Special issue. De-escalation of loco-regional treatment in breast cancer: Time to find the balance? Partial breast irradiation

Abstract

Breast cancer is the most common cancer in women worldwide. Over the past few decades, remarkable progress has been made in understanding the biology and pathology of breast cancer. A personalized conservative approach has been currently adopted addressing the patient's individual risk of relapse. After postoperative whole breast irradiation for early-stage breast cancer, a rate of recurrences outside the initial tumour bed lower than 4% was observed. Thus, the highest benefits of breast irradiation seem to result from the dose delivered to the tissue neighbouring the tumour bed. Nonetheless, reducing treatment morbidity while maintaining radiation therapy's ability to decrease local recurrences is an important challenge in treating patients with radiation therapy. In this regard, strategies such as partial-breast irradiation have been developed to reduce toxicity without compromising oncologic outcomes. According to the national and international published guidelines, clinical oncologists can refer to specific dose/fractionation schedules and eligible criteria. However, there are still some areas of open questions. Breast cancer represents a multidisciplinary paradigm; it should be considered a heterogeneous disease where a “one-treatment-fits-all” approach cannot be considered an appropriate option. This is a wide overview on the main partial breast irradiation advantages, risks, timings, techniques, and available recommendations. We aim to provide practical findings to support clinical decision-making, exploring future perspectives, towards a balance for optimisation of breast cancer.

Highlights

• •A personalized conservative approach address patient's individual risk of relapse.
• •A “one-treatment-fits-all” approach is not appropriate for breast cancer.
• •Partial breast irradiation as balance for breast cancer treatment optimisation.
• •Suitable criteria for partial breast irradiation should be followed for patient selection.

1. Introduction

Breast cancer is the most common cancer in women worldwide, with a lifetime incidence of approximately 13% [1]. A remarkable progress in understanding the biology and pathology of breast cancer has been done over the past few decades, resulting in a dramatic shift in the initial management of the disease, from a one size-fits-all approach with a Halsted mastectomy to a personalized conservative approach addressing the patient's individual risk of recurrence. The change in the treatment paradigm started with the publication of landmark trials [[2], [3], [4], [5], [6]] that showed equivalent overall survival for patients undergoing breast-conserving surgery (BCS) followed by whole breast irradiation (WBI) when compared to modified radical mastectomy alone. Several randomised trials demonstrated that the addition of WBI to BCS decreased the risk of ipsilateral breast tumour recurrence (IBTR) by 50% or more, even for patients considered to be at a low risk of tumour recurrence, reinforcing breast-conserving surgery combined with WBI as the standard treatment for breast cancer [[7], [8], [9]].

For early-stage breast cancer, it has been repeatedly observed that most local recurrences in the conserved breast occur in the original tumour bed [5,10,11], although more than two-thirds of mastectomies undertaken harbour occult cancer foci located throughout the breast [[12], [13], [14]]. Cancer recurrences outside the initial tumour bed occurred at a rate lower than 4%, with equal incidence whether postoperative WBI is used following BCS or not, likely representing a new primary tumour [15]. Thus, the highest benefits of WBI seems to result from the dose delivered in the tissue neighbouring the tumour bed [16,17].

Nonetheless, reducing treatment morbidity while maintaining radiation therapy's (RT) ability to decrease local recurrences is an important challenge in treating patients with WBI. Patients who undergo WBI are subjected to some radiation to the heart and lungs which may have a detrimental effect on their long-term health, with higher risks being associated with larger volumes of irradiated organs at risk [18,19]. As a result, techniques such as breathing-adapted image-guided RT and partial-breast irradiation (PBI) have been developed to reduce toxicity without compromising the oncologic outcomes [20]. While PBI represents an efficient irradiation technique allowing sparing organs-at-risk from radiation injury, accelerated PBI is also proposed to improve adjuvant breast irradiation observance by decreasing the number of transportations, with potential financial issues for the patient and health care payers as well as patient workflow in the RT departments.

This critical review contextualises PBI, overviewing different techniques and findings that led PBI to be recommended in certain breast cancer populations, examining its risks and advantages. It will also present some practical tips, based on cases, to help better plan RT treatments using PBI.

2. Existing data on PBI

PBI is defined as the irradiation of a limited volume of tissue around the tumour bed, in contrast to the more classical radiation of the whole breast, with the goal of reducing the dose to the normal breast tissue and adjacent organs at risk such as skin, lungs, heart, ribs, brachial plexus, oesophagus, to theoretically reduce the risk of acute and chronic toxicities [21]. Radiating only part of the breast allows to increase the dose per fraction and decrease the number of fractions required to achieve a similar biologic effect. Treatment is thus both hypofractionated and accelerated and is referred to as accelerated PBI, or APBI.

PBI can be delivered through different techniques that include both external beam RT (EBRT) and brachytherapy. Several factors need to be taken into consideration when choosing the most appropriate technique, including specific limitations inherent to each method, patient anatomic factors, physician expertise and patient preference. Ideally, each radiation oncologist should have multiple options at their disposal to optimally tailor treatment to the individual patient. The timing of delivery can be preoperative, intraoperative, or postoperative. Intraoperative RT (IORT) can be delivered either with EBRT, using electrons in the operating room during BCS, or with brachytherapy, in the form of low-energy x-rays (Intrabeam®), allowing to shield critical structures and to minimize the probability of a marginal miss. In the case of low energy x-ray IORT, radiation can be safely delivered in a standard operating room, while electron IORT often requires a shielded operating room with a linear accelerator (linac) setup. Linac-based electron IORT has been investigated in phase II and phase III trials [[22], [23], [24]]. Postoperative PBI is generally delivered using three-dimensional conformal RT (3DCRT), intensity-modulated RT (IMRT), and interstitial and intracavitary (balloon-based devices) brachytherapy.

Among all techniques, interstitial brachytherapy has the most mature results with follow-up intervals exceeding 10 years in some randomised controlled trials [25]. Technically, it consists in the implantation of catheters in the tissue surrounding the tumour bed under direct visualization at the time of or shortly after BCS. High- or low-dose-rate brachytherapy is then delivered by afterloading of radioactive sources, with catheter removal at the end of treatment.

Intracavitary brachytherapy is most often delivered using either Intrabeam®, single- or mutli-channel MammoSite® applicators and other strut-adjusted brachytherapy applicators (e.g., SAVI®, ClearPath®). Among all brachytherapy techniques, the multi-catheter interstitial brachytherapy still represents the method supported by the highest level of evidence. However, MammoSite® brachytherapy is widely adopted and consists of a single-lumen breast brachytherapy balloon catheter inserted in the tumour bed during the BCS, with radiation delivered post-operatively. The strut-based volume implant, SAVI® combines the advantages of both MammoSite® and multi-catheter using multiple peripheral struts with central-loading single catheter. Due to the simplicity of use as compared to interstitial brachytherapy, MammoSite® is one of most common forms of brachytherapy-based accelerated PBI techniques used in North America [26], with over 50,000 patients treated so far [27]. Very little phase III data supports its clinical use, although it was used in some patients in the NSABP B-39/RTOG 0413 phase III tr ial [28].

To democratize APBI, both in terms of cost and use of existing resources, investigators developed non-invasive and non-operative techniques relying on the delivery of EBRT with 3DCRT or IMRT using LINACs (Fig. 1, Fig. 2). Postoperative 3DCRT and IMRT to the tumour bed have now been tested in at several randomised controlled trials [[29], [30], [31]]. Preoperative RT has also been tested, but mainly in small phase I and phase II trials using RT to the primary tumour prior to surgery [[31], [32], [33]].

Fig. 1.

Beam configuration (A) and dosimetry (B) for a APBI case treated with multiple non-coplanar fields, with a prescribed dose of 38.5Gy in 10 fractions. Evaluation Planning Target Volume (PTV) is in red in Fig. 1B. (For interpretation of the references to colour in this figure legend, the reader is referred to the Web version of this article.)

Fig. 2.

Partial arc VMAT dose distribution for a APBI case treated with a prescribed dose of 30Gy in 5 consecutive fractions (obtained with an automated planning technique). Image courtesy of Livia Marrazzo (Medical Physics Unit, Radiation Oncology Department, Florence University Hospital, Florence, Italy).

Finally, a more recent and less common procedure is the implantation of permanent radioactive seeds, which consists in the insertion of radioactive iodine or palladium seeds around the tumour bed under ultrasound guidance and local anaesthesia. Such a technique is well-established for prostate cancer treatment and is now being tested for PBI in breast cancer [34].

2.1. Dose – fractionation schedule

Different dose and fractionation schedules have been investigated for PBI (Table 1) with the aim of finding an equivalent dose to 50Gy in 25 fractions based on the linear quadratic model [25,30,31,[35], [36], [37], [38]].

Table 1.

Dose and fractionation for brachytherapy or external beam PBI.

RT approach	Total fractionated dose	Dose per fraction	N fractions
Brachytherapy [25,31,35]	30Gy	4.3Gy	7, BID
	32Gy	4Gy	8, BID
	34Gy	3.4Gy	10, BID
External beam radiation therapy [30,31,[36], [37], [38]]	27.5–30Gy	6Gy	5, daily or every other day
	38.5Gy	3.85Gy	10, BID
	40Gy	2.67Gy	15, daily

Abbreviations: Gy, Gray; BID, bis in day.

The heterogeneity of PBI regimens is due to dosimetry and to specific radiation techniques used such as brachytherapy and external beam RT. Total fractionated dose and number of fractions with brachytherapy ranged from 30 to 34Gy in 7–10 twice daily fractions, respectively [25,31,35]. With regards to external beam PBI, the main RT schedules are based on a total fractionated dose of 30Gy and 40Gy in 5 and 15 fractions daily, respectively. A study design comparing 27.5Gy and 30Gy cosmetic outcomes is ongoing and published 3-year encouraging data toward lowering the total dose [38]. In 2020, the breast consensus working group of the UK Royal College of Radiologists stated that offering 26Gy in five fractions for PBI was very strongly supported [39]. Caution is still recommended with twice daily external beam PBI [30,31,36,37,40,41], due to toxic effects and cosmetic outcome concerns. Moreover, focus on shorter PBI schedules research is ongoing. A phase I/II trial tested 28Gy in 4 fractions twice daily with brachytherapy confirming high local control and a low rate of late toxicity [42]. Similarly, the TRIUMPH-T trial evaluated a brachytherapy-based regimen of 3-fraction accelerated PBI with a total dose of 22.5Gy. Preliminary results reported a low rate of acute and late toxicity, and overall good-excellent cosmetic outcome [43]. Moreover, very accelerated partial breast irradiation (VAPBI) with multi-catheter interstitial brachytherapy was tested by a phase I-II trial endorsed by the GEC-ESTRO Breast Working Group. Indeed four- or three-fraction VAPBI in 2–3 days is a feasible treatment and reports acceptable toxicity profile, improving patients’ compliance and reducing the workload of the brachytherapy units [44]. Similarly, the single-fraction VAPBI showed excellent oncologic results for elderly with early breast cancer. Mature results of single fraction elderly breast irradiation (SiFEBI) phase I/II trial confirmed 5-year locoregional-free survival and OS rates of 100% and 88.5%, respectively. Late toxicity (breast pain, hypopigmentation, and breast fibrosis) was reported in 5 out of 26 patients [45].

2.2. Advantages of PBI

Over the past decades, many authors have investigated the potential advantages of PBI as compared to WBI. First, the equivalence in local control was highlighted by large, randomised, trials. Indeed, Polgár et al. reported no difference in ipsilateral breast tumour recurrence (IBTR) between WBI and PBI (5.1 vs. 5.9%, p = 0.77) for the brachytherapy-based approach [25], confirming these results after a median follow up of 17 years [46]. Indeed, the updated results of Budapest trial reported a 20-year actuarial IBTR rates of 9.6% vs. 7.9% in the PBI and WBI groups, respectively [46]. Additionally, the Groupe Européen de Curiethérapie of the European Society for Radiotherapy and Oncology (GEC-ESTRO) trial evaluated interstitial multi-catheter brachytherapy PBI in comparison with WBI in 1184 patients confirming that IBTR was non-inferior at 5-year (0.9% vs. 1.4%, p = 0.42, WBI vs. PBI) [35] and 10-year (1.58% in the WBI group and 3·51% in the PBI group; p = 0.074) [47]. Overall survival (OS) was also comparable between WBI and PBI as reported in the Polgár et al. (20-year OS, 59.7% vs. 59.5%) [46] and GEC-ESTRO (10-year OS, 89.52% vs. 90.47%, p = 0.50; WBI vs. PBI respectively) analyses [47].

In line with brachytherapy-based data, external beam PBI showed excellent results. A small analysis of 102 patients treated with WBI and PBI confirmed no difference in IBTR at 5 years [41]. The Florence trial investigated 520 patients who received WBI and external beam accelerated PBI using an intensity modulated radiation therapy (IMRT) technique in five fractions. At 5 years, IBTR (1.5% vs. 1.5%, p = 0.86) and OS (96.6% vs. 99.4%, p = 0.057) were equivalent [29]. Results were confirmed at 10 years, and the cumulative incidence of IBTR was 2.5% versus 3.7% in the WBI and PBI arm, respectively (p = 0.40); in addition, no difference in OS was observed [36]. Similarly, the IMPORT-LOW [37] and RAPID [48] trials evaluated more than 2000 patients resulting in no difference in terms of IBTR and OS between WBI and external beam PBI. The NSABP-B39/RTOG 9413 trial was one of the largest PBI studies [31]. The investigators enrolled 4216 patients who were randomised to receive WBI or PBI using different techniques: external beam 3D conformal radiation, interstitial multi-catheter brachytherapy, or intracavitary brachytherapy. Although the trial did not find statistical equivalence as per study design, no meaningful clinical difference was reported in terms of IBTR at 10 years. Overall survival was also not different between WBI and PBI arms. Conversely, IORT approaches were evaluated in large sample sizes of patients in the ELIOT [24] and TARGIT trials reporting worse results in terms of local control. Indeed, Veronesi et al. found an IBTR of 4.4% versus 0.4% and Vaidya et al. showed a 5-year risk for local recurrence of 3.3% versus 1.3% (IORT vs. WBI, respectively), results that were quite controversial [49].

In addition to the equivalence in terms of local control and OS, PBI has the advantage of a safety profile with an overall good-excellent cosmetic outcomes. Late skin toxicity was improved with PBI in the Hungarian trial [25]. The GEC-ESTRO study [50] and RAPID trial [30] reported a lower rate of acute treatment-related adverse events in the PBI arm. Conversely, Olivotto et al. [48] reported a higher grade 2 late toxicity in the PBI arm suggesting that the twice daily fractionation used in the experimental arm may have caused this increased rate of late adverse events. Long-term results of RAPID trial [30] confirmed that patients treated with PBI reported higher late toxicity and worse cosmetic outcome. The Florence and IMPORT LOW trials found an improved acute and late toxicity profile with PBI. Particularly, the long-term results of accelerated PBI IMRT Florence trial [36] confirmed a significantly less acute toxicity (p = 0.0001), late toxicity (p = 0.0001), and improved cosmetic outcome as evaluated by both physician (p = 0.0001) and patient (p = 0.0001). Moreover, Polgár and colleagues collected significantly better cosmetic results (good to excellent) in patients treated with PBI (79.2% vs. 59.5%) [46]. Table 2 summarises the efficacy and safety profile of PBI across prospective trials [24,25,30,31,[35], [36], [37],41,49].

Table 2.

Efficacy and safety profile of PBI.

Trials	Follow up time (years)	Local control (WBI vs. PBI)	Toxicity	Cosmesis
Hungary NIO Polgár et al. [25]	17	IBTR: 7.9% vs. 9.6%, p = 0.59	No difference in moderate to severe late skin toxicities	Improved cosmetic outcome with PBI arm
GEC-ESTRO Strnad et al. [35]	10.36	IBTR: 1.58% vs. 3.51%, p = 0.074	Late skin toxicity reduction with PBI	No difference
BARCELONA Rodríguez et al. [41]	5	IBTR: 0% vs. 0%, p = NR	Acute skin toxicity reduction with PBI; no difference in late toxicity	No difference
FLORENCE Meattini et al. [36]	10.7	IBTR: 2.5% vs. 3.7%, HR 1.56	Acute and late toxicity reduction with PBI	Improved cosmetic outcome with PBI
UK IMPORT LOW Coles et al. [37]	6	IBTR 1.1% vs. 0.5%, p = 0.016	Acute and late toxicity reduction with PBI	No difference
RAPID Whelan et al. [30]	8	IBTR: 2.8% vs. 3.0%, HR 1.27	Acute toxicity reduction with PBI; late toxicity reduction with WBI	Improved cosmetic outcome with WBI
NSABP- B39/RTOG 0413 Vicini et al. [31]	10.2	IBTR: 3.9% vs. 4.6%, HR 1.22	No difference	No difference
ELIOT Veronesi et al. [24]	5.8	IBTR: 0.4% vs. 4.4%, HR 9.3	Skin toxicity reduction with IORT	NR
TARGIT Vaidya et al. [49]	2.5	IBTR: 1.3% vs. 3.3%, p = 0.042	Skin toxicity reduction with IORT	NR

Abbreviation: WBI, whole breast irradiation; PBI, partial breast irradiation; IORT, intraoperative radiation therapy; IBTR; ipsilateral breast tumour recurrence; NR, not reported; HR, hazard ratio.

Although different techniques and schedules of accelerated PBI are currently adopted, one of the main advantages of PBI, as compared to WBI (conventional or moderate hypofractionated schedules), is the reduction of RT treatment time. Shorter schedules of breast RT may lead to better compliance and health-related quality of life (HRQoL) of patients. In this regard, HRQoL final analysis from the Florence phase 3 trial reported that global health status (p = 0.0001) and several functional and symptom scores of QLQ-C30 and BR23 module questionaries were improved with accelerated PBI both at the end of RT and 2 years after irradiation [51]. In line with the previous analyses, the GEC-ESTRO trial confirmed that brachytherapy-based accelerated PBI did not provide a worse quality of life as compared to WBI [52]. APBI, with its inherent reduction in treatment time, also decreases health care costs [53]. Worldwide, the impact of PBI in terms of cost-effectiveness and reduction of waiting time is heterogeneous and data is still limited. In 2009, the Harvard Radiation Oncology Program published a cost-effectiveness analysis on PBI versus WBI for early-stage breast cancer patients. The authors developed a Markov model to describe health status over 15 years after RT. According to their findings, external beam PBI was the most cost-effective approach for post-menopausal patients [54].

2.3. Main limitations of PBI

PBI has become widely used in the treatment of early-stage, low-risk breast cancer, and while PBI appears to show some benefits over WBI, there are some limitations that can either make PBI less practical to use, or that need to be taken into consideration to balance its advantages over potential risks.

Despite overstated limitations due to the relative complexity of the procedure and the high level of technical expertise, interstitial brachytherapy is a cost-effective treatment. Additionally, regarding the learning curve, most radiation oncologists' curricula include the knowledge and training of brachytherapy as an integral part of residency programs. Indeed, high dose-rate (HDR) devices are widely available in most of the RT departments, and the price of the equipment is significantly less compared to LINAC. Moreover, most of the aforementioned devices are not used exclusively for breast brachytherapy but also for further clinical indications which lead to a significant reduction in the cost of each procedure [55,56]. However, some authors reported concerns about the greater dose heterogeneity within the target volume in brachytherapy, when compared to external-beam techniques, which may potentially lead to higher rates of fat necrosis and subcutaneous toxicity. Conversely, in the Budapest trial soft tissue adverse events and fat necrosis was not increased by brachytherapy [46]. Indeed, asymptomatic fat necrosis is very often reported after breast conserving surgery regardless the adopted RT technique [57]. Intraoperative modalities require additional operating room time which might not be available in the context of a global shortage of nurses. Moreover, the invasiveness of the procedure can be a crucial factor and should be discussed in detail with patients. Furthermore, PBI in this context is done before final pathology results are available and patients might require further whole breast RT if the pathology is considered high risk. EBRT, when delivered by IMRT, distributes low doses to larger volumes outside the lumpectomy and its long-term side effects on organs at risk has yet to be investigated. In addition, the optimal patient selection criteria for the PBI approach are not well defined, with different patient populations included in the multiple randomised controlled trials, and substantial differences in acceptable patient populations according to the various guidelines. The ASTRO and GEC-ESTRO criteria for the low-risk group are stricter than those recommended by the American Society of Breast Surgeons, which considers PBI to be a treatment option for a wider range of patients [58]. Similarly, some trials like the NSABP B-39/RTOG 0413 APBI trial [29] used less restrictive inclusion criteria, accepting patients from 18 years of age, with either invasive adenocarcinoma or DCIS up to 3 cm and up to 3 positive axillary nodes, as compared to other trials that only included lower risk patients [59]. Choosing high-risk patients can put patients at risk of recurrence, while restricting the inclusion group to an an extremely low-risk population warrants the question if those patients with very low rates of ipsilateral breast tumour recurrences (IBTR) need radiotherapy at all.

Another limitation of PBI is the theoretical risk of increased local recurrence due to geographic miss of the target volume, in the context of a reduced target volumes. For successful PBI, a precise localization of the clinical target volume (CTV) is essential. However, some studies have shown important variability in tumour bed contouring between clinicians, with a potential risk of geographical miss [60,61] of the target. Addressing this uncertainty with larger target volumes would forego the volume-reduction goal of PBI but irradiating too small a volume would bring higher chances of geographical misses, reflected in a theoretical risk of increased local recurrence.

Finally, although smaller volumes are being irradiated, radiation is being delivered in a hypofractionated and accelerated fashion, with a theoretical risk of increasing long-term toxicities such as fibrosis, and worsening cosmesis, especially if the dose fractionation schedule is not optimized. This theoretical risk was shown to be real in the RAPID trial, with worsened fibrosis and cosmetic outcomes using a very hypofractionated twice-daily schedule [47].

2.4. Tips and tricks for patient selection

The appropriate patient selection for PBI has been widely debated. According to the national and international published guidelines, such as GEC-ESTRO, American Brachytherapy Society (ABS), American Society of Radiation Oncology (ASTRO), and American Society of Breast Surgeons (ASBrS), clinical oncologists can refer to specific eligible criteria for PBI (Table 3) [[62], [63], [64], [65]]. Recently, ABS updated their PBI consensus statement including special clinical circumstances as re-irradiation for breast cancer occurring in a previously irradiated area [[66], [67], [68]].

Table 3.

Suitable criteria for PBI in published recommendations.

	ABS	ASTRO	ASBrS	GEC-ESTRO	ESTRO-ACROP
Age, years	≥45	≥50	≥45	≥50	≥50
Tumour size, mm	≤30	≤20	≤30	≤30	≤30
Subtypes	All invasive subtypes and DCIS	Invasive ductal carcinoma and selected DCIS°	All invasive subtypes and DCIS	Non-lobular invasive carcinoma	Non-lobular invasive carcinoma and selected DCIS°
Hormone receptors	ER positive or negative	ER positive	ER positive or negative	ER positive or negative	ER positive
Surgical margins	Negative^	≥2 mm	Negative^	≥2 mm	>2 mm
Other features	Unifocal No LVSI Negative lymph node status	Unifocal No LVSI No EIC Negative nodal status No neoadjuvant chemotherapy	Focal LVSI accepted Multifocal accepted (if span ≤30 mm) Negative nodal status No genetic mutation	Unifocal Unicentric No LVSI No EIC Negative nodal status No neoadjuvant chemotherapy	Unifocal Unicentric Negative nodal status No primary systemic therapy/neoadjuvant chemotherapy

° Screen-detected DCIS, tumour grade 1–2; tumour size ≤2.5 cm; surgical margins ≥3 mm.

^ No ink on tumour for invasive tumour and ≥2 mm for DCIS.

Abbreviation: ABS, American Brachytherapy Society; ASTRO, American Society of Radiation Oncology; ASBrS, American Society of Breast Surgeons; GEC-ESTRO, Groupe Européen de Curiethéapie-European Society for Therapeutic Radiology and Oncology; ESTRO-ACROP, ESTRO Advisory Committee in Radiation Oncology Practice; ER, Oestrogen receptor; DCIS, Ductal Carcinoma In Situ; LVSI, lymph vascular space invasion; EIC, Extensive intraductal component.

Notwithstanding the heterogeneity of suitable patients across the guidelines, the consensus for the optimal candidate can be met for patients aged 50 years or older with tumours less than 2 cm, negative lymph node status, and negative margins. Moreover, patients with multifocal tumours or treated with primary systemic therapy are commonly not eligible for PBI. However, there are still some areas of open questions such as eligibility of invasive lobular histology or the upper limit of tumour size. In addition, it is well-reported that very young patients or those with triple negative breast cancer are at a higher risk for local recurrence but data on superior efficacy outcome with WBI is still limited. The introduction of modern RT techniques opened a new field of research in the delineation of tumour bed. Some clinical features of the breast, such as a dense parenchyma, or of the tumour bed, such as a small volume, a retro-areolar location or a close location to the pectoralis muscle were associated with lower interobserver consensus in modern contouring [69]. Surgical clips are recommended for accurate tumour bed localization [70,71], although this has not been uniformly adopted. In this regard, magnetic resonance imaging (MRI) may represent an additional tool to increase tumour bed localization, as compared to CT. Conflicting results reported by several investigations may be related to the lack of consensus about the optimal MRI sequences [[72], [73], [74]].

To provide recommendations for external beam radiotherapy, the ESTRO Advisory Committee in Radiation Oncology Practice (ACROP) consensus aimed to define dose and fractionation for external beam WBI and PBI, chest wall irradiation, and regional nodal irradiation [40]. According to the final consensus statement, the suitable criteria for PBI were age ³50 years, luminal-like subtypes, small tumour size, no lymph vascular space invasion, non-lobular invasive carcinoma, tumour grade 1–2, low/intermediate grade DCIS, unicentric/unifocal tumour, clear surgical margins, negative nodes (including isolated tumour cells), and no use of primary systemic therapy and neoadjuvant chemotherapy. The panel of experts recommended that schedules of moderate hypofractionation (40Gy in 15 fractions) and ultra-hypofractionation (26–30Gy in 5 fractions) were appropriate regimens for external beam PBI. Moreover, twice a day external beam PBI schedule, as per the RAPID trial, was not supported.

3. Future perspectives

3.1. Preoperative radiation therapy

Although breast conserving surgery followed by postoperative RT is the standard of care for most early breast cancer, a few concerns exist about postoperative regimens such as postsurgical waiting time, treatment-related toxic effects, and uncertainty in tumour bed identification/delineation [75]. Therefore, preoperative RT has been gaining more attention in the context of early-stage breast cancer. Historically, rescheduling RT before surgery seemed to be safe and did not provide significantly higher perioperative side effects, like other tumour entities such as rectal cancer [76]. Data provided by large cohorts of patients [75,77] needs to be confirmed by prospective studies evaluating the optimal schedules of preoperative breast RT using PBI or stereotactic body radiation therapy (SBRT). To the best of our knowledge, findings deriving from phase I-II trials showed that preoperative PBI for early-stage breast cancer is feasible and well-tolerated, with high local control rates. The potential benefit of anticipating PBI before surgery is related to the reduction in target volumes, higher accuracy, limited risk of fibrosis (removing the area of the breast that received the highest RT dose), and good cosmetic results [[78], [79], [80]]. Strikingly, the PAPBI trial is a phase 2 study enrolling patients with tumour sized less than 3 cm treated with 40Gy in 10 fractions (years 2010–2013) and 30Gy in 5 fractions (after 2013) followed by surgery after 6–8 weeks [78]. The five-year results of PAPBI study were published in 2020, the authors confirmed a low rate of local relapse with only four recurrences out of 133 patients, with an overall good tolerability and cosmetic outcomes [79]. Similarly, in another phase II trial, 27 patients with early-stage breast cancer received accelerated PBI twice daily; surgery was performed at least 21 days after RT. The rate of pathological complete response (pCR) was 15%, and four cases experienced grade 3 seromas with a good-excellent patient-reported cosmetic outcome in most patients [80]. According to the published literature, preoperative SBRT is a novel approach to the multimodal treatment of breast cancer. The administration of RT schedules based on higher dose per fraction may enhance patient compliance and reduce health care costs [75]. However, the evidence on the role of preoperative SBRT, especially in breast cancer, is still limited. Table 4 lists the published SBRT/PBI preoperative trials [32,78,[80], [81], [82], [83]]. Data derived from a phase I trial showed that when compared with chemotherapy followed by surgery and conventional postoperative RT, the use of preoperative SBRT yielded a good toxicity profile with only a grade 3 skin dose-limiting toxicity with a pCR rate of 36% [81]. Furthermore, the phase 2 single-arm Signal trial analysed 27 early-stage breast cancer patients receiving a preoperative regimen of 21Gy in a single fraction. Surgery was performed one week after RT, and the authors reported no recurrences and no different cosmetic outcomes and HRQoL at 16 months. In line with previous experience, the recently published ROCK trial aimed to assess the toxicity and feasibility of a single 21 Gy-fraction preoperative robotic radiosurgery in 22 patients. Overall, pCR was reported in 9% of patients, no acute toxicity greater than G2 was recorded, and cosmetic results were scored excellent/good in 14 patients [32].

Table 4.

Published preoperative PBI/SBRT trials.

Study (year)	Eligibility	N	Follow-up (months)	RT schedule	Surgery timing	pCR	Efficacy	Toxicity
Bondiau et al. (2013) [81]	Not suitable for BCS, unifocal, HER2 negative	26	30	19.5–31.5Gy/3 fractions (robotic SBRT)	4–8 weeks after the last CT	36%	96% ORR, 92% BCS rate	None
Horton et al. (2015) [82]	Age >55 years, T1 or low-intermediate DCIS ≤2 cm, cN0, ER+ and/or PgR+, HER2-	32	23	15–21Gy/1 fraction (IMRT)	within 10 days after RT	NR	Increase in post- radiation vascular permeability, decreased cellular density	13 grade 2; 2 grade 3
Nichols et al. (2017) [80]	<3 cm, cN0, unifocal invasive	27	43.2	38.5Gy/10 fractions (3DCRT)	>3 weeks after RT	15%	Ki-67 decrease after RT in 70.4%, ORR 88.9%	1-year PRCO fair and poor in 17% and 5%, respectively
van der Leij et al. (2015) [78]	Age >60 years, ≤3 cm, invasive, unifocal, non-lobular, negative SNB	70	23	40Gy/10 fractions (3DCRT or IMRT or VMAT)	6 weeks after RT	NR	2 IBTR	At 12 months: 70-11% mild-moderate induration At 24 months: 46% mild-moderate fibrosis
Guidolin et al. (2019) [83]	≤3 cm, ductal, any grade, unifocal ER+, cN0, postmenopausal status	27	16.2	21Gy/1 fraction	1 week after RT	NR	All patients free from relapse	No significant differences in HRQoL and PRCO
Meattini et al. (2022) [32]	Age ≥50 years; hormone receptor positive and HER2-; any grade; unifocal; maximum size 25 mm; clinically node negative	22	18	21Gy/1 fraction (robotic radiosurgery)	2 weeks after RT	9%	No patients have locoregional neither distant recurrence	No acute toxicity greater than G2 was recorded, cosmetic results were scored excellent/good in 14 patients

Abbreviation: RT, radiotherapy; BCS; breast conservative surgery; ER, oestrogen receptor; HER2, human epidermal growth receptor factor 2; SBRT, stereotactic body radiotherapy; IMRT, intensity modulated radio-therapy; 3DCRT, three dimensional conformal radiotherapy; VMAT, volumetric modulated arc therapy; CT, chemotherapy; ORR, overall response rate; pCR: pathological complete response; MRI, magnetic resonance imaging; SNB, sentinel bode biopsy; IBTR, ipsilateral breast tumour recurrence; PRCO, patient reported cosmetic outcome; HRQoL, health-related quality of life.

3.2. Breast cancer as a paradigm of multidisciplinarity

Breast cancer represents a multidisciplinary paradigm. It should be considered a heterogeneous disease and a “one treatment fits all” approach cannot be the appropriate option. Patients should be given the possibility of sharing the decision-making process, especially in case of low-risk categories of breast cancer.

For the past few decades, research explored the need of postoperative RT after breast conserving surgery in the older adult population, and the results are a matter of open debate. Concerning local disease control, the absolute benefit of RT was small and potentially negligible for this population. Hence, breast RT can occasionally be omitted in low-risk breast cancer patients treated with adjuvant endocrine therapy. The LUMINA trial, a prospective multicentre cohort study, is evaluating the omission of RT after breast conserving surgery in T1N0 luminal A breast cancer patients [84]. The 5-year results were presented at ASCO 2022, and patients on endocrine therapy alone were found to have very low rates of local recurrence, suggesting that these patients may be appropriate candidates for omission of RT. Conversely, it is well-reported that patients receiving neither RT nor endocrine therapy have unacceptably increased local recurrence rates. Finally, in low-risk patients older than 70 years with hormone-positive breast cancer, evidence and clinical practice have also evaluated the option to de-escalate systemic therapy. In this regard, the different biological subtypes of breast cancer can be the key factors to define the clinical behaviours and the specific responses to therapy. According to literature, endocrine therapy may have a higher detrimental impact on HRQoL scores, especially in postmenopausal women [85]. Moreover, due to the potential toxic effects of endocrine therapy (i.e., bone frailty, thromboembolic events, sexual dysfunctional, and arthralgia/myalgia) the rate of adherence and compliance to systemic therapy decreases in older patients [86]. In this regard, several ongoing trials are currently focusing on the optimisation strategies (Table 5), adopting a precision oncology approach (i.e., EUROPA - NCT04134598 [87], EXPERT - NCT02889874, NATURAL - NCT03646955, PRECISION - NCT02653755, PRIMETIME - ISRCTN41579286 [88], IDEA - NCT02400190, LUMINA - NCT01791829). Notably, the EUROPA phase 3 trial enrolling elderly patients (≥70 years) with low-risk breast cancer aims to assess if exclusive postoperative irradiation can improve HRQoL by avoiding the toxicity of endocrine therapy, while maintaining an equivalent local control [87].

Table 5.

Ongoing trials on de-escalation/optimisation of treatment for early-stage breast cancer.

	EUROPA [87]	EXPERT	NATURAL	PRECISION	PRIMETIME [88]	IDEA	LUMINA
Study type (number of patients)	Phase 3 Randomised (926)	Phase 3 Randomised (1167)	Phase 3 Randomised (926)	Single arm (690)	Single arm (2400)	Single arm (202)	Single arm (500)
Age (years)	≥70	≥50	≥60	50–75	≥60	50–69	≥55
Stage, histology, biological subtype, margins	T1 N0 Any grade (≤10 mm) Grade 1–2 (11–19 mm) ER/PgR ≥10% HER2 neg Ki67 ≤ 20% Negative surgical margins (no ink)	pT1 N0 Grade 1–2 ER/PgR ≥10% HER2 negative ROR score ≤60 Negative surgical margins	pT1 N0 Grade 1–2 ER ≥ 10% HER2 negative Surgical margins ≥2 mm	pT1 N0 Grade 1–2 ER/PgR ≥10% HER2 negative Negative surgical margins	pT1 N0 Grade 1–2 Very low risk patients (based on IHC4 + C) ER/PgR positive HER2 negative Surgical margins ≥1 mm	pT1 N0 Any Recurrence Score ≤18 ER/PgR positive HER2 negative Surgical margins ≥2 mm	pT1 N0 Grade 1–2 ER ≥ 1% PgR >20% HER2 negative Surgical margins ≥1 mm
Method	IHC FISH for HER2 2+	PAM 50 FISH for HER2 2+	IHC FISH for HER2 2+	PAM 50 FISH for HER2 2+	IHC4+C FISH for HER2 2+	Oncotype-DX FISH for HER2 2+	IHC FISH for HER2 2+
Arms	RT vs ET	ET + RT vs ET	ET + RT vs ET	ET only	ET only	ET only	ET only
Primary endpoint(s)	5-year LR 2-year HRQoL	5-year LR	5-year LR	5-year LR	5-year LR	5-year LR	5-year LR

Abbreviations: LR, local recurrence; ET, endocrine therapy; IHC, immune histochemistry; FISH, fluorescent in situ hybridization; HRQoL, health-related quality of life; RT, radiation therapy; EIC, extensive intraductal component; IHC4 + C, immunohistochemical biomarkers plus clinical information; ER, oestrogen receptor; PgR, progesterone receptor; ROR score, risk of recurrence score.

In conclusion, further investigations are warranted to optimise and identify the most appropriate and personalized treatment for low-risk breast cancer patients. In this complex framework, PBI undoubtedly represents an elegant approach towards optimisation for breast cancer treatment, finding the balance between burden of toxicity and optimal effectiveness of local therapy.

Funding

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Declaration of competing interest

Icro Meattini discloses occasional small fees received for advisory board sponsored by Roche, Pfizer, Eli Lilly, Accuray, Novartis, Seagen.