Advances in breast cancer treatment: a systematic review of preoperative stereotactic body radiotherapy (SBRT) for breast cancer

Abstract

Breast conserving treatment typically involves surgical excision of tumor and adjuvant radiotherapy targeting the breast area or tumor bed. Accurately defining the tumor bed is challenging and lead to irradiation of greater volume of healthy tissues. Preoperative stereotactic body radiotherapy (SBRT) which target tumor may solves that issues. We conducted a systematic literature review to evaluates the early toxicity and cosmetic outcomes of this promising treatment approach. Secondary we reviewed pathological complete response (pCR) rates, late toxicity, patient selection criteria and radiotherapy protocols. We retrieved literature from PubMed, Scopus, Web of Science, Cochrane, ScienceDirect, and ClinicalTrials.gov. The study adhered to the PRISMA 2020 guidelines. Ten prospective clinical trials (7 phase II, 3 phase I), encompassing 188 patients (aged 18–75 years, cT1-T3 cN0-N3 cM0, primarily with ER/PgR-positive, HER2-negative status,), were analyzed. Median follow-up was 15 months (range 3–30). Treatment involved single-fraction SBRT (15-21Gy) in five studies and fractionated (19.5–31.5Gy in 3 fractions) in the rest. Time interval from SBRT to surgery was 9.5 weeks (range 1–28). Acute and late G2 toxicity occurred in 0–17% and 0–19% of patients, respectively, G3 toxicity was rarely observed. The cosmetic outcome was excellent in 85–100%, fair in 0–10% and poor in only 1 patient. pCR varied, showing higher rates (up to 42%) with longer intervals between SBRT and surgery and when combined with neoadjuvant systemic therapy (up to 90%). Preoperative SBRT significantly reduce overall treatment time, enabling to minimalize volumes. Early results indicate excellent cosmetic effects and low toxicity.

Graphical abstract

Background

The standard of care for breast cancer treatment is postoperative radiotherapy following breast-conserving surgery. However, accurately defining the tumor bed in this context is challenging and often leads to the irradiation of a greater volume of healthy tissues. Preoperative stereotactic body radiotherapy (SBRT) offers a promising alternative by enabling precise targeting of the tumor itself, as opposed to postoperative approaches that focus on the tumor bed. The precision of preoperative SBRT allows for a decreased target volume, reducing early treatment toxicity and enhancing pathologic complete response rates (pCR). Current data from cohort phase I and II trials provide valuable insights into early toxicity. Additionally, the paradigms of treatment sequences are evolving, with neoadjuvant treatments, such as systemic therapy, gaining prominence in the management of breast cancer. Therefore, determining the optimal timing for radiotherapy and understanding its impact on pCR and toxicity are key areas for future research. Given these advancements, SBRT may also become a standard neoadjuvant treatment option.

Introduction

In 2020, approximately 2.3 million cases of breast cancer were diagnosed in women worldwide and approximately 685,000 deaths were recorded. In Central and Eastern Europe, about 160 000 new cases were recorded. Out of 185 in 157 countries, breast cancer was the most frequently diagnosed cancer. It is estimated that by 2040 the number of diagnosed breast cancers will increase by more than 40%, i.e. by approximately 3 million cases per year [1]. A systematic review by Dafni et al. shows that Poland, together with Bulgaria, Slovakia and Romania, has been showing an increasing tendency in the incidence of breast cancer since 2010 compared to other countries in Central and Eastern Europe [2]. Prognosis and targeted treatment are tailored to the breast cancer biological subtype [3,4,5]. The treatment of early-stage breast cancer is based on an individual approach that depends on the molecular characteristics of the tumor, the stage, general condition and patient preferences, as recommended in the ESMO (European Society for Medical Oncology) and NCCN (National Comprehensive Cancer Network) guidelines [6, 7]. The classic treatment management for early breast cancer includes systemic therapy (if indicated), breast-conserving surgery, and then radiotherapy to the entire breast ± regional lymph nodes ± boost to the tumor bed, or partial breast irradiation (PBI) in selected low risk cases. Despite its effectiveness, this treatment concept can be associated with a certain degree of toxicity in individual cases, which could have a negative impact on quality of life in the perspective of long-term survival, which is why new solutions are being sought [8, 9]. Changing the classical sequence of up-front surgery in the treatment of breast cancer has been already applied in the setting of systemic therapy. Neoadjuvant chemotherapy is used in case of locally advanced disease to obtain higher rates of pCR which results in higher rates of breast preservation and nowadays is the mainstay of the treatment for many patients [10, 11]. A similar concept of neoadjuvant radiotherapy was introduced over the last 10 years, however it has not yet gained widespread acceptance. This approach could have several advantages: better tumor volume identification, possible tumor downstaging with improved rates of breast preservation rates, improved cosmesis, shortening of treatment time, reduction of complication rates in patients requiring breast reconstruction. A growing number of reports indicate that preoperative radiotherapy for early-stage breast cancer significantly improves disease-free survival (DFS), and more importantly, results in a lower risk of side effects and better cosmetic outcomes [12]. One of the most promising modalities of radiotherapy is stereotactic ablative radiotherapy (SABR), which involves the delivery of a very high dose of radiation to the tumor volume with high precision using one or several fractions administered usually in 1 to 10 days [13]. SABR is a method used preoperatively that could potentially also eliminate or be an alternative to the subsequent surgical intervention, in well selected patients. It is an important goal in terms of patients' quality of life, but also makes it possible to reduce the health care costs and the time required for hospitalization and convalescence after treatment [14].

Based on these data, we conducted a systematic literature review to evaluate the outcomes of this promising treatment approach. We assessed toxicity, cosmetic outcomes, pathological complete response (pCR) rates, patient selection criteria, and radiotherapy protocols.

Materials and methods

Search strategy

We conducted a systematic review according to the Population, Intervention, Control, Outcome, Study Design (PICOS) method which is shown in Table 1. We followed the PRISMA 2020 (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) statement.

Table 1 Study design according to the Population, Intervention, Control, Outcome, Study Design (PICOS) method

We searched five databases, namely PubMed, Scopus, Web of Science, Cochrane, ScienceDirect and ClinicalTrials.gov registry. An additional evaluation was conducted via citation searching from selected articles. Two blinded authors independently performed searches using the keywords: (breast cancer or breast neoplasm or breast tumor) and (stereotactic ablative body radiotherapy or stereotactic body radiation therapy or SBRT or SABR) and (neoadjuvant or preoperative or induction). In case of discrepancies, the third author verified the search. We identified potential studies and exported them to a reference management program (Mendeley Desktop) for inclusion based on title and abstract, and then the full article. The research involved an analysis of all studies published up to December 22, 2023.

Selection criteria

The inclusion criteria were as follows: (1) retrospective and prospective clinical trials with published results and (2) studies published in the English language.

Exclusion criteria were: (1) radiotherapy performed in postoperative setting only, (2) preoperative irradiation of the entire breast (3) non unifocal breast tumour (3) presence of distance metastases, (4) lack of access to the full text of the manuscript, (5) studies without results and unclear results (6) case reports, (7) review papers, (8) study protocols.

Data extraction

The extracted data consisted of the author, type of study, sample size, main endpoints, inclusion criteria, radiotherapy technique, contouring schema for gross tumor volume (GTV), clinical target volume (CTV) and planning target volume (PTV), dose and fractionation regimen, concomitant systemic treatment, doses to organs at risk (OARs), time from SBRT to surgery, rates of pCR, early and late toxicity, cosmesis analysis.

Results

During the initial database search found a total of 151 papers (49- Web of Science, 35—PubMed, 21- ScienceDirect, 16- Scopus, 14—Cochrane, 16- Clinicaltrials.gov). Before screening we have deleted 43 duplicates. In the next step, we excluded titles and abstracts that did not meet the inclusion and exclusion criteria (98 articles). We identified further 5 papers by searching for citations from the included articles. The full text of the qualified articles was analyzed and a selection was made, after which 5 papers were excluded. Finally, 10 primary studies were included in the systematic review process (two studies on same cohort). Figure 1 shows the PRISMA 2020 flowchart with screening results. The list and characteristics of the included studies and their outcomes is shown on the Table 2. All 10 included studies have a prospective design. Two studies were a phase I dose escalation studies, one phase I feasibility study. Seven reports were phase II studies. All of the included studies were single arm and non-randomized [15,16,17,18,19,20,21,22,23,24]. The number of included patients was 188 and ranged from 6 to 36 among studies. Median follow up time was 15 (3–30) months.

Fig. 1

Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 flow diagram for the literature selection process

Table 2 Characteristic of selected studies for systematic review

Qualification criteria

The main qualification criterion for study inclusion was tumor diameter determined by magnetic resonance imaging (MRI) in all but one study by Tiberi et al. where computed tomography (CT) only was used [15,16,17,18,19,20,21,22,23,24]. Four studies included patients with a tumor size of ≤ 20 mm [15,16,17, 19]. Vasmel et al. also used this criterion for patients ≥ 50 years but for patients ≥ 70 years tumors up to 30 mm were also included [21, 22]. In the ROCK trial patients with tumors up to 25 mm were treated [18]. Older patients who were at least 50 years old were eligible for preoperative radiotherapy [15,16,17,18,19, 21, 22]. Bondieu et al. qualified patients aged 18 years and older. Their cohort also included patients with cT2-3 tumors and node positive ( cN1) disease. A special feature of this study is that all patients of their cohort were not suitable for breast conserving surgery (BCS) [20]. Nine studies included low risk luminal A-like subtypes with ER or ER/PgR positive HER-2 negative and unifocal tumors [15,16,17,18,19,20,21,22, 24]. The inclusion criteria of the study of Horton et al. were absence of lymphovascular invasion (LVSI), ductal carcinoma in situ (DCIS) ≤ 2cm and low to intermediate grade tumors (G1-2) [19]. In contrast, Chen et al. included only triple negative breast cancer (TNBC) patients [23]. In this trial, inclusion criteria were patients aged 18–75 years with tumors ≥ 20 mm, mostly cT2 but also cT3, and cN0-N2 according to TNM [23]. In the Neocheck trial patients with cT2-3 cN0 and cT1b-3 cN1-3, with a tumor size of at least 15 mm were qualified [24]. Moreover, further inclusion criteria were a high-risk score in the MammaPrint genomic expression profiling test, high grade (G3) or a Ki67 of ≥ 15% [24]. In the SIGNAL trial an additional criterion for inclusion was a distance of ≥ 2 cm from the tumor to the skin and chest wall [15].

Target volumes definition and radiotherapy modalities

Gross tumor volume (GTV) was based on the planning CT with co-registered MRI [15, 17,18,19,20,21,22,23,24]. Tiberi et al. used only a planning CT only for GTV contouring [16]. The CTV was formed by adding an isotropic margin to the GTV which differed between the studies: 5 mm [15, 20], 10 mm [16], 15 mm [18,19,20,21, 22]. Liveringhouse et al. and De Caluwe et al. didn’t report the details regarding the magnitude of the CTV margins [17, 24], while Chen et al. didn’t include any information if any margins were added to the GTV [23]. The chest wall and pectoralis major muscle were excluded from the CTV in all studies, where CTV information was available. In the analysis of Meattini et al. and Bondiau et al. PTV were generated by adding 2–3 mm margin to the CTV [18, 20]. In their studies SBRT was performed on a Cyberknife system [18, 20]. PTV for conventional linear accelerators (LINACs) based SBRT was generated by adding 3 mm [19, 21, 22] or 5 mm [15] to the CTVs. Tiberi et al. used larger CTV-PTV margin which was 10 mm [16]. All studies used an intensity modulated radiation therapy (IMRT) or volumetric arc therapy (VMAT) techniques which were performed on Cyberknife [18, 20] or LINACs. [15,16,17, 19, 21,22,23,24].

Fractionation schemes

Two included phase I trials were dose escalation protocols [19, 20]. Horton et al. used a single fraction regimen and escalated the dose in three cohorts of patients. Fifteen Gy in 8 patients, 18 Gy in 8 patients and 21 Gy in 16 patients were prescribed [19]. Bondiau et al. used 3 fractions, in every other day regime, and escalated the dose in 5 cohorts consisting of 3 patients each. 19.5 Gy, 22.5 Gy, 25.5 Gy, 28.5 Gy and 31.5 Gy were used [20]. Guidolin et al. and Tiberi et al. prescribed 20 Gy in single fraction [15, 16]. In the ROCK trial 21 Gy in one fraction was administered [18]. Vasmel et al. used two dose levels with a simultaneous integrated boost technique (SIB) consisting of 20 Gy to the GTV and 15 Gy to the CTV [21, 22]. Liveringhouse et al. used a fractionated regimen and administered 28.5 Gy in 3 daily fractions [17]. When et al. used 24 Gy in 3 fractions administered every other day [23]. In the NeoCheck trial also 24 Gy in 3 fractions were used but patients were irradiated every day [24].

Dose constraints to organs at risk (OARs)

Dose constrains for individual OARs varied between publications. Table 3 summarizes them along with the dose fractionation schemes that were used. In the studies by Guanglei Chen et Al. and De Caluwe et al. [23, 24] guidelines for dose constrains were not included.

Table 3 Dose constraints to organs at risk (OARs) used in included studies

Timing of surgery after SBRT

The time interval from SBRT to surgery was different in all of the included studies. The median time from SBRT to surgery was 9.5 weeks and it ranged from 1 to 28 weeks [15,16,17,18,19,20,21,22,23,24]. In 3 studies the timing between SBRT and surgery was very short, with only 1–2 weeks [15, 18, 19]. Two analyses used longer intervals of 6–13 weeks [16, 17]. However, over half of the included studies waited 16–28 weeks until surgery [20,21,22,23,24].

Concurrent systemic therapy

In three trials SBRT were tested with concomitant systemic therapy [20, 23, 24]. As already mentioned in the inclusion criteria all of this studies included patients with higher risk or more advanced disease compared to other trials. In the study of Bondiau et al. neoadjuvant chemotherapy included 3 cycles of docetaxel and 3 cycles FEC (5-fluorouracil, epirubicin, cyclophosphamide) with SBRT given during the second chemotherapy cycle but not on the same day as chemotherapy [20]. The systemic therapy regimen in the Chen trial consisted of 8 cycles of selective PD-L1 inhibitor – adebrelimab and 6 cycles of nab-paclitaxel and carboplatin, where SBRT was performed during the second cycle of immunotherapy [23]. The regimen used in the De Caluwe trial consisted of 19 weeks used paclitaxel, cyclophosphamide-doxorubicin, anti-PD-L1 antibody durvalumab and anti-CD73 antibody oleclumab with SBRT given in week 4–5. In the Vasmel trial 6 (17%) patients initiated neoadjuvant endocrine treatment after SBRT according to national guidelines [21].

Acute and late toxicity profile related to SBRT

One of the important objectives of preoperative early breast cancer SBRT trials was to assess cosmetic effects and mostly acute toxicity due to the usually short follow- up time. In the study by Vasmel et al. late G2 toxicity, asseses 12 months from SBRT involved breast pain (n = 2), chest pain (n = 1) and wound infection (n = 5) and one G3 wound infection [21]. Bondiau et al. reported no late treatment-related toxicities after 30 months. [20] Similarly no late toxicities were reported in Chen and De Caluve papers [23, 24]. In the study by Horton et al. late breast fibrosis was reported in 71% (mostly G1 in 56%) and atrophy in 20% of patients but no dose correlation analysis was performed. Early toxicity was mild including breast pain, dermatitis and breast edema [19]. In the study by Tiberi et al. six patients (60%) had G1 dermatitis in the irradiated area. No other significant post-radiotherapy complications were reported [16]. In the Liveringhouse trial, 3 patients who did not receive postoperative whole-breast RT (n = 16) experienced G2 toxicity (19%-skin induration, breast pain, atrophy) and one case of G3 toxicity of wound complication which required a re-excision lumpectomy. In 4 patients who received additional postoperative whole-breast RT, the following G2 toxicity was detected: skin induration in 2 patients (50%), seroma in one (25%), atrophy in one patient (25%), G3 toxicity in 2 patients: abscess (n = 1), and breast pain (n = 1). In 7 included studies with late toxicity reports G3 were reported in 2 patients who did not receive postoperative whole breast radiotherapy(WBRT). Details of early and late toxicity are shown in Table 2.

Cosmetic effect assessment

The cosmetic outcome after preoperative SBRT was reported in 6 selected studies. In the trial of Guidolin et al. cosmetic assessment was performed by patients and physicians using the Harvard-Harris cosmetic scale [15]. There was no significant change in cosmetic compared to the baseline at 3 weeks and 6 months from surgery [15]. Meattini et al. used the BCCT.core software for cosmetic effect analysis and reported that 21 of 22 (95,4%) patient had “good” to “excellent” results, 1 patient (4.6%) reported a “fair” result after preoperative SBRT [18]. Horton et al. used the NSABP B-39/RTOG 0413 cosmetic evaluation scale. After 12 months 28 (100%) patients reported “good” or “excellent” cosmetic effects after SABR [19]. In the trial of Vasmel et al. 94% of the patients were very satisfied, satisfied, or not unsatisfied after preoperative stereotactic radiotherapy [21].

In Liveringhouse et al. cosmesis was rated “good” in 17 (85%), “fair” in 2 (10%), and “poor” in 1 (5%) patient, but in patients receiving additional postoperative RT (n = 4), cosmesis was “good” in 3 and “poor” in 1 patient [17]. Of all patients (n = 6) reported in the De Caluve trial 4 had “excellent” and 2 had a “good” cosmetic outcome, but out of 4 patients who received BCS, 3 were assessed as “excellent” and 1as “good”. [24] Bondiau et al. reported that overall 94% of patients were very satisfied and satisfied with the cosmetic outcome [20].

Pathological response

In 8 studies pCR was analyzed [16,17,18, 20,21,22,23,24] In two [15, 19] no pathological response was assessed. In four of the single fraction SBRT studies pCR were ranged between 0%, 9%,and 42% [16, 18, 20, 21]. The studies by Vasmel et al. showed highest pCR rates among those included: 15 (42%) in total, 5 of 15 (33%) after first 6 months, 10 of 21 (48%) after 8 months and 12 (33%) near pCR (< 10% residual tumor cells), in 7 patients (19%) partial response (10%-50% residual tumor cells) and in 2 (6%) stable disease (> 50% residual tumor cells with features of response to treatment) have been reported. There were no patients without evidence of response. Neoadjuvant endocrine therapy was administered in 6 patients of whom pCR was reached in 2 patients, near pCR in 3 patients and a partial response(PR) in one patient [21, 22]. In this study the time interval from SBRT to surgery was also the longest, 6 months in 15 patients and 8 months in 21 patients [21]. Bondiau et al. reported 36% pCR in the whole cohort. It was very heterogenic, with 67% at a dose level of 25,5 Gy, 43% at 28,5 Gy, 33% at 31,5 Gy with no pCR cases in the 19,5 Gy and 22,5 Gy dose levels groups [20]. Residual cancer burden (RCB) according to Symmans et al. was measured in the De Caluve trial were 2 of 6 patients (33.3%) had a complete pathological response (RCB 0), two (33.3%) had a near pCR (RCB1) one (16.7%) a moderate residual disease (RCB 2) and one (16.7%) an extensive residual disease (RCB 3) [24]. The same measure was used in the Chen et al. trial showing pCR (RCB 0) in 9 patients (90%) and near pCR (RCB 1) in one patient (10%) [23]. Liveringhouse et al., reported no case of pCR and the median RCB was 30% with 2 patients with a 80% residual cancer burden whereas all other patients had ≤ 50% residual cellularity after stereotactic fractionated radiotherapy, 3- fraction scheme, and after median of 49 days from SBRT to breast conserving surgery (BCT) [21].

Discussion

The use of radiotherapy as a main neoadjuvant treatment or in combination with chemotherapy in a preoperative setting represents a newly intensively researched approach in early-stage breast cancer treatment [12, 25, 26]. The results of studies using moderate hypofractionation, as a preoperative treatment, showed good cosmetic effect and local control (LC), which encouraged researchers to look for shorter and more intensive treatment regimens [27, 28].

To the best of our knowledge, the above systematic review represents the most up-to-date compilation of studies evaluating the feasibility of preoperative PBI with the use of SBRT limited to 5 fractional doses [14, 29,30,31]. For the above review 10 studies were included (in 7 studies SBRT was used as the only neoadjuvant treatment modality, in 3 of them SBRT was used with concomitant systemic therapy [20, 23, 24]. In two studies published recently, SBRT was performed preoperatively with immune-chemotherapy [23, 24]. The main advantages and disadvantages of preoperative radiotherapy in breast cancer were summarized in Table 4.

Table 4 Advantages and disadvantages of preoperative PBI. [32]

SBRT is a method of external beam radiotherapy that allows highly precise delivery of a high dose of radiation to a limited target area with a large dose drop around the target. The biological efficacy of SBRT is not only based on the mechanism of DNA damage at the molecular level, but also on additional effects at the tissue and cellular level (damaging the vasculature and cell membranes), as well as on the abscopal effect of enhancing the anti-tumor immune response due to the action of high doses of radiotherapy on the cancerous tumor, which produces a therapeutic effect beyond the irradiated field [33,34,35].

Preoperative radiotherapy has become the standard treatment for rectal cancer and sarcoma. In the case of breast cancer, it is currently the subject of clinical trials. Beyond the improved target visualization and reduced risk of tumor cell dissemination during surgery, preoperative radiotherapy offers multiple radiobiological advantages. This include better oxygenation of non-operating tissues and immune-priming as outlined by Brackstone et al. [36] Additionally preoperative radiotherapy may significantly enhance immune responses against tumors. It can transform tumor into personalized in situ vaccine, teaching the immune system to recognize and combat cancer, what cannot be observed after irradiation of tumor bed [37, 38]. This may be important in eradicating subclinical diseases and distant micrometastases, potentially leading to long-lasting immune memory against future tumors [37,38,39]. In this context, it's noteworthy that two studies in this review specifically explored the combination of SBRT and immunotherapy [23, 23].

Target volume definition

Stereotactic radiotherapy employed in radical breast cancer treatment can be utilized postoperatively as a boost after WBRT or PBI [40, 41]. Due to its targeted approach, it requires meticulous target definition during treatment planning and consistent positioning accuracy to minimize geographic error risk. In post-operative setting, surgical clips are required to accurately identify the tumor bed. For the increasingly popular oncoplastic procedures, the location of the tumor bed poses a major challenge for the radiation oncologists and need collaborative target determination with surgeon.

Despite guidelines for contouring the tumor bed in PBI, challenges in delineation remain. The main issues include: [42, 43].

• Extent and location: often, the contoured area is disproportionately large compared to the original tumor or located differently than indicated by pre-surgery examination and imaging studies [44].

• Scattered clips (in 43 -73% of patients undergoing surgery, clips on postoperative CT imaging were visualized outside the original quadrant of the tumor) [45, 46].

Preoperative tumor delineation on CT scans leads to less inter-observer variability compared to postoperative delineation of tumor bed [47]. The target volume, the tumor, can be demarcated by implanting fiducial markers around it during the biopsy. The potential for fusion of imaging studies, such as magnetic resonance imaging (MRI) with planning computed tomography (CT) scans, is instrumental in accurately determining the tumor's exact extent. Compared to CT scans MRI better visualize irregularities and spikes in the tumor [48]. Vasmel et al. published consensus on contouring primary breast tumors on MRI in the setting of neoadjuvant PBI in trials [49]. In all but one study MRI was co-registered with CT scans for planning radiotherapy [16]. The GTV in Tiberi et al. study was defined as the primary tumor based on physical exam, CT scans, and breast ultrasonography [16].

The technical aspects of neoadjuvant PBI have been elegantly highlighted by Zerella et al. in recently published narrative review [50].

Preoperative PBI implementation techniques

The implementation of radiotherapy can be performed in prone or supine position using various immobilization systems. Diagnostic contrast-enhanced MRI is typically performed in prone position, which makes it easier to perform image fusion when realizing radiotherapy in an analogous position. When treating patients in the supine position, the solution may be to perform deformable fusion with diagnostic MRI images or to perform another MRI scan in the supine position like in the ongoing CRYSTAL study [51]. Widespread clinical introduction of the MR-LINAC (a linear accelerator (LINAC) with integrated MR scanner can be particularly helpful in the delivery of radiotherapy for breast cancer [52].

Comparison between PBI and WBRT

Comparison of postoperative WBRT and PBI show no differences in overall survival (OS) with favorable toxicity profile for the PBI technique in well selected low risk early breast cancer patients [53, 54]. In extended follow-up periods (up to 15 years), PBI may result in a marginally higher rate of local recurrence(LR) compared to WBRT [55]. However, advancements in systemic treatments, the integration of adjuvant therapies, and enhancements in local treatments have reduced local recurrence rates in breast cancer by half [56]. Consequently, there are emerging considerations for omitting postoperative radiotherapy in certain cases [7]. Within this context, PBI could emerge as an optimal balance. It is noteworthy that none of the analyzed studies reported tumor progression which is opposite to postoperative PBI where mature data are available.

Toxicity profile

By limiting the irradiated volume, dose to OARs can be significantly reduced, which is particularly important for the heart, the left anterior descending coronary artery (LAD), lung or contralateral breast, as it reduces the risk of secondary malignances and the incidence of cardiac and lung complications [57, 58]. The volume of the irradiated area for preoperative PBI is smaller than postoperatively which may translate into reduced toxicity in the long term follow-up.

The early toxicity profile of preoperative SBRT in breast cancer seems to be favorable. Among studies selected for the review, in terms of G3 acute toxicity events, only one erythema (14%) from 28.5 Gy cohort in Bondiau study was reported [20]. The late G3 toxicity was reported in one patient (2.8%) in Vasmel et al. trial and in one (6.3%) in Liveringhouse trial [17, 21].

PBI performed postoperatively is associated with better cosmetic outcome and fewer late radiation toxicities than WBRT. However, no direct comparative studies exist on the toxicity of stereotactic PBI when applied either preoperatively or postoperatively. Notably, the levels of both early and late toxicities are reportedly low [59, 60].

Comprehensive data on the late toxicity of preoperative SBRT used as PBI is still limited, necessitating a longer period of observation.In the above analysis, the longest follow up-25.5 months was reported by De Caluwe et al. During this time no late effect was reported [24].

It is also important to mention that addition of SBRT to immunochemotherapy does not increase the percentage of grade 3 or higher adverse effects (AEs) observed after immunochemotherapy [23, 24].

The optimal SBRT dose guidelines in preoperative setting

There is no established fractionation scheme for preoperative SBRT. In the above study, 1 and 3 fractional regimens were analyzed. The highest total dose of 21 Gy was given in one fraction in the SIGNAL study. In the 3 fractional regimens, the highest total dose was 31.5 Gy. In the currently ongoing dose escalation study the highest prescribed dose is 38 Gy/1fr [61].

The optimal time gap from radiotherapy to surgery

Notable in the above systematic review is the lack of a standardized radiotherapy dose and time interval between the end of radiotherapy and the performance of surgery. In the studies reviewed, the time varies from 1 week to 8 months. In ongoing ABLATIVE-2 study, the time between radiation therapy and surgery it is 12 months [62]. This is the longest time interval used in the analyzed completed and ongoing studies of preoperative radiotherapy in breast cancer [9].

The pCR rate following preoperative SBRT seems to be positively correlated with the duration between radiotherapy and surgery in a cohort of early-stage breast cancer patients possessing favorable prognostic factors. Vasmel JE et al. [21, 22] reported 33% pCR after 6 months, and 48% pCR after 8 months from radiotherapy to BCS among early stage breast cancer patients with favorable risk factors. The above observation prompts us to look for a group of patients in whom surgery can be abandoned as in rectal cancer [63].

Bondiau et al. [20] analyzed cases of patients ineligible for BCS who received preoperative radiotherapy in combination with chemotherapy achieving a pCR of 36% after 21–24 weeks. Guanglei Chen et al. [23] in a group of patients with TNBC breast cancer using radiotherapy in combination with chemo-immunotherapy (ICI: adebrelimab) achieved higher pCR rates: 90% after 21–23 weeks. In analogous group of patients (TNBC breast cancer patient who are candidates to neoadjuvant chemotherapy and received immunochemotherapy without preoperative radiotherapy) KEYNOTE522 study pCR: 58–64,8% were achieved [64]. It is speculated that preoperative SBRT exerts synergy with immunochemotherapy.

Similarly, high percentage of pCR were achieved in the PEARL study pCR at 74% in TNBC after SBRT: 24Gy/3fr and: with anti-PD(L)1—pembrolizumab in addition to neoadjuvant chemotherapy (NAC) [65].

Pathologic CR was achieved in less than 10% of cases in studies where the time gap from the end of radiotherapy to surgery was less than 13 weeks [16,17,18,19].

Markers of response to preoperative SBRT

In addition to determining the optimal time gap from radiotherapy to surgery translating into the highest pCR rates, research is underway to identify markers indicative of response to preoperative treatment. Bosma et al. analyzed gene expression patterns among 77 patients who received preoperative radiotherapy (10 × 4 Gy in 10 days or 5 × 6 Gy in 5 days) and a lumpectomy 6 weeks thereafter and observed no or very limited response in 22 patients. Clinically significant differences in gene expression between patients with and without response to radiotherapy were not identified. However, the authors found, by comparing samples before and after radiotherapy, that genes involved in p53 signaling, TNFA1 signaling, apoptosis, epithelial mesenchymal transition, and inflammatory response were upregulated, and genes involved in mitotic spindle, G2M checkpoint, and E2F targets were downregulated [66]. High Ki-67 before NAC was a predictor for pCR in breast cancer patients. Ongoing trials may explore whether this approach will be effective in preoperative radio-chemotherapy [67]. In ABLATIVE trial Vasmel et al. revealed that after preoperative PBI the number of Tumor -Infiltrating Lymphocytes (TILs) in tumor tissue decreased, but no differences in numbers of pre irradiation TILs between responders and non-responders were observed [68]. Radiological, biomolecular or genomic biomarkers are searched to identify the group of good responders to radiotherapy for whom surgery could be omitted. In ongoing trials, the Ki67 levels, gene expression and circulating target free DNA are being analyzed as potential predictors of local control response. At the same time, there are reports of the possibility of omitting adjuvant radiotherapy in a group of patients over 65 with early-stage breast cancer with favorable prognostic factors [69]. The trend in de-escalation of breast cancer treatment translating into a reduction in toxicity has been strong in recent years. Perhaps in the future, patients with favorable prognostic factors will be able to choose to use SBRT or BCS as their sole treatment modality.

New technologies

New image-guided radiotherapy (IGRT) technologies are emerging including intra-fractional tracking of tracers placed in the tumor/tumor bed using Cyberknife (Accuray, Palo Alto CA), magnetic resonance-based linear accelerators (MR LINACS), or the Gamma-pod equivalent of Gammaknife for breast cancer treatment which are being used in more trials of preoperative stereotactic radiotherapy [52, 70,71,72].

Currently ongoing trials

The Table 5 summarizes currently ongoing trials using preoperative stereotactic radiotherapy in the treatment of breast cancer.

Table 5 Ongoing trials on preoperative PBI with SBRT

Conclusion

Preoperative SBRT is a promising treatment option for breast cancer patients. The precise localization of the irradiated area (targeting the tumor rather than the tumor bed) is a notable feature. Early treatment toxicity is reported to be relatively low. However, the existing data are derived from phase I and II trials focusing on small patient cohorts with limited follow-up, leading to a gap in information regarding late complications or long-term efficacy. Currently, MRI appears to be the optimal imaging modality for planning preoperative SBRT. While various fractionation schemes of SBRT are being explored, there is a lack of comparative studies among them. The key issue seems to be to determine the optimal time interval between the applied radiotherapy and surgery. Given the observed increase in percentage of clinical and pathological CR with the time between radiotherapy and surgery, it seems possible, in future, to select patients who obligatorily require surgical treatment and those in whom surgical treatment can be safely omitted.