To the best of our knowledge, this is the first study to assess the LAC radiation oncologists’ preferences related to the use of moderately hypofractionated post-operative radiation therapy in breast cancer patients. A total of 173 radiation oncologists corresponding to 13 countries responded the survey which made it possible to understand the treatment profile that has been carried out in these countries. The results of our study showed that moderately hypofractionated post-operative radiation therapy has been used not only for selected early-stage breast cancer patients, but also in cases after mastectomy and when regional nodal irradiation is needed. In other words, despite the greater tendency to use moderately hypofractionated post-operative radiation therapy for patients that do not need regional nodal irradiation, it is observed that the hypofractionation has been gaining ground in clinical practice, even when regional nodal irradiation is needed or after mastectomy with or without reconstruction.
In our study, the factors that most affected the decision to utilize moderately hypofractionated post-operative radiation therapy in clinical practice were percentage of time dedicated to breast cancer, regional nodal irradiation, implant-based breast reconstruction, and patient’s age. Moreover, breast cancer stage, and flap-based breast reconstruction were factors more commonly associated with absolute contraindications for the use of hypofractionated schedules. These findings are similar to the European study which, by evaluating the responses of 412 radiation oncologists from 44 countries, demonstrated that many factors can affect the decision to use hypofractionation in clinical practice [23]. It is important to recognise that the clinical application of the moderately hypofractionated post-operative radiation therapy differs across the globe, with rates ranging from 34.5% to 95% [24-29]. Previous authors reported breast laterality and volume, younger age, breast cancer stage, triple-negative tumour, and radiation plan inhomogeneity as factors related to lower hypofractionation utilization [26-28, 30].
Numerous prospective randomised trials studied several features of hypofractionated irradiation in breast cancer patients. Primarily, these studies with almost 8000 patients have demonstrated that hypofractionation is as safe and effective as conventional fractionation. Nevertheless, most of these studies involved mostly patients with early-stage disease who received breast-conserving therapy. Most patients underwent whole breast radiation therapy without regional nodal irradiation [12, 15-18, 20]. Therefore, the utilization of moderately hypofractionated post-operative radiation therapy is not globally adopted in patients who received mastectomy or need regional nodal irradiation due to overconcern about toxicity related to the treatment [8].
Some experts advocate that the use of moderate hypofractionation for regional nodal irradiation must be evaluated with attention until outcomes of other clinical trials are available due to the long-term side effects of this treatment, especially regarding heart and lung functions [31]. Furthermore, there could be unease related to the fact that chemotherapy was used in 14%, 11%, 35%, 22% of patients in the OCOG trial [14, 15], START A [17, 18] and START B [16, 17], respectively, and most patients received a non-standard chemotherapy regimen. Nonetheless, standard chemotherapy (anthracycline and taxane-based) schedules were used in the Chinese trial [19] and the Shaitelman et al [32] study with suitable side effects outcomes. Although these trials [19, 32] had a shorter follow-up, current evidence of using conventional dose radiation therapy after breast-conserving surgery and mastectomy (with or without regional nodal irradiation) comes from randomized trials that mostly used a non-standard chemotherapy regime as well [3, 4]. Moreover, the START trials’ data demonstrated that the rates of ischemic heart disease and lung fibrosis are remarkably low (less than 2%) [33]. Even though these values can be higher than those noticed by other authors using modern diagnostic instruments, patients rarely developed symptoms consistent with pulmonary and cardiac side effects that required medical intervention [34-37].
The treatment-related side effects are possibly more associated with the radiation therapy technique than the used dose scheme. The estimated absolute risks for second cancer or heart disease (with cardiac mortality) from modern radiation therapy were very low compared to older therapies [38]. Thus, the hypothesis of contemporary homogeneously delivered volume-based radiation therapy techniques can be applied to understanding that treatment effects should be undistinguishable regardless of the target volumes. Data from prospective and retrospective studies also showed that hypofractionated post-mastectomy radiation therapy with or without regional nodal irradiation is safe, with low rates of side effects and suitable local control results [22, 37, 39-48].
Many patients undergo implant and autologous breast reconstruction before and after RT [49]. Several studies demonstrated that radiation therapy might lead to post-operative increase of capsular contracture rates and infection. In some situations, this could result in the removal of the implant [50-53]. Interestingly, besides the fact that implant-based reconstruction significantly affected the decision for choosing the fractionation scheme, flap-based reconstruction was a categorical contraindication for the higher dose per fraction schedule in most responses. In our opinion, this finding reflects a higher fear of complications with irradiation of reconstructed breasts with higher doses per fraction, mainly with autologous tissue, that however should be demystified. And, if there are any concerns, they should be mostly related to implant-based reconstruction. It is important to highlight that none of the published randomized phase III trials that formally compared the results of moderate hypofractionation to conventionally fractionated irradiation [13, 15-19] included patients with implant and autologous breast reconstruction. On the other hand, all of these trials showed that most breast side effects that could be strongly associated with radiation-related toxicities in implant and autologous breast reconstruction (skin retraction, fibrosis and breast shrinkage) were lower or, at least, equal in patients who underwent hypofractionation. A retrospective experience from a Korean group [2] demonstrated that there were no differences in late effects regarding the timing and type of breast reconstruction related to both radiation therapy fractionation schemes. Additionally, there is no randomized phase III trial that validated the use of a conventional radiation dose after breast reconstruction. Historically, the conventional dose has been empirically used when breast reconstruction techniques were described [54, 55]. Over the past decades, in clinical practice, once the treatment was performed with conventional doses, there was the simple incorporation of reconstructive surgeries in this scenario. Thus, the available medical evidence of using hypofractionation or conventional fractionated irradiation can be considered equivalent in patients with breast reconstruction.
Even though there is high level evidence to support the use of hypofractionation-based radiation therapy for breast cancer and its use may have significant financial benefits, it fails at being widely adopted in many countries [56]. This might be explained because the adoption of shorter treatment regimens may have significant implications on health economics, resulting in a financial loss depending on the reimbursement arrangement [57]. While in countries like the Netherlands and the United Kingdom (where reimbursement is independent from the number of fractions), hypofractionated breast irradiation is used by most centres for nearly all patients (except in the case of re-irradiation and concomitant chemoradiation). However, in the more reimbursement-driven models with payment per fraction including Germany, France, the USA, a lot of reluctance exists towards applying hypofractionation in daily practice [57]. Despite the reimbursement issue being an important factor for the adoption of hypofractionation in clinical practice in many countries, our study showed that this factor is considered in a limited number of respondents.
Our study has some limitations, most notably limited sampling and respondent availability. Even though the survey participants offer some perception about moderately hypofractionated post-operative radiation therapy clinical practice for breast cancer patients in LAC, the responders are self-selected. So, the results would not be robustly representative, illustrating a lack of radiation oncology community representation. However, most responders (54.5%) declared that they treated at least 11 breast cancer patients per month, and the great majority (96.6%), at least five patients per month (Table 1). So, the sample seems to represent a community with experience in breast cancer treatment. In addition, the ones that dedicate less time of their clinical practice to breast cancer are those that would choose other fractionation scheme rather than the hypofractionated one (Table 2). Therefore, our study can positively stimulate radiation oncologists in their reflections and decision-making on whether or not to accept hypofractionated breast radiation therapy in their daily clinical practice, in order to turn the road towards higher convenience for the patients and less societal costs. The adoption of hypofractionation in emerging countries is not just a subject of cost-effectiveness but one of entrance to improved medical health assistance and patient survivorship [58, 59].
In conclusion, even though moderately hypofractionated post-operative radiation therapy for breast cancer is considered a new standard to many patients, its unrestricted and widely application in clinical practice across LAC still faces some reluctance.