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Radiation therapy plays an important role in the multidisciplinary management of breast cancer. Recent years have seen improvements in breast cancer survival and a greater appreciation of potential long-term morbidity associated with the dose and volume of irradiated organs. Proton therapy reduces the dose to nontarget structures while optimizing target coverage. However, there remain additional financial costs associated with proton therapy, despite reductions over time, and studies have yet to demonstrate that protons improve upon the treatment outcomes achieved with photon radiation therapy. There remains considerable heterogeneity in proton patient selection and techniques, and the rapid technological advances in the field have the potential to affect evidence evaluation, given the long latency period for breast cancer radiation therapy recurrence and late effects. In this consensus statement, we assess the data available to the radiation oncology community of proton therapy for breast cancer, provide expert consensus recommendations on indications and technique, and highlight ongoing trials' cost-effectiveness analyses and key areas for future research. (c) 2021 Elsevier Inc. All rights reserved.

Delineation of target and 'organ at risk' volumes is a critical part of modern radiation therapy planning, the next essential step after deciding the indication, patient discussion and image acquisition. Adoption of volume-based treatment planning for non-metastatic breast cancer has increased greatly along with the use of improved planning techniques, essential for modern therapy. However, identifying the vol-umes on a planning CT is no easy task. The current paper is written by ESTRO's breast course faculty, pro-viding tricks and tips for target volume definition and delineation for optimal postoperative breast cancer irradiation. (c) 2021 Elsevier B.V. All rights reserved. Radiotherapy and Oncology xxx (2021) xxx-xxx

Introduction: The aim of the present study was to estimate the impact of the addition of internal mammary chain (IMC) irradiation in node-positive left-sided breast cancer (BC) patients undergoing regional nodal irradiation (RNI) and comparatively evaluate excess relative and absolute risks of radiation-induced lung cancer/BC and ischaemic heart disease for intensity-modulated radiotherapy (IMRT) versus 3D conformal radiotherapy (3D-CRT). Methods: Four treatment plans were created (3D-CRT and IMRT –/+ IMC) for each of the 10 evaluated patients, and estimates of excess relative risk (ERR) and 10-year excess absolute risk (EAR) were calculated for radiation-induced lung cancer/BC and coronary events using linear, linear-exponential and plateau models. Results: The addition of IMC irradiation to RNI significantly increased the dose exposure of the heart, lung and contralateral breast using both techniques, increasing ERR for secondary lung cancer (58 vs. 44%, p = 0.002), contralateral BC (49 vs. 31%, p = 0.002) and ischaemic heart disease (41 vs. 27%, p = 0.002, IMRT plans). IMRT significantly reduced the mean cardiac dose and mean lung dose as compared to 3D-CRT, decreasing ERR for major coronary events (64% 3D-CRT vs. 41% IMRT, p = 0.002) and ERR for secondary lung cancer (75 vs. 58%, p = 0.004) in IMC irradiation, without a significant impact on secondary contralateral BC risks. Conclusion: Although IMC irradiation has been shown to increase survival rates in node-positive BC patients, it increased dose exposure of organs at risk in left-sided BC, resulting in significantly increased risks for secondary lung cancer/contralateral BC and ischaemic heart disease. In this setting, the adoption of IMRT seems advantageous when compared to 3D-CRT.

Aim To determine whether the addition of regional nodal irradiation (RNI) to whole-breast irradiation (WBI) would improve outcomes over WBI alone in T1-2N1 breast cancer after breast-conserving surgery (BCS) and adjuvant systematic therapy. Methods Data were obtained from two randomized controlled trials (NCT00174655 and NCT00312208). Univariate and multivariate Cox-regression analysis were performed to investigate predictors for overall survival and disease-free survival. A 1:1 propensity score matching (PSM) analysis was applied to eliminate selection bias. Results With median follow-up 80 months (range: 3–155 months), the 5-year local regional recurrence in the WBI group was 2% vs. 5% (p = 0.28) in the WBI + supraclavicular radiotherapy, and the rate of 5-year distant metastasis in the WBI group was 7% vs. 13% in the WBI + supraclavicular radiotherapy (p = 0.0748); In addition, the 5-year local regional recurrence in the WBI group was 3% vs. 9% (p = 0.19) in the WBI + internal mammary irradiation (IMI); However, the rate of 5-year distant metastasis in the in the WBI group was significantly lower than that in the WBI + IMI (8% vs. 24%, p = 0.036). After PSM, cox-regression analysis indicated that neither RNI nor IMI in combination with WBI in T1-2N1 breast cancer was associated with an improved overall survival and disease-free survival when compared to WBI alone. Conclusion The addition of RNI to WBI in T1-2N1 breast cancer after BCS and adjuvant systematic therapy did not improve outcomes in comparison with WBI alone. Further studies are still needed to identify patients who would most benefit from RNI in this patient population., Highlights • The addition of RNI to WBI in unselected T1-2N1 breast cancer after BCS and adjuvant systematic therapy does not significantly improve outcomes in comparison with WBI alone. • Early stage (pT1-2N1) breast cancer after BCS represents a diverse population. • An individualized risk analysis based on clinical-genomic models is recommended to identify patients who would benefits or omit from RNI in further prospective studies.

Ayfer Ay Eren,1 Mehmet Fuat Eren2 1Radiation Oncology Clinic, Kartal Dr. Lütfi Kırdar City Hospital, Istanbul, 34890, Turkey; 2Radiation Oncology Clinic, Marmara University Pendik Education and Research Hospital, Istanbul, 34899, TurkeyCorrespondence: Mehmet Fuat ErenMarmara University Pendik Education and Research Hospital, Radiation Oncology Clinic, Istanbul, 34899, TurkeyTel +90 530 690 05 04Email drmehmeteren@gmail.comBackground: This study aimed to examine the practice patterns of radiation oncologists in Turkey regarding radiotherapy to the regional lymph nodes, including internal mammary lymph nodes (IMNs), and identify the factors influencing their clinical decisions in breast cancer patients.Methods: A nationwide, 19-point questionnaire was sent to the physician members of the Turkish Society for Radiation Oncology (TROD).Results: In total, 165 radiation oncologists completed the survey, corresponding to a 27% response rate. Regional radiotherapy was used in 64.2% of the patients with 1– 3 axillary lymphatic involvement and unfavorable prognostic factors. In contrast, 61.2% of the respondents indicated that IMN should be included in the target volume for regional radiotherapy when the patient had one positive node after axillary lymph node dissection (ALND) in the inner quadrant and central region tumors. However, 71.5% of the respondents chose to include the IMN in the non-inner quadrant and non-central region tumors for patients with four or more positive nodes after ALND. The decision to offer internal mammary lymph node radiotherapy (IMNRT) varied widely and significantly among respondents, years in practice, and the rates of dedicating their clinical time to patients with breast cancer.Conclusion: The results of this survey revealed significant national variation in attitudes regarding the treatment of IMN. Thus, this study may also help document the impact of future studies on clinical practice.Keywords: survey, breast cancer, internal mammary lymph nodes, regional nodal irradiation, radiotherapy

Highlights • We establish selection criteria for the randomised DBCG Proton Trial. • DBCG proton selection criteria: mean heart dose ≥ 4 Gy and/or lung V17Gy/V20Gy ≥ 37%. • ~1 in 5 patients undergoing loco-regional radiotherapy will be eligible for the trial., Background and purpose Adjuvant radiotherapy of internal mammary nodes (IMN) improves survival in high-risk early breast cancer patients but inevitably leads to more dose to heart and lung. Target coverage is often compromised to meet heart/lung dose constraints. We estimate heart and lung dose when target coverage is not compromised in consecutive patients. These estimates are used to guide the choice of selection criteria for the randomised Danish Breast Cancer Group (DBCG) Proton Trial. Materials and methods 179 breast cancer patients already treated with loco-regional IMN radiotherapy from 18 European departments were included. If the clinically delivered treatment plan did not comply with defined target coverage requirements, the plan was modified retrospectively until sufficient coverage was reached. The choice of selection criteria was based on the estimated number of eligible patients for different heart and lung dose thresholds in combination with proton therapy capacity limitations and dose–response relationships for heart and lung. Results Median mean heart dose was 3.0 Gy (range, 1.1–8.2 Gy) for left-sided and 1.4 Gy (0.4–11.5 Gy) for right-sided treatment plans. Median V17Gy/V20Gy (hypofractionated/normofractionated plans) for ipsilateral lung was 31% (9–57%). The DBCG Radiotherapy Committee chose mean heart dose ≥ 4 Gy and/or lung V17Gy/V20Gy ≥ 37% as thresholds for inclusion in the randomised trial. Using these thresholds, we estimate that 22% of patients requiring loco-regional IMN radiotherapy will be eligible for the trial. Conclusion The patient selection criteria for the DBCG Proton Trial are mean heart dose ≥ 4 Gy and/or lung V17Gy/V20Gy ≥ 37%.

Background and PurposeOptimal radiation target volumes for breast cancer patients with their first isolated chest wall recurrence (ICWR) after mastectomy are controversial. We aimed to analyze the regional failure patterns and to investigate the role of prophylactic regional nodal irradiation (RNI) for ICWR.Materials and MethodsAltogether 205 patients with ICWR after mastectomy were retrospectively analyzed. Post-recurrence progression-free survival (PFS) and overall survival (OS) rates were calculated by Kaplan-Meier method and the differences were compared with Log-rank test. Competing risk model was used to estimate the subsequent regional recurrence (sRR) and locoregional recurrence (sLRR) rates, and the differences were compared with Gray test.ResultsThe 5-year sRR rate was 25.2% with median follow-up of 88.6 months. Of the 52 patients with sRR, 30 (57.7%) recurred in the axilla, 29 (55.8%) in supraclavicular fossa (SC), and five (9.6%) in internal mammary nodes. Surgery plus radiotherapy was independently associated with better sLRR and PFS rates (pConclusionPatients with ICWR have a high-risk of sRR in SC and axilla. Chest wall plus RNI is recommended.

Delineation of target and 'organ at risk' volumes is a critical part of modern radiation therapy planning, the next essential step after deciding the indication, patient discussion and image acquisition. Adoption of volume-based treatment planning for non-metastatic breast cancer has increased greatly along with the use of improved planning techniques, essential for modern therapy. However, identifying the vol-umes on a planning CT is no easy task. The current paper is written by ESTRO's breast course faculty, pro-viding tricks and tips for target volume definition and delineation for optimal postoperative breast cancer irradiation. (c) 2021 Elsevier B.V. All rights reserved. Radiotherapy and Oncology xxx (2021) xxx-xxx

Background Prone whole breast irradiation (WBI) leads to reduced heart and lung doses in breast cancer patients receiving adjuvant radiotherapy. In this feasibility trial, we investigated the prone position for whole breast + lymph node irradiation (WB + LNI). Methods A new support device was developed for optimal target coverage, on which patients are positioned in a position resembling a phase from the crawl swimming technique (prone crawl position). Five left sided breast cancer patients were included and simulated in supine and prone position. For each patient, a treatment plan was made in prone and supine position for WB + LNI to the whole axilla and the unoperated part of the axilla. Patients served as their own controls for comparing dosimetry of target volumes and organs at risk (OAR) in prone versus in supine position. Results Target volume coverage differed only slightly between prone and supine position. Doses were significantly reduced (P

Background The addition of regional nodal radiation (RNI) to whole breast irradiation for high risk breast cancer improves metastases free survival and new data suggests it contributes additional benefit to overall survival. Deep inspiration breath hold (DIBH) has been shown to reduce cardiac and pulmonary dose in the context of left-sided disease treated with or without RNI, yet few studies have investigated its utility for right-breast cancer. This study investigates the potential advantages of DIBH in local and locoregional radiotherapy for right-sided breast cancer. Methods Free-breathing (FB) and DIBH computed tomography datasets were obtained from twenty patients who previously underwent radiotherapy for left-sided breast cancer. Ten patients were retrospectively planned for whole right breast only irradiation and ten patients were planned for irradiation to the whole breast plus ipsilateral supra-clavicular (SC) nodes, with and without irradiation of the ipsilateral internal mammary nodes (IMN). Dose-volume metrics for the clinical target volume, lungs, heart, left anterior descending artery, right coronary artery (RCA) and liver were recorded. Differences between FB and DIBH plans were analysed using Wilcoxon signed-rank tests, with P Results DIBH increased the average total lung volume compared to FB in both breast only and breast plus RNI cohorts (P = 0.001). For the breast only group, there was no significant improvement in any ipsilateral lung dose-volume metric between FB and DIBH. However, for the breast plus RNI group, there was an improvement in ipsilateral lung mean dose (18.9 ± 3.2 Gy to 15.9 ± 2.3 Gy, P = 0.002) and V20Gy (45.3 ± 13.3% to 32.9 ± 9.4%, P = 0.002). In addition, DIBH significantly reduced the maximum dose to the RCA for RNI (11.6 ± 7.2 Gy to 5.6 ± 2.9 Gy, P = 0.03). Significant reductions in the liver V20Gy and maximum dose were observed in all cohorts during DIBH compared to FB. Conclusions DIBH is a promising approach for right-breast radiotherapy with considerable sparing of normal tissue, particularly when the ipsilateral IMNs are also irradiated.

Background While breast radiotherapy typically includes regional nodal basins, the treatment of the internal mammary nodes (IMN) has been controversial due to concern for long-term cardiac toxicity. For high risk patients where IMN treatment is warranted, there is limited data with regards to the degree of heart sparing conferred by modern techniques. In this study, we sought to analyze the specific heart sparing metrics conferred by deep inspiration breath hold (DIBH) in the setting of IMN irradiation. Methods From 2012 to 2015, 168 consecutive patients were treated with adjuvant left-sided radiotherapy using DIBH. Retrospective review identified 49 patients who received nodal irradiation, either to a supraclavicular field (SCF) and IMN (16), or to the SCF alone (33). Cardiac mean dose and dose volumes were calculated from free breathing (FB) and DIBH treatment plans, and compared by Wilcoxon signed-rank and Mann–Whitney U tests. Results DIBH achieved significant reductions in mean heart dose (p

Limited data are available examining the role of hypofractionated radiation schedules in the management of women requiring regional nodal irradiation (RNI). The purpose of this review is to examine the available literature for the efficacy (where available) and toxicity of hypofractionated radiation schedules in breast cancer with RNI limited to the axilla and supraclavicular regions. Multiple randomized and prospective studies have documented the safety and efficacy of hypofractionated schedules delivering whole breast irradiation (WBI) alone. Subsets from these randomized trials and smaller prospective/single-institution studies have documented the feasibility of hypofractionated RNI but the limited numbers prevent definitive conclusions and limited efficacy data are available. With regard to possible toxicity affecting organs at risk with RNI, key structures include the breast, skin, heart, lungs, axilla (lymphedema), and brachial plexus. Based on data from several randomized trials, hypofractionated radiation is not associated with significant changes in breast toxicity/cosmesis or cardiac toxicity; the addition of hypofractionated RNI would not be expected to change the rates of breast or cardiac toxicity. While RNI has been shown to increase rates of pulmonary toxicity, hypofractionated RNI has not been associated with more frequent pulmonary complications than standard RNI. Moving forward, future studies will have to evaluate for increased lung toxicity. With regard to lymphedema, data from randomized hypofractionated WBI trials failed to demonstrate an increase in lymphedema and smaller studies utilizing hypofractionated RNI have failed to as well. Data from head and neck cancer as well as hypofractionated breast radiation with RNI have failed to demonstrate an increase in brachial plexopathy with the exception of older trials that used much larger dose per fraction (>4Gy/fraction) schedules. At this time, published data support the feasibility of hypofractionated RNI and the need for a prospective randomized trial addressing clinical outcomes and toxicity of hypofractionated RNI compared with standard fractionation RNI.

Background The aim of the present work was to analyse the impact of mild hypofractionated radiotherapy (RT) of infra-supraclavicular lymph nodes after axillary dissection on late toxicity. Methods From 2007 to 2012, 100 females affected by breast cancer (pT1- T4, pN1-3, pMx) were treated with conservative surgery, Axillary Node Dissection (AND) and loco-regional radiotherapy (whole breast plus infra-supraclavicular fossa). Axillary lymph nodes metastases were confirmed in all women. The median age at diagnosis was 60 years (range 34–83). Tumors were classified according to molecular characteristics: luminal-A 59 pts (59 %), luminal-B 24 pts (24 %), basal-like 10 pts (10 %), Her-2 like 7 pts (7 %). 82 pts (82 %) received hormonal therapy, 9 pts (9 %) neo-adjuvant chemotherapy, 81pts (81 %) adjuvant chemotherapy. All patients received a mild hypofractionated RT: 46 Gy in 20 fractions 4 times a week to whole breast and infra-supraclavicular fossa plus an additional weekly dose of 1,2 Gy to the lumpectomy area. The disease control and treatment related toxicity were analysed in follow-up visits. The extent of lymphedema was analysed by experts in Oncological Rehabilitation. Results Within a median follow-up of 50 months (range 19–82), 6 (6 %) pts died, 1 pt (1 %) had local progression disease, 2 pts (2 %) developed distant metastasis and 1 subject (1 %) presented both. In all patients the acute toxicity was mainly represented by erythema and patchy moist desquamation. At the end of radiotherapy 27 pts (27 %) presented lymphedema, but only 10 cases (10 %) seemed to be correlated to radiotherapy. None of the patients showed a severe damage to the brachial plexus, and the described cases of paresthesias could not definitely be attributed to RT. We did not observe symptomatic pneumonitis. Conclusions Irradiation of infra-supraclavicular nodes with a mild hypofractionated schedule can be a safe and effective treatment without evidence of a significant increase of lymphedema appearance radiotherapy related.