Purpose
Accelerated partial breast irradiation (APBI) has emerged as a standard adjuvant radiotherapy approach following breast-conserving surgery (BCS) for selected patients with early-stage breast cancer [1-5]. Key advantages of this modality include a shorter overall treatment time and a reduced dose to surrounding organs at risk [6]. The non-inferiority of APBI using multicatheter brachytherapy compared with whole breast irradiation (WBI) in terms of local control was demonstrated in an innovative multicenter phase 3 randomized trial [7], providing robust evidence for its adoption in appropriate populations. However, the application of APBI in patients with invasive lobular carcinoma (ILC) remains a subject of debate [8]. The inherent biological characteristics of ILC, especially its propensity for multicentricity and multifocality, raise concerns regarding the adequacy of local control with limited-field irradiation techniques [9-11]. Some studies have shown higher local recurrence rates in patients with ILC treated with APBI compared with those with invasive ductal carcinoma (IDC) [12, 13]. These concerns stem from the risk of undertreating undetected disease outside the APBI target volume. To mitigate this risk, pre-operative magnetic resonance imaging (MRI) has emerged as a valuable tool to identify and exclude high-risk ILC patients [14, 15]. Despite these concerns, patients with ILC were included in major randomized APBI trials. Notably, long-term follow-up data, including 10-year results from the GEC-ESTRO trial [16], did not demonstrate a statistically significant difference in local recurrence rates between ILC and IDC patients. This suggests that with careful patient selection, appropriate staging, and modern treatment planning, the risk of local recurrence in ILC patients can be minimized. Our institution has adopted APBI as a treatment option for low-risk breast cancer patients in 2016, adhering to eligibility criteria from major randomized trials. Critically, ILC histology was not considered an exclusion criterion. In this study, we presented our institutional experience with APBI in patients diagnosed with ILC treated since 2016. The outcomes of eligible patients with a minimum follow-up of 24 months were retrospectively analyzed to evaluate the efficacy and safety of APBI in this histological sub-type.
Material and methods
Patient and treatment features
Institutional database were reviewed to identify all patients treated between February 2016 and March 2023 with pure or mixed ILC histology, who underwent BCS followed by adjuvant APBI delivered via multicatheter HDR brachytherapy. Patients were treated according to the GEC-ESTRO recommendations for interstitial multicatheter breast brachytherapy [17-19]. Catheter implantation was performed post-operatively after BCS using the closed cavity technique after sufficient wound healing. To reduce the risk of undetected multicentricity, our institutional policy includes pre-operative breast MRI as part of the standard staging workup for all patients considered for BCS. This facilitates a comprehensive assessment of disease extent and accurate target volume delineation. Computed tomography (CT) simulation scan was performed prior to implantation to visualize tumor bed using surgical clips placed during BCS. A second CT scan was performed after catheter implantation for delineation of clinical target volume (CTV) and organs at risk. CTV was defined as the excisional cavity, with a safety margin according to the GEC-ESTRO recommendations [19]. On the day of implantation, a single prophylactic dose of antibiotics was administered. 3D dose optimization was performed using Oncentra Brachy® (Elekta AB, Stockholm, Sweden). The prescribed dose was 32 Gy in 8 fractions (twice daily), covering at least 90% of the CTV (D90). Alternatively, a schedule of 30.1 Gy in 7 fractions (twice daily) was accepted. Volume receiving 150% of the prescribed dose (V150) was limited to below 25% of the CTV. All patients were treated with an iridium-192 (192Ir) HDR afterloading system (MicroSelectron® or Flexitron®, Elekta AB, Stockholm, Sweden).
Statistical analysis
Descriptive statistics were used to summarize clinical features. Analyses were performed using R Statistical software (v. 4.5.0; R Core Team 2025). Primary endpoints were ipsilateral breast tumor recurrence (IBTR), defined as the re-appearance of in situ or invasive carcinoma in the same breast (skin or parenchyma) after initial breast-conserving surgery and radiation, and overall survival (OS), defined as the percentage of patients remaining alive after start of treatment, estimated using the Kaplan-Meier method. Secondary endpoints included long-term clinical complaints and cosmetic outcomes.
Results
A total of 47 patients with ILC were treated with APBI following BCS during the study period. The patient and tumor characteristics are detailed in Table 1. The median patient age was 65 years (range, 49-80 years), and twenty patients (42.6%) were diagnosed via a mammography screening program. The median Charlson comorbidity index was 4 (range, 3-11). All patients (100%) were estrogen receptor (ER)-positive, and 34 (72.3%) were progesterone receptor (PR)-positive; HER2 was negative in all cases. The median Ki-67 proliferation index was 8% (range, 1-20%). All patients had unifocal tumors, and a sentinel node biopsy with no axillary lymph-node metastases (pN0). Although the protocol targeted low-risk criteria, focal LVSI was present in 3 patients (6.4%). Pre-operative breast MRI was performed in 37 patients (78.7%). The treatment characteristics are summarized in Table 1. Forty-four patients (93.6%) received 32 Gy in 8 fractions, while 3 patients (6.4%) received 30.1 Gy in 7 fractions. The median number of catheters implanted was 12. Adjuvant anti-hormonal therapy was administered to 42 patients (89.4%); one patient rejected therapy, one had contraindications, and one patient’s data was incomplete. Two patients (4.3%) discontinued therapy after approximately one year due to side effects. The follow-up outcomes are presented in Table 2. At a median follow-up of 47 months (range, 24-106 months), no ipsilateral breast tumor recurrence was observed. One patient died from non-breast cancer-related causes (head and neck cancer diagnosed two years post-APBI), resulting in a 4-year OS of 97%. Moreover, no regional relapses or distant metastases were noted. Regarding late toxicity (Table 3), 9 patients (19.1%) reported cosmetic side effects: two noted hyperpigmentation of the areola/nipple, 6 patients had skin hypopigmentation in the implant area, and one observed breast asymmetry related to BCS. Clinical grade 1 fibrosis in the surgical field was seen in 9 patients (19.1%), while no grade 2 or higher toxicities were observed. Asymptomatic low-grade fatty tissue necrosis in the treated area was detected in 7 cases (14.9%) via follow-up mammography.
Table 1
Patient and tumor characteristics and treatment parameters
Discussion
Due to the increased prevalence of multifocality and positive resection margins associated with ILC, this histological sub-type was historically considered a significant risk factor for local recurrence following APBI [8]. However, recent studies show the opposite, suggesting that ILC is not a significant predictor of IBTR following APBI [20-22]. For example, Braunstein et al. recently reported a 48-month cumulative incidence of local recurrence rate of 3% in patients with ILC treated with external beam APBI [23].
The current study presents the oncological outcomes of ILC patients treated at our institution with multicatheter interstitial brachytherapy. We observed excellent local control rates in this cohort of appropriately staged and selected patients. Our results compare favorably with previous reports, e.g., Mills et al. [13], who reported a 10-year actuarial IBTR rate of 14%. Several factors may explain this divergence. The Mills et al. study included higher-risk patients (grade 3, HER2+), and utilized intracavitary balloon brachytherapy for a significant portion of cases. In contrast, our study exclusively used multicatheter interstitial brachytherapy, which offers superior dose conformality and target coverage, and we excluded HER2+ and grade 3 tumor cases. Additionally, only one patient in our cohort had a resection margin of < 2 mm (due to proximity to the pectoral fascia). A strength of our study is the high utilization of pre-operative MRI (78.7%), which aids in excluding multifocal disease. Furthermore, long-term results of the GEC-ESTRO APBI trial indicated that histology does not impact local recurrence rates, further validating APBI for ILC [16]. We acknowledge several limitations, including the retrospective design and relatively small sample size (n = 47). Moreover, while a median follow-up of 47 months provides valuable mid-term data, it is insufficient to draw definitive conclusions in terms of late recurrences, which are more common in ILC patients.
