Randomized Trials Comparing APBI vs WBI
Randomized Trials Comparing APBI to WBI: Study Background
Four randomized trials have been published that compared conventional WBI vs APBI (Table 2). The first published trial was conducted at Christie Hospital in Manchester, UK and randomized more than 700 women to receive external beam APBI to the surgical cavity or an accelerated course of WBI.[50,51] With follow-up of 8 years, there was no difference in overall or disease-specific survival, but IBTR was significantly higher in the APBI arm compared with the WBI arm (25% vs 13%; P = .00008). The IBTR rate was 22% in the APBI arm vs 12% in the WBI arm for women with invasive ductal carcinoma, and 43% in the APBI arm vs 17% in the WBI arm for patients with invasive lobular carcinoma. The results of the trial suggest superior local control with WBI, but several factors limit its applicability. Microscopic margin status was not evaluated in these patients and axillary lymph node staging was not performed. The doses used for WBI are significantly lower than those typically used today, and no boost was given. Many patients had poor prognostic factors, including large tumor size, nonductal histology, high grade, and the presence of lymphovascular invasion that today would prompt more aggressive therapy.
The second published randomized APBI experience is from Leeds Hospital in the UK.[52] As in the Christie Hospital trial, women were randomized to external beam APBI or an accelerated course of WBI. At 8 years median follow-up, there were 4 IBTRs in the WBI arm compared with 10 in the APBI arm (P = .07), and 4 isolated axillary recurrences in the WBI arm compared with 10 in the APBI arm (P = .05). Once again, the lack of microscopic margin status severely limits the findings of this trial. APBI patients were treated with a variety of techniques, and no clear definition for field size was used.
A randomized trial comparing conventional WBI vs APBI was also conducted in Hungary.[53] The majority of APBI patients underwent multi-catheter Ir-192 brachytherapy, while a smaller percentage who were technically unsuited for brachytherapy were treated using external beam APBI. At a median follow-up of 66 months, IBTR as a first event occurred in six patients (4.7%) in the APBI arm and four patients (3.1%) in the WBI arm. In the APBI arm, two of the six IBTRs were in the treated volume or its margin. The rate of good-to-excellent cosmetic results was 77.6% in the APBI arm and 62.9% in the WBI arm (P = .009). In a separate publication, the reported rates of asymptomatic or symptomatic fat necrosis at 4 years did not differ between WBI and APBI patients.[54] The trial is limited by the relatively small number of patients, short follow-up, and variability in treatment within each arm across institutions.
The most recent published trial comparing conventional WBI vs APBI is the TARGIT-A trial.[55] APBI patients underwent wide local excision plus sentinel lymph node biopsy or axillary dissection followed by targeted intraoperative radiotherapy (TARGIT) to a prescribed surface dose of 20 Gy. Fourteen percent of patients treated with TARGIT had adverse pathologic features on final pathology and subsequently underwent WBI. At 4 years, there were six IBTRs in the TARGIT arm vs five in the WBI arm, and four axillary recurrences in the TARGIT arm vs three in the WBI arm. The number of patients with major toxicity was similar between arms; however, the types of complications varied. Seroma requiring three or more aspirations occurred more frequently in the TARGIT arm (2.1% vs 0.8%; P = .012), while RTOG grade 3 toxicity was more common in the WBI arm (2.1% vs 0.5%; P = .002).
The results of three of these APBI trials have been analyzed in a recent meta-analysis.[56] Although enrollment criteria and APBI techniques vary widely across studies, no difference in survival was noted in patients treated with APBI vs WBI (P = .55). APBI was associated with a higher risk of IBTR (odds ratio [OR] 2.15; 95% confidence interval [CI], 1.40-3.31) and axillary recurrence (OR, 3.43; 95% CI, 2.06-5.72).
Consensus Guidelines and Use of APBI
Given the expanding use of APBI in the treatment of early-stage breast cancer, task forces representing several professional societies have published consensus statements regarding its usage. ASTRO reviewed the available literature and reached a consensus regarding categories of patients for whom APBI is deemed “suitable,” “cautionary,” or “unsuitable.”[57] Suitable patients are those 60 years of age and older with small, unifocal tumors of ductal or other favorable histologic subtype without nodal involvement who have undergone complete surgical excision of their tumors, to negative margins, and have not received neoadjuvant chemotherapy. Only patients in the suitable category are recommended to undergo APBI outside of a clinical trial. Cautionary patients are those with larger tumors, less favorable histology, an extensive intraductal component (EIC), pure ductal carcinoma in situ (DCIS), or close surgical margins. Young patients or those with large tumors, positive margins, unfavorable pathologic features, or involved lymph nodes are considered unsuitable candidates for APBI. There is ongoing debate about whether more groups of patients should be considered suitable. Because of the variability of technical factors and the short available follow-up, recommendations regarding APBI techniques and treatment planning were not addressed by the ASTRO committee.
The American Brachytherapy Society (ABS) Breast Brachytherapy Task Group recommends limiting APBI with interstitial or intracavitary brachytherapy to patients 50 years of age and older with invasive ductal tumors measuring 3 cm or less and no nodal involvement.[58] Multifocal disease and an EIC are considered relative contraindications.
Despite the recommendations of such task forces, APBI usage and techniques vary widely. A 2011 analysis of Medicare data suggests that use of brachytherapy following BCS has increased from less than 1% of new breast cancer cases in 2001 to 10% of cases in 2006. This increase has correlated with FDA approval of MammoSite and its reimbursement by Medicare.[59] A similar analysis of the National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) database shows that the percentage of women receiving brachytherapy-based APBI increased from 0.4% in 2000 to 6.6% in 2007.[60] In the study, 65.8% of treated patients were classified as cautionary or unsuitable based on ASTRO criteria.
Although the use of APBI is increasing, the growth in APBI is variable across patient demographics and regions. Brachytherapy-based APBI is more common among Caucasian patients and in those with non-HMO (health maintenance organization) insurance. Metropolitan regions, regions with higher median income, and regions with a lower density of radiation oncologists are also more likely to have higher rates of APBI.[59,60]
Ongoing APBI Trials
Ongoing Studies
Several randomized trials comparing APBI vs WBI are ongoing (Table 3). The National Surgical Adjuvant Breast and Bowel Project (NSABP) B-39/RTOG 0413 trial is the largest of these investigations and has nearly completed randomization of 4300 post-lumpectomy patients to conventional WBI or APBI using multi-catheter brachytherapy, balloon catheter brachytherapy, or external beam radiation. Randomized trials are also underway in other countries and compare APBI against conventional WBI or AWBI. Although many of these trials are accruing briskly, and data on early toxicity may be available in the next several years, many more years will be required before data regarding long-term efficacy and safety are available. In total, more than 14,000 patients have been accrued to randomized phase III trials of APBI (compared with fewer than 4100 patients in the trials that established the equivalence of BCT to mastectomy), so definitive results should become available with time.
In the personal perspective of the senior author (JH) who was involved in the early use, and controversies regarding use, of BCS and WBI as an alternative to mastectomy:
• Those controversies, often intense, dissipated only when definitive results of randomized clinical trials became available. In the current situation, in which definitive results from trials comparing conventional WBI, accelerated WBI, and APBI are not available, there will inevitably be controversy where experts will differ in their opinions.
• The time course to assess efficacy and safety in local treatment of the breast using radiation is protracted, and many early assessments of BCS and WBI underestimated late IBTRs and side effects. This long-term follow-up, sometimes painful to see, provided information that helped to insure that future implementation of BCS and WBI would be safer and more effective.
Conclusions
Given their greater convenience and, in most cases, decreased costs, APBI and AWBI are becoming increasingly popular alternatives to conventional WBI for early-stage breast cancer patients who desire BCT. However, given the protracted time to local recurrence and complications following BCT, definitive results from randomized clinical trials comparing conventional WBI vs AWBI or APBI are limited. The results of the Canadian hypofractionation trial have been widely considered to be practice-changing, and forthcoming results of other first- and second-generation AWBI trials will continue to guide the expanded used of AWBI. Mature data for APBI is less robust, but results from several non-randomized studies suggest that, in carefully selected patients, APBI can provide rates of local control similar to those achieved with conventional WBI. However, a recent large retrospective analysis suggests that brachytherapy-based APBI may be inferior to WBI in certain populations. Results from published randomized trials comparing APBI vs WBI are also mixed, and data from the large ongoing randomized trials using contemporary techniques are needed to further characterize the safety and efficacy of APBI. Until mature randomized data are available, patients should be counseled that long-term results of APBI are limited, and providers should be judicious in their use of APBI outside of consensus guidelines or a clinical trial setting.
Financial Disclosure: The authors have no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.
