Introduction

Radiation therapy (RT) is an important part of breast cancer (BC) treatment. After conservative surgery for early-stage disease and after mastectomy for node-positive patients, RT halves the overall recurrence rate and reduces BC mortality by about one-sixth, with excellent cosmetic results [1, 2]. Radiation therapy deeply changed in the last 2 decades, because modern technologies permit more precise treatments, achieving a better distribution of dose, volume de-escalation approach and less toxicity. Furthermore, a better knowledge of tumor biology [3] and the availability of more effective systemic therapies [4] allow the adoption of alternative and personalized risk-adapted radiotherapy schemes. In the Radiation Oncologists’ modern vision, some topics represent open fields for discussion, such as post-mastectomy or regional nodal hypofractionated radiotherapy (hRT), partial-breast irradiation (PBI), re-irradiation (rRT) for BC recurrence and RT after neoadjuvant chemotherapy (post-NAC RT).

Regarding breast hRT, four randomized trials enrolling more than 7000 women affected by early-stage BC in UK and Canada between 1986 and 2002 have demonstrated that it is an effective and safe treatment option [5] to be unanimously considered “the new standard” [6,7,8,9]. The same consideration is not applicable to post-mastectomy or regional nodal hRT, because a very small number of patients received this treatment modality within the randomized trials.

Another open question due to lack of high-level evidence is the management of BC recurrence. The standard of care for loco-regional recurrence is a salvage mastectomy, although recently published data suggest that a second breast-conserving surgery (BCs) followed by rRT can be a possible option [10]. In the past decades, there have been some concerns about the safety and toxicity of rRT. However, in the last few years, emerging evidence has demonstrated that rRT can be feasible and safe [11]. Today, a large variety of treatment options and many different dose-fractionation schedules exist, including brachytherapy (BT) [12,13,14], external beam radiation (EBRT) [15, 16] and intraoperative radiotherapy (IORT) [17,18,19].

In the context of integration between systemic therapies and radiation treatment, a topic that generates uncertainty in the clinical practice, is the management of the patient affected by breast cancer and treated with NAC. This therapeutic uncertainty arises from the heterogeneity of the published data, relating to the predictive factors of loco-regional relapse [20,21,22,23,24,25,26,27,28] and to the lack of adequate follow-up in patients treated with or without post-NAC RT. NAC is currently used for patients with large tumors or aggressive histology, not only to reduce tumor size to facilitate breast conservation, but also to assess in vivo tumor response to the chemotherapy. The preoperative classification of breast cancer by molecular subtypes has influenced not only the response to chemotherapy, but also the choice of systemic agents, and it helps to predict the risk of recurrence [29, 30]. A 2012 study that used National Surgical Adjuvant Breast and Bowel Project (NSABP) B-18 and B-27 trial data identifies the clinical status of the lymph node, the size of the primary neoplasm and the response to the NAC treatment as the main risk factors [31].

Guided by this changing wind, surveys get a “snapshot” of the current medical practice about “gray questions” and stimulate a discussion leading to the development of tailored trials. The aim of this survey is to report Italian Radiation Oncologists practice in the management of BC on these controversial issues.

Materials and methods

In October 2017, a nationwide 21-point questionnaire was distributed online via SurveyMonkey to the Italian Radiation Oncologists using the mailing list of AIRO. Each individual Radiotherapy Cancer Care Center indicated, within its team, the Radiation Oncologist with the most expertise in the treatment of breast cancer, identifying him/her as the only respondent to the survey. The items of the questionnaire were defined over a multistep process by a panel of experts in BC working group of the AIRO. The survey was elaborated on SurveyMonkey’s online interface (http://www.SurveyMonkey.com). The first section referred to general topic regarding country, center characteristics and expertise in BC treatment. The questions were divided in three specific topics as follows: hRT, PBI and rRT, finally, post-NAC RT. For each issue, the following were indagated: clinical decision making; treatment volumes; RT techniques; dose prescription. In some questions, more than one answer was allowed. Answers were automatically analyzed by SurveyMonkey.

Results

Seventy-four of 195 (38%) Italian Radiotherapy Cancer Care Centers answered the survey. The questions and answers are summarized in Table 1. Ninety-seven percent of the responding centers treated more than 100 patients/years. Overall, the responding centers declared to treat 34,164 patients between January 2016 and December 2017. In almost all cases (91%), an expert multidisciplinary discussion was performed to choose the best treatment for each patient.

Table 1 Survey items and results obtained from Italian Radiation Oncologists
Full size table

Hypofractionated radiotherapy

Regarding the first topic, the 49% of participating centers answered to treat their patients with a hRT. The 95% of centers used this treatment approach as clinical practice after BCs for early-stage BC, mostly in women older than 50 years (40%) affected by invasive ductal carcinoma (IDC) (89%). Dose prescription ranged between 39 Gy and 45 Gy with high use of moderately hRT (40 Gy/15 fr or 42.5 Gy/16 fr in 62% of cases). Most of the centers (58%) responded to use hRT in all ages, mainly (40%) for women older than 50 years. However, when age was over 70 years, only 4% of them declared to use this fractionation in elderly patients. Regarding histology, patients with ductal carcinoma in situ (DCIS) were treated using hypofractionated scheme by the 48% of the responding centers. According to irradiation volumes, the hRT whole-breast irradiation (WBI) represented 100% of cases with a 72% of centers that used also hRT boost. Indeed, chest wall and lymph node area were irradiated with hypofractionated regimes in 13% and 15% of cases, respectively.

Partial-breast irradiation and re-irradiation

The second topic investigated the use of PBI and rRT. The 27% of the participating Radiation Oncologists answered this item; of them, the 60% practiced PBI with different techniques, often used in an alternative way within the same center: 89% EBRT, 34% IORT and 9% BT. Only 0.6% of the RT Centers answered that women with BC recurrence received rRT. In 80% of cases, the rRT was given more than 5 years after primary RT. The age factor was not related to the rRT chosen (68% of answers were “all age”), and the most frequent histological type was IDC (82%) alone or associated with other histology subtypes. The answers concerning the irradiation volumes were so represented below: 54% total rRT (WBI/chest wall irradiation) and 94% PBI (including 42% of tumor bed RT). Regarding the techniques, most of the centers used EBRT, while 6% and 10% of them used BT and IORT, respectively. The percentages of prescription dose for rRT were the following: 40 Gy/15 fr in 50%, 42 Gy/16 fr in 39%, 50 Gy/25 fr in 34%, 34 Gy/10 fr in 14% and 45 Gy/18 fr in 9% of cases, considering that more than one answer was allowed.

Radiotherapy after neoadjuvant chemotherapy

The last topic of this survey was RT after NAC, to which 11% of the participating RT Centers had replied. In most cases (98%), the NAC was prescribed by Medical Oncologist. Only 8% of Radiation Oncologists declared to prescribe NAC. In the 55% of cases, a clinical patient evaluation was performed by the Radiation Oncologist at the end of systemic therapy, in 40% before the start of NAC and 5% during it. Lymph node biopsy was performed before and after NAC in 40% and 60% of responding centers, respectively. Post-NAC, breast RT was administrated in 97% of women after BCs. The chest wall and the ipsilateral lymph nodes irradiation (LNI) was a shared choice by most of the Italian Radiation Oncologists (94% and 73%, respectively) in the case of locally advanced BC at the disease diagnosis (cT3-T4 and/or cN2-N3), regardless of the kind of response obtained after NAC (complete response vs partial response) and also independently of the axillary surgical approach (sentinel lymph node biopsy—SLB—vs axillary lymph node dissection—ALND). In the case of disease diagnosis with limited lymph node involvement (cN1), the same therapeutic option was chosen based on the response obtained after NAC but not based on the axillary surgical approach: in the case of residual disease after NAC (ypN +), post-mastectomy RT was performed in the 79% and 76% of cases after SLB and ALND, respectively. Regarding the volumes of LNI, in 39% of cases only the third nodal level was irradiated after ALND with ≥ 10 removed lymph nodes (rLNs); in 39% of cases, the second and third nodal levels were irradiated after ALND with < 10 rLNs; and in 44% of cases, the first–third nodal levels were irradiated after SLB without ALND. A prescription dose with a hypofractionated scheme was used in 49% of cases, exclusively as WBI. Only 11% of the centers had responded to use hRT on chest wall or lymph node area after NAC, while 40% of them did not choose hRT after NAC.

Discussion

The management of BC is a very complex matter. Considering that in 2017 the incidence of BC in Italy has been estimated to be around 50,500 new cases with a 5-year survival and 10-year survival of 87% and 80%, respectively [32], it is clear that the BC care represents an important part of the day-to-day clinical practice and significant commitment to resources for the health care system [33, 34]. According to the highest quality of care [35], in 91% of the Italian Cancer Care Centers an experts’ multidisciplinary discussion was performed to choose the best treatment for each patient.

The first topic of the Italian survey regarded hRT. Hypofractionation means a shorter radiation course with higher daily doses for the same biological effect [36]. Compared to a conventional regimen of 50 Gy in 25 fr, with a similar efficacy and toxicity profile, hRT is more suitable for patients and more cost-effective for health care system [33, 34]. The use of hRT-WBI has been gradually increasing in the most of Italian RT Centers in recent years, where it represents in the 95% of cases the standard of care with a prescription dose ranging between 39 Gy and 45 Gy with high use of moderately hRT (40 Gy/15 fr or 42.4 Gy/16 fr in 62% of cases). These results are in line with the recommendations of the main scientific societies [6,7,8,9] and reflect the effect of the long-term data derived by clinical randomized trials [5]. On the other hand, the characteristics of the population on which these trials focused (middle age women, prevalence of IDC, early-stage disease) make difficult to transpose the same evidence in different population groups or in different treatment options, such as young and elderly patients, pure DCIS, post-mastectomy and/or LNI. As a matter of fact, the choice to use a hypofractionated scheme in our national experience seems to be influenced by patient’s age and the histotype, remaining in patients’ age > 70 years [37] or in the case of DCIS [38, 39] a therapeutic choice not shared by the majority of Italian Cancer Care Centers, 4% and 48%, respectively. Regarding the irradiation volumes, if the hRT-WBI is performed by all interviewed centers, the hRT at the chest wall and/or lymph nodes areas is a reality limited to 13% and 15% of centers, respectively. Although data derived from both national [40, 41] and international [42, 43] studies encourage the use of hRT on the chest wall and lymph nodes, a prospective safety and efficacy trial is probably needed to allow a customs clearance of this therapeutic option.

A second topic of our survey regards PBI and re-treatment. The requirement of PBI is to achieve a high rate of local control, ensuring a low profile of loco-regional toxicity, through the irradiation of a smaller volume compared to WBI. Furthermore, it allows a shorter overall treatment time. The results obtained from the main randomized trials [44,45,46,47] that were focused on this therapeutic option, showed us that the correct selection of the patient is the key to success for PBI, regardless of the used technique. The 60% of the 27% of the Italian centers that answered to this topic, declare to use this approach in their clinical practice. Regarding the technique of PBI, 89% of the centers choose EBRT. This choice could be linked to the excellent quality of the data derived from IMPORT LOW trial [47], or more simply due to the technical equipment present in each center. In the recent years, the growing experience in PBI associated with the evidence of a low-toxicity profile has increased its use for a salvage breast conservation for ipsilateral recurrence after BCS followed by RT. Considerations regarding rRT include the initial treatment delivered, the time interval to relapse, the number of tumor foci within the breast, the ability to obtain negative margins, the ability to achieve a reasonable cosmetic outcome, the presence or absence of distant metastases, previous treatment modalities used and patient preference [10, 11]. Between these factors, the time interval to local recurrence of < 2 years is significantly predictive for local relapse. Despite the promising results achieved so far with second BCs and rRT [12,13,14,15,16,17,18,19], there is no robust evidence for considering such an approach as the standard management. The most important issue regarding BC ipsilateral local recurrence is the risk of patients developing metastatic disease, considering that often a recurrence of disease is marked by more aggressive biological behavior [48]. The risk of metastatic disease is related to pathological features of the BC recurrence and the time interval between the relapse of cancer and the primary diagnosis (48 months) [49]. In this framework, in which the local control affects less the overall survival of the patients with BC recurrence, an invasive surgical treatment such as mastectomy could lose meaning in favor of more conservative and safe treatment.

In line with these important criticisms, the rRT does not represent a current practice in the Italian scenario (0.6% of cases) where, to date, it remains a “no-fly zone” and needs a much more long-term effectiveness confirmation. Nevertheless, it is certainly a topic of growing interest, especially in the last year. About the re-irradiation volumes, the PBI represents the most frequent choice (98%) with fairly heterogeneous techniques and schedules of treatment. A common point of agreement is the time interval to relapse, and the 80% of the interviewed centers states that rRT is performed in the case of time interval between primary diagnosis and recurrence > 5 years.

Our last topic of great interest is regarding the management of RT after NAC. NAC is the standard treatment for locally advanced breast cancer at the disease diagnosis and an option for operable disease to allow a conservative surgery (downstaging and downsizing) [20]. It also includes the principle of early sterilization at a distance and the possibility of testing tumor aggressiveness in vivo on the basis of the obtained disease response. Several randomized trials have not documented significant differences in disease-free survival and overall survival between primary and adjuvant chemotherapy, identifying the advantage of NAC in the best loco-regional treatment of the disease [20]. Data on the predictive factors of loco-regional relapse after NAC are rather heterogeneous, but the clinical status of the lymph nodes, the size of the primary breast tumor and the NAC response represent the main risk factors [50]. After primary systemic treatment, the indications to the adjuvant RT and the treatment volumes, even today, are not always well defined because they derive from the results of retrospective studies and from the results of the prospective studies that have not been designed to evaluate the role of postoperative RT after NAC. The results of this survey reflect the heterogeneity in the therapeutic choices deriving from the lack of these data. Although recent studies show that the complete pathological response to NAC is a predictive prognostic factor and the results of a combined analysis of NSABP studies 18 and 27 suggest evaluating the indications to RT based on the response to NAC [51], in our study the factor that mostly seems to influence the indication to the chest wall and the ipsilateral lymph nodes irradiation after NAC is the extension of the disease at diagnosis (cT3-T4 and/or cN2-N3). An important randomized study, designed for this purpose, is still ongoing—NSABP B-51/RTOG 1304 [52]. Waiting to have conclusive evidence regarding this issue, the multidisciplinary discussion that allows agreeing on the best therapeutic choice for the individual patient remains a milestone.

Conclusions

Surveys allow to obtain a real picture of current clinical practice. Although the percentage of responding centers is relatively low, it is important to highlight that they are high-volume treatment institutes for breast disease and the Radiation Oncologists who participated in this survey are clinicians actively engaged within AIRO breast cancer working group. Regarding the radiation treatment in the management of breast cancer, these data are important considering the incidence, prevalence and complexity of this pathology, in addition to the heterogeneity of the possible clinical contexts and the treatment options that may be pursued. In the Italian scenario, the present report shows a fairly good use of hRT and a moderate practice of PBI. In the range of therapeutic possibilities, post-mastectomy or regional nodal hRT, rRT for BC recurrence and post-NAC RT are still under definition.

In conclusion, this survey supported by the AIRO Breast group is the first step, at the national level, to frame the most problematic topics in the field of breast cancer radiotherapy and to address a data collection aimed at standardizing clinical behavior. Future investigations are advocated to establish well-tailored future studies.