Radiotherapy For Breast Cancer Research Articles

The Impact of Supervised, Individualized Exercise on Fatigue and Quality of Life during Adjuvant Radiotherapy for Breast Cancer

Adjuvant radiation therapy in treatment for breast cancer has been shown to improve patient outcomes and reduce mortality rates. However, many patients experience debilitating fatigue as a result. Currently, there are limited treatment options for fatigue in cancer survivors. Options include pharmaceutical agents, psychological interventions, or nutrition strategies, all of which have limited efficacy. Exercise is recommended in survivorship care plans, but it not widely implemented beyond the use of generalized statements or resource guides given to patients. Therefore, the purpose of this study was the examine the impact of an individualized exercise program on fatigue, quality of life, and physical functioning during radiation therapy for breast cancer. This multi-institutional prospective trial evaluated the effects of supervised, individualized exercise therapy in 422 patients undergoing adjuvant radiotherapy for breast cancer. Following a comprehensive fitness assessment and the completion of the Brief Fatigue Instrument (BFI) questionnaire, each participant participated in a 12-week individualized exercise program offered through Maple Tree Cancer Alliance. At its conclusion, the patients repeated the assessment and questionnaire. Individualized exercise had a positive impact on fitness parameters and severity of fatigue. Specifically, cardiovascular endurance, muscular strength, muscular endurance, and flexibility all significantly improved following the exercise intervention (p<0.05). On average, patients fatigue levels decreased by 31.1% (P<0.01). These results signify that fatigue levels are positively impacted by exercise among patients with breast cancer.

Five-Fraction Accelerated Partial Breast Irradiation [APBI] may Reduce Health Care Disparity in Patients Receiving Adjuvant Radiation Therapy for Breast Cancer by Overcoming Treatment Barriers of Distance to Treatment Center, Age, and Ethnicity

Although changing, breast irradiation is still standard of care in many patients after breast conservation therapy (lumpectomy). Distance from radiation treatment center, Age, and Ethnicity have been shown to be barriers to completing needed adjuvant radiation therapy in breast and other cancers. In this retrospective review, it was hypothesized that the Meattini five-fraction partial breast treatment (APBI) would reduce these barriers to care, and more patients would complete treatment. Data from the radiation planning system was utilized to identify all patients treated with APBI at a single community cancer center from 3/6/2020 to 10/14/2022. The Electronic Medical Record (EMR) was used to identify home addresses and then online navigation software measured patient round trip driving distance to the treatment center. Records in EMR were reviewed to see if each patient completed treatment. Patients were divided into 2 groups for three variables: 1. Distance from clinic- <40 miles round trip vs. >40 miles round trip, 2. Age- 65 and older or less than 65, 3. Ethnicity- Hispanic or Non-Hispanic. Each variable consisting of 2 groups were then evaluated statistically using two proportion Z test. Eighty-one patients were identified who underwent APBI. There were 50 patients living <40 miles round trip and 31 living >40 miles from cancer treatment center. There were 48 patients age 65 and older and 33 patients under 65. Patients self- identified their ethnicity as: Hispanic (26 patients, 32.1%), non-Hispanic (55 patients, 67.9%: European Descent-52 patients, Native American- 2 patients, Asian American- 1 patient). 80/81 APBI patients completed the planned treatment. Using the two proportion Z-test, there was no statistical difference between patients with distance to treatment center less than 40 mi round trip commute vs greater than 40 miles round trip commute (Z score 1.28, p = .20), no statistical difference by age 65 or older vs under 65 (Z score = -.83, p = 0.40), and no statistical difference between ethnicity of Hispanic vs non-Hispanic patients (Z score 0.69, p = 0.49). Shorter course radiation therapy regimens for many reasons are easier to complete than longer treatment regimens. In this single-institution retrospective review, all but one short course five-fraction APBI patient (80/81) completed treatment. APBI short course five-fraction treatment (compared to traditional longer breast radiation therapy regimens) may help increase completion of adjuvant radiotherapy and reduce healthcare disparity in breast cancer patients and may overcome barriers to treatment such as Distance to treatment center, Age, and Ethnicity.

Assessing Depression and Anxiety Levels in English and Spanish-Speaking Patients throughout a Course of Radiation Therapy

An estimated 32.2% and 41.9% of breast cancer patients experience depression and anxiety, respectively. However, distress experienced by patients with breast cancer receiving radiation therapy may vary at different time points and differ in comparison to other patients with breast cancer, potentially due to differences in the understanding of radiotherapy and variability in the severity of side effects. This study sought to describe the changes in levels of depression and anxiety experienced by English and Spanish-speaking patients throughout a course of radiation therapy for breast cancer, along with the impact of different variables on these levels of distress to better understand and quantify potential gaps. Eligibility criteria included English and Spanish-speaking females, ages 18 or older, undergoing radiation therapy treatment for breast cancer at two institutions, including a safety-net hospital. Pre- and post-treatment surveys were completed before and after delivery of radiation therapy. Sociodemographic characteristics collected included: race, ethnicity, marital status, education level, longest residency location, housing, and food security. The survey ended with the standardized PHQ-4 questionnaire, which uses a maximum total score of 12 to assess anxiety and depression. Results were analyzed using the Analysis of Covariance procedure. A total of 160 participants completed pre- and post-treatment surveys. Half of the participants were non-white (50%), primarily married (42.5%), and had a high school or associate's level education (46.9%). The total baseline distress mean (BDM) was 2.96 (Standard deviation, SD = 3.11), and the final distress mean (FDM) was 2.78 (SD = 3.78). English-speaking patients comprised 82.5% (n = 132) of the sample and had a BDM of 2.91 with an adjusted change mean (ACM) decrease of 0.45. Spanish-speaking patients comprised 17.5% (n = 28) of the sample, with a BDM of 3.21 and an ACM increase of 1.03 (P = 0.002). Housing (P = 0.021) and food insecurity (P = 0.002) also showed increasing distress with increased insecurity at baseline. Our study shows that Spanish-speaking patients present with higher levels of distress than their English-speaking counterparts and their distress increased throughout treatment as opposed to English speakers. Other factors, such as housing and food insecurity, are also significantly associated with increased distress. As the number of Spanish speakers in the US continues to increase, it will be important to continue assessing potential differences in cancer care. In addition, understanding the distress changes throughout radiation treatment could help inform future interventions that address these disparities.

Standardizing Breast Adjuvant Radiation Therapy Practices in a Diverse Health System through Development of a Delphi Consensus Supported Clinical Algorithm

Adjuvant radiation therapy (RT) for early breast cancer is a highly effective treatment option. However, the multitude of available techniques backed by strong clinical evidence can result in a lack of consistency in treatment approaches, even within a single healthcare organization. This presents challenges for both providers and patients in making informed decisions. To address this issue, our radiation department, which serves a large and diverse health system, developed a clinical algorithm for adjuvant RT for breast cancer. This algorithm was created to enhance the quality and standardization of care delivered across our network. A modified Delphi technique was used. A panel of eight experienced breast radiation oncologists from our institution was assembled. The panel first identified the common clinical scenarios encountered in treating patients with adjuvant breast RT, and then made recommendations for the primary and alternative approaches for each scenario. NCCN guidelines, ASTRO executive summaries, and published national and international randomized trials were used for reference. In case of disagreements, the final recommendation was reached through a majority vote. The draft algorithm was also shared with medical oncologists, surgeons, and patient advocates to gather their input prior to final approval by the expert panel. Consensus was reached for three broad clinical scenarios for patients who have undergone lumpectomy or mastectomy: Ductal Carcinoma in Situ (DCIS), Invasive Cancer Node Negative (ICN0), and Invasive Cancer Node Positive (ICN+). The panel agreed subdivision of the scenarios into three risk groups (low, intermediate, and high) and three age groups, based on guidelines and consensus statements. For DCIS patients, size, grade, margin status, hormone receptor status, and tumor focality were used for further stratification. For ICN0 patients, HER2 receptor status and lymphovascular space invasion were also included. For ICN+ patients, nodal status (negative versus 1-3 positive nodes versus more than 3 positive nodes) was used for stratification. Additionally, DCIS and ICN0 patients were further divided into age groups. The panel reached consensus recommendations for RT, including whole breast RT, partial breast RT, chest wall RT, regional nodal irradiation, or omission of RT for each sub-group. Clinical trial enrollment was also recommended where appropriate. A breast cancer adjuvant RT algorithm was developed with the aim of standardizing care for patients with breast cancer. Implementation is expected to standardize treatment recommendations in our health system and to streamline the shared decision-making process with patients.

Quality Assurance in a Phase III, Multicenter, Randomized Trial of POstmastectomy radioThErapy in Node posiTive Breast Cancer with or without Internal mAmmary nodaL Irradiation (POTENTIAL): A Planning Dummy Run

To report the planning dummy run results of the POstmastectomy radioThErapy in Node posiTive breast cancer with or without Internal mAmmary nodaL irradiation (POTENTIAL) trial-a multicenter, randomized, phase 3 trial-to evaluate postmastectomy radiotherapy, with or without internal mammary nodal irradiation, for patients with high-risk breast cancer. All participating institutions were provided the contours of the dummy run case, and they generated radiotherapy (RT) plans per protocol guidelines. The plans were reviewed and feedback were provided by the quality assurance team, after which the institutions resubmitted revised plans. The information on beams arrangement, skin flash, inhomogeneity corrections, and protocol compliance was assessed both in the primary and final submission. Theplans from 26 institutions were included in the analysis. A number of major deviations were found in the primary submission, such as less strict constraint on organs at risk (OARs) V5Gy, and no application of chest wall skin flash. The protocol compliance rates of the dose coverage for the planning target volume of the chest wall (PTVcw), PTV of supra/infraclavicular fossa plus axilla levels I, II, III (PTVsc+ax), and PTV of the IMN region (PTVim) were all significantly improved in the final submission compared with those in the primary submission, which were 96.2% vs. 69.2%, 100% vs. 76.9%, and 88.4% vs. 53.8, respectively. For OARs, the protocol compliance rates of heart Dmean, left anterior descending coronary artery V40Gy, ipsilateral lung V5Gy, and stomach V5Gy were significantly improved. All major deviations were corrected and protocol compliance was significantly improved and of high level in the final submission. Moreover, the variations were reduced. Therefore, a planning dummy run was essential to guarantee good RT plan quality and inter-institutional consistency for multicenter trials.

Interpretable Deep Learning Identified the Significance of 1 Gy Volume on Lymphopenia after Radiotherapy in Breast Cancer

Lymphopenia is common after radiotherapy (RT) and is known for its significance on poor survival outcomes in patients with breast cancer. Previous work has demonstrated the significance of point dosimetric factors like the volume receiving 5 Gy. Considering the full dosimetric data together, this study aimed to develop and validate predictive models for lymphopenia after RT in breast cancer. Patients with breast cancer treated with radiation therapy in adjuvant setting and with complete dosimetric data were eligible. Combining dose-volume histogram (DVH) dosimetric and clinical factors, dense neural network (DNN) models were developed to predict both the reduction in lymphocyte counts and the graded lymphopenia in breast cancer patients after adjuvant RT. A Shapley additive explanation was applied to explain each feature's directional contributions. The generalization of DNN models was validated in both internal and independent external validation cohorts. P<0.05 was considered to be significant. A total of 928 consecutive patients with invasive breast cancer were eligible for this study. Treatment volumes of nearly all irradiation dose levels of DVH were significant predictors for lymphopenia after RT, including volumes at very low-dose 1 Gy (V1) of all structures considered including the lung, heart and body. DNN models using full DVH dosimetric and clinical factors were built and a simplified model was further established and validated in both internal and external validation cohorts. This simplified DNN AI model, combining full DVH dosimetric parameters of all OARs and five key clinical factors including baseline lymphocyte counts, tumor stage, RT technique, RT fields and RT fractionation, showed a predictive accuracy of 77% and above. This study demonstrated and externally validated the significance of an AI model of combining clinical and full dosimetric data, especially the volume of low dose at as low as 1 Gy of all critical structures on lymphopenia after RT in patients with breast cancer. The significance of V1 deserves special attention, as modern arc RT technology often has relatively high value of this parameter. Further study warranted for breast cancer RT plan optimization.

A Cascaded Deep Learning-Based Cardiac Substructures Segmentation Frame and on Non-Gated Non-Enhanced Planning CT Scans in Breast Cancer Patients

To develop a deep learning-based segmentation frame for cardiac substructures especially coronary arteries (CAs) on non-gated non-enhanced planning computed tomography (CT) scans in breast cancer (BC) patients. Non-gated non-enhanced CT scans of 39 BC patients receiving adjuvant radiotherapy (RT) were collected. Cardiac substructures were manually labelled, including four chambers, left main (LM), left anterior descending (LAD), left circumflex (LCX) and right coronary artery (RCA). The training, validation, and test sample is 28, 7 and 4, respectively. A cascaded network, using nnUNet as the backbone, is proposed to use chambers as prior information to constrain the segmentation of CAs. The mean Dice similarity coefficient (DSC), 95th percentile Hausdorff distance (HD95) and average symmetrical surface distance (ASSD) were used as geometric metrics. Dosimetric parameters of cardiac substructures was calculated based on the segmentation frame and manually labeled contouring, respectively. The data of cardiac examination including ultrasonography, electrocardiogram before and during the follow-up after RT were retrospectively collected. The cardiac event was any symptomatic heart disease or new-onset abnormality in the cardiac examination after RT. The mean DSC of heart, atriums and ventricles of the proposed frame was 0.93, 0.90, and 0.93, respectively. As shown in Table 1, compared with direct segmentation (as baseline), the proposed frame had a better performance in terms of HD95, ASSD, and the mean dose (Dmean) absolute error for all CAs. Compared to the dosimetric parameters of the heart collected based on the manual labelled contours, the relative errors of D5, D95, and V15Gy for LAD was 4.3±7.8%, 11.7±5.9%, and 14.6±13.0% collected based on the direct segmentation contours and 2.4±4.4%, 3.9±3.1%, 8.5±6.9% collected based on the auto-segmented contours, respectively. Multivariate analysis showed that increased V15Gy of LAD was an independent cardiac toxicity risk factor ([HR] = 1.07, 95% CI 1-1.15, p = 0.0387). We developed a cascaded network for cardiac substructures segmentation with dosimetric validation on non-enhanced CT scans in breast cancer radiotherapy. This is the first attempt to use chambers as prior information for CAs' segmentation and had a superior stable performance. Accurate segmentation will help radiation oncologists to better evaluate DVHs based on substructures and thus to estimate cardiovascular risk. An optimized cardiac substructure-based dosimetric constrain may be proposed accordingly.

Patterns and Longitudinal Changes in The Practice of Breast Cancer Radiotherapy in Korea: Korean Radiation Oncology Group 22-01

To analyze contemporary practice patterns in breast cancer radiotherapy (RT) and to assess longitudinal changes therein over 5 years in Korea. A nationwide survey was conducted among board-certified radiation oncologists in Korea by the Division for Breast Cancer of the Korean Radiation Oncology Group in March 2022. The survey consisted of 44 questions related to six domains: hypofractionated (HypoFx) whole breast RT, accelerated partial breast RT (APBI), regional nodal irradiation (RNI), RT for ductal carcinoma in situ (DCIS), postmastectomy RT (PMRT), and tumor bed boost. In total, 70 radiation oncologists from 61 of 101 (60%) institutions participated in the survey. HypoFx RT was used by 62 respondents (89%), which has significantly increased from 36% in 2017. The HypoFx RT was commonly administered at 40-42.5 Gy in 15-16 fractions. APBI was used by 12 respondents (17%), which has increased from 5% in 2017. The use of RNI did not change significantly: ≥ pN2 (6%), ≥ pN1 (33%), and ≥ pN1 with pathological risk factors (61%). However, the indications for use of internal mammary lymph node (IMN) irradiation have expanded. In particular, the rates of routine treatment of IMN (11% from 6% in 2017) and treatment in cases of ≥ pN2 (27% from 14% in 2017) have doubled; however, the rate of treatment for only IMN involvement, identified on imaging, has decreased to 31% from 47% in 2017. With regard to DCIS, the use of hypoFx RT increased to 75% from 25%, and the rate of omission on of RT after breast-conserving surgery decreased to 38% from 48% in 2017. The use of hypoFx RT for PMRT also increased to 36% from 8% in 2017. The adoption of HypoFx RT after breast-conserving surgery in invasive breast cancer and DCIS has increased significantly, whereas that for PMRT has increased moderately, compared to 2017. Further studies are required to determine the optimal use of RNI.

Variation in Left Anterior Descending Coronary Artery Accumulated Dose Estimates during Breast Cancer Radiotherapy

Left anterior descending (LAD) coronary artery RT dose has been associated with the risk of coronary ischemic events in patients with breast cancer treated with radiotherapy (RT). However, consensus dose constraints commonly utilize mean heart dose, which has been shown to be an inadequate surrogate for LAD dose. Given the LAD is adjacent to the steep dose gradients of the left breast/chest wall, we hypothesize that variations in patient positioning or depth of breath hold may contribute to significant deviations in daily LAD dose exposure compared to predicted. Our objective was to investigate variations in accumulated LAD dose in patients with left-sided breast cancer treated with RT. Retrospective analysis of 10 consecutive patients with left-sided breast cancer treated between 2019-2022 with volumetric modulated arc therapy (VMAT) in the supine position. RT was delivered using daily cone beam computed tomography (CBCT) image guidance with deep-inspiratory breath hold technique and an optical surface monitoring system. Daily CBCT scans were individually registered to each planning CT based on daily positional changes. The LAD was manually segmented and transformed to each CBCT. Daily fractional dose was calculated (mean, volume receiving 15 Gy [V15 Gy], V30 Gy, and max) and summed to produce an accumulated dose which was compared to the predicted dose. Significant deviations in accumulated dose were defined as at least ±15% from predicted. The RT targets included breast/chest wall only (n = 1), supraclavicular nodes (n = 8), and/or internal mammary chain (n = 5). All plans were prescribed to 50 Gy in 25 fractions. The median predicted mean heart dose was 5.1 Gy. Overall, there were no significant differences between the median predicted vs. accumulated LAD doses: mean 10.4 vs. 10.2 Gy, V15 Gy 21% vs. 25%, V30 Gy 0% vs. 1%, max 24.5 vs 25.7 Gy (all p>.05). However, there was a subset of patients (n = 5, 50%) with significant deviations in accumulated vs. predicted dose (at least ±15%). For LAD mean, n = 2 had higher accumulated vs. predicted doses (16.6 vs. 11.6 Gy; 14.6 vs. 12.8 Gy), while n = 3 had lower (21.8 vs. 26.5 Gy; 2.7 vs. 4.2 Gy; 13.9 vs. 16.5 Gy). For LAD V15 Gy, n = 3 had higher accumulated vs. predicted doses (43 vs. 35%; 51% vs. 25%; 14% vs. 9%), while n = 2 had lower (49% vs. 61%; 37% vs. 56%). For LAD V30 Gy, n = 4 had higher accumulated vs. predicted doses (12% vs. 5%; 5% vs. 0%; 4% vs. 0%; 4% vs. 2%), while n = 1 had lower (32% vs. 44%). Daily setup differences, including the extent of inspiratory breath hold, may contribute to deviations in accumulated LAD dose (more than 15% of predicted) in approximately half of patients and were more pronounced in V15 and V30 Gy metrics. The potential for significant LAD dose uncertainty in a clinically meaningful subset of patients should be recognized and warrants further analysis in an expanded cohort.

Dose-Volume Predictors for Radiation Esophagitis in Breast Cancer Patients Undergoing Hypofractionated Regional Nodal Radiotherapy

Radiation esophagitis (RE) is often overlooked in breast cancer radiotherapy. This study aimed to assess the incidence and dose-volume predictors of RE in breast cancer patients undergoing hypofractionated regional nodal irradiation (RNI). Eligible patients were included who received intensity-modulated radiotherapy (RT) at the chest wall, the supraclavicular/infraclavicular fossa, level II axilla, and/or the internal mammary chain after mastectomy. The prescribed dose was 43.5 Gy in 15 fractions. The dose constraint for the esophagus was maximum dose <48 Gy. RE was evaluated weekly during RT and at 1 and 2 weeks, followed by 3 and 6 months after RT, and was graded according to the Common Toxicity Criteria for Adverse Events v3.0. The esophagus was contoured from the lower border level of the cricoid cartilage to the lower margin of the aortic arch. Esophageal total volume, mean dose (Dmean), maximum dose (Dmax), and the relative and absolute volumes receiving at least 5-45 Gy by 5 Gy increments (RV5-RV45 and AV5-AV45) were evaluated. Univariable and multivariable logistics regression analyses were performed to determine risk factors for RE, and receiver operating characteristic curves were obtained to identify the thresholds of esophageal dosimetric parameters. In total, 298 patients were included between May 8, 2020 and January 5, 2022 (minimum post-RT follow-up: 6 months). A total of 153 (51.3%) patients had left-sided breast cancer and 145 (48.7%) patients received internal mammary nodal irradiation (IMNI). Grade 2 and 3 RE incidence was 40.9% (122/298) and 0.3% (1/298), respectively. No grade 4 or 5 RE was observed. All RE cases resolved within 1 month after RT, and the median duration of RE was 3 weeks (range, 1-5). Based on univariable analyses, tumor laterality (p < .001), IMNI (p = .056) and esophageal Dmean, Dmax, RV10-RV40, and AV10-AV40 were risk factors of ≥grade 2 RE. Esophageal RV10-RV40 and AV35-AV40 were significantly associated with the risk of ≥grade 2 RE after adjusting for tumor laterality and IMNI. Based on multivariable analyses, RV25 and AV35 were optimum dose-volume predictors for ≥grade 2 RE at thresholds 20% for RV25 (35.9% vs. 60.9%, p = .04) and 0.27 mL for AV35 (31.0% vs. 54.6%, p = .04). RE is common in breast cancer patients undergoing hypofractionated RNI. With the same esophageal contouring standard, maintaining the upper esophageal V25 at <20% and V35 at <0.27 mL may decrease the risk of RE and improve the quality of life of patients.

Surface Dose and Skin Toxicity Analysis in Breast Cancer Radiotherapy after Conserving Surgery with Five Treatment Modalities

The present study aimed to evaluate surface dose and skin toxicity in breast cancer after breast-conserving surgery with five treatment modalities: flattening filter mode of intensity modulated radiation therapy (IMRT-FF,6MV), flattening filter-free mode of intensity modulated radiation therapy (IMRT-FFF,6MV), direct mode of TOMO (TOMO-direct, FFF, 6MV), helical mode of TOMO (TOMO-helical, FFF, 6MV), intensity modulated proton therapy (IMPT, spot scanning). Ten patients with breast cancer treated at our institution after breast-conserving surgery were randomly selected for this study. Five plans were designed for each patient with the same target coverage and the prescription of 50Gy/25f, IMRT-6FF, IMRT-6FFF, TOMO-direct, TOMO-helical, and IMPT. Based on CT datasets, IMRT-6FFF, TOMO-direct, TOMO-helical, and IMPT were compared to IMRT-6FF with skin dose and skin toxicity. Among the five plannings, the angles of the IMRT-6FF vs. IMRT-6FFF and TOMO-direct were the same. We extracted the relative complement in the Body of its 3Derosion defined by a spherical structuring element of radius r = 3 mm and r = 5mm (skin3 and skin5). To calculate the relative Dose-surface histograms (DSH), we used the surface of patients receiving at least 5Gy to delimit the breast region's skin area and normalize the absolute DSH. Skin dose were assessed with V5Gy, V10Gy, V15Gy, V20Gy, V25Gy, V30Gy, V40Gy, V45Gy, V50Gy of the structure of skin3 and skin5. The published NTCP LKB (normal tissue complication probability, Lyman-Kutcher-Burman) model (TD50 = 39 Gy,m = 0.14,n = 0.38) was employed to evaluate severe acute radiation-induced skin toxicity. There was no statistically significant difference between the structure of skin3 and skin5 between IMRT-6FF and IMRT-6FFF. For the same PTV coverage, the TOMO-helical plans had significantly higher surface dose in terms of V5Gy, V10Gy, and V15Gy than the IMRT plans (p <0.005). For structure of skin3, mean V30Gy, V35Gy, V40Gy, V45Gy, V50Gy were (64.0%,65.8%,79.0%,70.0%,64.6%), (51.3%,55.4%,74.3%,61.7%,59.5%), (32.4%,36.6%,65.2%,53.0%,53.0%), (13.7%,14.1%,45.8%,35.7%,37.6%), (1.6%/0.8%/12.2%,6.6%,1.0%). For the structure of skin5, mean V30Gy, V35Gy, V40Gy, V45Gy, V50Gy were (66.1%,67.1%,76.4%,68.6%,62.6%), (57.9%,60.4%,72.3%,61.2%,57.7%), (45.5%,48.4%,65.2%,53.9%,51.8%), (28.4%,30.8%,51.2%,42.0%,40.0%), (6.8%,6.3%,22.6%,17.9%,8.0%).Compared to IMRT-6FF, TOMO-direct and TOMO-helical had higher surface dose(p<0.05). For IMRT-6FF/IMRT-6FFF/TOMO-direct/TOMO-helical/IMPT, the mean ratio of severe acute radiational skin toxicity were14.7%,17.1%,46.3%,29.4%, and 24.1%. For TOMO-direct and TOMO-helical planning, the skin dose and toxicity ratio were higher than IMRT-6FF. Compared to IMRT-6FF, V45Gy of skin3 and V40Gy of skin5 of IMPT were higher than IMRT-6FF, while the skin toxicity ratio was no significant difference.

Convolution Neural Network-Based Automatic Scoring of Coronary Artery Calcification and Its Value to Identify the Risk of Radiation-Induced Cardiac Toxicity on Radiotherapy Planning CT Scans in Breast Cancer Patients

To develop an automatic scoring of coronary artery calcification (CAC) on breast cancer radiotherapy (RT) planning computed tomography (CT) scans, and to explore its predictive value of CAC for radiation-induced cardiac toxicity. Planning CT scans of 668 breast cancer patients from two prospective clinical trials (NCT02942615, NCT03829553) were retrospectively reviewed. In total, 34 CTs containing CAC were identified. The training and test samples were 29 and 5, respectively. We proposed a two-stage model for CAC segmentation task with nnU-Net as backbone. The segmentation results were processed by threshold extraction and region growth algorithm. We also employed transfer learning to automatically identify calcification of left anterior descending artery (LAD), right coronary artery (RCA), left circumflex artery (LCX), and left main coronary artery (LM) based on a public dataset of 430 cases from Stanford University. The data of cardiac examination of these 34 patients before and during the follow-up after RT were collected. The cardiac event was any symptomatic heart disease or new-onset abnormality in the cardiac examination after RT. The mean dice coefficients (DSC) and 95% Harsdorf distance (95HD) of test samples were 0.992 and 0.599 mm, respectively. The mean absolute error (MAE) of CAC Angaston score between ground truth (GT) and predictions was 0.532. The detailed consistency parameters of 5 test samples were shown in Table 1. After 1:2 propensity score matching (PSM), 21 patients had CAC and 42 patients had no CAC were selected. The number of patients with CAC scores of 1 to 10, 11 to 100, and greater than 100 was 10, 9 and 2, respectively. During median follow-up of 9.2 months (range, 1-42.7), 90.5% and 38.1% of patients in CAC cohort and no CAC cohort developed cardiac event (p<0.001). Patients with CAC had significantly increased cardiac events (HR = 2.4; 95% CI, 1.22-4.75; p = 0.0117). The risk of cardiac events increased with CAC scores ([HR]1-10 = 2.1, 95% CI 0.9-4.9; [HR]11-100 = 2.5, 95% CI 1.0-5.9; [HR]>100 = 4.0, 95% CI 0.9-17.4). Our primary results showed that this two-stage segmentation model is capable of achieving automatic CAC scoring which might assist to predict the risk of post-RT cardiac events in breast cancer patients.

Methodological and Reporting Quality of Non-Inferiority or Equivalence Designs: A Systematic Review of Trial Characteristics, Design Consideration and Interpretation in Breast Cancer Radiotherapy Trials

To investigate the methodological and reporting quality of non-inferiority (NI)/equivalence trials of breast cancer radiotherapy and to provide suggestions for future NI/equivalence trials. Prospective phase III randomized controlled trials (RCTs) comparing different radiation modalities in patients with breast cancer and designed or interpreted as NI/equivalence were identified in PubMed, EMBASE and Cochrane library. Two reviewers independently extracted data on trial characteristics, statistical design assumptions and analysis considerations, primary end point results and conclusions. The relationship between the number of published trials and the year of publication was assessed by simple linear regression. Trials with pre-specified NI margins as absolute risk differences were reevaluated using margins as relative risk differences. A total of 1490 records were screened and 41 articles published between January 1, 2001 and May 9, 2022 were selected for full text review. A total of 21 trials were included (18 designed as NI and 3 as equivalence). Publication of these trials increased over time (p = 0.023). Trial interventions included dose fractionation (n = 10), partial/whole breast irradiation (n = 8) and tumor bed boost (n = 3). Eleven (52.4%) trials clearly described the non-efficacy benefits. The primary endpoints included 5-year local recurrence (LR) (n = 11), 5-year locoregional recurrence (n = 3), acute/late toxicities (n = 5), 2-year LR and cosmetic outcome (n = 1), and 10-year LR (n = 1). Only seven (33.3%) trials provided justification of the margins. The absolute and relative risk margins were both mentioned in nine (42.9%) trials' methods and reported in six (28.6%) trials' results. The analyzed populations were intention-to-treat (ITT) in 10, both ITT and per-protocol in 9 trials. Seventeen (81%) trials reported confidence interval (CI), with twelve reporting CI that agreed with the type I error used in sample size calculation, but only eight (38.1%) reported p value for NI/equivalence test. Fifteen (71.4%) trials concluded NI/equivalence. Five (23.8%) trials had misleading conclusions (four for not mentioning small sample size insufficient to confirm NI/equivalence and one for inconsistent with the published results). Thirteen (61.9%) trials reported that the protocol's initial accrual target was not met, with ten (47.6%) owing to overestimation of event rates. For trials that met NI only based on absolute margin, three of eight (37.5%) trials were classified as inconclusive with the assumed relative margins. The use of NI/equivalence trials of breast cancer radiotherapy has dramatically increased recently, but there is substantial room for improvement in the methodological and reporting quality of NI/equivalence trials.

Adjuvant Breast Radiation Therapy for Early-Stage Breast Cancer or Ductal Carcinoma In-Situ in the Breast: A Systematic Review and Network Meta-Analysis of Randomized Trials

For selected patients with early-stage breast cancer (BC) or ductal carcinoma in-situ (DCIS) in the breast, adjuvant breast radiation therapy (RT) approaches include partial breast irradiation (PBI), altered fractionation (AF) whole breast irradiation (WBI) or tumor bed boost (TBB). However, it is unclear which is the optimal approach. This study aims to compare the effects of different PBI, AF-WBI and TBB options on ipsilateral breast tumor recurrence (IBTR), overall survival (OS) and patient reported cosmesis (PRC) outcomes. We searched various biomedical electronic databases for eligible randomized trials (RCTs) from date of inception to January 2023. We constructed six separate random effects frequentist network meta-analyses (NMA) to compare the effects of various PBI options using WBI as the reference; various AF-WBI options using conventional fractionated (CF) WBI as the reference and various TBB options using no TBB as the reference on IBTR and OS. The GRADE approach was used to assess the certainty of evidence. The synthesis without meta-analysis approach was pre-specified for evaluation of PRC in anticipation of various assessment and reporting methods. We included 34 RCTs comprising 49,899 participants and 11 treatment options. Evidence suggests that accelerated PBI (Hazard Ratio (HR) 1.36 (95% confidence interval (CI) 0.77 - 2.41, moderate certainty), moderately hypofractionated (MHF) PBI (HR 1.38 (0.60 - 3.19), moderate certainty) and intraoperative PBI (HR 1.47 (0.81 - 2.68), low certainty) was associated with a modest but not statistically significant increase in the hazards for IBTR when compared to WBI. There was moderate certainty evidence that there were no significant differences among the accelerated ultra-hypo fractionated (AUHF) WBI (HR 0.76 (0.50 - 1.14)), MHF-WBI (HR 0.99 (0.84 - 1.16)) or UHF-WBI (HR (1.35 (0.47 - 3.92)) when compared with CF-WBI for IBTR. The effects of sequential TBB (seqTBB) (HR 0.61 (0.52 - 0.70), high certainty) and simultaneous integrated TBB (simTBB) (HR 0.77 (0.55 - 1.09), moderate certainty) on IBTR were similar when compared to no TBB. There were no significant differences in OS between PBI options and WBI, AF-WBI options and CF-WBI, TBB options and no TBB. Among the PBI vs WBI trials, MHF-PBI and APBI may be associated with fewer adverse PRC events. Among the AF-WBI vs CF-WBI trials, half of the included trials reported fewer adverse PRC events with MHF-WBI. SeqTBB and simTBB had similar adverse PRC outcome. There were no significant differences among the PBI, AF-WBI and TBB options for IBTR and OS. PBI and AF-WBI may be associated with less adverse PRC events compared with WBI and CF-WBI respectively. There was no evidence to suggest a difference between seqTBB and simTBB for PRC outcome. This study is registered with PROSPERO CRD 42021245074.

Cardiological Safety of 5-Fraction Whole Breast Irradiation

Our study aims to assess heart toxic effect using a reliable cardiac assessment with standard and 3-dimensional (3D) echocardiography and left ventricular (LV) global longitudinal strain (GLS) in patients receiving a 5-fraction (total dose 26 Gy) postoperative radiation therapy (RT) for breast cancer (BC). SAFE-FORWARD is an observational prospective cohort study (NCT04842409). Inclusion criteria were: (1) patients with invasive BC receiving ultra-hypofractionated whole breast irradiation (WBI) (26 Gy in 5 fractions) after breast conserving surgery (BCS) (2) without cardiovascular comorbidity and (3) previous thoracic irradiation. All enrolled patients are prospectively monitored for 12 months, receiving a complex cardiological assessment before RT start (baseline), and at 2-, 6-, and 12-month after RT end of treatment. Both acute and early-late toxicity are evaluated according to CTCAE (v.5) scales. The primary endpoint is defined as detection of any subclinical impairment in myocardial function and deformation (decrease ≥10%) measured with standard and 3D echocardiography and LV GLS. Overall, 40 women (median age 66 years; range, 48-84) were enrolled in the study. We analyzed patients who had completed the cardiological assessment at 12 months. Baseline patient's characteristics are summarized in Table 1. All patients received ultra-hypofractionated WBI (26 Gy in 5 fractions), 25 patients also received adjuvant endocrine therapy. GLS worsened 4% or less, both for the left- and right-side treated breast, and remained in normal range for all the time points. The only exception was for RVGLS at 6 months for right-sided treatment where it reached a borderline value (-17.4±4.9 SE). 3D-LVEF remains stable during observation, both for the left- and right-side treated breast CONCLUSION: The 5-fraction schedule after BCS is well tolerated and the intensive 1-year cardiological monitoring showed no significant differences overtime in cardiac functioning. DIBH, deep inspiration breath hold; AI, aromatase inhibitors; BCCT, Breast Cancer Conservation Treatment.

The Effect of Respiratory Motion in Breast Intensity-modulated Radiation Therapy: 3D-Printed Dynamic Phantom Study.

This study evaluated the dosimetric effect of respiratory motion in intensity-modulated radiation therapy (IMRT) for breast cancer using a three-dimensional (3D)-printed dynamic phantom. Computed tomography (CT) data from breast cancer patients were used to create a 3D-printed breast phantom. Various types of treatment plans were generated using CT images acquired at the exhalation phase. Different infill densities in the 3D-printed phantom were tested to validate their effect on simulating the average human breast tissue density. Plans were delivered to the 3D-printed dynamic phantom in the exhalation position and free-breathing motion. Dosimetric verification was performed using Gafchromic EBT3 films. After changing the infill density to obtain Hounsfield Unit values similar to those of human breast tissue, a realistic patient-specific breast phantom was fabricated using a 3D printer at 80% infill density. The gamma passing rates of the dose distribution delivered in the exhalation phase and free-breathing motion were 92% or more. In addition, the dynamic phantom doses with free-breathing motion were directly compared with the static phantom dose in terms of sagittal dose profiles. Gamma passing rates of >93% and 90% were achieved at 3%/3 mm and 3%/2 mm, respectively. Despite a blurred dose distribution, the dose map of the film measurement with respiratory motion could be delivered without significantly increasing the dose heterogeneity of the tumor bed or loss of target coverage. Our findings demonstrate that the impact of respiration on breast IMRT for whole-breast irradiation was not significant, even in the tumor bed.

Five Fraction Accelerated Partial Breast Irradiation vs. Intraoperative Radiation Therapy for Early-Stage Breast Cancer

Accelerated partial breast irradiation (APBI) represents an alternative to whole breast irradiation (WBI), reducing the target volume and potentially treatment duration. APBI delivered in 5 fractions with intensity modulated radiation therapy (IMRT) has been shown to have comparable outcomes to WBI with reduced toxicity profiles. In contrast, intraoperative radiation therapy (IORT) offers patients the potential to complete adjuvant radiation therapy in a single treatment. While early data were initially promising, concerns regarding long-term rates of local recurrence exist. We present a comparison of 5 fraction APBI versus IORT. We performed a retrospective review of 473 patients with early-stage breast cancer (Stage 0-IIA) treated at a single institution with 258 receiving APBI and 215 IORT from October 2011 to May 2021. APBI patients received 30 Gy in 5 fractions delivered with IMRT daily or every other day. IORT patients received 20 Gy in 1 fraction prescribed to the applicator surface delivered at the time of surgery. Kaplan-Meier analysis was used to estimate locoregional control rates and overall survival among the 2 groups. Mean age was 70.7 years old (IQR:67-74) for the IORT patients and 66.6 years old (IQR:62-72) for the APBI patients (p<0.001). Median follow up was 5.7 years for IORT patients and 2.4 years for APBI patients (p<0.001). For IORT patients, 11%/83.5%/5.5% of patients and for APBI 17.8%/77.5%/4.7% of patients had Tis/T1/T2 disease (p = 0.005). With regards to adjuvant therapies, 79%/76% of IORT/APBI patients were offered endocrine therapy (p = 0.50) and 1.4%/6.2% chemotherapy (p = 0.008). Recurrence at any time was seen in 7.9% (n = 17) of patients receiving IORT as compared to 0.8% (n = 2) of patients receiving APBI. APBI was however no differences in recurrence free survival (92.6% vs. 98.5%, p = .079) or overall survival were noted (92.8% vs. 95.1%, p = 0.99). In a series of almost 500 patients with stage 0-IIA breast cancer, IORT was associated with higher rates of locoregional recurrence compared to APBI with no survival difference at 5 years. These outcomes, consistent with other series and current guidelines, suggest a limited role for IORT as monotherapy following breast conserving surgery.

Insurance Plan Coverage Modeling of the Marginal Costs from One Week vs. Three Week Radiation Therapy in Standard-Of-Care Treatment of Post-Lumpectomy Early-Stage Breast Cancer Across Medicaid and Medicare Plans

For early-stage breast cancer (BC), the choice of radiation therapy (RT) duration (1- versus 3-weeks) is highly debated. Cost and financial toxicity are major concerns that BC patients face. Nonetheless, there remain limited discussions providing granular details of the role of insurance in the aggregate cost of 1 week versus 3 weeks of RT for patients. This project addresses this gap by disaggregating costs by insurance plan to increase transparency of out-of-pocket (OOP) cost estimates in RT. Surgical, medical, and radiation oncology treatment procedures were determined through the National Comprehensive Cancer Network guidelines; codes were identified using Current Procedural Terminology and Healthcare Common Procedure Coding System. OOP treatment costs, deductibles, and copay/coinsurance were calculated in accordance with insurance type, including Medicaid, Original Medicare, and Medigap Plan G. The medicare.gov, medicaid.oh.gov, and the physician fee schedule from cms.gov were used to determine pricing. Price estimates reflect actual costs per insurance plan rather than costs estimated from claims data. All procedures were considered to be performed in an Ohio hospital setting. One-week RT was defined as 5 fractions without boost, and 3-week RT was defined as 15 fractions without boost. Treatment charges for RT included initial radiation oncology office consultation and subsequent radiation oncology clinical treatment planning notes, complex 3D treatment plan, dosimetry calculations, complex treatment device design and construction, complex treatment planning simulation, simple verification treatment simulation, complex RT delivery, port verification films, on-treatment visits with radiation oncology, and continuing medical physics consultation. Original Medicare beneficiaries face an OOP cost of 20% for every Medicare Part B charge with no cost cap for all approved procedures after the deductible is met, resulting in a marginal OOP treatment charge of $649.24 for 1 week and $1006.20 for 3 weeks of RT. Assuming the deductible is met post-lumpectomy, Medigap Plan G beneficiaries are faced with no additional charges for both lengths of radiation treatment. Similarly, for Medicaid beneficiaries (assuming all treatments approved by Medicaid), all expenses are covered without limit, resulting in no OOP expense. Considerations of 1 week and 3 weeks of RT for post-lumpectomy early-stage BC are often dependent on cancer characteristic and patient preferences. This model (based on actual cost estimates per insurance plan rather than claims data) compares OOP costs across Medicaid and Medicare plans, which more holistically informs patients in their decision for choice of treatment.

Clinico-Genomics Model to Predict Survival in Non-Metastatic Breast Cancer: Comparing the Performance of Machine Learning Models

Breast cancer is a heterogenous spectrum of disease with variable outcome. This heterogeneity of outcome could be driven by underlying heterogeneity in the genotypes. There remains an unmet need of defining prognosis based on underlying genetic heterogeneity. The primary objective of this study was to build a combined clinic-genomics model to predict overall survival (OS) in patients with non-metastatic breast cancer. The Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) database is a combined Canada-UK Project which contains information on 31 demographic, clinical and treatment characteristics in addition to m-RNA level z-score for 331 genes for 1904 breast cancer patients. We excluded patients with metaplastic breast cancer (n = 1) or unknown histologic subtype (n = 13), and those with missing information on breast surgery (n = 22) and cellularity (n = 54). Demographic characteristics included age of the patient and menopausal status while clinical characteristics included tumor stage, number of positive lymph nodes, pathologic grade, cellularity, receptor status for estrogen and progesterone receptors, and HER2neu gene amplification status. Treatment included type of breast cancer surgery, chemotherapy, hormone therapy, and radiation therapy. The data was split randomly at an 80:20 ratio into training and testing dataset. Subsequently, two cross-validated supervised machine learning algorithms were applied to build the prognostic model - elastic net logistic regression and random forest classifier. We compared the performance of the models in the testing dataset using area under receiver operating curve (AUC). All analysis were done using sparklyr - an R interface to Apache SparkTM. Overall, 1814 patients were included in the analysis. The AUC for elastic net logistic regression model and random forest classifier was 0.74, and 0.73, respectively. The sensitivity and specificity of the elastic net logistic regression model was 0.84 and 0.45, respectively while those for the random forest classifier was 0.83 and 0.51, respectively. STAT5A, CASP8, HSD17b11, and CDKN2c were common to the list of important genes predicting OS in both models while age, lymph node count, Nottingham Prognostic Index (NPI), and type of breast surgery were common to the list of clinical factors predicting OS in both models. This study shows that a multivariable prognostic model with combination of clinical and demographic parameters with Z-score expression data can predict for overall survival.

Clinical Trials of Carbon Ion Radiotherapy for Early-Stage Breast Cancer

Our institute conducted a clinical trial of curative partial breast irradiation using carbon ion radiotherapy (CIRT) to patients with stage 0 and I breast cancer since 2013. The purpose of this report is to evaluate treatment outcomes up to now. To date, we have conducted three clinical trials and one advanced medical treatment (NIRS 9404 Comprehensive Research). The first study (UMIN000010848: commonly known as Breast I trial) was 4-split irradiation for stage I low-risk patients aged 60 years or older, and the next clinical study (UMIN000029478: commonly known as Breast II trial) was for Tis-1N0M0 cases of 2 cm or less. On the other hand, 4-split irradiation using standard adjuvant drug therapy according to risk combined with whole breast irradiation by X-ray, the latest clinical trial (UMIN000046859: commonly known as Breast III trial) is a single irradiation for Tis-1N0M0 patients aged 50 years or older. be. In each phase I, the dose increase test was performed, and in phase II, treatment was performed with the recommended dose determined in phase I. Advanced medical care was provided in parallel with breast I for stage I breast cancer that was difficult or rejected to participate in breast I trial. By January 2023, 60 cases were enrolled. A total of 19 were enrolled In Breast I, 7 in Phase I, 12 in Phase II of the recommended dose of 60.0 Gy (RBE). A total of 14 were enrolled in the 9404 Comprehensive Research. A total of 17 were enrolled In Breast II, 5 cases in Phase I, 12 cases in Phase II of recommended dose 60.0 Gy (RBE). A total of 10 were enrolled in Breast III, 6 cases in Phase I, and 4 in Phase II of recommended dose 50.0 Gy (RBE). As acute adverse events, grade 2 of acute radiation dermatitis were observed in 1 case, grade 1 of acute radiation dermatitis was observed in 31 cases, and grade 1 of mastitis was observed in 6 cases. As a late adverse event, grade 3 of pneumonia of unknown causality were observed in one case, but there were no other problematic adverse events, and breast cosmetic outcome was excellent in all cases. Tumor disappearance after CIRT took 3 to 24 months. Local recurrence and axillary lymph node metastasis were observed in one high-risk case of advanced medical treatment who refused any other therapy. Two cases had ipsilateral intramammary metachronous breast cancer with different subtypes. To date, no other recurrences or metastases have been observed. CIRT for early-stage breast cancer is expected to be effective with mild adverse events, and it is considered meaningful to continue research.