conserving surgery (Wang, 2021). A total of 10 RCTs representing 5,698 patients were included for analysis. The IORT group was associated with a significantly higher risk of local recurrence (relative risk [RR], 2.11; 95% CI, 1.13 to 3.94; p=.019). Pooled analyses did not find any statistically significant differences in overall survival, recurrence-free survival, distant metastasis-free survival, and cancer-specific survival between groups. While the risk of skin toxicity was significantly lower in the IORT group compared to the WBI group (RR, 0.28; 95% CI, 0.16 to 0.49; p<.0001), the incidence of fat toxicity, scar calcification, and edema were 3.1, 1.3, and 2.4 times higher than that in the WBI group, respectively. The authors concluded that IORT is not a better alternative to WBI.
2023 Update
Annual policy review completed with a literature search using the MEDLINE database through November 2023. No new literature was identified that would prompt a change in the coverage statement. The key identified literature is summarized below.
Ten-year outcomes of the GEC-ESTRO trial were published by Strnad et al in 2023 (Strnad, 2023). At a median follow-up of 10.36 years, rates of local recurrence were 1.58% (95% CI, 1.99 to 5.03) in the WBI group and 3.51% (95% CI, 1.99 to 5.03) in the APBI group (Table 3). Significantly fewer treatment-related grade 3 late adverse effects were observed in the APBI group (1%) compared to the WBI group (4%). No grade 4 adverse events or treatment-related deaths were reported. Additional publications with detailed analyses of late adverse effects (e.g., cosmesis) and quality of life outcomes are planned by the investigators.
Kim et al reported 5-year survival outcomes in 223 patients with early-stage breast cancer prospectively enrolled in a single-center registry (Kim, 2023). Patients were treated with breast-conserving surgery and individualized applicator-based brachytherapy administered via a Strut Adjusted Volume Implant (SAVI) device. After a median follow-up of 63 months, recurrence was reported in 19 (8.5%) patients with ipsilateral breast tumor recurrence occurring in 17 (7.6%). Rates of 5-year ipsilateral breast tumor-free survival, disease-free survival, and OS were 92.2%, 91.1%, and 97.8%, respectively. Significantly higher rates of 5-year ipsilateral breast tumor-free survival were noted in postmenopausal women (93.6% vs. 66.4%; p=.04), patients with body mass index <30 kg/m2 (97.5% vs. 88.1%; p=.02), and endocrine therapy adherence in postmenopausal women (97.5% vs. 88.6%; p=.02). Eight (3.6%) developed a grade 2 or higher treatment-related complication within 9 months of brachytherapy completion.
Meduri et al reported 5-year outcomes of the IRMA trial (Meduri, 2023). The IRMA trial randomly assigned women with early-stage breast cancer to breast-conserving surgery and WBI (n=1657) or twice-daily external-beam APBI (n=1602). At a median follow-up of 5.6 years, significantly higher rates of adverse cosmesis were reported in the APBI group (14% vs. 9.8%; p=.012) compared to WBI. Grade 3 late soft tissue (2.8% APBI vs. 1% WBI; p<.0001) and bone toxicities (1.1% APBI vs. 0% WBI) were significantly higher in the APBI arm. No significant differences in late skin or lung toxicities were observed. Five-year OS was 97.4% with APBI compared to 97.2% with WBI. The investigators plan to publish primary endpoint results (i.e., ipsilateral breast tumor recurrence) in a future study.
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