With a median follow-up of 6.7 years, our study showed a 5-year IBTR rate of 1.87% (95% CI 0.47–7.29%), which is comparable with the 5-year IBTR rate of the Belgian study and other APBI techniques (0.5–2.7%) [7, 9,10,11] and lower than that of ELIOT trial and Netherland trial, which is 4.2% and 10.6%, respectively.

Our IORT technique mirrored that of the ELIOT trial, which involved administering a single 21 Gy dose of electron beam radiotherapy intraoperatively after tumor excision. The difference may be due to our use of more favorable patient selection criteria, such as the exclusion of lymph node-positive and triple-negative patients, a greater proportion of estrogen receptor/progesterone receptor-positive patients, and a high rate of adjuvant systemic therapy.

Another contributing factor to our lower 5-year IBTR rate could be the use of larger cone sizes of 6 and 7 cm in 67.5% of our patients, covering a mean tumor size of 1.21 cm, and the mean difference between cone size and tumor size is 5.05 cm. This approach is in line with a Belgian study [7] that used an average cone size of 5.5 cm for tumors ≤ 2 cm in unifocal early-stage breast cancer, resulting in a 5-year IBTR rate of 2.7%. The reduced 5-year IBTR in our study may be attributable to our use of appropriate applicator cone sizes, paralleling the approach in the Belgian study.

Subgroup analysis in our study was performed based on the “ASTRO” definition. 5-year IBTR of 1.54% (95% CI 0.22–10.42%) was observed in the “suitable” group of patients which was lower than the result from a suitable subgroup in the ELIOT trial (2.0%, 95% CI 0.8–4.4%). In addition, we did not find any IBTR events in the unsuitable subgroup, however, it might be because of the extremely low number of patients in this subgroup.

Univariable and multivariable analyses were performed. LVSI was confirmed as a significant negative prognostic factor. We highly recommend excluding these groups of patients from IORT treatment. If the post-excision pathology shows a positive LVSI after IORT was giving, consideration might be given to adding external beam radiotherapy.

Another negative factor was the initial tumor location at the inner upper quadrant. In our study, four local recurrent patients were in the inner upper quadrant. The inner upper quadrant seems to have less breast tissue compared to other quadrants. Consequently, when performing IORT with electron beams, there can be challenges in aligning and stitching together the two breast-tissue flaps due to the tightness of the breast. This tightness could lead to some areas being inadequately encompassed by the electron beam, necessitating broader beam coverage.

Given the rarity of failures in the suitable and cautionary groups, we conducted a thorough review of the patients who experienced IBTR. All six patients with IBTR experienced in-field failures situated superficially, less than 1 cm from the skin dermis to superficial edge of recurrent tumor (Supplementary Fig. 2). To explain these findings, we developed the following hypothesis based on the surgical procedure described in the ELIOT trial.

The surgical technique in the ELIOT trial [15] employed a quadrantectomy with 1–2 cm clear margins. Following quadrantectomy, the breast tissue was typically reapproximated to close the surgical wound. During the IORT procedure, the separated anterior and posterior breast tissue flaps were temporarily stitched together before applying a vertically oriented radiation beam.

By employing this IORT method (Fig. 2), the breast tissue beneath the skin around the tumor cavity was detached to enable pulling and stitching it closely together after the tumor was removed. This additional step increases the likelihood of contamination area occurring during surgery in the area beneath the skin. Although the breast tissue under the skin was pulled together to receive the IORT treatment, another contamination area, the area beneath the skin, was intentionally not pulled, as we aim to keep the skin outside the IORT field. Despite the low number of IBTR events in this study, our observations suggest that the non-irradiated area could be a potential area of interest in this radiation method. While these findings are limited by the small sample size, they may indicate an aspect worth exploring in future research.

Surgical procedure and electron beam profile during IORT

Additionally, the most common settings in this study were 12 MeV energy with a 6- or 7-cm cone size. Based on the electron beam profiles (Fig. 2), the beam entry at the surface is sharply delineated by the applicator, creating a narrow penumbra. However, deeper within the tissue, the penumbra widens before the dose falls off sharply with depth. A wider penumbra implies that there is more coverage in the deeper areas compared to the superficial areas. The extremely narrow penumbra at superficial areas cannot cover the contamination area underneath the skin, as previously mentioned.

Our explanations might clarify why the recurrences in our study occurred near the tumor cavity and situated superficially, less than 1 cm from the skin dermis. These limitations in the surgical procedure and the characteristics of the electron beams might account for the predominance of superficial recurrences over deep tissue failures.

This finding is a novel aspect of our research. This hypothesis might explain why IORT with electron beams showed a higher IBTR rate than other accelerated partial breast irradiation techniques, such as EBRT, which do not demonstrate an increased IBTR rate [9, 10, 16]. Accelerated partial breast irradiation using EBRT requires covering all surgical distortion and cavities with an isotropic margin of 1 or 1.5 cm. This approach reduces the likelihood of missing the target area, a potential issue with IORT with electron beams in our study.

Our preliminary results point to a possibly important consideration in this radiation technique: the non-irradiated region. However, we acknowledge that the small number of IBTR cases limits the generalizability of these observations. This warrants further investigation through larger studies or comparisons with other methods to better understand its significance and potential implications for improving the technique.

According to the reasons mentioned earlier, our data suggested that IORT with electrons should be employed with extreme caution. It is highly recommended to incorporate an additional step in the surgery, such as changing the operation equipment before detaching the breast tissue beneath the skin or detaching the breast tissue beneath the skin as little as possible, to minimize the risk of increasing contamination in the non-irradiated area beneath the skin.

Our strength in this study was the strict policy and cone size technique. We believe that our finding of characteristics of failure has never been discussed and never been reported elsewhere. These findings could be the explanations for the high rate of IBTR in IORT with electron beams which has been argued for decades.

There are several limitations to consider in this study. First, it was a retrospective study, so we could not prospectively collect and measure certain important information. Second, this study had a relatively short-term follow-up of 6.7 years, which may limit our ability to fully assess the long-term outcomes and potential complications associated with IORT using electron beams. Although our study reported a low rate of IBTR, however, long-term follow-up is needed.

According to the recently published, ASTRO Clinical Practice Guideline for Partial Breast Irradiation [12], electron IORT is not recommended. However, supported by our data with a 5-year IBTR rate of 1.87% and a 5-year overall survival rate was 97.52% with excellent cosmetic outcomes. IORT with electron beams with strict patient selection criteria and large cone size may be a viable alternative treatment option for early-stage breast cancer.