Radiotherapy For Breast Cancer Research Articles

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.

Interim Analysis of a Non-Randomized Prospective Trial Comparing Hypofractionated Post-Mastectomy Radiotherapy (HF-PMRT) to Conventional Post-Mastectomy Radiotherapy (CF-PMRT) for Breast Cancer (BC) Patients

The standard of care for treatment for LABC patients who have undergone modified radical mastectomy (MRM) is PMRT. Post-mastectomy RT (PMRT) for LABC patients has been established in three trials to improve locoregional control and overall survival (OS). A published trial from China showed that HF-PMRT was non-inferior to CF-PMRT. This study was conducted to determine if HF-PMRT can provide similar efficacy and toxicity. A non-randomized prospective trial design was employed to compare HF-PMRT and CF-PMRT in post-MRM BC patients. Patients with pathologically proven BC who underwent MRM without positive margins and with less than 8 positive nodes were included. Informed consent was obtained. Patients decided which treatment they will receive. They received either HF-PMRT of 43.2 Gy in 16 fractions (fx) [2.7 Gy/fx] or CF-PMRT of 50-50.4 Gy in 1.8-2.0 Gy/fx to both chest wall and regional nodes (axillary and supraclavicular) in both regimens. Primary endpoints were 2-year OS and 2-year local recurrence free survival (LRFS). Secondary endpoints include acute and late toxicities. Analysis was done as intention-to treat. An interim analysis of 2-year results is presented. A total of 37 patients were enrolled in two separate cohorts: a single-arm cohort that recruited 10 HF-PMRT patients from 2014-2015 and a two-arm prospective trial that started recruitment last 2019 and included 12 HF-PMRT and 15 CF-PMRT patients. Median follow-up was 35 months. There were more Stage IIB and Stage III for the CF-PMRT arm [p = 0.040]. Treatment interruptions were more frequent in the CF-PMRT arm (100% vs 68%, p = 0.028). The duration of interruption was also longer in CF-PMRT (median 8 vs 3 days) [p < 0.003]. Acute and late toxicities were not statistically different. There was one patient each with RTOG Grade 2 acute skin toxicity in the HF-PMRT (4.55%) and CF-PMRT arms (6.67%) [p = 0.703]. For late toxicities, the HF-PMRT arm had 6 Grade 1 late skin toxicities and 1 Grade 3 late skin toxicity vs 1 Grade 1 late skin toxicity for CF-PMRT arm [p = 0.196]. 2-year OS rate (86.3% vs 100%, p = 0.403) 2-year DFS rate (68.18% and 73.33%, p = 0.126) were both not statistically different. There were no reported locoregional recurrences (LCR). In terms of local control, both arms have showed no LCRs. 2-year OS and DFS rate were no different. As the study has not yet reached the adequate sample size, the non-inferiority of HF-PMRT cannot be definitively concluded. Acute and late toxicities were no different. There was a significantly higher rate of treatment interruptions in the CF-PMRT compared to the HF-PMRT arm. The results of this interim analysis prove to be promising and patients will continue to be accrued. The final results of this study might have tremendous implications in local practice.

Expanding Radiotherapy Access in Sub-Saharan Africa: An Analysis of Travel Burdens and Patient-Related Benefits of Hypofractionation

The purpose of this project was to examine the travel burdens for radiotherapy patients in Nigeria, Tanzania, and South Africa, and to assess the patient-related benefits of hypofractionated radiotherapy (HFRT) for breast and prostate cancer patients in these countries. The outcomes can inform the implementation of the recent Lancet Oncology Commission recommendations on increasing the adoption of HFRT in Sub-Saharan Africa (SSA) to enhance radiotherapy access in the region. Data were extracted from electronic patient records at the NSIA-LUTH Cancer Center (NLCC) in Lagos, Nigeria and the Inkosi Albert Luthuli Central Hospital (IALCH) in Durban, South Africa, from written records at the University of Nigeria Teaching Hospital (UNTH) Oncology Center in Enugu, Nigeria, and from phone interviews at Ocean Road Cancer Institute (ORCI) in Dar Es Salaam, Tanzania. Google Maps was used to calculate the shortest driving distance between a patient's home address and their respective radiotherapy center. QGIS was used to map the straight-line distances to each center. Descriptive statistics were used to compare transportation costs, time expenditures, and lost wages when using HFRT versus conventionally fractionated radiotherapy (CFRT) for breast and prostate cancer. All transportation- and wage-related cost data were contextualized within each country's monthly adjusted net national income (MANNI) per capita, as reported by 2020 data from the World Bank. Patients in Nigeria (n = 390) traveled a median distance of 24.0 km (interquartile range (IQR) = 238.5 km) to NLCC and 86.7 km (IQR = 87.3 km) to UNTH, patients in Tanzania (n = 23) traveled a median distance of 537.0 km (IQR = 587.5 km) to ORCI, and patients in South Africa (n = 412) traveled a median distance of 18.0 km (IQR = 15.0 km) to IALCH. Estimated transportation cost savings for breast cancer patients in Lagos and Enugu were 12,895 Naira and 7,369 Naira (20% and 11% of MANNI per capita), respectively, and for prostate cancer patients were 25,329 and 14,276 Naira (38% and 22% of MANNI per capita), respectively. Prostate cancer patients in Tanzania saved a median of 137,765 Shillings (78% of MANNI per capita) in transportation costs. Significant time expenditures - a relevant consideration for patient convenience - were also saved for ORCI patients, including a median of 80.0 hours (includes travel, treatment, and wait times). Mean transportation cost savings for patients in South Africa were 4,777 Rand (72% of MANNI per capita) for breast cancer and 9,486 Rand (143% of MANNI per capita) for prostate cancer. Cancer patients in SSA travel considerable distances to access radiotherapy services. HFRT decreases patient-related costs and time expenditures, which may increase radiotherapy access and alleviate the growing burden of cancer in the region.

Intensity-Modulated Proton Therapy (IMPT) Offered Advantageous Dosimetry Compared to Volumetric Arc Therapy (VMAT) or Helical Tomotherapy (HT) in Patients with Synchronous Bilateral Breast Cancer

Radiotherapy of synchronous bilateral breast cancer poses some technical challenges with regards to dose coverage and sparing of organs at risk (OAR). In this study, we aimed to evaluate dosimetric characteristics of 3 different techniques, IMPT vs photon (VMAT and HT). We hypothesized that IMPT would result in lower doses to organs at risk, as compared to the other 2 techniques. A total of 10 patients with synchronous bilateral breast cancer who were treated with VMAT at our institution were retrospectively analyzed. Clinical target volume (CTV) included chest wall and regional nodes (supraclavicular fossa and internal mammary chain) and prescription dose was 40.05 Gy in 15 daily fractions. HT and IMPT plans were generated for each patient. Dose-volume statistics, including planning target volume (PTV) coverage and dose to OAR: lungs, heart, thyroid, spinal cord, brachial plexus and esophagus, were compared between modalities using a paired T-test. Mean age of patients was 61 years (43-84). Majority of the patients (80%) were ER+ PR+ and HER2-. 40% of patients underwent breast reconstruction following surgery. All 3 techniques provided adequate target volume distribution and OAR sparing. Compared to VMAT and HT plans, IMPT had better heart and lung sparing effects, resulting in lower mean and V25 Gy heart dose; mean, V20 Gy and V5 Gy lung dose (p<0.0001). There was no significant difference in VMAT and HT plans for mean heart and lung dose. VMAT plans showed significantly lower V25 Gy heart dose on average (p = 0.04). V5 Gy lung dose was slightly lower in HT compared to VMAT plans, approaching statistical significance (p = 0.08). PTV coverage was adequate for all 3 techniques. All techniques fulfilled cord, esophagus, thyroid and brachial plexus constraints. IMPT plans showed significantly better OAR sparing compared to photon techniques. All 3 techniques met OAR constraints, and resulted in adequate target volume coverage. As IMPT is significantly more costly than VMAT or HT techniques, appropriate patient selection is important to deliver treatment in the most resource-effective manner for patients who would derive the most benefit, for example those with young age or existing heart or lung comorbidities.

Simultaneous vs. Sequential Boost for Adjuvant Breast Radiotherapy.

During the last 10-15 years, alternative regimens for adjuvant radiotherapy (RT) of breast cancer have become more popular, including simultaneous integrated (SIB) instead of sequential boosts (SEB). We present long-term outcomes after conventional fractionation (CF) plus SIB vs. CF+SEB. Forty-eight patients receiving CF+SIB (treatment time=5.5 weeks) were matched to 72 patients (control group) receiving CF+SEB (6.5 weeks) considering twelve characteristics. Both groups were compared for radiation dermatitis, pneumonitis, local control (LC), metastases-free survival (MFS), cancer-specific survival (CSS), and overall survival (OS). Rates of grade ≥2 dermatitis were 35.4% (CF+SIB) and 45.8% (CF+SEB), respectively (p=0.26), and rates of grade ≥2 pneumonitis 0% and 4.2%, respectively (p=0.27). Six-year LC, MFS, CSS, and OS rates were 100% vs. 93% (p=0.11), 97% vs. 100% (p=0.29), 100% vs. 100% (p=1.00), and 98% vs. 100% (p=0.23), respectively. CF+SIB was similar to CF+SEB in terms of toxicities and outcomes but reduces total treatment time by one week.