Polgar et al. reported the 5-year results of a phase I/II study and initial findings of a randomized phase III trial assessing adjuvant brachytherapy alone following breast-conserving therapy for stage I breast cancer (Polgar et al. 2002). Initially, 45 patients with stage I breast cancer were prospectively selected to undergo adjuvant tumor bed radiotherapy (TBRT) via interstitial high dose-rate (HDR) implants used to deliver seven fractions of either 4.33 Gy or 5.2 Gy. With a median follow-up of 57 months, 4.4% local, 6.7% axillary, and 6.7% distant failures, and 4.4% deaths due to breast cancer were observed. The 5-year probability of cancer-specific, relapse-free and local recurrence-free survival was 90%, 85.9%, and 95.6%, respectively. Cosmetic results were excellent in 97.8% of patients and no toxicity greater than grade 2 was observed. Based on the technical feasibility and results of the study, a phase III study was initiated and 126 further patients were randomized to receive 50 Gy WBRT (n=63) or TBRT (n=63) alone consisting of interstitial HDR brachytherapy delivering 5.2 Gy in seven fractions (n=46) or electron beam irradiation used to deliver 50 Gy (n=17). At a mean follow-up of 30 months, locoregional control was 100% in both arms and the 3-year probability of cancer-specific and relapse-free survival rates were similar in both arms. Furthermore, radiation-related side effects were also not significantly different between the treatment arms. Based on these 5-year results demonstrating technical feasibility and acceptable cosmetic outcome with short-term follow-up demonstrating similar outcome to WBRT, the authors concluded that TBRT might be an appropriate alternative in appropriately selected patients. To our knowledge, this study represents one of only two phase III trials that have utilized external beam radiotherapy to deliver APBI.
The only other phase III prospective randomized trial comparing external beam APBI to whole-breast irradiation (WBI) was conducted at the Christie Hospital, Manchester, UK (Ribeiro et al. 1990, 1993). The study included 708 patients with clinically palpable breast carcinomas (invasive ductal or lobular) measuring 4 cm or less with no palpable axillary adenopathy. Following lumpectomy (with no sentinel or axillary node dissection), the patients were randomized to receive either limited field (LF) PBI including the tumor bed, or wide field (WF) radiation including the whole breast and regional lymph nodes. Although microscopic margin status was not reported, the primary tumor was reported as grossly completely excised in 80% of cases, incompletely excised in 10% of cases and could not be assessed in 10% of cases. In the LF group, 40 to 42.5 Gy was delivered in eight fractions over 10 days, using 8-14 MeV electrons prescribed to the 100% isodose line (IDL). The average field size was 8x6 cm. Patients in the WF arm were treated via an opposed tangential field arrangement using 4 MV photons to deliver 40 Gy in 15 fractions over 21 days. The anterior supraclavicular/axillary nodal region was treated with a separate field using 4 MV photons.
At 6 years from the first randomization, 96% of the WF group and 92% of the LF group were free of breast recurrence. The actuarial breast recurrence-free survival at 5 years was 94% and 87% for the WF and LF groups, respectively. In the 8-year update, overall survival rates were similar between the groups (73% and 71% for the LF and WF groups, respectively). The actuarial breast recurrence rates were 20% and 11% in the LF and WF arms, respectively (P=0.0008). However, when histology was factored into the analysis, invasive lobular histology appeared to account for a significant proportion of the local recurrences in the LF group compared to the WF group (34% and 8%, respectively). The local recurrence with invasive ductal carcinomas was similar in both arms (15% in the LF group, and 11% in the WF group). Extensive intraductal carcinoma in situ was associated with higher recurrence rates in both arms, 21% for the LF arm and 14% for the WF arm, with salvage surgery possible in 86% and 90% of patients in each arm, respectively. Of note, the marginal miss/true recurrence (outside the treated field) of invasive ductal carcinoma in the LF arm was 5.5%. The rate of fibrosis and telangiectasias was higher in the LF arm, with worse cosmetic outcome. However, unlike contemporary 3D conformal APBI, PBI was delivered by electron beams, not unexpectedly resulting in a higher skin dose and therefore a less than optimal cosmetic outcome.
Further differences between patient management in this study and the care provided today include lack of sentinel lymph node biopsy or axillary node dissection, systemic treatment, and evaluation of microscopic margins. Also, most patients did not have pre- or postoperative mammography, and therefore multicentric disease could not be excluded. Furthermore, tumor size was unknown in 42% of patients, extensive ductal carcinoma in situ was not excluded, and all histologies were allowed. The simulation and treatment delivery did not have quality assurance criteria, CT scan evaluation or planning, 3D treatment planning, localization of the lumpectomy cavity borders or depth, daily verification of treatment field, or DVH analysis. Although the authors conclude that limited field irradiation results in a higher recurrence rate, with the current standard of care and the fact that the rate of recurrence with invasive ductal carcinoma was similar between the two arms, 3D conformal APBI appears to have a significant role in the adjuvant treatment of early-stage breast cancer.
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