Introduction

The treatment of breast cancer has evolved along with changing its presentation over time [1]. For decades, mastectomy was considered the standard of care for all malignant breast lesions; however, currently, the goal is preserving the breast [2]. Breast-conserving surgery (BCS) is currently the treatment of choice for its equivalent clinical outcomes when combined with adjuvant whole-breast irradiation (WBI); however, BCS has less psychosocial impact [3,4,5]. Of note, this type of surgery is not possible in all circumstances, for instance, when the ratio of breast size to the tumoral mass is not enough to preserve breast cosmetic appearance. In this condition, neoadjuvant chemotherapy (NACT) or hormonal therapy may be effective choices for tumor shrinkage and increase the possibility of breast preservation [6,7,8,9,10]. Neoadjuvant therapy is the preferred initial approach in the setting of locally advanced breast cancer (LABC), especially for patients with triple-negative (TN) or HER2 + tumors [11]. However, its role in the management of early-stage breast cancer with the purpose of downstaging, increasing the chance of BCS, and improving cosmetic results is currently under investigation [12]. After BCS, regardless of neoadjuvant treatment, adjuvant WBI with a boost to the tumor bed is recommended [13]. The boost dose could be administered through intraoperative radiation therapy (IORT) during surgery or external beam radiotherapy (EBRT) during or after external WBI [14, 15]. The latter can be delivered sequentially after conventional EBRT or with the simultaneous integrated boost (SIB) technique using intensity-modulated radiation therapy (IMRT). The SIB technique has several benefits over the sequential boost. For example, shorter overall treatment time, fewer toxicities, more homogeneous dose distribution, and obviating the need for the application of electron therapy [16].

In this review article, we aimed to highlight the role of IORT in patients with LABC after NACT. In the following sections, first, we introduce the databases and keywords of the research. Then, we present the summary of studies evaluating the role of boost radiotherapy in patients with LABC who have received NACT followed by a short practical description of IORT modalities in the “Results” section. Thereafter, we discuss the studies specifically addressing the role of IORT in this group of patients.

Methods

Research Design and Search Strategy

This review article was carried out by searching studies in major available databases, including PubMed, Medline, Web of Science, EBSCO, IEEE, Scopus, and Springer, from 1998 to 2020. In addition, references of the selected articles and  grey literature were evaluated. To ensure that no relevant papers have been lost, the lists of review articles were also fully investigated. The keywords used for the search were “intraoperative radiotherapy” AND/OR “locally advanced breast cancer” AND/OR “neoadjuvant chemotherapy” AND/OR “Intraoperative radiotherapy with electrons” AND/OR “Intraoperative radiotherapy with photon”. The search strategy was modified and customized for each database.

Inclusion and Exclusion Criteria

The inclusion criteria were full-text available descriptive and clinical trials (in the English language) concerning the aforementioned keywords, which have been published from 1998 to 2020. Exclusion criteria were when only the abstract was available and not in the timeline of the study.

Quality Assessment

The present study employed the STROBE (strengthening the reporting of observational studies in epidemiology) for the quality assessment of the included articles.

Results

Thirteen studies were evaluated. Based on the results of the present review, IORT is beneficial in patients with LABC, and substitution of external beam irradiation boost (EBIB) by IORT does not compromise the outcome in terms of local recurrence.

Breast-Conserving Surgery After Neoadjuvant Chemotherapy

Table 1 demonstrates an overview of clinical trials dealing with breast-conserving therapy after NACT in patients with LABC. Primary studies on NACT in breast cancer, including phase III randomized trials, have revealed a minimal survival benefit but an increased likelihood of breast preservation. Moreover, response to NACT may guide chemotherapy in the adjuvant phase. Eight out of 13 studies evaluating NACT in LABC (mostly phase II–III trials) have reported the pathologic complete response (pCR) to NACT (median: 36%, range: 3–87%). Of note, the low rate of pCR did not translate to long-term local–regional and ipsilateral breast tumor recurrence.

Table 1 Overview of clinical trials dealing with breast-conserving therapy after neoadjuvant chemotherapy in cases of LABC
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Intraoperative Radiotherapy

The American Society for Radiation Oncology (ASTRO) has issued the inclusion criteria for accelerated partial breast irradiation (including IORT) of early-stage breast cancer, including negative surgical margins by ≥ 2 mm (suitable) or < 2 mm (cautionary), age ≥ 50 years old (suitable) or patients age 40–49 who meet other pathologic suitability criteria (cautionary), and patients with low-risk ductal carcinoma in situ (DCIS) disease. The original guideline has a few differences: (1) did not include DCIS, (2) named age ≥ 60 years old as suitable and 50–59 years old with the aforementioned condition as the cautionary group for IORT [17]. The main limitation of IORT is the lack of final pathologic information on tumor size, histology, margins, and nodal status. When unexpected findings (e.g., positive surgical margin or positive sentinel node) are encountered, additional WBI may be indicated, thereby reducing some of the convenience and low-toxicity advantages of sole IORT. However, IORT as a tumor bed boost has also been studied and appears to be a safe procedure [18]. One of the controversies in the application of IORT is the existence of several consensus guidelines for selection criteria (including ASTRO, Groupe Européen de Curiethérapie-European Society for Radiotherapy and Oncology [GEC-ESTRO], and the TARGIT group) that may result in varied indications of WBI after IORT that may influence the final results. Another controversy is that the results of previous IORT trials are difficult to apply to patients who have positive sentinel lymph node biopsy but no axillary dissection [19].

Patients with LABC require WBI after BCS, and to achieve optimum local control and possibly overall survival (OS), patients should also receive radiation boost to the tumor bed [20, 21]. The boost radiation can be delivered during surgery (i.e., IORT) or as a part of adjuvant EBRT. In the following section, the two common IORT approaches used during BCS are described [22].

Intraoperative Radiation Therapy with Electrons (IOERT)

There are three mobile electron-beam linear accelerators (LINAC) designed to deliver IORT, including Mobetron, LIAC, and Novac7.

The Mobetron® is an X-band LINAC. The X-band waveguide accelerates electrons to energies of 4, 6, 9, and 12 meV. Mobetron delivers 20 Gy at 2 min. LIAC accelerators can produce electron beams with four nominal energies of 4, 6, 9, and 12 meV [23]. Beam energies typically increase in steps of 2 meV or 3 meV [24]. If the NOVAC or LIAC machine is located in an operating room above ground level, using a combination of lead and borated polyethylene (5%) is good for shielding. The role of borated polyethylene is to stop the neutrons, and the lead is to eliminate the secondary photons [25].

Intraoperative Radiation Therapy with Photons

This method consists of two systems, INTRABEAM and Axxent. The INTRABEAM® system (Carl Zeiss Meditec AG, Oberkochen, Germany) consists of a graphic interface between the user and control console (named the user terminal), X-ray source (a.k.a., XRS 4 Miniaturized Linear Accelerator), the control console (controls the X-ray source), quality assurance (QA) equipment, a support stand, and different applicators. XRS 4 consists of an electron gun which emits electrons, the accelerating unit which accelerates the electrons to a maximum of 50 kilovoltages (kV), and two pairs of bending coils which guide the electron beam through a 10 cm hollow tube (i.e. the probe) that drifts electrons to the gold target and generates X-rays through the Bremsstrahlung effect. This design provides a spherical dose distribution [26]. The INTRABEAM system has the capability of using four types of applicators: (1) spherical applicators, (2) surface applicators, (3) flat applicators, and (4) needle applicators [27,28,29]. Treatment time depends on the prescribed dose and applicator size. The treatment time to deliver 20 Gy is between 7 and 49 min. Table 2 summarizes the treatment time for different applicators to deliver 20 Gy.

Table 2 Treatment time for different applicators to deliver 20 Gy [25]
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The Xoft S700 Axxent™ system operates at energies between 20 and 50 kV, but the more practical energy is 50 kV. This system has a microminiature X-ray tube that is located inside a flexible and disposable sheath. Inside this sheath is filled with water, and the device cools down. The nominal dose rate of the machine is 0.6 Gy/min at 3 cm of water, which is higher than that for the INTRABEAM system because of the cooling effect of water on the X-ray target.

The radiation protection of an intraoperative 50 kV X-ray unit has largely been investigated. Shielding the treatment field with a tungsten sheet combined with a movable shield for anesthesiologist and physicist—that monitor the treatment—is sufficient to reduce doses to an acceptable level [30].

Discussion

In the study by Fastner et al. (2015), tumor bed boost by IOERT during BCS was compared with EBIB (by electrons or photons) in patients with LABC who have received NAC and adjuvant WBI in terms of local control rate (LCR) and locoregional control rate (LRCR). The 6-year LCR and LRCR were nonsignificantly higher in the IOERT group than in the EBIB group (98.5 vs 88.1%, p-value 0.2 and 97.2 vs 88.1%, p-value = 0.3, respectively) [31]. This may be due to a highly accurate dose prescription in IORT with the elimination of effects of geometric and temporal miss. Moreover, in situ delivery of radiation during IORT permits higher doses that may positively affect the results. In the retrospective study by Kolberg et al. (2016), the clinical outcomes of IORT with the targeted intraoperative radiotherapy (TARGIT) technique using an intraoperative dose of 20 Gy (with a 50 kV X-ray source) were compared with EBIB in patients with LABC who have received NAC. While the differences in local recurrence-free survival (LRFS), disease-free survival (DFS), and breast cancer mortality (BCM) were not statistically significant, the 5-year OS was significantly in favor of the TARGIT-IORT group (hazard ratio [HR] = 0.19 (0.04–0.87), p = 0.016) [32]. The toxicity of IORT as a boost after was comparable with the average postoperative morbidity after BCS [33]. The higher OS in the IORT group may be due to the rapid effect of IORT on the local tumor microenvironment and wound fluid that could be absorbed and cause systemic beneficial effects [34]. Subsequently, Kolberg et al. (2017) compared the results of the TARGIT-IORT technique with EBIB as the tumor bed boost during BCS after NACT in patients with TN or HER2 + LABC. By demonstrating the nonsignificant trend for better 5-year OS (HER2 + : 100% vs. 91.7%, p = 0.22 and TN: 87.5% vs. 74.1%, p = 0.488) and 5-year DFS (HER2 + : 83.3% vs. 77.0%, p = 0.38 and TN: 87.5% vs. 60%, p = 0.22) for TARGIT-IORT, the authors concluded noninferiority of TARGIT-IORT as an intraoperative boost in these high-risk patients [35].

Spaich et al. (2017) reported the acute and late complications of IORT following NACT in patients with LABC. By reporting no severe toxicity, they concluded that IORT during BCS after NACT is a safe procedure that may enhance the treatment strategies in this group of patients. In this retrospective study, 13 patients received IORT with low-energy X-rays (50 kV). After a median follow-up of 37 months, local recurrence occurred in one patient who had several risk factors for recurrence, including young age, advanced tumor size with poor response to chemotherapy (ypT2), high-grade biology (G3), and lymphovascular invasion [36]. In a prospective cohort by Manikhas et al. (2018), 51 patients with cT2N0M0 breast cancer who received NACT (62.7%) or exemestane (37.3%) followed by BCS with IORT (using the INTRABEAM system) and WBI were evaluated for clinical outcomes. Following a median follow-up of 24 months, the authors found no local recurrence and considered IORT as an effective modality in local control. The authors reported nonsignificant results for delayed toxicity of IORT and WBI [37]. In a retrospective study, Cotrina et al. (2019) reported their experience on IORT (using INTRABEAM) in patients with LABC who have received NACT. After a minimum 6-month follow-up, the rate of local recurrence was 7.1% [38].

To compare the efficacy of IORT (50 kV X-ray) and EBRT as a boost dose in patients with breast cancer, Moini et al. (2020) conducted a retrospective analysis. In this study, 576 patients with stage 1–3 breast cancer were enrolled. With a median follow-up of 54 months, the investigators found nonsignificant superiority for the IORT group in terms of local control (1.2 vs 2.5%, p = 0.36) and concluded that IORT may provide better local control. Although 15% of the IORT group and 13% of the EBRT group received neoadjuvant chemotherapy, a subanalysis was not separately provided [39]. In a single-arm phase II clinical trial, Homaei Shandiz et al. (2020) evaluated the clinical efficacy and toxicities of IORT in patients with LABC who have received NAC. In this study, 20 Gy IORT was delivered during BCS using the INTRABEAM system. By reporting a local recurrence of 4% and grade 3–4 toxicity of 12.5%, the authors concluded that IORT following NAC is an effective and safe procedure [40]. Table 3–5 summarize the patients’ demographics, treatment details, and clinical outcomes of the abovementioned studies.

Table 3 Demographic data of patients enrolled in the studies on IORT after neoadjuvant chemotherapy in patients with locally advanced breast cancer
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Table 4 Treatment details of studies on IORT after neoadjuvant chemotherapy in patients with locally advanced breast cancer
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Table 5 Outcome of IORT after neoadjuvant chemotherapy in patients with locally advanced breast cancer
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Conclusions

In this review, we presented a basis for the use of IORT after NACT in patients with LABC and discussed the current evidence regarding its clinical outcome. Highly accurate dose prescription, evasion of the proliferative cytokine cascade, and elimination of the effects of geometric and temporal miss all lead to this conclusion that boost IORT may be superior to EBIB. In this context, most of the data have reported comparable results with an external boost in terms of local control. A retrospective study addressed the survival benefit of IORT as a boost. Until well-designed randomized trials become available, these findings must be interpreted with caution.