The aim of this review is to give an overview of the results of prospective and retrospective studies using allogenic reconstruction and postmastectomy radiotherapy (PMRT) in breast cancer and to make recommendations regarding this interdisciplinary approach. A PubMed search was conducted to extract relevant articles from 2000 to 2024. The search was performed using the following terms: (breast cancer) AND (reconstruction OR implant OR expander) AND (radiotherapy OR radiation). Data from the literature on allogenic breast reconstruction and radiation are presented and discussed in relation to toxicity and cosmesis. Breast reconstruction is also feasible if PMRT is necessary. Patients need to be informed about the relevant risk of capsular fibrosis and implant failure. A planned reconstruction is no reason to forgo PMRT nor is an indication for PMRT a reason to forego implant-based breast reconstruction if desired by the patient. It is important to provide detailed information here to enable shared decision-making. There is still no clear consensus regarding implant-based reconstruction (IBR) and PMRT. However, in clinical practice, both a one-stage (immediate “implant-direct” IBR) procedure with PMRT up to the final implant and a two-stage (immediate-delayed IBR) procedure with PMRT up to the tissue expander (TE) and later exchange of the TE are used; both approaches have their specific advantages and disadvantages. Depending on patient-specific factors and the surgeon’s experience and estimates, both IBR procedures are also possible in combination with PMRT. When using a TE/implant approach, completing skin stretching by adequately filling the expander before PMRT may be favorable. This approach is particularly practical when adjuvant chemotherapy is planned but may lead to postponement of radiotherapy when primary systemic therapy is given. According to the latest data, moderate hypofractionation also appears to be safe in the context of the IBR approach. It is important to have a closely coordinated interdisciplinary approach and to fully inform patients about the increased rate of potential side effects.

Background:Amino acid PET using the tracer O-(2-[18F]fluoroethyl)-l-tyrosine (FET) is one of the most reliable imaging methods for detecting glioma recurrence. Here, we hypothesized that functional MR connectivity between the metabolic active recurrent tumor region and resting-state networks of the brain could serve as a prognostic imaging biomarker for overall survival (OS). Methods:The study included 82 patients (26-81 years; median Eastern Cooperative Oncology Group performance score, 0) with recurrent gliomas following therapy (WHO-CNS 2021 grade 4 glioblastoma, n = 57; grade 3 or 4 astrocytoma, n = 12; grade 2 or 3 oligodendroglioma, n = 13) diagnosed by FET PET simultaneously acquired with functional resting-state MR. Functional connectivity (FC) was assessed between tumor regions and 7 canonical resting-state networks. Results:WHO tumor grade and IDH mutation status were strong predictors of OS after recurrence (P < .001). Overall FC between tumor regions and networks was highest in oligodendrogliomas and was inversely related to tumor grade (P = .031). FC between the tumor region and the dorsal attention network was associated with longer OS (HR, 0.88; 95%CI, 0.80-0.97; P = .007), and showed an independent association with OS (HR, 0.90; 95%CI, 0.81-0.99; P = .033) in a model including clinical factors, tumor volume and MGMT. In the glioblastoma subgroup, tumor volume and FC between the tumor and the visual network (HR, 0.90; 95%CI, 0.82-0.99, P = .031) were independent predictors of survival. Conclusions:Recurrent gliomas exhibit significant FC to resting-state networks of the brain. Besides tumor type and grade, high FC between the tumor and distinct networks could serve as independent prognostic factors for improved OS in these patients.

Abstract BACKGROUND Functional connectivity between glioma-infiltrated brain tissue and remote cortical regions has been linked to overall survival (OS) in patients with newly diagnosed glioblastoma. We studied the association of functional connectivity between tumor and resting-state networks and OS in patients with recurrent gliomas. PATIENTS AND METHODS The study included 82 patients (26-81 years; median ECOG performance score, 0) with recurrent gliomas (grade 4 glioblastoma, n=57; grade 3 and 4 astrocytoma, n=12; grade 2 and 3 oligodendroglioma, n=13) who had undergone first-line therapy. Diagnosis of recurrence was confirmed by amino acid PET using the tracer O-(2-[18F]-fluoroethyl)-L-tyrosine (FET). FET PET and resting-state functional MRI were simultaneously acquired on a 3T hybrid PET/MR scanner. We performed a seed-based dual regression analysis to determine the functional connectivity between metabolically active tumors and seven canonical resting state networks. RESULTS Average functional connectivity was highest in oligodendrogliomas (z-score, 6.9±1.9) and was inversely related to the tumor grade (p=0.031). Univariate Cox regression analysis revealed a significant (p<0.05) positive association between OS and tumor connectivity with the visual, somatomotor, and dorsal attention networks. Subsequent stepwise multivariate Cox regression analysis refined this association to the dorsal attention network alone (HR, 0.88; 95% CI, 0.80-0.97; p=0.007). Patients with the highest functional connectivity (z-score>8.3, n=21) had a median OS of 31.4 months, while those with the lowest functional connectivity (z-score<4.3, n=21) had 10.6 months. Functional connectivity between tumors and the dorsal attention network showed an independent association with OS (HR, 0.90; 95% CI, 0.81-0.99; p=0.033) in a multivariate model, including various prognostic factors. CONCLUSION Recurrent gliomas exhibit significant functional connectivity to most of the major known resting-state networks, highest in oligodendrogliomas. The data suggest that high functional connectivity between the tumor and the dorsal attention network is an independent prognostic factor for improved OS.

The aim of this review was to evaluate the existing evidence for radiotherapy for brain metastases in breast cancer patients and provide recommendations for the use of radiotherapy for brain metastases and leptomeningeal carcinomatosis. For the current review, a PubMed search was conducted including articles from 01/1985 to 05/2023. The search was performed using the following terms: (brain metastases OR leptomeningeal carcinomatosis) AND (breast cancer OR breast) AND (radiotherapy OR ablative radiotherapy OR radiosurgery OR stereotactic OR radiation). Despite the fact that the biological subtype of breast cancer influences both the occurrence and relapse patterns of breast cancer brain metastases (BCBM), for most scenarios, no specific recommendations regarding radiotherapy can be made based on the existing evidence. For a limited number of BCBM (1–4), stereotactic radiosurgery (SRS) or fractionated stereotactic radiotherapy (SRT) is generally recommended irrespective of molecular subtype and concurrent/planned systemic therapy. In patients with 5–10 oligo-brain metastases, these techniques can also be conditionally recommended. For multiple, especially symptomatic BCBM, whole-brain radiotherapy (WBRT), if possible with hippocampal sparing, is recommended. In cases of multiple asymptomatic BCBM (≥ 5), if SRS/SRT is not feasible or in disseminated brain metastases (> 10), postponing WBRT with early reassessment and reevaluation of local treatment options (8–12 weeks) may be discussed if a HER2/Neu-targeting systemic therapy with significant response rates in the central nervous system (CNS) is being used. In symptomatic leptomeningeal carcinomatosis, local radiotherapy (WBRT or local spinal irradiation) should be performed in addition to systemic therapy. In patients with disseminated leptomeningeal carcinomatosis in good clinical condition and with only limited or stable extra-CNS disease, craniospinal irradiation (CSI) may be considered. Data regarding the toxicity of combining systemic therapies with cranial and spinal radiotherapy are sparse. Therefore, no clear recommendations can be given, and each case should be discussed individually in an interdisciplinary setting.

It is known that the diagnosis of breast cancer often causes anxiety and depression. Radiotherapy of the breast as an obligatory part of a breast-conserving treatment concept can markedly increase these psychological symptoms in many, but not all patients. In this clinical observational study, we aimed at identifying cognitive, health-related and social factors that may either enhance or reduce the emergence of anxiety and depression. Using a longitudinal study design with 25 women (mean age: 52.9 years; SD = 10.6; age range 29–70 years) with a first diagnosis of nonmetastatic breast cancer, measures of anxiety, depression, situational emotional states, intelligence, and aspects of social frameworks were assessed before, during, and after radiotherapy of the breast. At 4 time-points, standard and self-constructed questionnaires were used to assess the course of anxiety and depressive symptoms across the radiotherapy intervention. We found that anxiety is highest immediately before the start of radiation therapy, while the anxiety level was lowest on the day that therapy was completed. Anxiety and depression were enhanced in women with a lifetime history of chronic diseases at all time points of measurement. Moreover, women with high intelligence and low social support had stronger symptoms of depression than women with low intelligence and a stable family background at some time points of measurement. The degree of anxiety was neither related to intelligence nor to social support. For the first time, we demonstrate empirical pilot data on cognitive and social modulators of anxiety and depression in women with breast cancer over the course of radiotherapy. Our results may help to optimize clinical procedures and thereby reduce symptoms of anxiety and depression in these patients.

O-(2-[18F]fluoroethyl)-L-tyrosine (FET) is a widely used amino acid tracer for positron emission tomography (PET) imaging of brain tumours. This retrospective study and survey aimed to analyse our extensive database regarding the development of FET PET investigations, indications, and the referring physicians’ rating concerning the role of FET PET in the clinical decision-making process. Between 2006 and 2019, we performed 6534 FET PET scans on 3928 different patients against a backdrop of growing demand for FET PET. In 2019, indications for the use of FET PET were as follows: suspected recurrent glioma (46%), unclear brain lesions (20%), treatment monitoring (19%), and suspected recurrent brain metastasis (13%). The referring physicians were neurosurgeons (60%), neurologists (19%), radiation oncologists (11%), general oncologists (3%), and other physicians (7%). Most patients travelled 50 to 75 km, but 9% travelled more than 200 km. The role of FET PET in decision-making in clinical practice was evaluated by a questionnaire consisting of 30 questions, which was filled out by 23 referring physicians with long experience in FET PET. Fifty to seventy per cent rated FET PET as being important for different aspects of the assessment of newly diagnosed gliomas, including differential diagnosis, delineation of tumour extent for biopsy guidance, and treatment planning such as surgery or radiotherapy, 95% for the diagnosis of recurrent glioma, and 68% for the diagnosis of recurrent brain metastases. Approximately 50% of the referring physicians rated FET PET as necessary for treatment monitoring in patients with glioma or brain metastases. All referring physicians stated that the availability of FET PET is essential and that it should be approved for routine use. Although the present analysis is limited by the fact that only physicians who frequently referred patients for FET PET participated in the survey, the results confirm the high relevance of FET PET in the clinical diagnosis of brain tumours and support the need for its approval for routine use.

Evidence from a few small randomized trials and retrospective cohorts mostly including various tumor entities indicates a prolongation of disease free survival (DFS) and overall survival (OS) from local ablative therapies in oligometastatic disease (OMD). However, it is still unclear which patients benefit most from this approach. We give an overview of the several aspects of stereotactic body radiotherapy (SBRT) in extracranial OMD in breast cancer from a radiation oncology perspective. A PubMed search referring to this was conducted. An attempt was made to relate the therapeutic efficacy of SBRT to various prognostic factors. Data from approximately 500 breast cancer patients treated with SBRT for OMD in mostly in small cohort studies have been published, consistently indicating high local tumor control rates and favorable progression-free (PFS) and overall survival (OS). Predictors for a good prognosis after SBRT are favorable biological subtype (hormone receptor positive, HER2 negative), solitary metastasis, bone-only metastasis, and long metastasis-free interval. However, definitive proof that SBRT in OMD breast cancer prolongs DFS or OS is lacking, since, with the exception of one small randomized trial (n = 22 in the SBRT arm), none of the cohort studies had an adequate control group. Further studies are needed to prove the benefit of SBRT in OMD breast cancer and to define adequate selection criteria. Currently, the use of local ablative SBRT should always be discussed in a multidisciplinary tumor board.

We thank Dr. Loap and Dr. Kirova for their thoughtful comments.In principle, we can support the comments.We agree that with ultra-hypofractionation, such as the regimens tested in the FAST and FAST-Forward trials [1, 2], caution should be exercised with regard to cardiac constraints.The recommended dose constraints [3] cannot simply be adopted for ultra-hypofractionation in the case of breast cancer radiotherapy.The FAST-Forward trial protocol recommended to keep the volume of the heart receiving 7 Gy (Gray) and 1.5 Gy to less than 5% and less than 30%, respectively.So far, only 6-year data are available for the FAST-Forward trial with regard to cardiac toxicity.This is too early to be able to make reliable recommendations regarding cardiac side effects.

Background:During the last decade, partial breast irradiation (PBI) has gained traction as a relevant treatment option for patients with early-stage low-risk breast cancer after breast-conserving surgery. The TARGIT-A prospective randomized trial compared a "risk-adapted" intraoperative radiotherapy (IORT) approach with 50-kv X-rays (INTRABEAM®) as the PBI followed by optional whole-breast irradiation (WBI) and conventional adjuvant WBI in terms of observed 5-year in-breast recurrence rates. Recently, long-term data were published. Since the first publication of the TARGIT-A trial, a broad debate has been emerged regarding several uncertainties and limitations associated with data analysis and interpretation. Our main objective was to summarize the data, with an emphasis on the updated report and the resulting implications.Summary:From our point of view, the previously unresolved questions still remain and more have been added, especially with regard to the study design, a change in the primary outcome measure, the significant number of patients lost to follow-up, and the lack of a subgroup analysis according to risk factors and treatment specifications.Key Message:Taking into account the abovementioned limitations of the recently published long-term results of the TARGIT-A trial, the German Society of Radiation Oncology (DEGRO) Breast Cancer Expert Panel adheres to its recently published recommendations on PBI: "the 50-kV system (INTRABEAM) cannot be recommended for routine adjuvant PBI treatment after breast-conserving surgery."

Moderate hypofractionation is the standard of care for adjuvant whole-breast radiotherapy after breast-conserving surgery for breast cancer. Recently, 10-year results from the FAST and 5‑year results from the FAST-Forward trial evaluating adjuvant whole-breast radiotherapy in 5 fractions over 5 weeks or 1 week have been published. This article summarizes recent data for moderate hypofractionation and results from the FAST and FAST-Forward trial on ultra-hypofractionation. While the FAST trial was not powered for comparison of local recurrence rates, FAST-Forward demonstrated non-inferiority for two ultra-hypofractionated regimens in terms of local control. In both trials, the higher-dose experimental arms resulted in elevated rates of late toxicity. For the lower dose experimental arms of 28.5 Gy over 5 weeks and 26 Gy over 1 week, moderate or marked late effects were similar in the majority of documented items compared to the respective standard arms, but significantly worse in some subdomains. The difference between the standard arm and the 26 Gy of the FAST-Forward trial concerning moderate or marked late effects increased with longer follow-up in disadvantage of the experimental arm for most items. For now, moderate hypofractionation with 40–42.5 Gy over 15–16 fractions remains the standard of care for the majority of patients with breast cancer who undergo whole-breast radiotherapy without regional nodal irradiation after breast-conserving surgery.

Purpose This consensus statement from the Breast Cancer Working Group of the German Society for Radiation Oncology (DEGRO) aims to define practical guidelines for accelerated partial-breast irradiation (APBI). Methods Recent recommendations for relevant aspects of APBI were summarized and a panel of experts reviewed all the relevant literature. Panel members of the DEGRO experts participated in a series of conferences, supplemented their clinical experience, performed a literature review, and formulated recommendations for implementing APBI in clinical routine, focusing on patient selection, target definition, and treatment technique. Results Appropriate patient selection, target definition for different APBI techniques, and basic rules for appropriate APBI techniques for clinical routine outside of clinical trials are described. Detailed recommendations for APBI in daily practice, including dose constraints, are given. Conclusion Guidelines are mandatory to assure optimal results of APBI using different techniques.

Purpose Following neoadjuvant chemotherapy for breast cancer, postoperative systemic therapy, also called post-neoadjuvant treatment, has been established in defined risk settings. We reviewed the evidence for sequencing of postoperative radiation and chemotherapy, with a focus on a capecitabine and trastuzumab emtansine (T-DM1)-based regimen. Methods A systematic literature search using the PubMed/MEDLINE/Web of Science database was performed. We included prospective and retrospective reports published since 2015 and provided clinical data on toxicity and effectiveness. Results Six studies were included, five of which investigated capecitabine-containing regimens. Of these, four were prospective investigations and one a retrospective matched comparative analysis. One randomized prospective trial was found for T‑DM1 and radiotherapy. In the majority of these reports, radiation-associated toxicities were not specifically addressed. Conclusion Regarding oncologic outcome, the influence of sequencing radiation therapy with maintenance capecitabine chemotherapy in the post-neoadjuvant setting is unclear. Synchronous administration of capecitabine is feasible, but reports on possible excess toxicities are partially conflicting. Dose reduction of capecitabine should be considered, especially if normofractionated radiotherapy is used. In terms of tolerance, hypofractionated schedules seem to be superior in terms of toxicity in concurrent settings. T‑DM1 can safely be administered concurrently with radiotherapy.

Background: Gene expression assays are increasingly used for decision-making regarding adjuvant chemotherapy in patients with hormone receptor-positive, HER2-negative breast cancer. There are some clinical situations in which there is also a need for better prognostic and predictive markers to better estimate the amount of benefit from adjuvant radiotherapy. The rising availability of gene expression analyses prompts the question whether their results can also be used to guide clinical decisions regarding adjuvant radiation. Summary: Multiple studies suggest a correlation between results from gene expression assays and locoregional recurrence rates. Only few publications addressed the predictive value of results from gene expression analysis for the role of adjuvant radiotherapy in different settings. Key Messages: To date, the available evidence on the possible predictive value of gene expression assays for radiotherapy does not support their inclusion into the decision-making process for adjuvant radiation. This is due to methodological weaknesses and limitations regarding patient selection, the nonrandomized design of all studies in terms of radiotherapy use, and limited availability of tissue from prospective trials. Thus, utilization of the present knowledge for clinical indication of radiotherapy should be very cautious.

Background Skin-sparing (SSME) and nipple-sparing mastectomy (NSME) were developed to improve the cosmetic results for breast cancer (BC) patients, both allowing for immediate breast reconstruction. Recommendations for post-mastectomy radiotherapy (PMRT) are primarily derived from trials where patients were treated by standard mastectomies. Due to their more conservative character, SSME and especially NSME potentially leave more glandular tissue at risk for subclinical disease. Methods Rates and sites of locoregional failures following SSME and NSME plus/minus reconstruction were analyzed regarding tumor stage and biological risk factors. In particular, the role of PMRT in "intermediate"-risk and early stage high-risk breast cancer patients was revisited. Implications on targeting and dose delivery of PMRT were critically reviewed. Results The value of PMRT in stage III BC remains undisputed. For node-negative BC patients, the majority of reports classify clinical and biological features such as tumor size, close surgical margins, premenopausal status, multicentricity, lymphangiosis, triple-negativity, HER2-overexpression, and poor tumor grading as associated with higher rates of locoregional relapse, thus, building an "intermediate" risk group. Surveys revealed that the majority of radiation oncologists use risk-adaptive models also considering the number of coinciding factors for the estimation of recurrence probability following SSME and NSME. Constellations with a 10-year locoregional recurrence risk of >10% are usually triggering the indication for PMRT. There was no common belief that the amount of residual tissue, e.g., tissue thickness over flaps, serves as additional decision aid. Modern treatment planning can ensure optimal dose distribution for PMRT in almost all patients with SSME. There are no reliable data supporting a reduction of the treatment volume from the CTV chest wall, e.g., to the nipple-areola complex, to the dorsal aspect behind the implant volume, the pectoralis muscle, nor the regional interpectoral, axillary, or complete regional lymph nodes only. The omission of a skin bolus in intermediate-risk BC does not compromise oncological safety. Conclusions For intermediate-risk as well as early stage high-risk BC patients, the DEGRO Breast Cancer Expert Panel recommends the use of PMRT following SSME and NSME when a 10-year locoregional recurrence risk is likely to be greater than 10%, as estimated by clinical and biological risk factors. Subvolume-only radiation is discouraged outside of trials. The impact of adequate systemic treatment and the value of radiotherapy on optimal locoregional tumor control, with the goal of less than 5% LRR at 10-years follow-up, has to be verified in prospective trials.

Purpose The aim of this review was to analyze the respective efficacy of various heart-sparing radiotherapy techniques. Material andmethods Heart-sparing can be performed in three different ways in breast cancer radiotherapy: by seeking to keep the heart out of treated volumes (i.e. by prone position or specific breathing techniques such as deep inspiration breath-hold [DIBH] and/or gating), by solely irradiating a small volume around the lumpectomy cavity (partial breast irradiation, PBI), or by using modern radiation techniques like intensity-modulated radiation therapy (IMRT), volumetric modulated arc therapy (VMAT) or protons. This overview presents the available data on these three approaches. Results Studies on prone position are heterogeneous and most trials only refer to patients with large breasts; therefore, no definitive conclusion can be drawn for clinical routine. Nonetheless, there seems to be a trend toward better sparing of the left anterior descending artery in supine position even for these selected patients. The data on the use of DIBH for heart-sparing in breast cancer patients is consistent and the benefit compared to free-breathing is supported by several studies. In comparison with whole breast irradiation (WBI), PBI has an advantage in reducing the heart dose. Of note, DIBH and PBI with multicatheter brachytherapy are similar with regard to the dose reduction to heart structures. WBI by IMRT/VMAT techniques without DIBH is not an effective strategy for heart-sparing in breast cancer patients with "standard" anatomy. A combination of DIBH and IMRT may be used for internal mammary radiotherapy. Conclusion Based on the available findings, the DEGRO breast cancer expert panel recommends the use of DIBH as the best heart-sparing technique. Nonetheless, depending on the treatment volume and localization, other techniques may be employed or combined with DIBH when appropriate.

BACKGROUND:Late cardiac toxicities caused by (particularly left-sided) breast radiotherapy (RT) are now recognized as rare but relevant sequelae, which has prompted research on risk structure identification and definition of threshold doses to heart subvolumes. The aim of the present review was to critically discuss the clinical evidence on late cardiac reactions based on dose-dependent outcome reports for mean heart doses as well as doses to cardiac substructures.METHODS:A literature review was performed to examine clinical evidence on radiation-induced heart toxicities. Mean heart doses and doses to cardiac substructures were focused upon based on dose-dependent outcome reports. Furthermore, an overview of radiation techniques for heart protection is given and non-radiotherapeutic aspects of cardiotoxicity in the multimodal setting of breast cancer treatment are discussed.RESULTS:Based on available findings, the DEGRO breast cancer expert panel recommends the following constraints: mean heart dose< 2.5 â Gy; DmeanLV (mean dose left ventricle) â< 3â Gy; V5LV (volume of LV receiving≥ 5â Gy) â< 17%; V23LV (volume of LV receiving≥ 23â Gy) â< 5%; DmeanLAD (mean dose left descending artery) â< 10â Gy; V30LAD (volume of LAD receiving≥ 30â Gy) â< 2%; V40LAD (volume of LAD receiving≥ 40â Gy) â< 1%.CONCLUSION:In addition to mean heart dose, breast cancer RT treatment planning should also include constraints for cardiac subvolumes such as LV and LAD. The given constraints serve as a clinicians' aid for ensuring adequate heart protection. The individual decision between sufficient protection of …