Background: To date, in breast cancer (BC) treatment, adjuvant chemotherapy (A-CT) has preceded adjuvant radiotherapy (A-RT). In the last twenty years, the adjuvant treatment of BC has quickly evolved due to better knowledge of its molecular biology, genetic profile, and α/β ratio of 3/4 Gy for tumor and normal tissue radiosensitivity. Thus, new schedules with hypofractionated radiotherapy have been tested, and a third generation of A-CT has been introduced, raising the question of whether it is time to rethink the sequencing between these two approaches. Methods: In the last 20 years, many attempts have been made worldwide to optimize the best sequencing strategy between these two approaches in terms of sequential CT-RT and RT-CT and concomitant and sandwich modalities using drugs and schedules. This paper presents a comprehensive review of the state of the art, analyzing all the available studies to assess the sequencing between A-CT and A-RT with different generations of chemotherapy schedules. Results: More than 8000 patients from 30 studies treated with adjuvant chemotherapy and whole breast radiotherapy who were enrolled in randomized, retrospective, and prospective studies were analyzed. Sequential, concomitant, and sandwich modalities of chemotherapy with conventional or hypofractionated RT schedules from the most important studies were included. The most used sequence was adjuvant chemotherapy followed by conventional or hypofractionated radiotherapy. In the concomitant approach, i.v. CMF has been the most important adopted schedule, while the concomitant use of anthracyclines and taxanes with conventional or hypofractionated radiotherapy has been found to be more toxic. One study analyzed the benefit in terms of reducing adjuvant treatment time with upfront hypofractionated radiotherapy and third-generation chemotherapy. Conclusions: At present, the best sequencing strategy has not yet been defined. This comprehensive review is a journey among the most important randomized, retrospective, and prospective studies that highlights the past, current, and novel time sequencing proposals between A-CT and A-RT to assess the state of the art and provide useful information for future adjuvant approaches in breast cancer treatment.

Up to now in breast cancer (BC) treatment, adjuvant chemotherapy (A-CT) precedes adjuvant radiotherapy (A-RT). It’s beyond question that A-RT improves local control while A-CT improves the Disease Free Survival (DFS) due to the reduction of metastatic distant recurrences. Taken togheter these two approaches impact favourably on the reduction of breast cancer mortality. In the last twenty years, the adjuvant treatment of BC has evolved quickly due to a better knowledge of its molecular biology , genetic prohile and its α/β ratio 3 / 4 Gy for the tumor and normal tissues radiosensitivity. Thus new schedules with hypofractionated radiotherapy have been tested and third generation of A-CT have been introduced leading to a better survival rate but a further delay in A-RT starting, raising the question to rethink the sequencing between these two approaches. However the sequencing timing between these two approaches still remains unchanged with A-CT before A-RT as the standard of care. Many attempts have been provided in order to optimize this sequencing. This comprehensive review is a journey among randomised, retrospective and prospective studies which highlights the past, the current and the novelties on timing sequencing proposals between these two modalities to assess the state of art. Sequential, concomitant and sandwitch modalities of chemotherapy with conventional or hypofractionated RT schedules from the most important studies will be analysed in this review.

Over the past two decades, interest in prone-position whole breast irradiation (WBI) as an effective and practical alternative to supine treatment has been growing a lot. Although solid scientific data has provided evidence of substantial dosimetric benefit with decreased toxicity, there is still conflict in the radiotherapy community over whether to adopt prone-position WBI as a valid alternative to supine radiotherapy (RT) in routine clinical practice. A large number of prone trials have been conducted to assess and address concerns related to prone treatment in large and pendulous breasts and in left and right breast cancer (BC), nodal irradiation, and its reproducibility with deep inspiration breath hold (DIBH) delivery with photons or protons. Appropriate atlases have been defined to improve prone nodal irradiation. Additionally, more comfortable customized immobilization couches have been constructed to permit IMRT beams and VMAT arrangements with modern LINACs. Although our search in literature databases shows a growing body of evidence from the past two decades on this issue, prone WBI is still underused. Given the paradox of the advances and benefits of this positioning and the lack of drive in the radiotherapy community towards its clinical implementation, the purpose of this comprehensive review is to evaluate the true advantages of this position in real life and contextualize it in scenarios like large breasts, left-sided breast cancer, and nodal irradiation to encourage its implementation in clinical practice.

Whole breast radiotherapy in adjuvant breast cancer (BC) treatment has been commonly delivered in supine positioning for more than 50 years. Its widespread use is related to the broad availability of simple and common breast board immobilization devices, which exploit the natural recumbent position of the body with arms above the head, the good match with linac tables and well-established set up procedures. However, in scenarios like painful arm discomfort in patients with post-surgery arm or arthritic limitation, unfavorable chest geometry like pectus excavatum (PE), large and pendulous breasts in obese women and cardiac morbidity in left sided BC, supine position seems very uncomfortable for patients and troublesome for radiation oncologists. The question is how to proceed when supine IMRT or DIBH are ineffective strategies? Alternative positions have been analyzed over the past twenty years, starting with a lot of trials testing prone positioning variants with and without DIBH, lateral decubitus or upright standing radiotherapy. A better recognition of new treatment position options in BC adjuvant therapy may provide more opportunities for personalized radiotherapy in this population, to ensure they receive an appropriate, safe and comfortable treatment.

Whole breast radiotherapy in adjuvant breast cancer (BC) treatment is commonly delivered in supine positioning since more than 50 years ago. Its widespread use is related to the broad availability of simply and common breast board immobilization devices which exploit the natural recumbent position of the body with arms above the head, the good match with linac tables and well established set up procedures. However, several criticisms have been raised over time in case of scenarios like painful arm discomfort in patients with post-surgery arm or arthritic limitation, unfavorable chest geometry like pectus excavatum, large and pendulous breasts in obese women, cardiac morbidity in left sided BC. In these scenarios supine position seems very uncomfortable for patients and troublesome for radiation oncologists. Heart dosimetry in pectus excavatum (PE) and left sided breasts, breast size and shape matter when DIBH is not allowed. In fact, not all patients are suitable DIBH candidates because of the limiting factors like obesity or pulmonary morbidities. Thus, adjuvant whole breast radiotherapy in supine positioning could be very critical. Alternative positions have been analyzed in these last twenty years starting from a lot of trials testing prone positioning variants with and without DIBH, lateral decubitus or up-right standing radiotherapy. Customized immobilization devices have been developed to make these alternative positions more comfortable and consistent with beams angles arrangements and modern RT delivery avoiding collisions with the device or the Linac. To standardize the target delineation in these positions, customized guidelines have been also provided and recently several atlas-based segmentation processes have been provided to reduce bias by incorporating an interobserver quality analysis. Researches and a better recognition of new treatment position options in BC adjuvant therapy may provide more opportunities for a personalized radiotherapy mainly in that population not suitable for supine RT, to ensure them an appropriate, safe and comfortable treatment.

Breast-conserving surgery followed by adjuvant whole-breast irradiation (WBI) remains the standard of care for patients with early-stage breast cancer. In this setting, irradiation of the tumor bed with an additional boost dose has historically been used to reduce the risk of ipsilateral breast tumor recurrence (IBTR). Major randomized trials established that boost irradiation improved local control, particularly in younger patients, but did not confer a consistent overall survival (OS) benefit and was associated with increased late toxicity, like fibrosis, and poorer cosmetic outcomes as well. More recent evidence, including systematic reviews and contemporary consensus recommendations, suggests that boost irradiation may be safely omitted in selected low-risk patients, especially when the estimated absolute reduction in 10-year local recurrence is less than 3%. At the same time, the routine use of boost irradiation has been challenged by modern systemic therapy treatments questioning if boost could be really omitted in this set. Further advances in radiation techniques are redefining the scheduling and timing of boost administration, shifting from a conventional fractionation to hypofractionation and from the sequential (SEB) to simultaneous delivery with simultaneous integrated boost (SIB). In light of increasingly minimally invasive surgery and a de-escalation RT policy, unresolved clinical issues still remain about the management of positive or close margins and the role of boost irradiation in ductal carcinoma in situ. This narrative review summarizes the biological rationale, historical trial evidence, and recent literature addressing these evolving scenarios. Current evidence supports a more individualized approach to boost prescription based on recurrence risk, patient age, tumor biology, margin status, treatment techniques (surgery and radiotherapy), and patient preference.