The standard of care for patients affected by early invasive breast cancer (BC) is currently whole-breast irradiation (WBI) after breast-conserving surgery (BCS). WBI reported a reduction in first relapse with a lower absolute 10-year risk decrease of any locoregional or distant recurrence [1]. Currently, shorter schedules based on moderate hypofractionated regimens should be the standard of care for WBI reporting a level-1 evidence on equivalent locoregional control and late toxicity rates [2]. Recently, a brand-new approach in adjuvant breast radiation therapy is the ultra-hypofractionated schedule given over just one-week, feasible in selected low-risk patients. In this regard, the FAST Forward trial compared 26 Gray (Gy) or 27 Gy in 5 fractions over 1 week to 40 Gy in 15 fractions over 3 weeks. At 5 years, the two experimental regimens proved to be non-inferior to control group regarding local recurrence, with a safety profile in favor of 26 Gy in 5 fractions as compared to a total dose of 27 Gy [3]. If we advocate BC patients who received mastectomy, it is well known that post-mastectomy radiotherapy (PMRT) improves long-term outcomes by decreasing local failure and cancer mortality [4, 5, 6]. The use of PMRT has been widely validated for patients with four or more positive lymph nodes but there are still questions regarding the value of PMRT for those with one to three positive nodes [6]. Moreover, patients with axillary nodal involvement persistent after primary systemic therapy should receive PMRT [6]. According to the National Comprehensive Cancer Network (NCCN) panel, the recommended schedule for PMRT is a conventional regimen of 46–50 Gy delivered in 23–25 fractions to the chest wall [7]. However, the optimal PMRT schedule is still controversial and underreported. In the last decades, many authors have investigated the reduction of toxicity, overall treatment time and cost thanks to the adoption of hypofractionated regimen after mastectomy [8]. High-quality data coming from five-fraction randomized clinical trials have catalyzed the interest of the radiation oncology community in the implementation of hypofractionated schedules. In this context, the still ongoing COVID-19 pandemic has reinforced the urgent need also to minimize exposure of patients to virus without compromising oncological outcome [9, 10]. The aim of the present critical overview is to discuss the evidence regarding hypofractionated (HF) PMRT in BC patients in order to identify the current treatment approach. Therefore, the additional purpose of the present paper is to highlight what we have learned from COVID-19 era regarding HF schedules for PMRT in BC patients.

Between February and November 2021, we conducted literature and database research. Key references were retrieved from a PubMed query, using the combination of the following keywords: (chest wall OR thoracic wall) AND (breast cancer OR breast neoplasm OR breast OR mastectomy) AND (hypofractionated) AND (radiotherapy OR radiation treatment OR radiation therapy OR postmastectomy radiotherapy). The range of publication date was between 2000 and 2021. Selection criteria included English language publications in humans. Hand searching included meeting proceedings of the European Society for Radiotherapy and Oncology (ESTRO), European Society of Medical Oncology (ESMO), American Society of Clinical Oncology (ASCO) and American Society for Radiation Oncology (ASTRO). The website clinicaltrials.gov was also searched. Reference lists of the identified studies were explored and cross references were allowed. We removed duplicates and excluded studies which did not report a correct population, study design, type of treatment, survival outcome and completeness of published data. Data extraction was conducted independently by two researchers (VSa and IMo) and disagreements were resolved on a case-by-case basis with a discussion among three co-authors (ID, CB, LV).

Randomized controlled trials evaluating HF-PMRT were included in the analysis. Our research returned 87 published papers. Fourteen trials were included in our final analysis and main findings are summarized in Table 1 (Ref. [2, 3, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22]). All patients included between 1998 and 2017 had early or locally advanced invasive breast cancer without distant metastases and underwent breast conservative surgery or, in most cases, mastectomy. All received adjuvant radiation treatment, whereas systemic therapy either with neoadjuvant or adjuvant intent was delivered according to physician’s choice in consideration of additional risk factors. Patients were assigned to conventional fractionation treatment (50 Gy in 25 fractions) or to a hypofractionated schedule which varied among studies. Primary endpoint used to measure the efficacy of hypofractionated radiation treatment in comparison with a conventional schedule was locoregional control, in terms of recurrence in the ipsilateral breast/chest wall or regional nodal basin. Toxicity rates were also reported, with a specific focus on cutaneous adverse events. In most studies HF-PMRT proved non-inferior to conventional fractionated (CF)-PMRT in terms of locoregional control and skin reactions. All hypofractionated schedules reported the same response and favorable outcomes. Just one study [15] resulted in higher acute skin reactions in the HF group, but no significant difference was detected for what concerns local recurrence or late radiation-induced effects. Hypofractionation also showed the advantage of reducing overall treatment time, treatment burden and cost, with a consequent better compliance to therapy.

In clinical trials investigating hypofractionated regimens, most of patients enrolled received WBI and data about chest wall and regional nodal irradiation are currently missing. Therefore, the role of HF-PMRT is debated and still underreported. Recently Marta et al. [10] conducted a critical review on the adoption of moderately hypofractionated post-operative radiation therapy for BC suggesting that there is no radiobiological evidence that patients treated with HF-PMRT should report different outcomes. However, the lack of consensus among the authors has resulted in the unmet need for the optimal management of BC patients receiving PMRT. With this regard, data coming from a randomized, non-inferiority, open-label, phase 3 trial reported that HF-PMRT was non-inferior to and had similar toxicities to conventional fractionated radiation therapy in patients with high-risk BC [11]. Wang et al. [11] evaluated 810 patients with locally advanced BC showing no significant differences in the 5-year incidence of locoregional failure, overall survival or disease-free survival between HF-PMRT with conventional fractionated (CF) PMRT. Furthermore, acute and late period side effects of treatments were comparable in two groups [11]. Additionally, the FAST-Forward trial provided strong evidence referring to the adoption of ultra-hypofractionated schedules (26 Gy in 5 daily fractions) in early BC [3]. Notwithstanding the restricted sample of patients receiving HF-PMRT, the authors concluded that the five-fraction regimen may be adopted as a new standard approach for patients with BC who received whole breast or chest wall irradiation. Furthermore, 15% and 8% of patients treated with HF-PMRT were enrolled in the START-A and START-B studies, respectively. The UK trial reported no significant difference in terms of local recurrence or late RT-related side effects between the two arms after 10 years of follow-up [2]. To the best of our knowledge, the comparisons of a number of different schedules of HF-PMRT with CF-PMRT provided comparable results in terms of locoregional disease control without the increase of toxicity [2, 3, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22]. Particularly, an acute skin toxicity incidence grade 2 or higher ranged between 10 and 25% among the studies we analyzed [2, 3, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22]. In line with the literature, the meta-analysis and systematic review of Liu et al. [8] reported a rate of skin reactions in the acute period of 17.3%. Similarly, the subgroup of patients who received HF-PMRT of the UK START study was 12% and no significant difference was collected in terms of lymphedema or moderate/marked breast symptoms [2]. The above-mentioned findings suggest that HF-PMRT may provide a good tolerability profile confirming high rates of local control of disease for high-risk breast cancer patients. Clinically, the adoption of HF-PMRT could decrease workload, cost of oncological care, increase compliance and allow the treatment of more patients. Despite the number of patients receiving HF-PMRT is increasing worldwide, there is still the need for general consensus regarding the optimal schedules of PMRT. Therefore, Meattini et al. [23] recently published the findings from the European Society for Radiotherapy and Oncology Advisory Committee in Radiation Oncology Practice confirming that hypofractionated radiotherapy can be adopted for the treatment of whole breast, chest wall, and nodal volumes. Moreover, the consensus states that ultra- hypofractionated schedules can also be offered for breast or chest wall in patients who received mastectomy without reconstruction and no nodal involvement [23]. In the last two years, the rapid escalation of severe acute respiratory syndrome coronavirus (SARS-CoV)-2-related disease (COVID-19) led to the need of guidelines for prioritizing health services and procedures [24]. Cancer patients have been identified as a fragile population due to their comorbidity. In this regard, many authors have focused their efforts on minimizing the possibility of infection without compromising the oncological outcome of cancer patients [25, 26]. Concerning the low/intermediate-risk patients with breast cancer, ESMO guidelines recommended that the use of hypofractionated regimens for adjuvant postoperative radiotherapy should be considered to reduce hospital visits [25]. Similarly, Coles et al. [26] stated that the moderate hypofractionation should be adopted for the whole breast, chest wall and nodal radiotherapy during the COVID-19 Pandemic. In conclusion, the results of our literature review highlighted that safety and efficacy of HF-PMRT is comparable with conventional schedules, but prospective studies and further randomized controlled trials (RCTs) are expected. However, COVID-19 pandemic has enhanced the need for increasingly personalized treatment protocols. With similar toxicity profile and oncological outcome, the optimal radiotherapy schedule should be based on the tumor biology, risk of disease and patients’ characteristics, taking into consideration also the reduction of overall treatment time and cost. Modern hypofractionated regimens should continue to be the standard of care in breast cancer patients who receive PMRT also in the post-COVID-19 era.

VSa, CB, LV, ID, IMe and LL gave the idea and wrote the main manuscript text. VSc, MB, LO, SB, GF and JN wrote the method of the critical review. ES, CC, IB, NB, BB and IMo reviewed references and prepared the table. All authors read and approved the final manuscript.

Not applicable.

Not applicable.

This research received no external funding.

The authors declare no conflict of interest.