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Highlights • Cutaneous angiosarcoma has poor outcomes with no standardized treatment regimen. • Paclitaxel-based chemoRT (CRT) was compared to other therapies at two US institutions. • Similar oncologic outcomes and improved survival with paclitaxel CRT. • Paclitaxel CRT + surgery provided best oncologic outcomes and survival. • Paclitaxel CRT + surgery regimen now being studied in a prospective phase II trial., Introduction We compared clinical outcomes in patients with cutaneous angiosarcoma receiving concurrent paclitaxel-based chemoradiotherapy (CRT) vs. other modalities (Non-CRT). Materials and methods Patients with non-metastatic cutaneous angiosarcoma diagnosed from 1998 to 2018 at two institutions were identified. In the CRT cohort, paclitaxel 80 mg/m2 weekly was given for up to 12 weeks and patients received radiotherapy (RT) during the final 6 weeks of chemotherapy. The RT dose was 50–50.4 Gy delivered in 1.8–2 Gy per fraction with an optional post-operative boost of 10–16 Gy. Kaplan-Meier and log-rank statistics were used to compare the outcomes between the two groups. P 60 years (100% vs. 60%, p 5 cm (68.2% vs 54.3%, p = 0.023). The median follow-up was 25.8 (1.5–155.2) months. There was no significant difference in 2-year local control (LC), distant control (DC), or progression-free survival (PFS) between the two groups. The 2-year overall survival (OS) was significantly higher for the CRT cohort (94.1% vs. 71.6%, p = 0.033). Amongst the subset of patients in the CRT cohort who received trimodality therapy, the 2-year LC, DC, PFS, and OS was 68.6%, 100%, 68.6%, and 100%, respectively. Conclusion The use of concurrent paclitaxel CRT demonstrates promising outcomes. Given these results, we are currently evaluating the safety and efficacy of this regimen in prospective, phase 2 trial (NCT 03921008).

PURPOSE. To evaluate the cost-effectiveness of axillary observation versus sentinel lymph node biopsy (SLNB) after negative axillary ultrasound (AUS). In patients with clinical T1-T2 N0 breast cancer and negative AUS, SLNB is the current standard of care for axillary staging. However, SLNB is costly, invasive, decreasing in importance for medical decision-making, and is not considered therapeutic. Observation alone is currently being evaluated in randomized clinical trials, and is thought to be noninferior to SLNB. METHODS. We performed cost-effectiveness analyses of observation versus SLNB after negative AUS in post-menopausal women with clinical T1-T2 N0, HR(+)/HER2(−) breast cancer. Costs at the 2016 price level were evaluated from a third-party commercial payer perspective using the MarketScan® Database. We compared cost, quality-adjusted life years (QALYs), and net monetary benefit (NMB). Multiple sensitivity analyses varying baseline probabilities, costs, utilities, and willingness-to-pay thresholds were performed. RESULTS. Observation was superior to SLNB for patients with N0 and N1 disease, and for the entire patient population (NMB in US$: $655,659 for observation versus $641,778 for SLNB for the entire patient population). In the N0 and N1 groups, observation incurred lower cost and was associated with greater QALYs. SLNB was superior for patients with >3 positive lymph nodes, representing approximately 5% of the population. Sensitivity analyses consistently demonstrated that observation is the optimal strategy for AUS-negative patients. CONCLUSION. Considering both cost and effectiveness, observation is superior to SLNB in post-menopausal women with cT1-T2 N0, HR(+)/HER2− breast cancer and negative AUS.

Purpose To perform a comprehensive validation of plans generated on a preconfigured Halcyon 2.0 with preloaded beam model, including evaluations of new features and implementing the patient specific quality assurance (PSQA) process with multiple detectors. Methods A total of 56 plans were generated in Eclipse V15.6 (Varian Medical System) with a preconfigured Halcyon treatment machine. Ten plans were developed via the AAPM TG‐119 test suite with both IMRT and VMAT techniques. 34 clinically treated plans using C‐arm LINAC from 24 patients were replanned on Halcyon using IMRT or VMAT techniques for a variety of sites including: brain, head and neck, lung, breast, abdomen, and pelvis. Six of those plans were breast VMAT plans utilizing the extended treatment field technique available with Halcyon 2.0. The dynamically flattened beam (DFB), another new feature on Halcyon 2.0, was also used for an AP/PA spine and four field box pelvis, as well as ten 3D breast plans. All 56 plans were measured with an ion chamber (IC), film, portal dosimetry (PD), ArcCHECK, and Delta4. Tolerance and action limits were calculated and compared to the recommendations of TG‐218. Results TG‐119 IC and film confidence limits met those set by the task group, except for IMRT target point dose. Forty‐four of 46 clinical plans were within 3% for IC measurements. Average gamma passing rates with 3% dose difference and 2mm distance‐to‐agreement for IMRT/VMAT plans were: Film – 96.8%, PD – 99.9%, ArcCHECK – 99.1%, and Delta4 – 99.2%. Calculated action limits were: Film – 86.3%, PD – 98.4%, ArcCHECK – 96.1%, and Delta4 – 95.7%. Extended treatment field technique was fully validated and 3D plans with DFB had similar results to IMRT/VMAT plans. Conclusion Halcyon plan deliveries were verified with multiple measurement devices. New features of Halcyon 2.0 were also validated. Traditional PSQA techniques and process specific tolerance and action limits were successfully implemented.

Background: Pathologic complete response (pCR) after neoadjuvant chemotherapy (NAC) for triple-negative breast cancer (TNBC) predicts decreased distant metastasis. However, most patients do not experience pCR, and other risk factors for distant metastasis after NAC are poorly characterized. This study investigated factors predictive of distant metastasis in TNBC without pCR after NAC. Methods: Women with TNBC treated with NAC, surgery, and radiation therapy in 2000 through 2013 were reviewed. Freedom from distant metastasis (FFDM) was compared between patients with and without pCR using the Kaplan-Meier method. In patients without pCR, univariate and multivariable Cox analyses were used to determine factors predictive of distant metastasis. Results: We identified 153 patients with median follow-up of 4.0 years (range, 0.5–14.0 years). After NAC, 108 had residual disease (pCR, 29%). Five-year FFDM was 98% and 55% in patients with and without pCR, respectively (PP=.001) and lymphovascular space invasion (hazard ratio, 1.91; 95% CI, 1.07–3.43; P=.030). Patients with a greater number of factors had worse FFDM; 5-year FFDM was 76.5% for patients with no factors (n=38) versus 54.9% and 27.5% for patients with 1 (n=44) and 2 factors (n=26), respectively (PConclusions: Lack of pCR after NAC resulted in worse overall survival and FFDM, despite trimodality therapy. In patients with residual disease after NAC, pathologic lymph node positivity and lymphovascular space invasion predicted worse FFDM.

Purpose To develop and evaluate deep learning based auto-segmentation of cardiac substructures from non-contrast planning computed tomography (CT) images in patients undergoing breast cancer radiotherapy and to investigate the algorithm sensitivity to out-of-distribution data such as CT image artifacts. Methods Nine substructures including Aortic Valve (AV), Left Anterior Descending (LAD), Tricuspid Valve (TV), Mitral Valve (MV), Pulmonic Valve (PV), Right Atrium (RA), Right Ventricle (RV), Left Atrium (LA) and Left Ventricle (LV) were manually delineated by a radiation oncologist on non-contrast CT images of 129 patients with breast cancer; among them 90 were considered in-distribution data, also named 'clean' data. The image/label pairs of 60 subjects were used to train a 3D deep neural network while the remaining 30 were used for testing. The rest of the 39 patients were considered out-of-distribution ('outlier') data which were used to test robustness. Random rigid transformations were used to augment the dataset during training. We investigated multiple loss functions, including Dice Similarity Coefficient (DSC), Cross-entropy (CE), Euclidean loss as well as the variation and combinations of these, data augmentation, and network size on overall performance and sensitivity to image artifacts due to infrequent events such as the presence of implanted devices. The predicted label maps were compared to the ground truth labels via DSC and mean and 90th percentile symmetric surface distance (90th -SSD). Results When using modified Dice combined with cross-entropy (MD-CE) as the loss function, the algorithm achieved a mean DSC = 0.79±0.07 for chambers and a mean DSC = 0.39±0.10 for smaller substructures (valves and LAD). The mean and 90th -SSD for chambers was 2.7±1.4 mm and 6.5±2.8 mm and was 4.1±1.7 mm and 8.6±3.2 mm for smaller substructures. Models with MD-CE, Dice-CE, MD, and weighted CE loss had highest performance, and were statistically similar. Data augmentation did not affect model performances on both clean and outlier data and model robustness was susceptible to network size. For a certain type of outlier data, robustness can be improved via incorporating them into the training process. The execution time for segmenting each patient was on average 2.1s. Conclusions A deep neural network provides a fast and accurate segmentation of large cardiac substructures in non-contrast CT images. Model robustness to two types of clinically common outlier data were investigated and potential approaches to improve them were explored. Evaluation of clinical acceptability and integration into clinical workflow are pending. This article is protected by copyright. All rights reserved.

Highlights • Re-irradiation using proton therapy for recurrent breast cancer has excellent local control. • Re-irradiation using proton beam radiation therapy increases risk of skin toxicity. • There is minimal increase in the late toxicity due to re-irradiation using proton beam therapy., Purpose Repeat radiation therapy (RT) using photons/X-rays for locally recurrent breast cancer results in increased short and long-term toxicity. Proton beam RT (PBRT) can minimize dose to surrounding organs, thereby potentially reducing toxicity. Here, we report the toxicity and clinical outcomes for women who underwent re-irradiation to the chest wall for locally recurrent breast cancer using PBRT. Materials and methods This was a retrospective study analyzing 16 consecutive patients between 2013 and 2018 with locally recurrent breast cancer who underwent re-irradiation to the chest wall with PBRT. For the recurrent disease, patients underwent maximal safe resection, including salvage mastectomy, wide local excision, or biopsy only per surgeons recommendations. Systemic therapy was used per the recommendation of the medical oncologist. Patients were treated with median dose of 50.4 Cobalt Gray Equivalent (CGyE) in 28 fractions at the time of re-irradiation. Follow-up was calculated from the start of second RT course. Acute toxicities were defined as those occurring during treatment or up to 8 weeks after treatment. Late toxicities were defined as those occurring more than 8 weeks after the completion of therapy. Toxicities were based on CTCAE 4.0. Results The median age at original diagnosis and at recurrence was 49.8 years and 60.2 years, respectively. The median time between the two RT courses was 10.2 (0.7–20.2) years. The median follow-up time was 18.7 (2.5–35.2) months. No local failures were observed after re-irradiation. One patient developed distant metastasis and ultimately died. Grade 3–4 acute skin toxicity was observed in 5 (31.2%) patients. Four (25%) patients developed chest wall infections during or shortly (2 weeks) after re-irradiation. Late grade 3–4 fibrosis was observed in only 3 (18.8%) patients. Grade 5 toxicities were not observed. Hyperpigmentation was seen in 12 (75%) patients. Pneumonitis, telangiectasia, rib fracture, and lymphedema occurred in 2 (12.5%), 4 (25%), 1 (6.3%), and 1 (6.3%) patients, respectively. Conclusions Re-irradiation with PBRT for recurrent breast cancer has acceptable toxicities. There was a high incidence of acute grade 3–4 skin toxicity and infections, which resolved, however, with skin care and antibiotics. Longer follow-up is needed to determine long-term clinical outcomes.

Purpose The superior soft-tissue contrast achieved using magnetic resonance imaging (MRI) compared to x-ray computed tomography (CT) has led to the popularization of MRI-guided radiation therapy (MR-IGRT), especially in recent years with the advent of first and second generation MRI-based therapy delivery systems for MR-IGRT. The expanding use of these systems is driving interest in MRI-only RT workflows in which MRI is the sole imaging modality used for treatment planning and dose calculations. To enable such a workflow, synthetic CT (sCT) data must be generated based on a patient's MRI data so that dose calculations may be performed using the electron density information derived from CT images. In this study, we propose a novel deep spatial pyramid convolutional framework for the MRI-to-CT image-to-image translation task and compare its performance to the well established U-Net architecture in a generative adversarial network (GAN) framework. Methods Our proposed framework utilizes atrous convolution in a method named atrous spatial pyramid pooling (ASPP) to significantly reduce the total number of parameters required to describe the model while effectively capturing rich, multi-scale structural information in a manner that is not possible in the conventional framework. The proposed framework consists of a generative model composed of stacked encoders and decoders separated by the ASPP module, where atrous convolution is applied at increasing rates in parallel to encode large-scale features. The performance of the proposed method is compared to that of the conventional GAN framework in terms of the time required to train the model and the image quality of the generated sCT as measured by the root mean square error (RMSE), structural similarity index (SSIM), and peak signal-to-noise ratio (PSNR) depending on the size of the training data set. Dose calculations based on sCT data generated using the proposed architecture are also compared to clinical plans to evaluate the dosimetric accuracy of the method. Results Significant reductions in training time and improvements in image quality are observed at every training data set size when the proposed framework is adopted instead of the conventional framework. Over 1042 test images, values of 17.7 ± 4.3 HU, 0.9995 ± 0.0003, and 71.7 ± 2.3 are observed for the RMSE, SSIM, and PSNR metrics, respectively. Dose distributions calculated based on sCT data generated using the proposed framework demonstrate passing rates equal to or greater than 98% using the 3D gamma index with a 2%/2 mm criterion. Conclusions The deep spatial pyramid convolutional framework proposed here demonstrates improved performance compared to the conventional GAN framework that has been applied to the image-to-image translation task of sCT generation. Adopting the method is a first step toward an MRI-only RT workflow that enables widespread clinical applications for MR-IGRT including online adaptive therapy.

Hyperthermia therapy (HT) raises tissue temperature to 40–45°C for up to 60 minutes. Hyperthermia is one of the most potent sensitizers of radiation therapy (RT). Ultrasound-mediated HT for radiosensitization has been used clinically since the 1960s. Recently, magnetic resonance-guided high-intensity focused ultrasound (MRgHIFU), which has been approved by the United States Food and Drug Administration for thermal ablation therapy, has been adapted for HT. With emerging clinical trials using MRgHIFU HT for radiosensitization, there is a pressing need to review the ultrasound HT technology. The objective of this review is to overview existing HT technology, summarize available ultrasound HT devices, evaluate clinical studies combining ultrasound HT with RT, and discuss challenges and future directions.

Background:This study evaluated factors predictive of locoregional recurrence (LRR) in women with triple-negative breast cancer (TNBC) treated with neoadjuvant chemotherapy who do not experience pathologic complete response (pCR).Methods:This is a single-institution retrospective review of women with TNBC treated with neoadjuvant chemotherapy, surgery, and radiation therapy in 2000 through 2013. LRR was estimated between patients with and without pCR using the Kaplan-Meier method. Patient-, tumor-, and treatment-specific factors in patients without pCR were analyzed using the Cox proportional hazards method to evaluate factors predictive of LRR. Log-rank statistics were then used to compare LRR among these risk factors.Results:A total of 153 patients with a median follow-up of 48.6 months were included. The 4-year overall survival and LRR were 70% and 15%, respectively, and the 4-year LRR in patients with pCR was 0% versus 22.0% in those without (PP=.002) and extranodal extension (ENE; hazard ratio, 3.32; 95% CI, 1.35–8.15;P=.009) were significant predictors of LRR in multivariable analysis. In these patients, the 4-year LRR with LVSI was 39.8% versus 15.0% without (PP=.002). In patients without pCR, the presence of both LVSI and ENE were associated with an even further increased risk of LRR compared with patients with either LVSI or ENE alone and those with neither LVSI nor ENE in the residual tumor (PConclusions:In patients without pCR, the presence of LVSI and ENE increases the risk of LRR in TNBC. The risk of LRR is compounded when both LVSI and ENE are present in the same patient. Future clinical trials are warranted to lower the risk of LRR in these high-risk patients.

BACKGROUND Triple negative breast cancer (TNBC) has worse prognosis than other subtypes of breast cancer, and many patients develop brain metastasis (BM). We developed a simple predictive model to stratify the risk of BM in TNBC patients receiving neo-adjuvant chemotherapy (NAC), surgery, and radiation therapy (RT). METHODS Patients with TNBC who received NAC, surgery, and RT were included. Cox proportional hazards method was used to evaluate factors associated with BM. Significant factors predictive for BM on multivariate analysis (MVA) were used to develop a risk score. Patients were divided into three risk groups: low, intermediate, and high. A receiver operating characteristic (ROC) curve was drawn to evaluate the value of the risk group in predicting BM. This predictive model was externally validated. RESULTS A total of 160 patients were included. The median follow-up was 47.4 months. The median age at diagnosis was 49.9 years. The 2-year freedom from BM was 90.5%. Persistent lymph node positivity, HR 8.75 (1.76-43.52, P = 0.01), and lack of downstaging, HR 3.46 (1.03-11.62, P = 0.04), were significant predictors for BM. The 2-year rate of BM was 0%, 10.7%, and 30.3% (P

Background Patients with triple-negative breast cancers (TNBC) are at an increased risk of distant metastasis compared to patients with other subtypes of breast cancer. While TNBCs are aggressive as a group, many are potentially curable, reflecting an underlying heterogeneity. As such, there is an interest in identifying factors that may allow further stratification of patients in relation to the risk of distant metastasis and, ultimately, better tailor treatment plans to individual patients. With the increasing use of neoadjuvant chemotherapy (NAC), past studies have shown that patients who achieve a pathological complete response (pCR) following NAC have a decreased risk of distant metastasis. However, beyond the presence or absence of pCR, other risk factors for distant metastasis have not been well characterized. Methods This is a single institution, retrospective study of women with TNBC treated with NAC, surgery, and radiation therapy (RT) between 2000 and 2013. The rate of distant metastasis was estimated and compared between patients who achieved pCR versus those who did not achieve pCR using Kaplan-Meier method. In patients who failed to achieve pCR, patient-specific and treatment-specific factors including age, race, menopause status, family history, smoking history, clinical stage, histology, NAC regimen, whether breast conserving surgery was performed, response to NAC, treatment with adjuvant chemotherapy, and use of RT boost were analyzed using multivariable cox proportional hazards method to evaluate factors associated with distant metastasis. Results A total of 153 patients with a median follow up of 48.6 months were included. Of the 153 patients, 108 (70.9%) were identified as not having pCR following NAC. Among those 45 patients that did achieve a pCR, only 1 patient (2.2%) went on to have distant metastasis. In contrast, of the 108 patients that failed to achieve a pCR, 47 (43.5%) went on to have distant metastasis. On univariable analysis, factors associated with distant metastasis in patients that did not achieve a pCR included increasing clinical and pathological T and N stage, positive pathologic lymph node status, multifocality, lymphovascular space invasion (LVSI), extranodal extension, and failure of downstaging after NAC. After controlling for potential confounders in multivariable analysis, higher pathological N stage (HR 2.18, 95% CI 1.12 - 4.22), positive pathologic lymph nodes (HR 2.21, 95% CI 1.02 - 4.80), LVSI (HR 1.87, 95% CI 1.04 - 3.37), and multifocality (HR 2.05, 95% CI 1.05 - 4.03) were found to be independent predictors of distant metastasis. Conclusions Approximately 43.5% of patients with TNBC that did not achieve a pCR went on to develop distant metastasis, perhaps reflecting an underlying chemo-resistance of these non-pCR tumors. Here we identify multiple risk factors associated with distant metastasis among patients not achieving a pCR, including positive lymph nodes, LVSI, high pathologic N stage, and multifocality. This data can be used to inform prognoses and treatment decisions in this high-risk cohort of patients and future clinical trials are warranted to lower the risk of distant metastasis in this population. Citation Format: Tricarico CJ, Gabani P, Weiner AA, Ochoa LL, Thomas MA, Zoberi I. Predictors of distant metastasis in patients with triple negative breast cancer who failed to achieve a pathological complete response after neoadjuvant chemotherapy [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P2-08-39.

Purpose: To evaluate the feasibility and assess safety parameters of magnetic resonance-guided high-intensity focused ultrasound (MRgHIFU)-mediated hyperthermia (HT; heating to 40–45 °C) in various pelvic targets in a porcine model in vivo. Methods: Thirteen HT treatments were performed in six pigs with a commercial MRgHIFU system (Sonalleve V2, Profound Medical Inc., Mississauga, Canada) to muscle adjacent to the ventral/dorsal bladder wall and uterus to administer 42 °C (±1°) for 30 min (±5%) using an 18-mm target diameter and 100 W power. Feasibility was assessed using accuracy, uniformity, and MR-thermometry performance-based metrics. Safety parameters were assessed for tissues in the targets and beam-path by contrast-enhanced MRI, gross-pathology and histopathology. Results: Across all HT sessions, the mean difference between average temperature (Tavg) and the target temperature within the target region-of-interest (tROI, the cross-section of the heated volume at focal depth) was 0.51 ± 0.33 °C. Within the tROI, the temperature standard deviation averaged 1.55 ± 0.31 °C, the average 30-min Tavg variation was 0.80 ± 0.17 °C, and the maximum difference between Tavg and the 10th- or 90th-percentile temperature averaged 2.01 ± 0.44 °C. The average time to reach ≥41 °C and cool to ≤40 °C within the tROI at the beginning and end of treatment was 47.25 ± 27.47 s and 66.37 ± 62.68 s, respectively. Compared to unheated controls, no abnormally-perfused tissue or permanent damage was evident in the MR images, gross pathology or histological analysis. Conclusions: MRgHIFU-mediated HT is feasible and safety assessment is satisfactory for treating an array of clinically-mimicking pelvic geometries in a porcine model in vivo, implying the technique may have utility in treating pelvic targets in human patients.

Purpose To evaluate the targetability of late-stage cervical cancer by magnetic resonance-guided high-intensity focused ultrasound (MRgHIFU)-induced hyperthermia (HT) as an adjuvant to radiation therapy (RT). Methods Seventy-nine cervical cancer patients (stage IIIB–IVA) who received RT with lesions visible on positron emission tomography-computed tomography (PET-CT) were retrospectively analyzed for targetability using a commercially-available HT-capable MRgHIFU system. Targetability was assessed for both primary targets and/or any metastatic lymph nodes using both posterior (supine) and anterior (prone) patient setups relative to the transducer. Thirty-four different angles of rotation along subjects’ longitudinal axis were analyzed. Targetability was categorized as: (1) Targetable with/without minimal intervention; (2) Not targetable. To determine if any factors could be used for prospective screening of patients, potential associations between demographic/anatomical factors and targetability were analyzed. Results 72.15% primary tumors and 33.96% metastatic lymph nodes were targetable from at least one angle. 49.37% and 39.24% of primary tumors could be targeted with patient laying in supine and prone positions, respectively. 25°–30° rotation and 0° rotation had the highest rate of the posterior and anterior targetability, respectively. The ventral depth of the tumor and its distance to the coccyx were statistically correlated with the anterior and posterior targetability, respectively. Conclusion Most late-stage cervical cancer primaries were targetable by MRgHIFU HT requiring either no/minimal intervention. A rotation of 0° or 25°–30° relative to the transducer might benefit anterior and posterior targetability, respectively. Certain demographic/anatomic parameters might be useful in screening patients for treatability.

Introduction Accelerated partial breast irradiation (APBI) seeks to reduce irradiated volumes and radiation exposure for patients while maintaining acceptable clinical outcomes. Magnetic resonance image-guided radiotherapy (MRgRT) provides excellent soft-tissue contrast for treatment localization, which can reduce setup uncertainty, thus reducing margins in the external beam setting. Additionally, stereotactic body radiotherapy (SBRT)-style regimens with high gradients can also be executed. This MR-guided stereotactic APBI (MRgS-APBI) approach can be utilized for a lower number of fractions and spare a greater volume of healthy tissues compared to conventional 3D external beam APBI. Methods Our MRgS-APBI program was developed for two prospective non-randomized phase I/II clinical trials (20Gyx1 and 8.5Gyx3). Both breast SBRT treatment planning and MRgRT delivery techniques were described in this study. Simulation included both CT and MRI with specialized immobilization to accommodate MR-guided setup and cine-MRI treatment gating. Dosimetry data from 48 single-fraction and 19 three-fraction patients were collected and evaluated. This included planning objectives and SBRT-specific indices. During treatment, setup errors were calculated to evaluate setup reproducibility and duty cycle was calculated using cine-MRI data during gated delivery. Results In both the single- and three- fraction trials combined, 88.5% of the possible dosimetric objectives across all patients were met during planning. The majority of the planning objectives were easily achievable indicating the potential for stricter objectives for subsequent S-APBI treatments. The average magnitude of setup uncertainties was 1.0 cm ± 0.6 cm across all treatments. In the three-fraction trial, the average beam-on duty-cycle for the MRI-gated delivery was 83.0 ± 13.0%. There were no technical MRgS-APBI related issues that resulted in discontinuation of treatment across all patients. Conclusion SBRT-style dosimetry and delivery for APBI is feasible using MR-guidance. The program development and dosimetric outcomes reported here can serve as a guide for other institutions considering the clinical implementation of MR-guided stereotactic APBI.

Purpose Our purpose was to describe the risk of radiation-induced brachial plexopathy (RIBP) in patients with breast cancer who received comprehensive adjuvant radiation therapy (RT). Methods and Materials Records for 498 patients who received comprehensive adjuvant RT (treatment of any residual breast tissue, the underlying chest wall, and regional nodes) between 2004 and 2012 were retrospectively reviewed. All patients were treated with conventional 3 to 5 field technique (CRT) until 2008, after which intensity modulated RT (IMRT) was introduced. RIBP events were determined by reviewing follow-up documentation from oncologic care providers. Patients with RIBP were matched (1:2) with a control group of patients who received CRT and a group of patients who received IMRT. Dosimetric analyses were performed in these patients to determine whether there were differences in ipsilateral brachial plexus dose distribution between RIBP and control groups. Results Median study follow-up was 88 months for the overall cohort and 92 months for the IMRT cohort. RIBP occurred in 4 CRT patients (1.6%) and 1 IMRT patient (0.4%) (P = .20). All patients with RIBP in the CRT cohort received a posterior axillary boost. Maximum dose to the brachial plexus in RIBP, CRT control, and IMRT control patients had median values of 56.0 Gy (range, 49.7-65.1), 54.8 Gy (47.4-60.5), and 54.8 Gy (54.2-57.3), respectively. Conclusions RIBP remains a rare complication of comprehensive adjuvant breast radiation and no clear dosimetric predictors for RIBP were identified in this study. The IMRT technique does not appear to adversely affect the development of this late toxicity.

To comprehensively characterize dosimetric differences between calculations with a commercial model-based dose calculation algorithm (MBDCA) and the TG-43 formalism in application to accelerated partial breast irradiation (APBI) with the strut-adjusted volume implant (SAVI) applicator.Dose for 100 patients treated with the SAVI applicator was recalculated with an MBDCA for comparison to dose calculated via TG-43. For every pair of dose calculations, dose-volume histogram (DVH) metrics including V90%, V95%, V100%, V150%, and V200% for the PTV_EVAL were compared. Features were defined for each case including (1) applicator size, (2) ratio between PTV_EVAL contour and 1-cm rind surrounding SAVI applicator, (3) ratio between dwell time in central catheter and total dwell time, and (4) mean computed tomography (CT) number within the lumpectomy cavity. Wilcoxon rank sum tests were performed to test whether treatment plans could be stratified according to feature values into groups with statistically significant dosimetry differences between MBDCA and TG-43.For all DVH metrics, differences between TG-43 and MBDCA calculations were statistically significant (P.05). Minimum (maximum) relative percent differences between the MBDCA and TG-43 for V90%, V95%, and V100% were -2.1% (0.1%), -3.1% (-0.1%), and -5.0% (-0.5%), respectively. The median relative percent difference in mean PTV_EVAL dose between the MBDCA and TG-43 was -3.9%, with minimum (maximum) difference of -6.5% (-1.8%). For V90%, V95%, and V100%, plan quality worsened beyond defined thresholds in 26, 23, and 31 cases with no instances of coverage improvement. Features 1, 2, and 4 were shown to be able to stratify treatment plans into groups with statistically significant differences in dosimetry metrics between MBDCA and TG-43.Investigated dose metrics for SAVI treatments were found to be systematically lower with MBDCA calculation in comparison to TG-43. Plans could be stratified according to several features by the magnitude of dosimetric differences between these calculations.

Aims Magnetic resonance image-guided radiotherapy (MRIgRT) has been clinically implemented since 2014. This technology offers improved soft-tissue visualisation, daily imaging, and intra-fraction real-time imaging without added radiation exposure, and the opportunity for adaptive radiotherapy (ART) to adjust for anatomical changes. Here we share the longest single-institution experience with MRIgRT, focusing on trends and changes in use over the past 4.5 years. Materials and methods We analysed clinical information, including patient demographics, treatment dates, disease sites, dose/fractionation, and clinical trial enrolment for all patients treated at our institution using MRIgRT on a commercially available, integrated 0.35 T MRI, tri-cobalt-60 device from 2014 to 2018. For each patient, factors including disease site, clinical rationale for MRIgRT use, use of ART, and proportion of fractions adapted were summated and compared between individual years of use (2014–2018) to identify shifts in institutional practice patterns. Results Six hundred and forty-two patients were treated with 666 unique treatment courses using MRIgRT at our institution between 2014 and 2018. Breast cancer was the most common disease, with use of cine MRI gating being a particularly important indication, followed by abdominal sites, where the need for cine gating and use of ART drove MRIgRT use. One hundred and ninety patients were treated using ART in 1550 fractions, 67.6% (1050) of which were adapted. ART was primarily used in cancers of the abdomen. Over time, breast and gastrointestinal cancers became increasingly dominant for MRIgRT use, hypofractionated treatment courses became more popular, and gastrointestinal cancers became the principal focus of ART. Discussion MRIgRT is widely applicable within the field of radiation oncology and new clinical uses continue to emerge. At our institution to date, applications such as ART for gastrointestinal cancers and accelerated partial breast irradiation (APBI) for breast cancer have become dominant indications, although this is likely to continue to evolve.

Since mild hyperthermia therapy (MHT) requires maintaining the temperature within a narrow window (e.g. 40-43 °C) for an extended duration (up to 1 h), accurate and precise temperature measurements are essential for ensuring safe and effective treatment. This study evaluated the precision and accuracy of MR thermometry in healthy volunteers at different anatomical sites for long scan times.A proton resonance frequency shift method was used for MR thermometry. Eight volunteers were subjected to a 5-min scanning protocol, targeting chest wall, bladder wall, and leg muscles. Six volunteers were subjected to a 30-min scanning protocol and three volunteers were subjected to a 60-min scanning protocol, both targeting the leg muscles. The precision and accuracy of the MR thermometry were quantified. Both the mean precision and accuracy1 °C were used as criteria for acceptable thermometry.Drift-corrected MR thermometry measurements based on 5-min scans of the chest wall, bladder wall, and leg muscles had accuracies of 1.41 ± 0.65, 1.86 ± 1.20, and 0.34 ± 0.44 °C, and precisions of 2.30 ± 1.21, 1.64 ± 0.56, and 0.48 ± 0.05 °C, respectively. Measurements based on 30-min scans of the leg muscles had accuracy and precision of 0.56 ± 0.05 °C and 0.42 ± 0.50 °C, respectively, while the 60-min scans had accuracy and precision of 0.49 ± 0.03 °C and 0.56 ± 0.05 °C, respectively.Respiration, cardiac, and digestive-related motion pose challenges to MR thermometry of the chest wall and bladder wall. The leg muscles had satisfactory temperature accuracy and precision per the chosen criteria. These results indicate that extremity locations may be preferable targets for MR-guided MHT using the existing MR thermometry technique.

Purpose The purpose of the study was to develop an optimized, efficient workflow for using the day-of-implant (DOI) CT for treatment planning of accelerated partial breast irradiation brachytherapy using the strut-adjusted volume implant (SAVI) device. Methods and Materials For 62 consecutive SAVI patients, a DOI CT was acquired and used for treatment planning. A “verification” CT was acquired 24–72 h after implant and immediately before the first fraction, then registered to the DOI CT. If the DOI CT–based plan was no longer optimal, a replan was performed. An array of metrics describing the geometry of the device and its relative position in the patient from the DOI CTs for these patients was collected. These metrics from the DOI CT were evaluated to determine what features could predict for the need to replan before the first treatment fraction. Logistical regression analysis including χ2 tests was used to determine if different factors correlated with replanning. Results Twenty-two of 62 patients (35%) required replanning. Only the presence of splayed struts, where splay was toward the skin, and the use of a nine strut (“8-1”) SAVI were significantly correlated (p Conclusions For strut-based accelerated partial breast irradiation brachytherapy, it was feasible to treat with a plan based on the DOI CT for a majority (65%) of patients. Some factors correlate to needing replanning; recognizing these could be used to optimize treatment workflow for certain patients, increasing clinical efficiency while enhancing the quality of patient care.

Purpose/Objective(s) To report the initial tolerance, quality-of-life (QoL), and cosmetic outcomes from a single institutional prospective phase I/II clinical trial of three fraction accelerated partial breast irradiation (Tri-APBI). Materials/Methods Eligible breast cancer patients were treated with breast conserving surgery to negative margins and were at least 50 years old, postmenopausal, with hormone sensitive, HER-2 negative cancers, and stage pTis-1N0M0 (2 cm or less in size). HDR brachytherapy using a SAVI applicator (22.5 Gy in 3 fractions) or external beam radiation (EBRT) (25.5 Gy in 3 fractions) over 2-3 days was used to deliver Tri-APBI. APBI modality was chosen by the treating physician, based on physical exam and ultrasound assessment of the surgical bed. In general, those surgical beds suitable for brachytherapy were treated with SAVI. EBRT was delivered using MR-guidance, unless contraindicated. The PTV for all patients was created using a 1-cm expansion of breast tissue around the surgical bed limited 0.5 cm from the skin surface, and for SAVI patients excluded the applicator. Coprimary endpoints were grade 3+ CTCAEv4.0 toxicity and ipsilateral breast tumor recurrence (IBTR). Patient-reported QOL and cosmesis via qualitative and quantitative methods were also assessed. Results From August 2018 to January 2021, 73 of a planned 75 patients have been treated. Stage I disease was present in 78% and EBRT was used in 59%. Median follow-up was 14 months from completion of Tri-APBI (range, 1 - 28). There has been no grade 3+ CTCAEv4.0 toxicities, and no cancer recurrences. Qualitative cosmesis, as measured by the Aaronson-modified Harris scale, was evaluated by patients and providers respectively as good-to-excellent in 94% and 98% pre-treatment and 94% and 95% at latest follow-up. Quantitative cosmesis was assessed by percentage of breast retraction assessment (pBRA) and showed that breast asymmetry did not significantly worsen compared to pre-treatment, with a baseline mean pBRA of 7.2% (range 2.1 - 22.6%) and a 12-month mean pBRA of 6.9% (range 1.6 - 26.8%). There was no significant decline in QOL over time after APBI as assessed by the EORTC core (QLQ-C30) and breast cancer-specific (QLQ-BR23) QOL questionnaires. Conclusion Tri-APBI as delivered with EBRT or SAVI in this trial was safe, with a minimal initial impact on patient-reported quality of life, qualitative and quantitative cosmesis. Further follow-up is needed to evaluate efficacy.

PURPOSE/OBJECTIVE(S) External beam accelerated partial breast irradiation (APBI) utilizes Planning Target Volume (PTV) expansions of 2 to 2.5 cm beyond the surgical cavity to assure treatment of target breast tissue. Decreasing the volume of irradiated breast with external beam accelerated partial breast irradiation (APBI) is a potential way to minimize dose to organs at risk and adverse cosmetic outcomes. Magnetic resonance guided radiation therapy (MRgRT) allows detailed pre-fraction imaging and continuous intrafraction monitoring which allows for external beam APBI treatments using a brachytherapy-style 1 cm surgical bed to PTV margin. We have previously shown that MRgRT APBI results in an average 52% reduction in PTV. In this study we report the outcomes of patients treated with reduced-margin APBI via MRgRT. MATERIALS/METHODS Patients included women with early stage, node negative breast cancers treated with breast conserving surgery and adjuvant MRgRT APBI from March 2014 to July 2019. PTV was defined as the surgical cavity plus a uniform 1-cm margin of breast tissue (excluding chest wall, pectoral muscles, and 5mm from skin). The PTV received 38.5 Gy in ten fractions over five treatment days. Volumetric MR imaging was acquired prior to each fraction to localize the surgical cavity and a sagittal cine MR imaging during each treatment to monitor intrafraction motion; gating to the surgical bed was used as needed. RESULTS 242 patients were treated with MRgRT APBI with reduced margins. Eighty-one (33.5%) patients had pure DCIS and 161 (66.5%) patients had pT1N0 disease. Seventy-three (90.1%) patients with pure DCIS had hormone sensitive disease and 141 (87.6%) patients with invasive disease had hormone sensitive, her2/neu negative disease. Stratifying by ASTRO APBI Consensus guidelines, 36% of patients were categorized as Cautionary and one patient was Unsuitable solely due to age < 40. At a median follow up of 36 months (range, 14 - 82), two patients (0.8%) had biopsy-proven in-breast tumor recurrence (IBTR), both of whom were successfully salvaged. Per the Aaronson-modified Harris scale, providers reported 100% of patients had good/excellent cosmesis prior to APBI and at last follow-up. Nearly two thirds of patients experienced no acute skin toxicity with the remaining having small regions of grade 1 erythema. There were no observed CTCAEv4.0 grade 3+ toxicities following APBI. CONCLUSION APBI with reduced margins using MR-IGRT is safe and has excellent cosmetic outcomes with acceptably low initial rates of IBTR.

To develop a consensus report for the quality practice of accelerated partial breast irradiation (APBI) using interstitial multicatheter brachytherapy (IMB).The American Brachytherapy Society Board appointed an expert panel with clinical and research experience with breast brachytherapy to provide guidance for the current practice of IMB. This report is based on a comprehensive literature review with emphasis on randomized data and expertise of the panel.Randomized trials have demonstrated equivalent efficacy of APBI using IMB compared with whole breast irradiation for select patients with early-stage breast cancer. Several techniques for placement of interstitial catheters are described, and importance of three-dimensional planning with appropriate optimization is reviewed. Optimal target definition is outlined. Commonly used dosing schemas include 50 Gy delivered in pulses of 0.6-0.8 Gy/h using pulsed-dose-rate technique and 34 Gy in 10 fractions, 32 Gy in eight fractions, or 30 Gy in seven fractions using high-dose-rate technique. Potential toxicities and strategies for toxicity avoidance are described in detail. Dosimetric constraints include limiting whole breast volume that receives ≥50% of prescription dose to60%, skin dose to ≤100% of prescription dose (≤60-70% preferred), chest wall dose to ≤125% of prescription dose, Dose Homogeneity Index to0.75 (0.85 preferred), VIMB is an effective technique to deliver APBI for appropriately selected women with early-stage breast cancer. This consensus report has been created to assist clinicians in the appropriate practice of APBI using IMB.

Purpose Magnetic resonance image guided radiation therapy (MR-IGRT) has been used at our institution since 2014. We report on more than 2 years of clinical experience in treating patients with the world's first MR-IGRT system. Methods and materials A clinical service was opened for MR-IGRT in January 2014 with an MR-IGRT system consisting of a split 0.35T magnetic resonance scanner that straddles a ring gantry with 3 multileaf collimator-equipped 60 Co heads. The service was expanded to include online adaptive radiation therapy (ART) MR-IGRT and cine gating after 6 and 9 months, respectively. Patients selected for MR-IGRT were enrolled in a prospective registry between January 2014 and June 2016. Patients were treated with a variety of radiation therapy techniques including intensity modulated radiation therapy and stereotactic body radiation therapy (SBRT). When applicable, online ART was performed and gating on sagittal 2-dimensional cine MR was used. The charts of patients treated with MR-IGRT were reviewed to report on the clinical and treatment characteristics of the initial patients who were treated with this novel technique. Results A total of 316 patients have been treated with the MR-IGRT system, which has been integrated into a high-volume clinic. The cases were most commonly selected for improved soft tissue visualization, ART, and cine gating. Seventy-six patients were treated with 3-dimensional conformal radiation therapy, 146 patients with intensity modulated radiation therapy, and 94 patients with SBRT. The most commonly treated disease sites were the abdomen (28%), breast (26%), pelvis (22%), thorax (19%), and head and neck (5%). Sixty-seven patients were treated with online ART over a total of 244 adapted fractions. Cine treatment gating was used for a total of 81 patients. Conclusions MR-IGRT has been successfully implemented in a high-volume radiation clinic and provides unique advantages in the treatment of a variety of malignancies. Additional clinical trials are in development to formally evaluate MR-IGRT in the treatment of multiple disease sites with techniques such as SBRT and ART.

Background We evaluate the impact of radiation and its early versus late effects on internal mammary vessel histomorphometry and implications for autologous breast reconstruction. Methods Patients received no radiation or radiation within the previous 6 weeks (early) or at least 6 months prior to biopsy (late) of the internal mammary vessels during free flap surgery. Clinical outcomes, and vessel measurements and markers for macrophages, smooth muscle actin (SM-ACTIN), elastin, and collagen were analyzed. Results We analyzed 36 internal mammary arteries (IMAs) and veins (IMV) in 22 patients. Six had no radiation, 12 had radiation less than 6 weeks, and 18 had radiation more than 6 months ago. Demographics, surgical variables, and cardiovascular comorbidity did not differ between groups. Macrophage counts were higher in patients who had radiation (p Conclusion Higher macrophage counts but less intimal thickening of the IMA differentiates donor vessels utilized within 6 weeks of radiotherapy and those performed after 6 months or more. Although the timing of reconstruction is based on several other factors, histologic parameters support reconstruction within 6 weeks of radiation therapy.

Purpose We sought to evaluate the feasibility and tolerability of a novel accelerated partial breast irradiation regimen delivered in a single fraction postoperatively. Methods and Materials We enrolled 50 patients with low-risk, hormone-sensitive breast cancer from 2015 to 2018 on a prospective phase 1/2 trial to receive single-fraction, high-gradient partial-breast irradiation (SFHGPBI) 2 to 8 weeks after lumpectomy for node-negative, invasive, or in situ breast cancer. The high gradient was achieved by prescribing 20 Gy to the surgical bed and 5 Gy to the breast tissue within 1 cm of the surgical bed simultaneously in 1 fraction using external beam. Results The median age was 65 (range, 52-84). Ten patients (20%) had small-volume ductal carcinoma in situ while the remainder had stage I disease. At a median follow-up of 25 months, we evaluated toxicity, patient- and physician-reported cosmesis, patient-reported quality of life (QOL), and initial tumor control. There was no Common Terminology Criteria for Adverse Events v4.0 grade 3+ toxicity. Only 34% of patients experienced grade 1 erythema. Good-to-excellent pretreatment cosmesis was present in 100% and 98% per physicians and patients, respectively, and did not change post-SFHGPBI. Quantitative cosmesis by percentage of breast retraction assessment significantly improved over time during the post-SFHGPBI period per mixed repeated measures modeling (P = .0026). QOL per European Organization for Research and Treatment of Cancer QOL Questionnaires C30 and BR-23 did not decline other than temporarily in the systemic therapy effects and hair loss domains, both of which returned to pretreatment values. There was 1 noninvasive in-breast recurrence in a separate untreated quadrant 18 months post-SFHGPBI and 1 isolated axillary recurrence 30 months post-SFHGPBI, both salvaged successfully. There were no distant recurrences or cancer-related deaths observed. Conclusions Accelerated partial-breast irradiation delivered in a single fraction postoperatively using external beam techniques is a novel, feasible, well-tolerated regimen. SFHGPBI does not adversely affect cosmesis or QOL as reported by both physicians and patients. Initial tumor control rates are excellent, with longer follow-up required to confirm efficacy.

Long-term tumor control and cosmetic outcomes for accelerated partial breast radiation (APBI) delivered with 3-dimensional conformal external beam radiation (3D-CRT) remain limited. We seek to address these concerns by reporting our experience of 3D-CRT APBI with extended follow-up.All patients treated with APBI delivered with 3D-CRT from January 2006 through December 2012 at a single institution were identified. Those with more than a year of follow-up were analyzed for ipsilateral breast tumor recurrence (IBTR), progression-free survival (PFS), cosmesis, and pain. Disease outcomes were analyzed by margin status (2 mm, ≥2 mm), total radiation dose prescribed, presence of invasive disease, and American Society for Radiation Oncology (ASTRO) 2016 updated consensus groupings (suitable, cautionary, and unsuitable).Two hundred ninety-three patients were identified, of whom 266 had1 year of follow-up. Median follow-up was 87 months (range, 13-156). Of the 266, 162 (60.9%) were ASTRO "suitable," 87 (32.7%) were "cautionary," and 17 (6.4%) were "unsuitable." Seven-year rates of IBTR and PFS were 1.8% and 95.2%, respectively. Margin status, invasive versus in situ disease, prescribed dose, and ASTRO grouping were not prognostic for either IBTR or PFS on univariate analysis. Cosmesis was good to excellent in 75.2%. Two patients (0.8%) had subsequent plastic surgery owing to poor cosmesis. Narcotic medication for treatment site pain was needed by 6 (2.3%).External beam APBI results in excellent long-term disease control. Good to excellent cosmetic outcomes are achieved in most patients, although increasing dose per fraction and greater percentage of irradiated breast were predictive of adverse posttreatment cosmetic outcomes. Select patients in "cautionary" and "unsuitable" consensus groupings do not appear to have inferior outcomes.

Purpose To use magnetic resonance image guided radiation therapy (MR-IGRT) for accelerated partial-breast irradiation (APBI) to ( 1 ) determine intrafractional motion of the breast surgical cavity; and ( 2 ) assess delivered dose versus planned dose. Methods and Materials Thirty women with breast cancer (stages 0-I) who underwent breast-conserving surgery were enrolled in a prospective registry evaluating APBI using a 0.35-T MR-IGRT system. Clinical target volume was defined as the surgical cavity plus a 1-cm margin (excluding chest wall, pectoral muscles, and 5 mm from skin). No additional margin was added for the planning target volume (PTV). A volumetric MR image was acquired before each fraction, and patients were set up to the surgical cavity as visualized on MR imaging. To determine the delivered dose for each fraction, the electron density map and contours from the computed tomography simulation were transferred to the pretreatment MR image via rigid registration. Intrafractional motion of the surgical cavity was determined by applying a tracking algorithm to the cavity contour as visualized on cine MR. Results Median PTV volume was reduced by 52% when using no PTV margin compared with a 1-cm PTV margin used conventionally. The mean (± standard deviation) difference between planned and delivered dose to the PTV (V95) was 0.6% ± 0.1%. The mean cavity displacement in the anterior–posterior and superior–inferior directions was 0.6 ± 0.4 mm and 0.6 ± 0.3 mm, respectively. The mean margin required for at least 90% of the cavity to be contained by the margin for 90% of the time was 0.7 mm (5th-95th percentile: 0-2.7 mm). Conclusion Minimal intrafractional motion was observed, and the mean difference between planned and delivered dose was less than 1%. Assessment of efficacy and cosmesis of this MR-guided APBI approach is under way.

Purpose We report the toxicity of patients treated with strut-adjusted volume implant (SAVI) for accelerated partial breast irradiation treated at our institution. Methods and Materials Patients treated from January 2013 to July 2015 with SAVI planned for 10 b.i.d. fractions for a total dose of 34 Gy were included. Acute and late toxicities were prospectively collected on patients in followup and graded by the Common Terminology Criteria for Adverse Events, version 4.0. Results A total of 132 patients were included, with 1 patient having synchronous breast cancer treated in each breast. Median followup was 20.0 months (range, 2.7–37.4 months). The median age at diagnosis was 61 years (range, 41–83 years). Forty-two lesions (32%) were in situ, 88 lesions (66%) were Stage 1, and 3 (2%) lesions were Stage 2. The median planning target volume was 58.2 cc (range, 24.2–109.9 cc), median V150 was 26.3 cc (range, 11.5–47.5 cc), and median V200 was 13.0 cc (range, 6.3–26.1 cc). On a pain scale of 0–10 (10 = worst pain), pain was worst on Day 2 of treatment, with an average score of 0.46. There was one acute skin infection; there were three late skin infections, two of which was Grade 3. Other late toxicities were Grade 1 or 2: hyperpigmentation (44%), telangiectasia (0.8%), seroma (9%), fat necrosis (5%), and fibrosis (12%). Crude local recurrence rate was 4%. Conclusion SAVI is a safe treatment option for patients who are candidates for accelerated partial breast irradiation. Local control seems to be excellent, but longer followup is needed.

Background Axillary surgery is not considered therapeutic in patients with clinical T1-T2 N0 breast cancer. The importance of axillary staging is eroding in an era in which tumor biology, as defined by biomarker and gene expression profile, is increasingly important in medical decision making. We hypothesized that axillary ultrasound (AUS) is a noninvasive alternative to sentinel lymph node biopsy (SLNB), and AUS could replace SLNB without compromising patient care. Study Design Patients with clinical T1-T2 N0 breast cancer and normal AUS were eligible for enrollment. Subjects were randomized to no further axillary staging (arm 1) vs SLNB (arm 2). Descriptive statistics were used to describe the results of the pilot phase of the randomized controlled trial. Results Sixty-eight subjects were enrolled in the pilot phase of the trial (34 subjects in arm 1, no further staging; 32 subjects in arm 2, SLNB; and 2 subjects voluntarily withdrew from the trial). The median age was 61 years (range 40 to 80 years) in arm 1 and 59 years (range 31 to 81 years) in arm 2, and there were no significant clinical or pathologic differences between the arms. Median follow-up was 17 months (range 1 to 32 months). The negative predictive value (NPV) of AUS for identification of clinically significant axillary disease (>2.0 mm) was 96.9%. No axillary recurrences have been observed in either arm. Conclusions Successful completion of the pilot phase of the randomized controlled trial confirms the feasibility of the study design, and provides prospective evidence supporting the ability of AUS to exclude clinically significant disease in the axilla. The results provide strong support for a phase 2 randomized controlled trial.

Younger age diagnosis of breast cancer is a predictor of adverse outcome. Here, we evaluate prognostic factors in young women with locally advanced breast cancer (LABC). We present a retrospective review of 104 patients younger than 40 years with LABC treated with surgery, radiotherapy (RT), and chemotherapy from 2003 to 2014. Patient‐, tumor‐, and treatment‐related factors important for overall survival (OS), local/regional recurrence (LRR), distant metastasis (DM), and recurrence‐free survival (RFS) were evaluated. Mean age at diagnosis was 34 years (23–39 years) with a median follow‐up of 47 months (8–138 months). Breast‐conserving surgery was performed in 27%. Axillary lymph node dissection was performed in 85%. Sixty percent of patients received neoadjuvant chemotherapy with 19% achieving pathologic complete response (pCR), and 61% downstaged. Lymph node positivity was present in 91% and lymphovascular space invasion (LVSI) in 35%. Thirty‐two percent of patients had triple negative tumors (TN, ER‐/PR‐/HER2 nonamplified). Four‐year OS and RFS was 84% and 71%, respectively. Factors associated with worse OS on multivariate analysis include TN status, LVSI, and number of positive lymph nodes. LVSI was also associated with DM and LRR, as well as worse RFS. Downstaging was associated with improved 4 year RFS in patients receiving neoadjuvant chemotherapy (74% vs. 38%, P = 0.002). With high risks of recurrence and inferior OS compared to older women, breast cancer in young women can be difficult to treat. Among additional factors, presence of LVSI and lack of downstaging portends a particularly worse prognosis.

Trastuzumab/pertuzumab improved outcomes for patients (pts) with HER2+ breast cancer. Increased survival coupled with limited blood-brain barrier (BBB) penetration of these agents apparently contributes to increased incidence of brain metastases (BM). Lapatinib (L) crosses the BBB and demonstrates activity against BM. Based upon pre/early clinical data, it’s hypothesized that L + whole brain radiotherapy (WBRT) or Stereotactic Radiosurgery (SRS) would improve intracranial control compared to WBRT/SRS (RT) alone. This randomized phase II trial included HER2+ breast cancer pts with ≥ 1 measurable, unirradiated parenchymal BM. Pts were randomized 1:1 to WBRT (37.5 Gy/3 weeks) or SRS +/- concurrent L (1000 mg dailyx6 weeks), andwere stratified by graded prognostic assessment (GPA), use of non-CNS penetrating anti-HER2 therapies, and previous SRS/resection. The primary endpoint was intracranial complete response (CR) rate 12weeks (wk) after RT. Secondary endpoints included objective response rate (ORR), lesion-specific response rate, CNS progression-free survival, and overall survival. 114 of 143 pts were evaluable for 12-wk CR (52 RT, 62 RT+L). Rate of grade 3 and 4 adverse events were 8% and 0% for RT and 29% and 6% for RT+L. 92% and 90% pts received concurrent and adjuvant L per protocol/acceptable variation. There were no significant differences in 12 or 4wk CR rates (p=0.97 and p=0.77); 5.8% and 0% at 12wk and 3.6% and 1.5% at 4wk for RT and RT+L, respectively. The ORR at 4 wk was 42% and 56% (p=0.059, RECIST), 40% and 58% (p=0.027, WHO) in the RT and RT+L, respectively. Although the addition of lapatinib to WBRT/SRS did not improve the 12wk CR rate, it showed meaningful clinical benefit by demonstrating a trend toward improvement of 4 wk ORR. Results of ongoing central review of MRIs using RECIST1.1, WHO and RANO-BM criteria including secondary endpointswill be reported. Support: NCI grants U10CA180868, U10CA180822, UG1CA189867, and Novartis

Purpose Cardiac radiation is associated with cardiotoxicity in patients with thoracic and breast malignancies. We conducted a prospective study using cine magnetic resonance imaging (MRI) scans to evaluate heart motion. We hypothesized that cine MRI could be used to define population-based cardiac planning organ-at-risk volumes (PRV). Methods and Materials A total of 16 real-time acquisitions were obtained per subject on a 1.5 Tesla MRI (Philips Ingenia). Planar cine MRI was performed in 4 sequential sagittal and coronal planes at free-breathing (FB) and deep-inspiratory breath hold (DIBH). In-plane cardiac motion was assessed using a scale-invariant feature transformation–based algorithm. Subject-specific pixel motion ranges were defined in anteroposterior (AP), left-right (LR), and superoinferior (SI) planes. Averages of the 98% and 67% of the maximum ranges of pixel displacement were defined by subject, then averaged across the cohort to calculate PRV expansions at FB and DIBH. Results Data from 20 subjects with a total of 3120 image frames collected per subject in coronal and sagittal planes at DIBH and FB, and 62,400 total frames were analyzed. Cohort averages of 98% of the maximum cardiac motion ranges comprised margin expansions of 12.5 ± 1.1 mm SI, 5.8 ± 1.2 mm AP, and 6.6 ± 1.0 mm LR at FB and 6.7 ± 1.5 mm SI, 4.7 ± 1.3 mm AP, and 5.3 ± 1.3 mm LR at DIBH. Margins for 67% of the maximum range comprised 7.7 ± 0.7 mm SI, 3.2 ± 0.6 mm AP, and 3.7 ± 0.6 mm LR at FB and 4.1 ± 0.9 mm SI, 2.7 ± 0.8 mm AP, and 3.2 ± 0.8 mm LR at DIBH. Subsequently, these margins were simplified to form PRVs for treatment planning. Conclusions We implemented scale-invariant feature transformation-based motion tracking for analysis of the cardiac cine MRI scans to quantify motion and create cohort-based cardiac PRVs to improve cardioprotection in breast and thoracic radiation.

Tracking the heart motion during radiation treatment of cancer patients can provide important information for designing strategies to reduce radiation-induced heart toxicity. Recently, in-treatment cine MRI images are used for guiding radiation therapy. However, dynamic changes of heart shape and limited-contrast of cine MRI images make automatic heart motion tracking a very challenging task. This paper proposes a deep generative shape model-driven level set method to address these challenges and automatically track heart motion on 2D cine MRI images. First, we use a three-layered Deep Boltzmann Machine (DBM) to train a heart shape model that can characterize both global and local heart shape variations. Second, the shape priors inferred from the trained heart shape model are incorporated into the distance regularized level set evolution-based segmentation method to guide frame-by-frame heart segmentation on cine MRI images. We demonstrate the superior performance of the proposed method on cine MRI image sequences acquired from seven volunteers and also compare it with four other methods.

Purpose To standardize and automate the high-dose-rate (HDR) brachytherapy planning quality assurance (QA) process utilizing scripting with application programming interface (API) in a commercially available treatment planning system (TPS). Methods and Materials Site- and applicator-dependent plan quality (PQ) evaluation criteria and plan integrity (PI) checklists were established based on published guidelines, clinical protocols, and institutional experience. User designed C# programs (“scripts”) were created and executed through the API to access planning information in TPS. A set of standardized quality control reports, focusing on PQ evaluations and PI checks, were automatically generated. Information derived from the TPS was compared against predetermined QA metrics with color-coded pass/fail indicators to aid and enhance the efficiency of plan evaluation. Five independent, blinded observers reviewed mock plans with simulated errors to validate the scripts and to quantify the improvement of plan review efficiency. Results Scripts were developed for HDR prostate and breast. Forty-one parameters were reported/checked in the PI report; the PQ report returned dose-volume indices and an independent check of dwell time. All simulated errors were detected by the PI scripts with appropriate warning messages displayed, and any values failing to meet the planning constraints were red-flagged successfully in the PQ report. An average time reduction of 16 min for plan review was observed when using the scripts. Conclusions API scripting-based automated planning QA for HDR brachytherapy including PI checks and PQ evaluations was designed and implemented. The simulated error study showed promising results in terms of error catching and efficiency improvement.

Purpose Long-term outcome reports of accelerated partial-breast irradiation (APBI) are limited. Here, we report the 10-year outcomes of APBI delivered using multicatheter interstitial implant (ISI) brachytherapy. Methods and materials Patients with early-stage breast cancer treated with APBI via ISI brachytherapy were enrolled in a prospective registry. Selection criteria included age ≥40 years, ductal carcinoma in situ or invasive tumor ≤3 cm, negative margins (≥2 mm), and negative axillary nodes. 34 Gy in 10 twice-daily fractions was administered to 2 cm of breast tissue surrounding the surgical bed. Toxicity and cosmetic outcomes were collected prospectively. Results A total of 175 patients were included. The median followup time was 10.0 years. Ten-year ipsilateral breast tumor control, regional control, freedom from distant metastasis, breast cancer–specific survival, and overall survival were 92.1%, 96.9%, 97.4%, 97.1%, and 81.2%, respectively. High-grade disease was correlated with increase in the rate of ipsilateral breast tumor recurrence. Grade 1 or 2 skin toxicity was present in 44 patients, and Grade 3 skin toxicity was present in only 1 patient. There were no Grade 4 or higher toxicities observed. Thirty-seven patients developed fat necrosis. Dose Homogeneity Index of ≤0.85 and integrated reference air-kerma of >3400 cGycm2/h correlated with higher rates of fat necrosis. There were 115 (66%), 51 (29%), 8 (5%), and 0 (0%) patients having excellent, good, fair, and poor cosmetic outcomes, respectively. Conclusions APBI using ISI brachytherapy offers excellent clinical outcomes in appropriately selected patients with excellent cosmetic outcomes and low rates of toxicities such as symptomatic fat necrosis.

Background: The American College of Surgeons Oncology Group Z0011 prospective randomized trial demonstrated no local control or survival advantage with more extensive axillary surgery, even in the setting of known axillary disease. These results convincingly showed that axillary surgery provides little, if any, therapeutic benefit. Given that axillary surgery is not associated with local control or survival benefit, the current role of sentinel lymph node (SLNB) is limited to staging the axilla (in other words, SLNB provides staging information but is not therapeutic). Objectives: In this randomized, controlled non-inferiority trial we aim to determine the utility of axillary ultrasound (AUS) as a pre-operative staging modality for patients with clinically node-negative invasive breast cancer with the hope that it will be a minimally invasive replacement for SLNB. 1. Primary Objective: To assess whether axillary recurrence rates for patients randomized to Arm 1 (no SLNB) is equivalent to axillary recurrence rates for patients randomized to Arm 2 (SLNB). 2. Secondary Objective: To assess disease-free survival in Arm 1 vs. Arm 2. 3. Tertiary Objective: To assess overall survival in Arm 1 vs. Arm 2. Study Design: A randomized non-inferiority trial comparing no further axillary staging versus SLNB in women with clinical T1-T2, N0 M0 breast cancer and negative AUS. Following a negative AUS, four hundred sixty women will be randomized in a 1:1 fashion to no further axillary staging or SLNB. Subjects will be monitored for local-regional and distant recurrence per NCCN guidelines. We have recruited 28 study participants. Eligibility Criteria: To be eligible the patient must be 18-y.o. or older; female; have tissue-diagnosis of invasive breast cancer; cT1-2N0M0 cancer; negative AUS; ECOG Statistical Methods: Power analysis: A power analysis was performed to determine the accrual goal. The power analysis is based on axillary recurrence, our primary endpoint. We expect an axillary recurrence rate of 1% in patients undergoing SLNB. By assuming a noninferiority limit of 2% difference, our sample size will allow us 80% power at 1-sided 0.1 significance level to assure such a noninferiority. Data analysis: Longer-term formal data analysis for the study will be performed following the intent-to-treat (ITT) principle. Demographic and clinical characteristics of the sample, as well as efficacy, complication rates and loss to follow-up will be summarized using descriptive statistics. The balance of demographic and baseline clinical characteristics between two arms will be compared using t-test, Mann-Whitney rank-sum test, or Chi-square test as appropriate. The differences in OS and DFS between treatment arms will be compared using log-rank test. Citation Format: Natalia S Tucker, William E Gillanders, Timothy Eberlein, Rebecca Aft, Julie Margenthaler, Feng Gao, Catherine Appleton, Imran Zoberi, Ademuyiwa Foluso, Amy Cyr. A prospective, randomized trial of sentinel lymph node biopsy versus no additional staging in patients with T1-T2 invasive breast cancer and negative axillary ultrasound [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr OT3-5-01.

Purpose To report the incidence and potential predictors of fat necrosis in women with early stage breast cancer treated with adjuvant high-dose-rate (HDR) multicatheter interstitial brachytherapy. Methods and Materials Between 2003 and 2010, 238 treated breasts in 236 women were treated with accelerated partial breast irradiation using HDR interstitial brachytherapy. Selection criteria included patients with Tis–T2 tumors measuring ≤3 cm, without nodal involvement, who underwent breast-conserving surgery. Ninety-nine percent of treatments were to a total dose of 34 Gy. The presence and severity of fat necrosis were prospectively recorded during followup. Cosmesis was qualitatively scored in all patients. Cosmesis was quantitatively measured via the percentage breast retraction assessment in 151 cases. Results Median followup was 56 months. The crude rate of fat necrosis was 17.6%. The rate of symptomatic fat necrosis was 10.1%. In univariate analysis, acute breast infection and anthracycline-based chemotherapy, number of catheters, volume encompassed by the prescription isodose, volume encompassed by the 150% isodose (V150), volume encompassed by the 200% isodose, and integrated reference air kerma were significantly associated with fat necrosis. There was significant collinearity between the brachytherapy-related factors; of these, V150 was most predictive. In multivariate analysis, only V150 was significantly associated with fat necrosis. At 3 years, patients with fat necrosis were more likely to have a fair or poor cosmetic outcome and a larger percentage breast retraction assessment. Conclusions Mammary fat necrosis is a common adverse event after breast-conserving surgery and HDR interstitial brachytherapy. Fat necrosis is associated with worse qualitative and quantitative cosmetic outcomes. Minimizing exposure volumes, such as V150, may decrease the incidence of fat necrosis and improve cosmesis.

Background To evaluate whether the timing of surgery after radiation in autologous breast reconstruction affects major complications. Methods We performed a retrospective review of 454 free flaps (331 patients) for breast reconstruction at a single institution from 2003 to 2014. Charts were reviewed for age, BMI, laterality, flap type (TRAM, msTRAM, DIEP), surgeon, donor vessels (IMA, TD), chemotherapy, smoking, diabetes, hypertension, DVT, venous anastomoses, vein size, and time from radiation (none

Summary Background Treatment with bisphosphonates decreases bone loss and can increase disease-free survival in patients with breast cancer. The aim of our study was to assess the effect of zoledronic acid on clearance of disseminated tumour cells (DTCs) from the bone marrow in women undergoing neoadjuvant chemotherapy for breast cancer. Methods Patients were recruited for this open-label, phase 2 randomised trial between March 17, 2003, and May 19, 2006, at a single centre. Eligible patients had clinical stage II–III (≥T2 and/or ≥N1) newly diagnosed breast cancer, Eastern Cooperative Oncology Group performance status of 0 or 1, and normal cardiac, renal, and liver function. 120 women were randomly assigned, using allocation concealment, to receive 4 mg zoledronic acid intravenously every 3 weeks (n=60), or no zoledronic acid (n=60), for 1 year concomitant with four cycles of neoadjuvant epirubicin (75 mg/m 2 ) plus docetaxel (75 mg/m 2 ) and two cycles of adjuvant epirubicin plus docetaxel. The primary endpoint was the number of patients with detectable DTCs at 3 months. Final analysis was done 1 year after the last patient was enrolled. Analyses were done for all patients with available data at 3 months. This study is registered with ClinicalTrials.gov, number NCT00242203. Findings Of the 120 patients initially enrolled, one withdrew after signing consent and one patient's baseline bone marrow was not available. Both of these patients were in the control group. At 3 months, 109 bone-marrow samples were available for analysis. In the zoledronic acid group, bone marrow was not collected from one patient because of disease progression, one patient was taken off study because of severe diarrhoea, and two patients had not consented at the time of surgery. In the control group, bone marrow was not collected from two patients because of disease progression, one patient withdrew consent, and three patients were not consented at the time of surgery. At baseline, DTCs were detected in 26 of 60 patients in the zoledronic acid group and 28 of 58 patients in the control group. At 3 months, 17 of 56 patients receiving zoledronic acid versus 25 of 53 patients who did not receive zoledronic acid had detectable DTCs (p=0·054). The most common grade 3–4 toxicities were infection (five of 60 patients in the zoledronic acid group and six of 59 in the control group) and thrombosis (five of 60 in the zoledronic acid and two of 59 in the control group). There was one documented case of osteonecrosis in the zoledronic acid group. Interpretation Zoledronic acid administered with chemotherapy resulted in a decreased proportion of patients with DTCs detected in the bone marrow at the time of surgery. Our study supports the hypothesis that the antimetastatic effects of zoledronic acid may be through effects on DTCs. Funding Novartis Pharmaceuticals and Pfizer Inc.

Background and purpose The Tomotherapy Hi-Art II system allows acquisition of pre-treatment MVCT images to correct patient position. This work evaluates the dosimetric impact of uncorrected setup errors in breast-cancer radiation therapy. Materials and methods Breast-cancer patient-positioning errors were simulated by shifting the patient computed-tomography (CT) dataset relative to the planned photon fluence and re-computing the dose distributions. To properly evaluate the superficial region, film measurements were compared against the Tomotherapy treatment planning system (TPS) calculations. A simulation of the integrated dose distribution was performed to evaluate the setup error impact over the course of treatment. Results Significant dose differences were observed for 11-mm shifts in the anterolateral and 3-mm shifts in the posteromedial directions. The results of film measurements in the superficial region showed that the TPS overestimated the dose by 14% at a 1-mm depth, improving to 3% at depths ⩾5 mm. Significant dose reductions in PTV were observed in the dose distributions simulated over the course of treatment. Conclusions Tomotherapy’s rotational delivery provides sufficient photon fluence extending beyond the skin surface to allow an up to 7-mm uncorrected setup error in the anterolateral direction. However, the steep dose falloff that conforms to the lung surface leads to compromised dose distributions with uncorrected posteromedial shifts. Therefore, daily image guidance and consequent patient repositioning is warranted for breast-cancer patients.