BlueCross and BlueShield of Montana Medical Policy/Codes
Accelerated Breast Irradiation after Breast-Conserving Surgery for Early Stage Breast Cancer and Breast Brachytherapy as Boost with Whole-Breast Irradiation
Chapter: Radiology
Current Effective Date: December 27, 2013
Original Effective Date: June 09, 2009
Publish Date: September 27, 2013
Revised Dates: July 27, 2011, March 7, 2012; September 6, 2013
Description

Radiation therapy is the standard care for patients with breast cancer undergoing breast-conserving surgery (BCS), as it reduces recurrences and lengthens survival. The conventional radiation therapy regimen consists of approximately 25 treatments of 2 Gray (Gy; a measure of absorbed radiation dose) delivered over 5 to 6 weeks. Nonetheless, not all patients undergo radiation therapy following BCS; the duration and logistics of treatment may be barriers for some women. Accelerated radiotherapy approaches have been proposed to make the regimen less burdensome for patients with early-stage breast cancer at low risk of recurrence:

  • Accelerated (also called hypofractionated) whole-breast irradiation (AWBI) reduces the number of fractions and the duration of treatment to about 3 weeks. This approach has been commonly used in Canada and Europe.
  • Accelerated partial-breast irradiation (APBI) irradiates a limited part of the breast in and close to the tumor cavity. By reducing the area irradiated, fewer treatments are needed, and the total treatment takes about 1 week. Several approaches can be used to deliver APBI, including interstitial brachytherapy, balloon brachytherapy, external beam radiotherapy, or intraoperative radiotherapy (which occurs on only 1 day).

The critical question is whether these three approaches are equivalent in outcomes and adverse events.

Background

Breast Conservation Therapy

Survival after breast-conservation therapy (BCT) is equivalent to survival after mastectomy for patients diagnosed with tumors categorized as stage I or II. BCT is a multimodality treatment that consists of BCS to excise the tumor with adequate margins, followed by whole-breast external-beam radiation therapy administered as 5 daily fractions per week over 5 to 6 weeks. Local boost irradiation to the tumor bed often is added to whole-breast irradiation to provide a higher dose of radiation at the site where recurrence most frequently occurs. For some patients, BCT also includes axillary lymph node dissection, sentinel lymph node biopsy, or irradiation of the axilla. A number of randomized, controlled trials (RCTs) have demonstrated that the addition of radiotherapy after BCS reduces recurrences and mortality. In an individual-level meta-analysis, the Early Breast Cancer Trialists’ Collaborative Group (EBCTCG) reported 5-year risk of local recurrence of 7.3% among breast-conserving-surgery patients allocated to radiotherapy versus 25.9% among those not (2p<0.00001; n=51,958 woman-years). (1) Whole-breast irradiation reduced the 15-year breast cancer mortality risk from 35.9% to 30.5% (breast cancer death rate ratio: 0.83; standard error [SE]=0.05; 95% confidence interval [CI]: 0.75, 0.91; 2p=0.0002; n=7,311 women); there was a similar reduction in mortality from all causes (5.3%, SE=1.8, 2p=0.005). Radiotherapy provided benefits for both node-negative and node-positive women.

Consequently, radiation therapy is generally recommended following BCS. A potential exception is for older women at low risk of recurrence. For example, the National Comprehensive Cancer Network (NCCN) guidelines state that women aged 70 or older may omit radiotherapy if they have estrogen-receptor positive, T1 tumors, clinically negative lymph nodes, and plans to take adjuvant endocrine therapy. (2)

Eight to 10 years of follow-up is needed to assess the outcomes from different treatments for early stage breast cancer. The EBCTCG individual-level meta-analysis provides data on the pattern of recurrences among BCS patients with and without radiotherapy for more than 10 years. In web figure 6a (Available online at: http://www.ctsu.ox.ac.uk/~ebctcg/local2000/annex.pdf , data on the percentage of patients per year with isolated local recurrence is 2.7% and 9.0% for those with and without whole-breast irradiation, respectively, in year 0; 1.5% and 4.8% in years 1–2; 1.1% and 3.7% in years 3–4; 0.8% and 1.9% in years 5–9; and 0.2% for both groups in years 10 and higher (trend χ21=4.3, 2p=0.04). While the recurrence rate falls over time, it persists for more than 10 years. In another study, local recurrence was highest between years 3 to 5 of follow-up, and 67% of events took place in the first 5 years. However, that means 33% of events took place after 5 years. (3) For additional information on the length of follow-up needed, see the two TEC Assessments on APBI. (4,5)

Most patients diagnosed with stage I or II breast cancer now are offered a choice of BCT or modified radical mastectomy, but BCT is selected less often than expected. Studies have shown that those living furthest from treatment facilities are least likely to select BCT instead of mastectomy and most likely to forgo radiation therapy after BCS. (6-8) A study using data from the National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) tumor registries from 1992 to 2002 examined how many women with early stage (I or II) breast cancer received radiotherapy within 4 months following BCS. (9) After adjusting for age, they found that in 2002, 30.8% of Caucasian women and 44.7% of African-American women had not received radiotherapy. Furthermore, these rates had increased from 24.7% for Caucasians and 34.0% for African Americans in 1992.

Given that duration and logistics appear to be barriers to completion of treatment, there has been interest in developing shorter radiotherapy regimens. Two approaches have been explored.

The first method is to provide the same dose to the whole breast in a shorter time by increasing the dose provided per treatment (hypofractionation). This approach was initially avoided out of concern that increasing doses to target the tumor more effectively might induce more severe adverse events from radiation exposure, thus, tipping the balance between benefits and harms. More recent research, some of which is highlighted below, has allayed some of these concerns. AWBI has been used especially in Canada and Europe.

The second approach to reducing radiotherapy treatment time is APBI. It differs from conventional whole-breast irradiation in several ways. First, the radiation only targets the segment of the breast surrounding the area where the tumor was removed, rather than the entire breast. This approach was based in part on the finding that recurrences are more likely to occur close to the tumor site rather than elsewhere in the breast. Second, the duration of treatment is 4 to 5 days (or 1 day with intraoperative radiotherapy) rather than 5 to 6 weeks, because the radiation is delivered in fewer fractions at larger doses per fraction to the tumor bed. Third, the radiation dose is intrinsically less uniform within the target volume when APBI uses brachytherapy (i.e., the implantation of radioactive material directly in the breast tissue). The major types of radiotherapy used after BCS are outlined in Table 1. They differ in their techniques, instrumentation, dose delivery, and possibly in their outcomes.

Table 1. Major types of radiation therapy following breast-conserving surgery

RT Type

 

Accelerated?

 

Whole (W) or partial (P) breast

 

External beam (E) or brachytherapy (B)?

 

Approx duration of treatment

 

Published RCTs (length of follow-up in yrs)

 
Conventional whole-breast irradiation   5-6 wks  Multiple; >15 yrs2 
Accelerated whole-breast irradiation   3 wks  4; 10 yrs  
Interstitial APBI*   1 wk  2; 5.4yrs 
Balloon APBI§  1 wk 
External beam APBI#  1 wk 
Intraoperative APBI  Not applicable  1 day 

* 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.

  • 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.
  • 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 three-dimensional, conformal radiation therapy (3D-CRT) or intensity-modulated radiation therapy (IMRT).
  • Intraoperative APBI is performed during breast-conserving surgery, when a single dose of radiation is delivered to the exposed tumor bed.

To appreciate the differences among radiotherapy techniques, it is useful to understand attributes of radiation delivery. The goals of cancer radiotherapy are usually to provide the tumor or tumor bed with a high dose of homogeneous radiation (e.g., all parts of the tumor cavity receive close to the targeted dose). Areas adjacent to the tumor may be treated with a lower dose of radiation (e.g., with whole-breast irradiation, to treat any unobserved cancerous lesions). Radiation outside the treatment area should be minimal or non-existent. The goal is to target the tumor or adjacent areas at risk of harboring unseen cancer with an optimum dose, while avoiding healthy tissues.

Brachytherapy Boost with Whole Breast Irradiation

Brachytherapy has been used as an alternative to external beam radiation therapy to deliver boost radiation therapy combined with whole-breast external-beam radiation therapy. Most of the studies of local boost brachytherapy use temporarily implanted needles, wires, or seeds after patients recovered from surgery and completed whole-breast radiation therapy.  Studies have not shown the superiority of boosting with brachytherapy compared to photon and electron boost, and brachytherapy may yield an inferior cosmetic result.  Therefore brachytherapy as a boost is not considered medically necessary. 

Regulatory Status

The various radiotherapy modalities presented in this report have been approved or cleared for marketing by the U.S. Food and Drug Administration (FDA) (for more details, see Appendix in TEC 2010 [4]). All brachytherapy devices have been approved through the 510(k) process and are either balloon brachytherapy or hybrid balloon-interstitial brachytherapy devices. The FDA has required a black box warning on each stating that “The safety and effectiveness of the … [brachytherapy device] as a replacement for whole breast irradiation in the treatment of breast cancer has not been established.

Policy

Participating Providers are required to Prior authorize radiation oncology/therapy for Blue Cross Blue Shield of Montana (BCBSMT) Members eligible for the CareCore Program. To authorize, Utilize CareCore National’s website: http://www.carecorenational.com/  or call 1-866-668-7446, option1. Services that are not prior authorized will be denied. For benefit questions call (BCBSMT) Customer Service at 1-800-447-7828.

For Non-Eligible Members, Out of State Providers, and Non-participating providers Prior authorization is recommended. To authorize, call Blue Cross and Blue Shield of Montana (BCBSMT) Customer Service at 1-800-447-7828 or fax your request to the Medical Review Department at 406-441-4624. A retrospective review is performed if services are not prior authorized.

Each benefit plan or contract defines which services are covered, which are excluded, and which are subject to dollar caps or other limits.  Members and their providers have the responsibility for consulting the member's benefit plan or contract to determine if there is any exclusion or other benefit limitations applicable to this service or supply.  If there is a discrepancy between a Medical Policy and a member's benefit plan or contract, the benefit plan or contract will govern.

Medically Necessary

BCBSMT considers accelerated whole breast irradiation and partial breast irradiation medically necessary for clinically appropriate patients.

  • Patients considered clinically appropriate for accelerated whole breast irradiation are those in whom a 3D treatment plan does not result in hot spots or in-homogeneities that would lead to unacceptable acute and chronic reactions from a higher daily dose.
  • Patients considered clinically appropriate for accelerated partial breast irradiation include those with clinical criteria conforming to published guidelines of one of the major societies.  Acceptable techniques include Externam Beam Radiation Therapy (EBRT) 3D conformational and inverse-planned IMRT and interstitial high dose rate (HDR) brachytherapy (Ir-192 or kilovolt energy), up to a total of 10 fractions.
  • Interstitial or balloon brachytherapy may be considered medically necessary for patients who are candidates for partial breast irradiation.
  • A boost may be clinically indicated following whole breast irradiation and is considered medically necessary.  Boost techniques considered medically necessary include electron and photon energies.  For photon energies, up to 3 gantry angles is considered medically necessary.

Not Medically Necessary

BCBSMT considers the use of interstitial or intracavitary brachytherapy boost to be not medically necessary.

Investigational

BCBSMT considers the use of single-fraction adjuvant intraoperative radiotherapy and the AccuBoost technique to be experimental, investigational, and unproved.

Policy Guidelines

There are several techniques of APBI:

  1. Interstitial technique in which multiple needles are placed percutaneously and catheters are threaded into the breast (BRACHYTHERAPY)
  2. Intracavitary single catheter balloon catheter, in which a device is placed into the surgical cavity (BRACHYTHERAPY)
  3. Intracavitary multiple catheter device – single device with multiple catheter channels inserted into surgical cavity (BRACHYTHERAPY)
  4. Multiple coplanar or non-coplanar field external beam radiation techniques (EBRT)
  5. Single fraction intraoperative radiation using (IORT) using electrons or photons

The ASTRO and NCCN practice guidelines state that appropriate schemes for APBI are 34 Gy in 10 fractions delivered twice per day with brachytherapy or 38.5 Gy in 10 fractions delivered twice per day.  It is therefore appropriate at present to reimburse for up to 10 fractions (whether external-beam or brachytherapy) for APBI.

Interstitial brachytherapy was commonly used for performing the boost during the development of breast-conserving therapy.  While the use of brachytherapy in giving the boost is recognized in the current NCCN guidelines, it does not improve tumor control compared to external-beam boost and results in worse cosmesis.  Other brachytherapy techniques (such as Mammosite balloon brachytherapy system) and intraoperative radiotherapy have also been used to perform the boost, but again they have not been shown to be superior to external-beam boosts.  Therefore, the use of interstitial or intracavitary brachytherapy or intraoperative radiotherapy in this role is considered not medically necessary.  Rare exception to this guideline will be considered for patients who underwent intracavitary brachytherapy or intraoperative radiotherapy under the assumption that these modalities would be used for definitive treatment with APBI, but in whom additional information during or after the completion of the procedure was felt to warrant the use of WBI (e.g., finding positive excision margins).

 

Rationale

This policy regarding accelerated breast irradiation following breast-conserving surgery (BCS) for early stage breast cancer is based on a TEC Assessment released in July 2010. (4) This policy substantially revises and replaces, Breast Brachytherapy after Breast-Conserving Surgery, as Boost with Whole Breast Irradiation, or Alone as Accelerated Partial-Breast Irradiation. The use of brachytherapy as boost with whole breast irradiation continues to be considered medically necessary and is not discussed further in this policy. A new radiotherapy regimen, accelerated whole-breast irradiation (AWBI) therapy, has been added to this policy. Intraoperative radiation therapy is also added to this policy.

Accelerated Whole-Breast Irradiation

Four randomized, controlled trials (RCTs) compared accelerated whole-breast radiotherapy to 5-week whole-breast radiotherapy, as well as a fifth, older, nonrandomized study. (3,10-14) Two of the studies are particularly useful, as they directly compare a 5-week to a 3-week regimen. They are both prospectively designed noninferiority trials. Both trials accepted a maximum loss of efficacy of 5 percentage points in local or local-regional recurrence in the accelerated group at 5 or 10 years (one-sided α=0.025 or 0.05). Although the studies differ in the specific fractionation schedules and patient characteristics, they report no difference in local recurrence rates (i.e., recurrence of the cancer in the same breast) across treatment arms.

One study from the United Kingdom includes women with grade 1–3 tumors. (10) Approximately 75% of the women have negative lymph nodes, and approximately 42% had a radiation boost to the tumor bed. Randomization was stratified for hospital, type of surgery (about 15% had a mastectomy), and plans for tumor bed boost. Systemic therapy, primarily tamoxifen, was used by some patients and appears to be fairly evenly distributed across treatment groups. The treatment arms compared a total dose of 40 Gy in 15 fractions over 3 weeks to 50 Gy in 25 fractions over 5 weeks. The hazard ratios for 40 Gy accelerated whole breast radiotherapy versus conventional whole breast radiotherapy were not statistically significant (using the log-rank test) for local or local-regional relapse. The absolute difference in local-regional relapse rates after 5 years was −0.7% (95% CI: −1.7%, 0.9%). There were statistically significant differences in the two treatment regimens for distant relapse and overall survival (OS), with relapse more frequent and survival longer for the 40 Gy accelerated whole breast irradiation (AWBI). This unexpected difference between treatment arms began to appear at about 1 year. The authors speculate that it could be due to chance and might change with longer follow-up. An article on patient-reported breast, arm, and shoulder symptoms, as well as body image, over 5 years of follow-up for both Standardisation of Breast Radiotherapy (START) trials was published in March 2010. (15) At 5 years’ follow-up, there is no evidence that providing radiotherapy in fewer, larger fractions increases these adverse events. The 6-year follow-up period on this trial is too short to reach firm conclusions; follow-up continues.

The second RCT from Canadian researchers compared AWBI versus whole-breast irradiation. (11,12) Of 2,429 eligible patients, 51% agreed to participate in the trial. Intention-to-treat (ITT) analysis was used. The 10-year local recurrence was 6.2% for the 42.5 Gy arm AWBI arm and 6.7% for the conventional 50 Gy whole-breast irradiation (absolute difference: −0.5%, 95% CI: −2.5%, 3.5%). Local recurrence rates with accelerated whole breast radiotherapy were not worse than conventional whole breast irradiation, when applying a noninferiority margin of 5%. In “exploratory” subgroup analyses, treatment effects were similar by age, tumor size, estrogen-receptor status, and chemotherapy use (48% had no systemic therapy). However, local recurrence at 10 years for patients with high-grade tumors was 4.7% for the conventional whole breast irradiation arm and 15.6% for the 42.5 Gy AWBI arm. The absolute difference equals −10.9 percentage points (95% CI: −19.1, −2.8, test for interaction, p=0.01).

The overall body of evidence on AWBI compared to conventional whole-breast irradiation suggests local recurrence rates with accelerated whole breast radiotherapy were not worse than conventional whole breast irradiation in patients meeting the criteria of the Canadian trial, when applying a noninferiority margin of 5%. Longer follow-up is needed for the United Kingdom trial.

Patient selection is key, and at this point, only patients similar to those in the Canadian trial should be considered for this therapy. Outcomes could vary in women with other disease characteristics. The patients in this trial all had invasive carcinoma of the breast with negative lymph nodes and surgical margins, and they did not have a radiotherapy boost to the tumor site. Exclusion criteria for the trial included “invasive disease or ductal carcinoma in situ involving the margins of excision, tumors that were larger than 5 cm in diameter, and a breast width of more than 25 cm at the posterior border of the medial and lateral tangential beams, which could increase the heterogeneity of the radiation dose to the breast.” In the trial, lymph node status was determined by axillary dissection, but recent reports suggest that sentinel lymph node biopsy is likely to be as effective. (e.g., see 16) Forty-one percent of the women took tamoxifen, despite the fact that 71% were estrogen-receptor positive.

Patients selecting this accelerated whole breast radiotherapy should be told that while the current evidence on this radiotherapy regimen is strong, it is not as strong as that for conventional whole-breast irradiation. Additional RCTs or longer follow-up of the existing trials could uncover additional concerns. Some potential adverse events, such as cardiac ischemia, may take longer to become evident. This regimen has been widely used outside the U.S. without substantial reports of major adverse events. Potential patients should be carefully selected and given full information, while the results of longer follow-up for the START B trial are awaited.

Accelerated Partial-Breast Irradiation

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. (17-28) 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. (17-19) 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. (20,21) 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 and was published online after the completion of the TEC Assessment. (22) 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. (23-31)

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. Fortunately, a number of large RCTs are underway.

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; see Appendix I). 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. (32) 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.

Use as Local Boost Radiotherapy

This section is based on a 1996 TEC Assessment that concluded net health outcomes after brachytherapy for local boost were equivalent to outcomes after external beam radiation therapy for local boost in women given BCS plus whole-breast radiation therapy as initial treatment for stage I or stage II breast cancer. In 7 nonrandomized comparisons (total N=2,022), 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.

Clinical Input Received through Physician Specialty Societies and Academic Medical Centers

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. 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. There was near-unanimous support for the policy statement regarding accelerated whole-breast irradiation (AWBI). The input was mixed regarding accelerated partial-breast irradiation (APBI); those agreeing with the conclusion noted the need to define the risks and benefits of this approach in patient subgroups and noted that current data are inconclusive concerning the effectiveness of APBI compared to whole-breast irradiation.

Summary

The overall body of evidence on accelerated whole-breast irradiation (AWBI) compared to conventional whole-breast irradiation suggests local recurrence rates with accelerated whole breast radiotherapy were not worse than conventional whole breast irradiation in patients meeting the criteria of the Canadian trial, when applying a noninferiority margin of 5%. Patient selection is important, and at this point, only patients similar to those in the Canadian trial should be considered for this therapy. Thus, accelerated whole-breast irradiation may be considered medically necessary for these patients with clinical characteristics noted in the medically necessary policy statement. Outcomes could vary in women with other disease characteristics.

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. Thus, these techniques are considered investigational. Fortunately, a number of large randomized, controlled trials are underway to provide additional data.

Practice Guidelines and Position Statements

According to the National Comprehensive Cancer Network (NCCN) guidelines, (2) “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. If not trial eligible, per the consensus statement from the American Society for Radiation Oncology (ASTRO), patients who may be suitable ….” (see below). Intraoperative radiotherapy with a single dose can be performed at those institutions with the expertise and experience. For whole-breast radiotherapy, NCCN recommends either a conventional whole-breast irradiation regimen or a total dose of 42.5 Gy with 2.66 Gy per fraction, which equals 16 fractions. Although the NCCN guidelines do not specify the duration of treatment, the latter is presumably an accelerated whole-breast irradiation regimen. A boost to the tumor bed is recommended for higher risk whole breast radiotherapy patients, i.e., those who are younger than 50 years-old and have positive axillary nodes, lymphovascular invasion, or close margins.

The American Society of Breast Surgeons and the American Society for Radiation Oncology (ASTRO) have issued guidelines for the selection of patients for APBI, which are summarized in Table 2. (33) 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.

Table 2. Professional medical society criteria for performing APBI

Categories

 

Factor

 

ASTRO Criteria: “Suitable”

 

ASTRO Criteria: “Cautionary”

 

ASTRO Criteria: “Unsuitable”

 

Criteria for APBI from American Society of Breast Surgeons

 

Patient factors

 
Age  > 60 y   50-59 y  < 50 y  > 45 y  
BRCA1/2 mutation   Not present  ♦  Present  ♦ 

Pathologic factors

 
Tumor size  < 2 cm   2.1-3.0 cm  > 3 cm  < 3 cm  
T stage  T1  T0 or T2  T3-4  ♦ 
Margins   Negative > 2 mm   Close (< 2 mm)  Positive  Microscopically negative  
Grade  Any  ♦  ♦  ♦ 
LVSI  No  Limited/focal  Extensive  ♦ 
ER status  Positive  Negative*  ♦  ♦ 
Multicentricity   Unicentric  ♦  Present  ♦ 
Multifocality  Clinically unifocal, total size < 2.0 cm   Clinically unifocal, total size: 2.1-3.0 cm   Clinically multifocal or microscopically multifocal, total size > 3 cm   ♦ 
Histology  Invasive ductal or other favorable subtypes   Invasive lobular   ♦  Invasive ductal carcinoma or DCIS  
Pure DCIS  Not allowed  < 3 cm   > 3 cm  < 3 cm  
EIC  Not allowed  < 3 cm   > 3 cm  ♦ 
Associated LCIS   Allowed  ♦  ♦  ♦ 

Nodal factors

 
N stage  pN0 (i, i+)   ♦  pN1, pN2, pN3  SN pN0 
Nodal surgery  SN Bx, ALND  ♦  None performed 

Treatment factors

 
Neoadjuvant therapy   Not allowed  ♦  If used  ♦ 

♦ = not reported

*Strongly encouraged to enroll in NSABP B-39/RTOG 04-13 trial.

Key: DCIS, ductal carcinoma in situ; EIC, extensive intraductal component; ER status, estrogen receptor status; LCIS, lobular carcinoma in situ; LVSI, lymphovascular space invasion; N stage, nodal stage; T stage, tumor stage.

Sources: 33-35

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. (36) 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. (37) A third study compared 199 patients at a single institution who underwent APBI with 199 matched controls who received whole breast irradiation. (38) 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.

ASTRO released guidelines on fractionation for whole breast irradiation in 2010. (39) They rely on the Canadian trial (11,12), START A (14) and START B, (10) and the Owen/Yarnold trial (3,13). They conclude that “Data are sufficient to support the use of HF-WBI [hypofractionated or accelerated, whole breast irradiation] for patients with early breast cancer who meet all of the aforementioned criteria,” including aged 50 years or older, disease Stage pT1-2 pN0, no chemotherapy, and treatment with radiation dose homogeneity within + 7% in the central axis plane. The task force did not agree on whether it is recommended to use HF-WBI when receiving a tumor boost.

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There is no national coverage determination.

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ICD-9 Codes
174.0-174.9, 175.0-175.9, 198.81
Procedural Codes: 19296, 19297, 19298, 77261, 77262, 77263, 77280, 77285, 77290, 77295, 77299, 77326, 77327, 77328, 77776, 77777, 77778, 77785, 77786, 77787, 0182T, C1717, C9726, Q3001
References
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  2. National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology: Breast Cancer. V.2.2011. Available online at: www.nccn.org  Last accessed April 2011.
  3. Owen JR, Ashton A, Bliss JM et al. Effect of radiotherapy fraction size on tumour control in patients with early-stage breast cancer after local tumour excision: Long-term results of a randomized trial. Lancet Oncol, 2006; 7(6):467-71.
  4. Blue Cross and Blue Shield Association Technology Evaluation Center (TEC). Accelerated Radiotherapy after Breast-Conserving Surgery for Early Stage Breast Cancer. TEC Assessments 2010, Volume 24, No. 9.
  5. Blue Cross and Blue Shield Association Technology Evaluation Center (TEC). Accelerated Partial Breast Radiotherapy as Sole Radiotherapy after Breast-Conserving Surgery for Early Stage Breast Cancer. TEC Assessments 2007, Volume 22, No. 4.
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  11. Whelan T, MacKenzie R, Julian J et al. Randomized trial of breast irradiation schedules after lumpectomy for women with lymph node-negative breast cancer. J Natl Cancer Inst, 2002; 94(15):1143-50.
  12. Whelan T, Pignol J, Levine MN et al. Long-term results of hypofractionated radiation therapy for breast cancer. N Engl J Med, 2010; 362(6):513-20.
  13. Yarnold J, Ashton A, Bliss J et al. Fractionation sensitivity and dose response of late adverse effects in the breast after radiotherapy for early breast cancer: long-term results of a randomised trial. Radiother Oncol, 2005; 75(1):9-17.
  14. The START Trialists’ Group. The UK Standardisation of Breast Radiotherapy (START) Trial A of radiotherapy hypofractionation for treatment of early breast cancer: a randomised trial. Lancet Oncol 2008; 9(4):331-41.
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  19. Polgar C, Fodor J, Major T et al. Breast-conserving treatment with partial or whole breast irradiation for low-risk invasive breast carcinoma—5-year results of a randomized trial. Int J Radiat Oncol Biol Phys, 2007; 69(3):694-702.
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  23. Antonucci JV, Wallace M, Goldstein NS et al. Differences in patterns of failure in patients treated with accelerated partial breast irradiation versus whole-breast irradiation: A matched-pair analysis with 10-year follow-up. Int J Radiat Oncol Biol Phys 2009; 74(2):447-52.
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  27. Ott OJ, Schulz-Wendtland R, Uter W et al. Fat necrosis after conserving surgery and interstitial brachytherapy and/or external-beam irradiation in women with breast cancer. Stahlenther Onkol 2005; 181(10):638-44.
  28. Polgar C, Major T, Fodor J et al. High-dose-rate brachytherapy alone versus whole breast radiotherapy with or without tumor bed boost after breast-conserving surgery: Seven-year results of a comparative study. Int J Radiat Oncol Biol Phys 2004; 60(4):1173-81.
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  31. Wadasadawala T, Sarin R, Budrukkar A et al. Accelerated partial-breast irradiation vs conventional whole-breast radiotherapy in early breast cancer: A case-control study of disease control, cosmesis, and complications. J Cancer Res Ther, 2009; 5(2):93-101.
  32. Mannino M, Yarnold J. Accelerated partial breast irradiation trials: diversity in rationale and design. Radiother Oncol, 2009; 91(1):16-22.
  33. Smith BD, Arthur DW, Buchholz TA et al. Accelerated partial breast irradiation consensus statement from the American Society for Radiation Oncology (ASTRO). Int J Radiat Oncol Biol Phys 2009; 74(4):987-1001.
  34. Prosnitz LR, Horton J, Wallner PE. Accelerated partial breast irradiation: Caution and concern from an ASTRO Task Force. Int J Radiat Oncol Biol Phys 2009; 74(4):981-4.
  35. American Society of Breast Surgeons. Consensus Statement for Accelerated Partial Breast Irradiation, revised 7 Oct 2008. Accessed 9 November 2009. Available online at: http://www.breastsurgeons.org/statements/PDF_Statements/APBI_statement_revised_100708.pdf  Last accessed April 2011.
  36. Beitsch P, Vicini F, Keisch M et al. Five-year outcome of patients classified in the “unsuitable” category using the American Society of Therapeutic Radiology and Oncology (ASTRO) Consensus Panel Guidelines for the Applications of Accelerated Partial Breast Irradiation: An Analysis of Patients Treated on the American Society of Breast Surgeons MammoSite® Registry Trial. Ann Surg Oncol 2010; 17(Suppl 3):S219-25.
  37. Shaitelman SF, Vicini FA, Beitsch P et al. Five-year outcome of patients classified using the American Society for Radiation Oncology Consensus Statement Guidelines for the application of accelerated partial breast irradiation. Cancer 2010; 116(20):4677-85.
  38. Vicini F, Arthur D, Wazer D et al. Limitations of the American Society of Therapeutic Radiology and Oncology Consensus Panel Guidelines on the use of accelerated partial breast irradiation. Int J Radiat Oncol Biol Phys 2011; 79(4):977-84.
  39. Smith BD, Bentzen SM, Correa CR et al. Fractionation for whole breast irradiation: An American Society for Radiation Oncology (ASTRO) evidence-based guideline. Int J Radiat Oncol Biol Phys 2010 [Epub ahead of print].
History
July 2011 Policy updated with literature review and TEC Assessment; clinical input reviewed; policy extensively edited; new references added. Title changed to “Accelerated Breast Irradiation after Breast-Conserving Surgery for Early Stage Breast Cancer and Breast Brachytherapy as Boost with Whole-Breast Irradiation” (from Brachytherapy-Accelerated Partial Breast Irradiation); accelerated whole breast irradiation may be considered medically necessary in specific situations; accelerated partial breast irradiation (APBI), including intraoperative APBI, remains investigational.
March 2012 Policy reviewed; Authorization statement to REQUIRED; Updated policy medically necessary
September 2013 Policy statements revised.  ABPI criteria expanded.  Change in boost criteria and boost type.  Changed interstitial or intracavitary brachytherapy boost to be not medically necessary.  Intraoperative or Mammosite balloon therapy are experimental, investigational, and unproven.
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Accelerated Breast Irradiation after Breast-Conserving Surgery for Early Stage Breast Cancer and Breast Brachytherapy as Boost with Whole-Breast Irradiation