TEC Assessment Index

Accelerated Partial Breast Irradiation as Sole Radiotherapy After Breast-Conserving Surgery for Early Stage Breast Cancer

Assessment Program
Volume 22, No. 4
September 2007

Executive Summary

Background

Survival after breast-conserving therapy (BCT) is equivalent to survival after mastectomy for patients diagnosed with tumors categorized as stage I or II. BCT is a multi-modality treatment that consists of breast-conserving surgery to excise the tumor with adequate margins, followed by whole-breast external-beam radiation therapy (WB-EBRT) administered as 5 daily fractions per week over 5 to 6 weeks. Local boost irradiation to the tumor bed often is added to whole-breast irradiation 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 or irradiation of the axilla. Brachytherapy for breast cancer is the implantation of radioactive material directly in the breast tissue.

Accelerated partial-breast irradiation (APBI) differs from WB-EBRT in two ways. First, the radiation targets only a segment surrounding the tumor rather than the entire breast. Second, since the duration of treatment is 4 to 5 days rather than 5 to 6 weeks, radiation is delivered in fewer fractions at larger doses per fraction. There are several methods of delivering APBI, including interstitial or balloon brachytherapy, intensity-modulated radiotherapy (IMRT), 3-dimensional conformal radiotherapy (3D-CRT), and intraoperative radiotherapy. A prior Assessment (Vol. 17, No. 18; 2002) concluded that APBI using brachytherapy did not meet the Blue Cross and Blue Shield Association Technology Evaluation Center (TEC) criteria, because there was insufficient evidence to determine whether it was as beneficial as WB-EBRT following BCT. The current Assessment updates the 2002 Assessment.

Note that treatment of early stage breast cancer by brachytherapy without surgical excision has not been studied adequately and is not addressed in this Assessment.

Objective

To evaluate whether evidence shows that for women with tumors smaller than 2–3 cm, clean margins, and no more than 3 positive nodes, APBI as sole radiation post breast-conserving surgery improves net health outcomes at least as much as WB-EBRT.

Search Strategy

A literature search was conducted on MEDLINE® from 2004 through December 2006, using the following search terms: the Medical Subject Headings (MeSH®) terms "breast neoplasms" and "brachytherapy," plus text word searching for "breast" and ["brachytherapy" or "radiation" or "radiotherapy"]. Reference lists were also reviewed. The search yielded 87 references, which were searched for studies on the impact of accelerated partial breast irradiation on recurrence rates and mortality. The search was updated in May 2007, using the search terms "accelerated partial breast irradiation" or "APBI," "breast neoplasm," "radiotherapy," and "brachytherapy." At that time, 199 citations were reviewed.

Selection Criteria

All English-language articles in peer-reviewed journals on APBI that reported on breast cancer recurrence with at least 25 subjects were included if they reported on a control group (n=6). Uncontrolled studies with a mean or median follow-up of at least 5 years were also included (n=2). Abstracts were excluded.

Main Results

There is only one randomized trial comparing APBI using interstitial brachytherapy and the established alternative, WB-EBRT, for patients with early stage breast cancer undergoing breast-conserving surgery. The recurrence rates for APBI and WB-EBRT were similar. However, the trial was small (n=126); and the preliminary report covered only 30 months of follow-up, far short of the 8 years needed to assess the impact of radiotherapy on breast cancer recurrence and on mortality. It also included two types of APBI, because 17 patients were unsuitable for interstitial brachytherapy, and one cannot determine whether the impact is the same for each kind of brachytherapy.

Five nonrandomized, controlled studies (n=1,001) compared interstitial brachytherapy with whole-breast irradiation. No significant differences in recurrence rates were found between the two types of radiotherapy. However, these studies have a number of limitations, including relatively small sample sizes, short follow-up (one study), and most importantly, potential baseline differences between the intervention and control arms. Two noncontrolled studies examined interstitial brachytherapy (n=84) and had a median follow-up of 57 and 91 months. The ipsilateral failure rate was 4% in the study with shorter follow-up and 15% in the other study, which had 15% node-positive subjects.

Of the many studies on balloon brachytherapy, none met the Assessment study selection criteria: All were uncontrolled, and all either had insufficient follow-up or failed to report on recurrence and/or mortality rates. No studies were found that addressed outcomes from APBI using 3D-CRT or IMRT. Two studies examined intraoperative APBI; however, they either did not have long enough follow-up or they did not report on recurrences.

Author's Conclusions and Comments

The critical question is whether APBI is as effective as WB-EBRT in reducing recurrences and mortality in patients undergoing BCT. To assess APBI as a sole alternative to WB-EBRT, trials are needed that compare the two approaches in similar populations (ideally randomized) for at least 8 years. In a patient-level meta-analysis, the Early Breast Cancer Trialists' Collaborative Group found that the use of WB-EBRT reduced 15-year breast cancer absolute mortality risk by 5.4%, from 35.9% to 30.5% (SE=1.7, 2p=0.0002); there was a similar reduction in absolute mortality from all causes of 5.3% (SE=1.8, 2p=0.005). Thus, evidence clearly demonstrates that radiotherapy following BCS reduces recurrences and prolongs survival.

There are 32 studies on APBI, but only 6 are controlled studies; and the rest are uncontrolled. There is only one small, randomized trial (n=126) with inadequate follow-up (30 months). It is uncertain whether controls in the nonrandomized studies are sufficiently similar to the intervention groups. Recurrence rates vary substantially based on multiple clinical factors, not all of which have been identified; thus, one cannot be sure that 5-year recurrence rates in nonrandomized trials are equivalent between WB-EBRT treatment and APBI. Given the various APBI techniques, there may also be differences in dosimetry, delivery, and adverse effects, and outcomes among the modalities.

There are a number of randomized, controlled trials on the use of APBI currently underway, comparing whole-breast irradiation to 1) intraoperative electron beam radiation therapy (European Institute of Oncology, n=824); 2) interstitial or balloon brachytherapy or 3D-CRT (NSABP B 39/RTOG 0413, n=3,000); 3) interstitial brachytherapy (European Brachytherapy Breast Cancer GEC-ESTRO, n=1,170); 4) interstitial brachytherapy or electrons (National Institute of Oncology, Hungary, n=570); and 5) 3D-CRT (Ontario Clinical Oncology Group, n=2,128).

Some proponents of APBI have pointed to the number of women who forego radiotherapy following BCS. They assert that APBI is more convenient than WB-EBRT, and therefore, its availability might reduce the number of patients with no radiotherapy. Radiotherapy use is less frequent among African-Americans and those living farther from radiotherapy facilities; however, adequate information is lacking on other factors influencing women who do not get radiotherapy. Therefore, it is not known whether patients currently omitting radiotherapy would choose APBI if it were readily available. Also, some women may choose to forego radiotherapy because of older age, as suggested in the National Comprehensive Cancer Care Network (NCCN) guidelines, or the presence of other life-threatening comorbidities.

Furthermore, if convenience is the primary impediment to getting radiotherapy following BCS, several accelerated whole-breast protocols have been tested. For example, a randomized controlled trial in Canada compared the traditional 50-Gy protocol delivered in 25 fractions over 35 days with an accelerated protocol of 42.5 Gy delivered in 16 fractions over 22 days. With 1,234 patients followed a median of 69 months, there was no statistically significant difference in local recurrence-free, disease-free, or overall survival between the two regimens. Another study comparing 3 whole-breast fractionation regimens suggested that hypofractionation is a reasonable alternative; a larger trial is underway to confirm these findings. Other accelerated, whole-breast regimens are currently being tested, but the studies reported to date are uncontrolled and the follow-up is too short to evaluate the impact on recurrence rates. Because accelerated whole-breast irradiation changes only one parameter in the traditional radiotherapy regimen, i.e., fraction size but not the breast volume treated, it may be a more conservative approach than APBI for women who do not want to undergo the traditional 5- to 6-week protocol. This may be a more prudent approach until further follow-up reveals the long-term effectiveness of APBI versus the conventional WB-EBRT protocol.

Based on the available evidence, the Blue Cross and Blue Shield Association Medical Advisory Panel made the following judgments about whether accelerated partial-breast irradiation (APBI) as sole radiotherapy meets the Blue Cross and Blue Shield Association Technology Evaluation Center (TEC) criteria to decrease recurrence after breast-conserving surgery for early stage breast cancer.

1. The technology must have final approval from the appropriate governmental regulatory bodies.

Iodine-125 seeds were marketed prior to enactment of the 1976 Medical Device Amendments. Thus, they were cleared for marketing on a "grandfathered" basis. Subsequent radioactive isotope implants, including iridium-192, were approved via 510(k) as substantially equivalent to the radioactive iodine seeds.

A number of breast brachytherapy devices have received U.S. Food and Drug Administration's (FDA) 510(k) marketing clearance. The MammoSite™ RTS was cleared for marketing via 510(k) in May 2002 as substantially equivalent to other commercially available brachytherapy applicators used with sealed radiation sources. The FDA's Office of Device Evaluation judged it reasonably likely that the device will be used in ways outside those specified in the proposed labeling, and that such use could cause harm. Therefore, the FDA required inclusion of the following statement in the "Warnings" section of the device's labeling: "The safety and effectiveness of the MammoSite RTS as a replacement for whole breast irradiation in the treatment of breast cancer has not been established."

In December 2005, the FDA cleared for marketing 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.

Three additional devices used for breast brachytherapy recently received 510(k) clearance from the FDA. First is a remote-controlled radionuclide applicator system by BioLucent, Inc. (Aliso Viejo, CA), called the Strut-Adjusted Volume Implant or SAVI™, which was cleared on October 20, 2006. This device is described by the manufacturer as a hybrid approach, combining interstitial brachytherapy and balloon brachytherapy. Like balloon brachytherapy, the device is inserted in the tumor cavity through a small incision. A bundle of catheters is then spread out to form an ellipsoid shape inside the cavity. Second is the Adjustable Multi-Catheter Source Applicator or ClearPath™ from North American Scientific, Inc. (Chatsworth, CA), which was cleared on November 9, 2006. The third is the SenoRad Multi-Lumen Balloon Source Applicator for Brachytherapy from SenoRx, Inc. (Aliso Viejo, CA), which was cleared on May 18, 2007.

2. The scientific evidence must permit conclusions concerning the effect of the technology on health outcomes.

The Assessment sought to compare outcomes of APBI, with those of WB-EBRT, after breast-conserving surgery. Follow-up of at least 8 years is needed to demonstrate their equivalence.

The single randomized, controlled trial reported follow-up of only 30 months, far short of the minimum needed. Other studies reported on longer follow-up but were uncontrolled, did not report on recurrences, included patients who did not meet the eligibility criteria, or had other important flaws. All of the studies that met the study selection criteria for this Assessment focused on interstitial brachytherapy, a technique with a steep learning curve for practitioners. These findings cannot be extrapolated automatically to other types of APBI.

Consequently, the evidence on APBI as sole radiotherapy for early stage breast cancer is insufficient to permit conclusions concerning its effect on health outcomes.

3. The technology must improve the net health outcome.

Since available evidence is insufficient to permit conclusions, it cannot be determined whether APBI as sole radiotherapy improves net health outcomes of women undergoing breast-conserving surgery for early stage breast cancer.

4. The technology must be as beneficial as any established alternatives.

Since available evidence is insufficient to permit conclusions, it cannot be determined whether APBI as sole radiotherapy is as beneficial as WB-EBRT after breast-conserving surgery for early stage breast cancer.

5. The improvement must be attainable outside the investigational settings.

Whether APBI using as sole radiotherapy improves health outcomes after breast-conserving surgery for early stage breast cancer has not been demonstrated in the investigational setting.

Based on the above, accelerated partial breast irradiation as the sole radiation treatment after breast-conserving surgery for early stage breast cancer does not meet the TEC criteria.

TEC Assessment Index

Oncology (category); SurgerySurgicalAlternativesInterventionalRadiology (category); Women'sHealth (category); adjuvant; APBI; axilla; Axxent; BCT; boost; brachytherapy; breast cancer; breast carcinoma; breast-conserving therapy; catheter; ClearPath; conformal radiation; conservation; distant recurrence; Early Breast Cancer Trialists’ Collaborative Group; early stage; EB; hypofractionated; implantation; interstitial; intraoperative; IORT; ipsilateral; iridium; local recurrence; lumpectomy; lymph node, intracavitary; MammoSite; multicatheter; multi-catheter; partial breast irradiation; partial mastectomy; quadrantectomy; radiation; radiotherapy; SAVI; SenoRad; WBRT; Xoft;