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.
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
||> 60 y
||< 50 y
||> 45 y |
||< 2 cm
||> 3 cm
||< 3 cm |
||T0 or T2
||Negative > 2 mm
||Close (< 2 mm)
||Microscopically negative |
||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
||Invasive ductal or other favorable subtypes
||Invasive ductal carcinoma or DCIS |
||< 3 cm
||> 3 cm
||< 3 cm |
||< 3 cm
||> 3 cm
||pN0 (i–, i+)
||pN1, pN2, pN3
||SN pN0 |
||SN Bx, ALND
||None performed |
♦ = 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.
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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