MP 8.01.13

Breast Brachytherapy after Breast-Conserving Surgery, as Boost with Whole Breast Irradiation, or Alone as Accelerated Partial Breast Irradiation (APBI)

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Medical Policy
Section Therapy	Original Policy Date 7/31/96	Last Review Status/Date Reviewed with literature search/5:2008
Issue 5:2008		Return to Medical Policy Index

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Disclaimer

Our medical policies are designed for informational purposes only and are not an authorization, or an explanation of benefits, or a contract.  Receipt of benefits is subject to satisfaction of all terms and conditions of the coverage.  Medical technology is constantly changing, and we reserve the right to review and update our policies periodically.

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Description

Breast conservation therapy (BCT) is a multi-modality alternative to mastectomy to treat early (stage I or II) breast cancer. In current practice, most conventional BCT includes breast-conserving surgical excision of the tumor (lumpectomy, segmentectomy, or quadrantectomy) and whole-breast radiotherapy (WBRT), delivered 5 days/week over 5–7 weeks using external beam radiation (EBR). For those at higher risk of recurrence (based on age younger than 50 years, tumor size >2–3 cm, nodal involvement, inadequate tumor-free margins etc.), "boost" radiotherapy narrowly directed to the tumor bed is included in WBRT. In randomized trials, WBRT reduced local (i.e., in-breast) recurrence, and meta-analysis showed it also improved survival compared with breast-conserving surgery alone. Other trials and meta-analysis showed that efficacy of BCT with WBRT is equivalent to mastectomy. The radiation is hypothesized to eliminate residual cancer near the surgical site and treat any undetected multicentric disease. Radiation alone (i.e., without resection) is not recommended in current guidelines to manage early breast cancer.

Breast brachytherapy uses radiation sources placed inside the breast. Interstitial brachytherapy uses multiple sources spaced in 2 or more planes through the breast, with computerized treatment planning to optimize dose homogeneity in the target. The number, spacing, and radiation strength of sources vary with the breast volume to be treated. Balloon brachytherapy uses a single source placed in an inflatable catheter inside the surgical cavity. It treats the cavity plus a surrounding margin of 1–2 cm, with radiation dose declining as a function of distance from the source.

Differences between interstitial and balloon brachytherapy in geometry and target dose homogeneity are of less concern for boost therapy, since the target volume is limited to the tumor bed close to the radiation source. External beam radiation separate from the boost adequately treats breast tissue outside the tumor bed. When brachytherapy is used without EBR to the remaining breast, i.e., for partial breast irradiation (PBI), target volume extends beyond the tumor bed, and these differences may have greater impact on outcomes. For PBI, it is thus uncertain whether outcomes of interstitial brachytherapy reliably predict outcomes of balloon brachytherapy.

Methods other than brachytherapy are also used for APBI, such as several types of external beam therapy. They are not discussed in this policy.

This policy separately addresses use of interstitial or balloon brachytherapy as alternatives to external beam radiation therapy in two settings:

1. To replace external beam for boost radiation therapy, combined with whole-breast external-beam radiation therapy and breast-conserving surgery.

2. Alone, for accelerated partial breast radiation therapy after breast-conserving surgery.

This second, more recent application of brachytherapy methods is based partly on the observation that most ipsilateral breast recurrences after breast-conserving surgery and radiation therapy occur near the tumor bed, with only a minority of recurrences located elsewhere in the breast. In addition, in trials of breast-conserving surgery with versus without radiation therapy, most recurrences also occurred near the tumor bed, suggesting that undetected multicentric disease may not be common. Together these findings suggested that tumor bed irradiation may provide the major benefit from external beam radiation therapy. Also, the extended treatment course for WBRT may be difficult for some patients, for example those living in remote locations, or the elderly or disabled.

Both methods of brachytherapy usually are delivered over a week. This shortened, more convenient treatment course, which has been termed “accelerated partial-breast irradiation (APBI),” may increase the proportion of patients choosing breast-conserving surgery. On the other hand, APBI may sacrifice some or all of the radiobiological advantage associated with fractionated doses and the slower repair of sublethal radiation damage in tumor versus normal cells.

Various interstitial brachytherapy techniques have been investigated. They differ in the timing of implantation relative to other components of breast-conserving therapy, the radiation dose rate, the loading technique, the number and volumetric distribution of radioactive sources, and the radioisotopes used. Most older studies of local boost brachytherapy temporarily implanted needles, wires, or seeds after patients recovered from surgery and completed whole-breast radiation therapy. Since the 1990s, investigators have perioperatively implanted hollow needles or catheters that guide placement of the radioactive material. This can be done during the initial lumpectomy if brachytherapy has been selected already or at re-excision if the lumpectomy specimen has positive surgical margins. Intraoperative implantation avoids the need for a separate surgical procedure with anesthesia for brachytherapy.

Both low- and high-dose rate interstitial techniques are used, with high-dose rate techniques increasing in popularity. In the low-dose rate technique, radioactive seeds are temporarily implanted in hospitalized patients. They deliver radiation continuously over 4 days and then are removed. In the high-dose rate technique, a computer-controlled device loads highly radioactive isotope sources into catheters that have been placed into the tumor bed. The patient is exposed to the radiation therapy for a brief period—e.g., 15 minutes—and then the radioactive sources are withdrawn. High-dose rate brachytherapy is typically administered to outpatients as 8 fractions given twice daily over 4 days.

A balloon catheter system (the Mammosite™ RTS device; Cytyc Corp; Alpharetta, GA) is also available for brachytherapy. The device is implanted in the lumpectomy cavity during or shortly after breast-conserving surgery. The balloon is inflated with sterile solution of contrast media in saline solution, and its position is confirmed radiographically using computed tomography. A high-dose rate source of iridium-192 is then centrally positioned within the applicator by a remote afterloader. This system is used to deliver 34 Gy in 10 fractions over 5 days. Thus, balloon brachytherapy uses a single radioactive source that delivers radiation to a spherical or elliptical target volume. Like interstitial brachytherapy, it can be used to deliver local boost or accelerated partial-breast radiation therapy.
In December 2005, the U.S. Food and Drug Administration (FDA) cleared the Axxent Electronic Radiotherapy device (Xoft, Inc., Fremont, CA) via 510(k) as substantially equivalent to the Mammosite and other brachytherapy systems. The Axxent device is a balloon brachytherapy system that uses a disposable, microminiature radiation source to deliver the radiation rather than radioisotopes. Additional brachytherapy devices have received FDA 510(k) marketing clearance, e.g., the SenoRad multi-lumen balloon source applicator for brachytherapy (SenoRx, Inc., Aliso Viejo, CA, May 18 2007).

Policy

Policy Guidelines

Benefit Application

Rationale

Use as Local Boost Radiotherapy

This policy is based in part on a 1996 TEC Assessment (1) 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 breast-conserving surgery 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.

Use as Sole Form of Radiotherapy (APBI)

TEC’s 1996 Assessment (1) and 2002 revised Assessment (2) found data insufficient to permit conclusions on outcomes of interstitial or balloon brachytherapy as the only form of radiation therapy (i.e., accelerated partial breast irradiation, APBI) in patients given breast-conserving surgery for stage I or stage II breast cancer. Available studies included 3 years or less of follow-up, which is inadequate to determine whether local control after APBI was equivalent to local control after WBRT. In contrast, trials comparing lumpectomy with versus without radiation therapy reported that in-breast recurrences continued to occur through 5–8 years after treatment.

2004–2006 Updates

A 2004 literature search identified 1 new report each from uncontrolled phase II trials of interstitial (3) and balloon (4) 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. Thus, the conclusions of the 2002 TEC Assessment still stood, and this policy remained unchanged.

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). (5) 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 (6-8) and 4 reports from single-arm studies on balloon APBI. (9-12) 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 (13, 14) and a non-randomized comparison (15, 16) on interstitial brachytherapy as APBI. One of the series (13) included few patients (n=7); the other (n=99) followed patients for a median 2.7 years (14). 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. (15) 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. (16)

Five new uncontrolled series reported on patients managed with balloon APBI (17-21). 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. (18)

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. (22, 23)

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). (24) 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. (12)

A randomized intergroup trial comparing WBRT and APBI sponsored by the U.S. National Cancer Institute and led byNational Surgical Adjuvant Breast and Bowel Projectand theRadiation Therapy Oncology Group opened in early 2005 (NSABP B-39/RTOG-0413). (25, 26) 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. Lacking data with adequate follow-up from this or similar randomized, controlled trials, conclusions of the 2002 TEC Assessment still stand, and the Policy Statement remains unchanged.

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. (27) Included in the Assessment were studies on initial treatment of stage I or II breast cancer 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. Studies were included that reported outcomes on 25 or more patients and, for uncontrolled studies, had a mean or median follow-up of at least 5 years.
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="to" 4="4" cm),="cm)," width="width" of="of" tumor-free="tumor-free" margins="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 (5, 28-32, 34), 2 uncontrolled studies (33-35) with at least 5 years of follow-up, and 1 randomized controlled trial with only 30 months of follow-up. (34) 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. (34) 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. (15, 28) 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 and 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. (5) 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. (29) 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. (30) 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. (31, 32)
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. (33, 34) The other trial includes node-positive patients and demonstrates a high rate of nodal failure (13% vs. 5% in Polgar et al). (35) 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; therefore, the policy statement is unchanged.

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. (27) 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. (37)

Criteria recommended by theAmerican 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 2.2006; current as of September 15, 2006), 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."(39) Their recommendation is thus consistent with this policy.

2008 Update
Longer follow-up data are now available for 2 of the controlled studies of interstitial brachytherapy described above (15, 28, 34). Polgar and colleagues (40) 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. Therefore, the study may not have sufficient power to detect a difference between the 2 approaches. In addition, results for the 2 types of partial breast irradiation (PBI) were not reported separately.
Vicini and colleagues (41) 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. (42)
Data continue to accrue from uncontrolled studies on the use of Mammosite balloon brachytherapy (e.g., 43, 44). The longest follow-up found was 5 years in a study of 36 patients; no local recurrences were reported. (45) 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 [41]), 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. (46) 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. (47)
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, see reference 48).
Given the above evidence, the policy statements are unchanged at this time.

References:

1. 1996 TEC Assessment; Tab 7.
2. 2002 TEC Assessment: Tab 18.
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Index

Policy History

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