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PURPOSE Renovation of the brachytherapy program at a leading cancer center utilized methods of the AAPM TG-100 report to objectively evaluate current clinical brachytherapy workflows and develop techniques for minimizing the risk of failures, increasing efficiency, and consequently providing opportunities for improved treatment quality. The TG-100 report guides evaluation of clinical workflows with recommendations for identifying potential failure modes (FM) and scoring them from the perspective of their occurrence frequency O, failure severity S, and inability to detect them D. The current study assessed the impact of differing methods to determine the risk priority number (RPN) beyond simple multiplication. METHODS AND MATERIALS The clinical workflow for a complex brachytherapy procedure was evaluated by a team of 15 staff members, who identified discrete FM using alternate scoring scales than those presented in the TG-100 report. These scales were expanded over all clinically relevant possibilities with care to emphasize mitigation of natural bias for scoring near the median range as well as to enhance the overall scoring-system sensitivity. Based on staff member perceptions, a more realistic measure of risk was determined using weighted functions of their scores. RESULTS This new method expanded the range of RPN possibilities by a factor of 86, improving evaluation and recognition of safe and efficient clinical workflows. Mean RPN values for each FM decreased by 44% when changing from the old to the new clinical workflow, as evaluated using the TG-100 method. This decreased by 66% when evaluated with the new method. As a measure of the total risk associated with an entire clinical workflow, the integral of RPN values increased by 15% and decreased by 31% with the TG-100 and new methods, respectively. CONCLUSIONS This appears to be the first application of an alternate approach to the TG-100 method for evaluating the risk of clinical workflows. It exemplifies the risk analysis techniques necessary to rapidly evaluate simple clinical workflows appropriately.

Purpose The noninvasive image-guided breast brachytherapy (NIBB) technique is a novel noninvasive yet targeted method for accelerated partial breast irradiation. We established a multi-institutional registry to evaluate the toxicity and efficacy of this technique across various practice settings. Methods and Materials Institutions using the NIBB technique were invited to participate. Data for acute/late toxicity, cosmetic outcome, and tumor recurrence were collected. Toxicity and cosmetic outcome were graded based on the Common Terminology Criteria for Adverse Events version 3.0 and NRG/Radiation Therapy Oncology Group scale, respectively. Treatment variables were analyzed for association with outcomes. Results A total of 252 patients from eight institutions were analyzed. The median age was 69 years. The mean tumor size was 1.1 cm (0.1–4.0 cm). Treatment was delivered 10 fractions (34–36 Gy) in 75% and five fractions (28.5 Gy) in 22%. B.i.d. fractionation was used in 9%. Acute radiation dermatitis was Grade 0–1, 2, and 3 in 77%, 19%, and 4%, respectively. One hundred ninety-one patients with a median followup of 18 months (4–72 months) were evaluable for late outcomes. Late toxicity Grades 2 and 3 were observed in 8.8% and 1%, respectively. Cosmetic outcome was excellent, good, and fair/poor in 62%, 36%, and 2%, respectively. B.i.d. fractionation was associated with higher acute and late toxicity. Second-generation applicators were associated with lower late toxicity and better cosmetic outcome. Actuarial freedom from ipsilateral breast tumor recurrence and true recurrence were 98.3% and 98.3% at 2 years and 90.9% and 95.4% at 5 years, respectively. Conclusions Accelerated partial breast irradiation using NIBB was well tolerated with a low rate of acute and late toxicity across various practice settings. Ipsilateral breast tumor recurrence and cosmetic outcomes were favorable. b.i.d. fractionation was associated with higher toxicity. Longer followup is needed to confirm late endpoints.

Noninvasive image guided breast brachytherapy (NIBB) is a novel approach to delivery of accelerated partial breast irradiation (APBI) that may hold advantages over established techniques. NIBB is not invasive but maintains a high level of precision by using breast immobilization via breast compression and image guidance; it therefore does not require large planning tumor volume margins. We present the primary outcomes of this prospective phase 2 study (BrUOG Br-251).Eligible patients with early-stage breast cancer underwent NIBB APBI using a dose 34 Gy in 10 fractions delivered daily or twice a day. Treatment was delivered using an Ir-192 high-dose-rate source via specialized applicators. Two orthogonal treatment axes were used for each fraction. The primary endpoints were late toxicity and cosmesis assessed at 2 and 5 years. Toxicity was assessed using the National Cancer Institute Common Terminology Criteria for Adverse Events v3.0. Cosmesis was assessed using the NRG/Radiation Therapy Oncology Group scale. Ipsilateral breast tumor recurrence was defined as any recurrence or new primary in the treated breast.Forty patients underwent protocol treatment. Median patient age was 68 years (50-92 years). Mean tumor size was 1.1 cm (0.3-3.0 cm). Among the cohort, 62.5% had invasive carcinoma and 37.5% had ductal carcinoma in situ. Thirty-nine percent elected to receive hormone therapy. No grade ≥3 late toxicities were observed at any time point. Grade 2 toxicity was 5% and 10% at 2 and 5 years, respectively. Telangiectasia grade 1 and 2 occurred in 27.5% and 5%, respectively. Breast separation of7 cm was associated with telangiectasia (P.01). The rate of good to excellent cosmetic outcome was 95% at 2 years and 100% at 5 years. With a median follow-up of 68 months, the actuarial 5-year freedom from ipsilateral breast tumor recurrence was 93.3% (±4.8%), and overall survival was 93.7% (±4.4%).NIBB to deliver APBI is well tolerated with a low incidence of significant late toxicity and has favorable cosmetic outcomes. Continued evaluation of the NIBB APBI technique in a larger cohort is warranted.

Brain metastasis velocity (BMV) is a prognostic metric that describes the recurrence rate of new brain metastases after initial treatment with radiosurgery (SRS). We have previously risk stratified patients into high, intermediate, and low-risk BMV groups, which correlates with overall survival (OS). We sought to externally validate BMV in a multi-institutional setting.Patients from nine academic centers were treated with upfront SRS; the validation cohort consisted of data from eight institutions not previously used to define BMV. Patients were classified by BMV into low (4 BMV), intermediate (4-13 BMV), and high-risk groups (13 BMV). Time-to-event outcomes were estimated using the Kaplan-Meier method. Cox proportional hazards methods were used to estimate the effect of BMV and salvage modality on OS.Of 2829 patients, 2092 patients were included in the validation dataset. Of these, 921 (44.0%) experienced distant brain failure (DBF). Median OS from initial SRS was 11.2 mo. Median OS for BMV 4, BMV 4-13, and BMV 13 were 12.5 mo, 7.0 mo, and 4.6 mo (p 0.0001). After multivariate regression modeling, melanoma histology (β: 10.10, SE: 1.89, p 0.0001) and number of initial brain metastases (β: 1.52, SE: 0.34, p 0.0001) remained predictive of BMV (adjusted RThis multi-institutional dataset validates BMV as a predictor of OS following initial SRS. BMV is being utilized in upcoming multi-institutional randomized controlled trials as a stratification variable for salvage whole brain radiation versus salvage SRS after DBF.

Several studies evaluating stereotactic radiosurgery (SRS) for patients with4 brain metastases (BM) demonstrated similar outcomes after treatment of 1, 2 to 4, and 5 to 15 BM; others found clinically significant survival decrements in the latter group. In this review of 8 academic centers, we compared outcomes of patients undergoing initial SRS for 1, 2 to 4, and 5 to 15 BM.A total of 2089 patients treated with initial SRS for BM were included. Overall survival (OS) was estimated using the Kaplan-Meier method and compared using the log-rank test. Patient and disease characteristics were evaluated for association with OS and cumulative incidence of distant brain failure (DBF) using stepwise multivariable Cox proportional hazards and competing risk regression modeling.In this series, 989 (47%) patients had 1 metastasis, 882 (42%) had 2 to 4 metastases, and 212 (10%) had 5 to 15 metastases treated. Median OS for the 1, 2 to 4, and 5 to 15 BM groups was 14.6, 9.5, and 7.5 months, respectively (log-rank P .01). Univariate and multivariable analyses revealed no difference in survival between 2 to 4 and 5 to 15 BM. DBF at 1 year was 30%, 41%, and 50%, respectively (Gray's P .01). Two-year cumulative incidence of salvage SRS decreased with increasing number of BM (1: 21% vs 2-4: 19% vs 5-15: 13%; P .01), but no difference in salvage whole brain radiation therapy was observed (1: 12% vs 2-4: 15% vs 5-15: 16%, P = .10). At the time of DBF, median brain metastasis velocity was 3.9, 6.1, and 11.7 new metastases per year in the 1, 2 to 4, and 5 to 15 BM groups, respectively (P .01).Patients treated with initial SRS for 5 to 15 BM experienced survival similar to that in patients with 2 to 4 BM. Lower rates of salvage SRS were observed in the 5 to 15 BM group, with no difference in rates of salvage whole brain radiation therapy.

Purpose Brachytherapy is utilized in the treatment of many different malignancies; although traditionally performed with low-dose-rate or high-dose-rate techniques, more recently, electronic brachytherapy (EB) has emerged as a potential alternative. At this time, there are no evidence-based guidelines to assist clinicians in patient selection for EB and concerns exits regarding differences in dosimetry as compared to traditional brachytherapy techniques. As such, the American Brachytherapy Society appointed a group of physicians and physicists to create a consensus statement regarding the use of EB. Methods and Materials Physicians and physicists with expertise in brachytherapy created a site-directed consensus statement for appropriate patient selection and utilization of EB based on a literature search and clinical experience. Results EB has been utilized to deliver accelerated partial breast irradiation with, thus far acceptable local control and toxicity rates including a randomized trial that used EB to deliver intraoperative radiotherapy; however, prospective data with large patient numbers and long-term follow up are needed. Increasing numbers of patients have been treated with EB for nonmelanomatous skin cancers; although, preliminary data are promising, there is a lack of data comparing EB to traditional radiotherapy techniques as well as a lack of long-term follow up. For treatment of the vaginal cuff with EB, small retrospective studies have been reported without long-term follow up. Conclusions In light of a randomized trial in breast showing higher rates of recurrence and the lack of prospective data with mature follow up with other sites, as well as concerns regarding dosimetry, it is not recommended that EB be utilized for accelerated partial breast irradiation, nonmelanomatous skin cancers, or vaginal cuff brachytherapy outside prospective clinical trials at this time.

Purpose BioZorb® (Focal Therapeutics, Aliso Viejo, CA) is an implantable 3-dimensional bioabsorbable marker used for tumor bed volume (TBV) identification during postoperative radiation therapy (RT) planning. We aimed to calculate and compare RT TBVs between two cohorts managed with and without the device. Methods and Materials Data from patients with breast cancer who were treated at Rhode Island Hosptial, Providence RI between May 1, 2015 and April 30, 2016 were retrospectively reviewed and grouped based on 3-dimensional bioabsorbable marker placement. Pathology reports were used to calculate tumor excision volume (TEV) after breast conservation. Specifically, the three dimensions provided were multiplied to generate a cubic volume, defined as TEV. TBV was calculated using treatment volumes generated with Philips Pinnacle3 treatment planning software (Andover, MA). Linear regression analyses assessed the relationship between excised TEV and TBV. T tests compared the slopes of the best fit lines for plots of TEV versus TBV. Results In this retrospective case-control study, 116 patients undergoing breast RT were identified; of whom 42 received a 3-dimensional bioabsorbable marker and 74 did not. The mean TEVs were 102.7 cm3 with the device and 103.2 cm3 without the device, and the mean TBVs for the same groups were 27.5 cm3 and 40.1 cm3, respectively. The TBV standard errors for patients who did and did not receive 3-dimensional bioabsorbable markers were 23.739 and 38.685, respectively. The t tests found the slopes of the lines of best fit for these cohorts to be statistically significantly different (P = .001), with smaller TBVs achieved with 3-dimensional bioabsorbable marker placement. Conclusions When comparing TBVs between patients contemporaneously treated with or without a 3-dimensional bioabsorbable marker, device placement was associated with statistically significantly smaller TBVs in the setting of similar TEVs.

BACKGROUND The Individualized Screening Trial of Innovative Glioblastoma Therapy (INSIGhT) is a phase II platform trial with Bayesian adaptive randomization and deep genomic profiling to more efficiently test experimental agents in newly diagnosed glioblastoma and to prioritize therapies for late-stage testing. METHODS In the ongoing INSIGhT trial, patients with newly diagnosed MGMT-unmethylated glioblastoma are randomized to the control arm or one of three experimental therapy arms (CC-115, abemaciclib, and neratinib). The control arm therapy is radiotherapy with concomitant and adjuvant temozolomide, and primary endpoint is overall survival. Randomization has been adapted based on Bayesian estimation of biomarker-specific probability of treatment impact on progression-free survival (PFS). All tumors undergo detailed molecular sequencing, and this is facilitated with the companion ALLELE protocol. To evaluate feasibility of this approach, we assessed the status of this ongoing trial. RESULTS Since INSIGhT was activated 4.3 years ago, it has expanded to include 12 sites across the United States. A total of 247 patients have been enrolled. Randomization probabilities have been repeatedly adjusted over time based upon early PFS results to alter the randomization ratio from standard 1:1:1:1 randomization. All three arms have completed accrual and efficacy estimates are available based upon comparison to the common control arm in context of relevant biomarkers. There are 87 patients alive and in follow-up, and there are ongoing plans to add additional arms to evaluate further treatments in the future. CONCLUSION The INSIGhT trial demonstrates that a multi-center Bayesian adaptive platform trial is a feasible and effective approach to help prioritize therapies and biomarkers for newly diagnosed GBM. The trial has maintained robust accrual, and the simultaneous testing of multiple agents, sharing a common control arm and adaptive randomization serve as features to increase trial efficiency relative to traditional clinical trial designs.

BACKGROUND The cyclin D-CDK4/6-Rb pathway is activated in most glioblastomas. Abemaciclib is a potent CDK4/6 inhibitor with good brain penetration approved for ER/PR/HER2- breast cancer. In order to efficiently evaluate the potential impact of abemaciclib on overall survival (OS) in newly diagnosed glioblastoma and to simultaneously develop information regarding potential genomic biomarker associations, abemaciclib was included as an arm on the Individualized Screening Trial of Innovative Glioblastoma Therapy (INSIGhT) trial. INSIGhT is a phase II platform trial using response adaptive randomization and deep genomic profiling to more efficiently test experimental agents in MGMT unmethylated glioblastoma and potentially accelerate identification of novel therapies for phase III testing. Initial randomization was equal between abemaciclib, control, and two other experimental arms but subsequent randomization was adapted based on efficacy as determined by progression-free survival (PFS). Ineffective arms were discontinued and new arms added by protocol amendment. We report preliminary results for the abemaciclib arm which has completed accrual. METHODS Patients with newly diagnosed MGMT-unmethylated glioblastoma were randomized to receive either radiotherapy with concomitant and adjuvant temozolomide at standard doses or standard radiochemotherapy followed by adjuvant abemaciclib (150–200 mg orally BID) without temozolomide. Treatment continued until progression or development of unacceptable toxicities. The primary endpoint was OS. Association between abemaciclib efficacy and cyclin D-CDK4/6-Rb pathway genomic alterations was also investigated. RESULTS There were 123 patients (50 control; 73 treated with abemaciclib). Abemaciclib was generally well-tolerated with no new toxicity signals identified. PFS was significantly longer (p=0.03, logrank test) with abemaciclib (median 6.31 months 95% CI [5.29, 8.18]) compared to the control arm (5.16 months 95% CI [4.37, 6.28]). 28/50 control and 36/73 abemaciclib patients remain alive. CONCLUSION Preliminary analysis suggests that abemaciclib increases PFS compared to control. Updated toxicity, PFS and survival data and potential genomic biomarker associations will be presented.

BACKGROUND CC-115 is an oral, CNS-penetrant, selective inhibitor of mammalian target of rapamycin kinase (mTOR) and deoxyribonucleic acid-dependent protein kinase (DNA-PK). Both targets are important in glioblastoma; PI3K/Akt/mTOR signaling is hyperactive in most glioblastomas, and DNA-PK is integral to repair of radiotherapy-mediated DNA damage. To investigate CC-115 in newly diagnosed glioblastoma and explore potential genomic biomarker associations, CC-115 was evaluated in the Individualized Screening Trial of Innovative Glioblastoma Therapy (INSIGhT) trial, an adaptive platform trial designed to efficiently test experimental agents. METHODS Adults with newly diagnosed MGMT-unmethylated glioblastoma, with genomic data available, are eligible for this ongoing trial. Patients are adaptively randomized to one of several experimental arms or the control arm: standard radiotherapy with concurrent and adjuvant temozolomide. The primary endpoint is overall survival (OS). Patients randomized to CC-115 (10mg po BID) received it concurrently with radiotherapy and as adjuvant monotherapy. As the first in-human use of CC-115 with radiation, a safety lead-in 3 + 3 design was used. RESULTS Twelve patients were randomized to CC-115; seven patients had possible treatment-related CTCAE grade > 3 toxicity, including four pre-specified dose-limiting toxicities: liver function abnormality (n=1), hyperlipidemia (n=1), lipase elevation (n=1) and cerebral edema (n=1). There was no significant difference in progression-free survival (PFS, median 4.2 months [CC-115] vs. 5.2 months, p=0.9) or OS (median 10.1 months [CC-115] vs. 14.5 months, p=0.9) compared to the 50 patients randomized to the control arm. Based on early PFS results, randomization probability to CC-115 decreased from 25% to < 10% at time of the trial arm closure. CONCLUSION Concurrent and adjuvant CC-115 was associated with toxicity and failed to improve PFS or OS. The INSIGhT trial design allowed for more efficient testing of CC-115, decreasing patients and resources allocated to a therapy that was discontinued due to concerns about toxicity and unfavorable risk-to-benefit ratio.

Purpose Mammographically based noninvasive image-guided breast brachytherapy (NIBB) partial breast irradiation (PBI) is ideally suited for preoperative treatment. We hypothesize that delivering NIBB PBI to the preoperative tumor volume compared with the postoperative lumpectomy bed would simplify target identification and allow for a reduction in irradiated volume along each orthogonal axis. Methods and Materials Patients with invasive breast cancer treated with NIBB PBI at our institution were identified. Preoperative NIBB treatments were modeled along orthogonal craniocaudal and mediolateral axes with an applicator encompassing the gross lesion plus a 1 cm clinical target volume margin. Preoperative treatment volumes were calculated along each axis using the selected applicator surface area multiplied by the preoperative mammogram separation. The actual applicator size and breast separation from the first fraction of postoperative treatment was used to calculate the postoperative treatment volume. Paired -test was used to compare the preoperative and postoperative treatment separation, area, and volume for each patient. Results Forty-eight patients with Stage I–II breast cancer had imaging and treatment data available for review. Along the axis, the mean preoperative treatment volume was significantly less than the mean postoperative treatment volume (116 cm 3 vs. 204 cm 3, respectively; p Conclusions Based on our retrospective comparison, PBI delivered using NIBB to the preoperative tumor may reduce the volume of healthy breast tissue receiving radiation as compared with NIBB to the postoperative tumor bed.

For early-stage breast cancer, partial breast irradiation (PBI) allows for reduction in the irradiated volume of normal tissues by confining the radiation target to the area surrounding the lumpectomy cavity after breast-conserving surgery. This approach has been supported by phase 2 data. However, widespread adoption of PBI has awaited the results of randomized controlled trials. This review discusses the results of randomized controlled trials comparing whole breast irradiation to PBI, including the recently published National Surgical Adjuvant Breast and Bowel Project (NSABP) B39/Radiotherapy Oncology Group (RTOG) 0413, and the Canadian RAPID trials. PBI techniques, dose/fractionation schedules, and patient selection are also reviewed.

BACKGROUND Brain metastases (BM) occur in ∼5% of breast cancer patients. BRCA1-associated cancers are often basal-like and basal-like cancers are known to have a predilection for central nervous system metastases. We performed a matched-pair analysis of breast cancer patients with and without BRCA mutations and compared the frequency of BM in both groups. MATERIALS AND METHODS From a database of 1935 patients treated for localized breast cancer at our institution from 2009 to 2014 we identified 20 patients with BRCA1 or BRCA2 mutations and manually matched 40 patients without BRCA mutations accounting for age, stage, estrogen receptor expression, and human epidermal growth factor receptor 2 (HER2) expression. Comparisons of freedom from brain metastasis, brain metastasis-free survival, and overall survival were made using the log rank test. Testing for a basal-type phenotype using the immunohistochemistry definition (ER/PR/HER2 and either CK 5/6 or EGFR) was performed for BRCA patients who developed BM and their matched controls. RESULTS We analyzed 60 patients: 20 BRCA and 40 were matched controls. Median follow-up was 37 and 49 months, respectively. Three years freedom from brain metastasis was 84% for BRCA patients and 97% for BRCA controls (P=0.049). Three years brain metastasis-free survival was 84% and 97% for the BRCA+ and controls, respectively (P=0.176). Mean time to brain failure was 11 months from diagnosis for the BRCA patients. All 3 BRCA1 patients who developed BM were of a basal-type triple negative phenotype. CONCLUSIONS Breast cancer patients with germline BRCA1 mutations appear to have a shorter interval to brain progression while accounting for confounding factors.

Purpose Single-fraction radiation surgery for spine metastases is highly effective. However, a high rate (20-39%) of vertebral body fracture (VBF) has been associated with large, single-fraction doses. We report our experience using multifraction stereotactic body radiation therapy (SBRT). Methods and materials All patients who were treated with multifraction SBRT for spine metastases at our institution between 2009 and 2017 were retrospectively analyzed. SBRT was delivered in 2 to 5 fractions using the Cyberknife System (Accuray, Sunnyvale, CA). Patients were followed clinically and with magnetic resonance imaging every 3 to 6 months. Local control, complications (including VBF), and overall survival were evaluated. Patient, disease, and treatment variables were analyzed for a statistical association with outcomes. Results A total of 83 patients were treated to 98 spine lesions with a median follow-up of 7.6 months. Histologies included non-small cell lung cancer (NSCLC; 24%), renal cell carcinoma (RCC; 18%), and breast cancer (12%). Surgery or vertebroplasty were performed before SBRT in 21% of cases. Patients received a median SBRT dose of 24 Gy in a median of 3 fractions. Local control was 93% at 6 months and 84% at 1 year. Higher prescribed dose, higher biologic effective dose, higher minimum dose to 90% of the planning target volume, tumor histology, and smaller tumor volume predicted improved local control. The cumulative dose was 23 Gy versus 26 Gy for patients with and without failure ( P = .02), higher biologic effective dose 39 Gy versus 46 Gy, ( P = .01), and higher minimum dose to 90% of the planning target volume 23 Gy versus 26 Gy ( P = .03). VBF occurred in 4.2% of all cases and 5.3% of those without surgery or vertebroplasty prior to SBRT. Only preexisting VBF predicted risk of post-SBRT VBF ( P Conclusions Multifraction SBRT results in a high local control rate for metastatic spinal disease with a low VBF rate, which suggests a favorable therapeutic ratio compared with single-fraction SBRT.

OBJECTIVES: Radiation therapy (RT) is often an integral component of postoperative breast cancer management. Three dimensional (3D) bioabsorbable markers have been designed to assist CT-based tumor bed targeting during the RT process. There have been limited reports detailing complications following placement of such devices. This retrospective analysis attempts to identify demographic and treatment characteristics associated with complications after 3D bioabsorbable marker placement in a cohort of breast cancer patients treated at an academic medical center. METHODS: Records of 160 patients receiving a 3D bioabsorbable marker during initial breast surgery for DCIS or breast cancer were reviewed. Ten devices were removed at subsequent re-excision or mastectomy; therefore, 150 patients were ultimately evaluable. Demographic, tumor and operative/treatment characteristics were collected. Variables including body mass index (BMI), diabetes mellitus (DM), smoking, chemotherapy or RT use and excision volume (EV) were analyzed using multivariable logistic regression analysis (MVA). Endpoints included reoperation for wound complications (re-op), receipt of postoperative antibiotics (abx) and clinically palpable 3D bioabsorbable marker. RESULTS: Median follow-up was 8.2 months. Six (6/150, 4%) patients required re-op for wound complications and 5 required 3D bioabsorbable marker removal due to complications. Twenty (20/150, 13.3%) patients received abx for clinically detected postoperative wound infections. At last follow-up, 61 (61/150, 40.6%) patients noted persistent perceived fullness of the device at the lumpectomy site, and the 3D bioabsorbable marker remained palpable by the physician in 95 (95/150, 63.3%) patients. On MVA, DM and larger EV were associated with greater rates of re-op (p=0.020 and 0.012, respectively, Table 1). Mean EV was 279 cc among the re-op cohort and 85.5 cc among the no re-op cohort. DM, receipt of chemotherapy and larger EV were associated with postoperative abx prescription (p=0.005, 0.009 and 0.005, respectively, Table 2). Mean EV was 169.6 cc among those who received abx and 81.5 cc among those who did not. Larger EV was the only statistically significant predictor of a clinically palpable bioabsorbable marker during follow-up (p=0.044). Table 1. Multivariable Analysis: Reoperation for Wound ComplicationsVariablep-valueBMI0.986Diabetes0.020Smoking0.999Excision Volume0.012Chemotherapy0.079Radiation0.113 Table 2. Multivariable Analysis: Prescription of AntibioticsVariablep-valueBMI0.571Diabetes0.005Smoking0.099Excision Volume0.005Chemotherapy0.009Radiation0.958 CONCLUSIONS: Rates of re-op for wound complications (4%) and postoperative infection (13.3%) were higher than expected among this cohort receiving 3D bioabsorbable markers, and were relatively high compared to historical surgical series managed without such devices. The present analysis suggests that those with larger EV, DM or receiving chemotherapy may be at greater risk for post-operative complications when a 3D bioabsorbable marker is placed. These factors should be considered when assessing candidacy for device placement. Citation Format: Foster BC, Graves TA, Taneja C, Wiggins DL, Hepel JT, Wazer DE, Leonard KL. Identifying optimal candidates for three-dimensional bioabsorbable marker placement during breast cancer treatment: Incidence and predictors of postoperative complications [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P2-12-12.

PURPOSE: To develop clinical guidelines for the quality practice of accelerated partial breast irradiation (APBI) as part of breast-conserving therapy for women with early-stage breast cancer. METHODS AND MATERIALS: Members of the American Brachytherapy Society with expertise in breast cancer and breast brachytherapy in particular devised updated guidelines for appropriate patient evaluation and selection based on an extensive literature search and clinical experience. RESULTS: Increasing numbers of randomized and single and multi-institution series have been published documenting the efficacy of various APBI modalities. With more than 10-year followup, multiple series have documented excellent clinical outcomes with interstitial APBI. Patient selec- tion for APBI should be based on a review of clinical and pathologic factors by the clinician with particular attention paid to age ($50 years old), tumor size (#3 cm), histology (all invasive subtypes and ductal carcinoma in situ), surgical margins (negative), lymphovascular space invasion (not present), and nodal status (negative). Consistent dosimetric guidelines should be used to improve target coverage and limit potential for toxicity following treatment. CONCLUSIONS: These guidelines have been created to provide clinicians with appropriate patient selection criteria to allow clinicians to use APBI in a manner that will optimize clinical outcomes and patient satisfaction. These guidelines will continue to be evaluated and revised as future publications further stratify optimal patient selection. 2013 Published by Elsevier Inc. on behalf of American Brachytherapy Society.

PURPOSE/OBJECTIVE(S) The accuracy of tumor bed (TB) delineation is essential for targeting boost dose or partial breast irradiation. Surgical clip markers (CM) are standardly used. However, despite using CM, multiple studies have shown high interobserver variability in TB delineation. We hypothesize that a radiopaque filament marker (FM) woven along the TB at the time of lumpectomy will improve accuracy of TB delineation. MATERIALS/METHODS An FDA-approved radiopaque filament was intraoperatively used to outline the tumor bed of patients undergoing lumpectomy. Between January 2020 and September 2020, 10 consecutive patients with the FM and 10 consecutive patients with the standard CM were identified for comparison. Five "experts," defined as board-certified radiation oncologists specializing in breast cancer, independently contoured all 20 tumor beds. Dice coefficients were then calculated for each patient by comparing the intersection and aggregate of each expert's contours with that of the other experts individually. An intersection and aggregate of the contours of all 5 experts was also analyzed for each patient. Dice coefficient of 1 represents perfect contour agreement, and 0 represents no agreement. Two-tailed paired samples t-tests were performed to compare dice coefficients between FM and CM cohorts. Furthermore, the center of mass (COM) coordinates were calculated to analyze the distance of the COM of each expert's contour to that of the aggregate of the other experts' contours for each patient. Two-tailed unpaired samples t-tests were performed to compare COM distances between FM and CM cohorts. RESULTS For FM, mean dice coefficient and standard deviation for each expert was: 0.61 ± 0.09, 0.60 ± 0.10, 0.60 ± 0.10, 0.60 ± 0.09, and 0.55 ± 0.11, respectively. By comparison, for CM, mean dice coefficient and standard deviation for each expert was: 0.48 ± 0.22, 0.42 ± 0.25, 0.47 ± 0.21, 0.47 ± 0.22, and 0.40 ± 0.22, respectively. Thus, TB delineation agreement was significantly improved with FM (P = 0.0013, P = 0.0001, P = 0.0013, P = 0.0006, and P = 0.0008, respectively). Furthermore, the COM distance of each expert's contour to that of the aggregate of all experts' contours was significantly reduced (P < 0.001) from a mean of 0.96 cm ± 0.89 cm for CM to 0.25 cm ± 0.19 cm for FM. CONCLUSION Radiopaque filament resulted in significantly improved interobserver variability in tumor bed delineation compared with standard surgical clips. This difference was clinically meaningful with a reduction in mean COM contour disagreement from almost 1cm to 2.5mm, and suggests marked superiority of the radiopaque filament in targeting boost dose and/or partial breast irradiation.

Purpose/Objective(s) Lobectomy followed by adjuvant chemotherapy is the standard of care for patients with clinically T1-T2N1 non-small cell lung cancer (NSCLC). However, the optimal treatment of patients who cannot undergo or refuse to undergo surgical resection is controversial. Currently, NCCN guidelines recommend concurrent chemoradiation; however, limited evidence exists to substantiate this recommendation for this particular patient population. Many groups advocate for radiation alone with standard or hypofractionated approaches. We hypothesized that concurrent chemoradiation would be associated with longer overall survival (OS) compared to hypofractionated or conventionally fractionated radiation. Materials/Methods We queried the National Cancer Database (NCDB) for patients with cT1-T2N1M0 NSCLC treated non-surgically with definitive radiation or concurrent chemoradiation between 2004 and 2016. We further restricted our cohort to patients receiving RT doses with an EQD2 ≥ 58.4 Gy and > 5 fractions. Patients were divided into four treatment groups: standard fractionated radiation (SFRT), hypofractionated radiation (HFRT), standard fractionated chemoradiation (SFRT+CT), and hypofractionated chemoradiation (HFRT+CT). Chemoradiation was defined as chemotherapy and radiation with start dates within 30 days. To address confounding by indication, inverse probability of treatment weights (IPTW) were constructed regressing sociodemographic, clinical, and facility characteristics on treatment group in a multinomial regression model. Weighted Cox proportional hazard regression models were then used to evaluate the relative hazard of death with SFRT set as the referent treatment group. Results A total of 2,534 patients met inclusion criteria and of these 2,200 patients (57,462.83 person-months) had complete data for all confounders and were included in the analytic sample. Of the 2,200 patients 26.6% received SFRT, 7% received HFRT, 62.1% received SFRT+CT, and 4.2% received HFRT+CT. The median EQD2 (IQR) were: SFRT 66 Gy (60-68), HFRT 66.7 Gy (62.5-71.9), SFRT+CT 65.5 Gy (60-66), and HFRT+CT 67.6 Gy (65.1-72.3). 27% of patients were still alive 36 months after the initiation of RT (17.3% of SFRT, 20.3% of HFRT, 33.2% of SFRT+CT, and 21.8% of HFRT+CT). After IPTW propensity weighting, the probability of death at 3 years was compared between the treatment groups and only SFRT+CT was associated with longer OS. Compared with SFRT, the hazard ratio for all-cause mortality for those treated with SFRT+CT was 0.67 (95% CI: 0.57-0.75), for HFRT was 0.86 (95% CI: 0.61-1.06), and for HFRT+CT was 0.81 (95% CI 0.61-1.06). Conclusion To our knowledge, this is the first large database propensity weighted analysis of patients with cT1-T2N1M0 NSCLC managed non-surgically with definitive radiation or chemoradiation. In this group, treatment with SFRT+CT is associated with longer OS relative to treatment with radiation alone.

PURPOSE/OBJECTIVE(S) The PACIFIC Trial established durvalumab consolidation after definitive chemo-radiation (CRT) as the standard of care for Stage III Non-small cell lung cancer (NSCLC) in those not undergoing surgery. The rate of G3+ pneumonitis risk in this trial was less than 5% in the durvalumab arm. However, there is limited data regarding radiotherapy (RT) lung dosimetry from the PACIFIC trial to determine whether it accurately reflect real-world patients with locally advanced NSCLC who often require high lung dose to obtain target coverage. It is unclear whether established constraints accurately predict pneumonitis risk in this population. We aim to report outcomes and pneumonitis risk in a real word population of patients treated with CRT and durvalumab and determine risk of pneumonitis based on RT lung dosimetry. MATERIALS/METHODS We identified patients treated with CRT and durvalumab at a single institution for NSCLC not undergoing surgical resection. Patients were excluded if RT dosimetry was not available. NCI CTCAE v5.0 was used for grading pneumonitis. Differentiation of radiation pneumonitis (RP) vs durvalumab pneumonitis (DP) was determined by a radiation oncologist. Kaplan-Meier method was used to analyze overall survival (OS), progression free survival (PFS), and pneumonitis incidence and were compared using log rank test. RESULTS 40 patients treated with CRT and consolidative durvalumab were identified with median follow-up of 19 months. 90% of patients were Stage IIIA or IIIB (IIA-IIIC). Median RT dose was 63 Gy (54-70 Gy). Median MLD was 16 Gy (7-21 Gy). Median lung V20 was 29.5% (10%-38%). OS and PFS at 2 years was 69.7% was 60.3% respectively. Grade 2+ and 3+ combined RP and DP for the overall cohort was 29.0% and 24.0% respectively. Median time to pneumonitis from completion date of RT was 129 days. 22.5% (9/40) of patients required steroids for treatment of pneumonitis. 15% (6/40) of patients had a new O2 requirement attributed to pneumonitis. Pneumonitis led to discontinuation of durvalumab in 20% (8/40) of patients. Of the 9 cases of pneumonitis, 7 (77.8%) were consider RP, and 2 (22.2%) DP. Grade 2+ pneumonitis risk was 64.5% in patients with lung V20 > 30% versus 8.3% in patients with lung V20 ≤ 30% (P > 0.001). Grade 2+ pneumonitis risk was 59.4% in patients with a MLD > 17 Gy versus 8.3% in those with MLD ≤ 17 Gy (P 30% versus 8.3% in patients with lung V20 ≤ 30% (P = 0.003). Grade 3+ pneumonitis risk was 47.0% in patients with a MLD > 17 Gy versus 8.3% in those with MLD ≤ 17 Gy (P 30% or MLD > 17 Gy. Larger series are needed to determine optimal dose constraints in this patient population in the era of durvalumab.

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 /Objective(s): The outcomes of repeat stereotactic radiosurgery (SRS) after failure of previous SRS are not well established. We report our overall experience using SRS for the retreatment of locally recurrent brain metastases. Methods Patients with brain metastases diagnosed between 2003-2015 who underwent repeat SRS for local tumor progression following prior SRS were identified. Rates of local control, radiation necrosis, and overall survival were analyzed. Factors affecting local failure and radiation necrosis were assessed by Chi-squared test. Results 24 lesions in 22 patients underwent repeat SRS in a single fraction. Median age was 59 years. The median SRS-1 dose was 18 Gy and the median SRS-2 dose was 15.5 Gy. The median SRS-1 target volume was 2.25 cm 3 and the median SRS-2 target volume was 3.30 cm 3. The median follow up from SRS-2 was 8.8 months. The actuarial local control for SRS-2 was 94.1% and 61.1% at 6 and 12 months, respectively. Actuarial radiation necrosis was 9.2% and 9.2% at 6 and 12 months, respectively. Volume of tumor >4 cm 3 correlated with increased risk of local failure (p=0.006) with no local failures recorded with volumes ≤4 cm 3 . SRS-2 dose, cumulative SRS dose, receipt of WBRT, and use of SRS-2 as boost after surgery did not correlate with local failure or radiation necrosis. Median overall survival after SRS-2 was 8.78 months. Conclusion Repeat SRS is feasible for select patients particularly for those with tumor volume ≤4 cm 3 . Further evaluation is needed to establish the most appropriate treatment doses and volumes for this approach.

Purpose: Accreditation based on peer review of professional standards of care is essential in ensuring quality and safety in administration of radiation therapy. Traditionally, medical chart reviews have been performed by a physical onsite visit. The American College of Radiation Oncology Accreditation Program has remodeled its process whereby electronic charts are reviewed remotely. Methods: Twenty-eight radiation oncology practices undergoing accreditation had three charts per practice undergo both onsite and online review. Onsite review was performed by a single reviewer for each practice. Online review consisted of one or more disease site–specific reviewers for each practice. Onsite and online reviews were blinded and scored on a 100-point scale on the basis of 20 categories. A score of less than 75 was failing, and a score of 75 to 79 was marginal. Any failed charts underwent rereview by a disease site team leader. Results: Eighty-four charts underwent both onsite and online review. The mean scores were 86.0 and 86.9 points for charts reviewed onsite and online, respectively. Comparison of onsite and online reviews revealed no statistical difference in chart scores ( P = .43). Of charts reviewed, 21% had a marginal (n = 8) or failing (n = 10) score. There was no difference in failing charts ( P = .48) or combined marginal and failing charts ( P = .13) comparing onsite and online reviews. Conclusion: The American College of Radiation Oncology accreditation process of online chart review results in comparable review scores and rate of failing scores compared with traditional on-site review. However, the modern online process holds less potential for bias by using multiple reviewers per practice and allows for greater oversight via disease site team leader rereview.

Background Stereotactic radiosurgery (SRS) alone is an attractive option for treatment of brain metastases. SRS avoids whole-brain radiotherapy (WBRT)-associated morbidity, but is limited by regional central nervous system (CNS) failures and short survival in some patients. We evaluated a subgroup of patients with controlled systemic disease that could represent a favorable patient population for SRS alone. Methods All patients with brain metastases treated with SRS without WBRT at our institution between 2004 and 2014 were grouped into two cohorts: those with controlled systemic disease (CSD) for 1 year or longer before prior to presentation with brain metastases and those without (i.e., uncontrolled systemic disease [USD]). Rates of local and regional CNS failure, and overall survival were assessed with χ 2 and Student t tests. Cox regression analysis was performed to evaluate independent predictors of regional control and overall survival. Results Two hundred ninety-four patients underwent SRS to 697 lesions, of which 65 patients had CSD. Median follow-up was 9.7 months. There was no difference in local control between the two cohorts ( P = 0.795). Regional CNS control was significantly better for patients with CSD (68% vs. 48%; P = 0.001). Overall survival at 1 and 5 years for CSD were 65% and 13% with USD yielding 41% and 7%, respectively ( P P = 0.008) and shorter overall survival (HR, 1.55; P = 0.007). Conclusions Patients with brain metastases after 1 year or longer of primary and systemic disease control represent a particularly favorable cohort, with lower regional CNS failure and prolonged survival, for an approach of SRS alone.

Purpose The role of surgical clips as markers of the tumor bed cavity for radiation therapy boost targeting after oncoplastic surgery is not well understood. Therefore, we sought to evaluate whether the placement of surgical clips can reduce interobserver variability in the delineation of the tumor bed cavities of oncoplastic surgery patients and ultimately determine an optimal number of clips to place. Methods and Materials We reviewed records of 39 women with breast cancer who underwent oncoplastic breast surgery and adjuvant radiation therapy at our institution. Three radiation oncologists contoured tumor bed cavity volumes on planning computed tomography simulation images. Interobserver variability was measured both by a coefficient of variation of radiation oncologists contour volume and a concordance index defined as the quotient of the intersecting and aggregated volume of the contours. Patients were stratified by the number of surgical clips placed and compared by 1-way analysis of variance. Simple linear regression was used to evaluate the relationship of total excised volume and interobserver variability in patients with a sufficient quantity of surgical clips. Results Interobserver variability in the delineation of the tumor bed cavity as measured by concordance index was significantly reduced in patients who received intraoperative surgical clips (F = 5.755; P = .001). A similar trend was seen in contour volume (F = 2.616; P = .052). Results of 1-way analysis of variance and post hoc analysis showed that 4 clips are effective and sufficient for reproducible delineation of the tumor bed cavity for the radiation therapy boost. Increasing excision volume does not result in an increase in interobserver variability (r2 = 0.00003). Conclusions In oncoplastic surgery patients, intraoperative placement of surgical clips is beneficial and effective in improving the delineation of the tumor bed cavity for the radiation therapy boost. Four clips are necessary and sufficient for accurate boost targeting after lumpectomy with oncoplastic reconstruction.

Purpose To evaluate cardiac imaging abnormalities after modern radiotherapy and trastuzumab in breast cancer patients. Patients and Methods All patients treated with trastuzumab and radiotherapy for breast cancer between 2006 and 2014 with available cardiac imaging (echocardiogram or multigated acquisition scan) were retrospectively analyzed. Cardiac abnormalities included myocardial abnormalities (atrial or ventricular dilation, hypertrophy, hypokinesis, and impaired relaxation), decreased ejection fraction > 10%, and valvular abnormalities (thickening or stenosis of the valve leaflets). Breast laterality (left vs. right) and heart radiation dose volume parameters were analyzed for association with cardiac imaging abnormalities. Results A total of 110 patients with 57 left- and 53 right-sided breast cancers were evaluated. Overall, 37 patients (33.6%) developed a new cardiac abnormality. Left-sided radiotherapy was associated with an increase in new cardiac abnormalities (relative risk [RR] = 2.51; 95% confidence interval [CI], 1.34-4.67; P = .002). Both myocardial and valvular abnormalities were associated with left-sided radiotherapy (myocardial: RR = 2.21; 95% CI, 1.06-4.60; P = .029; valvular: RR = 3.30; 95% CI, 0.98-10.9; P = .044). There was no significant difference in decreased ejection fraction between left- and right-sided radiotherapy (9.6% vs. 2.1%; P = .207). A mean heart dose > 2 Gy as well as volume of the heart receiving 20 Gy (V20), V30, and V40 correlated with cardiac abnormalities (mean heart dose > 2 Gy: RR = 2.00; P = .040). Conclusion New cardiac abnormalities, including myocardial and valvular dysfunction, are common after trastuzumab and radiotherapy. The incidence of new abnormalities correlates with tumor laterality and cardiac radiation dose exposure. Long-term follow-up is needed to understand the clinical significance of these early imaging abnormalities.

2014 Background: The cyclin D-CDK4/6-Rb pathway is activated in most glioblastomas. Abemaciclib is a potent CDK4/6 inhibitor with good brain penetration approved for HR+/HER2- breast cancer. In order to efficiently evaluate the potential impact of abemaciclib on overall survival (OS) in newly diagnosed glioblastoma and to simultaneously develop information regarding potential genomic biomarker associations, abemaciclib was included as an arm on the Individualized Screening Trial of Innovative Glioblastoma Therapy (INSIGhT) trial. INSIGhT is a phase II platform trial using response adaptive randomization and deep genomic profiling to more efficiently test experimental agents in MGMT unmethylated glioblastoma and potentially accelerate identification of novel therapies for phase III testing. Initial randomization was equal between abemaciclib, control, and two other experimental arms but subsequent randomization was adapted based on efficacy as determined by progression-free survival (PFS). Ineffective arms were discontinued and new arms added by protocol amendment. We report preliminary results for the abemaciclib arm which has completed accrual. Methods: Patients with newly diagnosed MGMT-unmethylated glioblastoma were randomized to receive either radiotherapy with concomitant and adjuvant temozolomide at standard doses or standard radiochemotherapy followed by adjuvant abemaciclib (150-200 mg orally BID). Treatment continued until progression or development of unacceptable toxicities. The primary endpoint was OS which was assessed using the log-rank test estimated via the Kaplan Meier method using a type I error of 5%. The hazard ratio (HR) was estimated using a cox proportional hazards model. Association between abemaciclib efficacy and cyclin D-CDK4/6-Rb pathway genomic alterations was also investigated. Results: There were 142 patients (69 control; 73 treated with abemaciclib). Abemaciclib was generally well-tolerated with no new toxicity signals identified. PFS was significantly longer (HR 0.67; p = 0.03, logrank test) with abemaciclib (median 6.54 months) compared to the control arm (median 5.88 months). For patients with activation of the CDK4 pathway the PFS HR was 0.64 (p-value = 0.04). However, there was no significant improvement in overall survival (HR 0.9; p-value > 0.05) between abemaciclib (median 15.5) compared to the control arm (median 15.5). Conclusions: Abemaciclib was well-tolerated and prolonged PFS but there is no evidence of an overall survival improvement compared to standard radiochemotherapy. Clinical trial information: NCT02977780.

Stereotactic body radiation therapy (SBRT) boost to primary and nodal disease after chemoradiation has potential to improve outcomes for advanced non-small cell lung cancer (NSCLC). A dose escalation study was initiated to evaluate the maximum tolerated dose (MTD).Eligible patients received chemoradiation to a dose of 50.4 Gy in 28 fractions and had primary and nodal volumes appropriate for SBRT boost (120 cc and60 cc, respectively). SBRT was delivered in 2 fractions after chemoradiation. Dose was escalated from 16 to 28 Gy in 2 Gy/fraction increments, resulting in 4 dose cohorts. MTD was defined when ≥2 of 6 patients per cohort experienced any treatment-related grade 3 to 5 toxicity within 4 weeks of treatment or the maximum dose was reached. Late toxicity, disease control, and survival were also evaluated.Twelve patients (3 per dose level) underwent treatment. All treatment plans met predetermined dose-volume constraints. The mean age was 64 years. Most patients had stage III disease (92%) and were medically inoperable (92%). The maximum dose level was reached with no grade 3 to 5 acute toxicities. At a median follow-up time of 16 months, 1-year local-regional control (LRC) was 78%. LRC was 50% at24 Gy and 100% at ≥24 Gy (P=.02). Overall survival at 1 year was 67%. Late toxicity (grade 3-5) was seen in only 1 patient who experienced fatal bronchopulmonary hemorrhage (grade 5). There were no predetermined dose constraints for the proximal bronchial-vascular tree (PBV) in this study. This patient's 4-cc PBV dose was substantially higher than that received by other patients in all 4 cohorts and was associated with the toxicity observed: 20.3 Gy (P.05) and 73.5 Gy (P=.07) for SBRT boost and total treatment, respectively.SBRT boost to both primary and nodal disease after chemoradiation is feasible and well tolerated. Local control rates are encouraging, especially at doses ≥24 Gy in 2 fractions. Toxicity at the PBV is a concern but potentially can be avoided with strict dose-volume constraints.

Purpose To report updated feasibility and reproducibility results for high-dose-rate noninvasive breast brachytherapy (NIBB) for tumor bed boost with whole breast radiation therapy (WBRT) in the setting of expanded patient and treatment facility number. Methods and Materials Fifteen independent community-based and academic centers reported 518 early-stage breast cancer patients from July 2007 to February 2015 on a privacy-encrypted online data registry. All patients' treatment included lumpectomy followed by combination of WBRT and NIBB. NIBB was completed with commercially available (AccuBoost, Billerica, MA) mammography-based system using high-dose-rate 192 Ir emissions along orthogonal axes. Harvard scale was used to grade cosmesis. Results Total patient cohort had median followup of 12 months (1–75 months) with subset of 268 having available cosmesis. Greater than 2- and 3-year followup was 29% and 14%, respectively. Entire cohort had 97.4% excellent/good (E/G) breast cosmesis and freedom from recurrence of 97.6% at the final followup. WBRT timing with respect to NIBB delivery demonstrated no statistically significant difference in E/G cosmesis. Achieved E/G cosmesis rate was also not statistically significant ( χ 2 p -value = 0.86) between academic and community institutions with 97.8% vs. 96.6%. Conclusions NIBB represents an alternative method for delivery of breast tumor cavity boost that has shown feasibility in a diverse group of both academic and community-based practices with reproducible early cosmesis and tumor control results. Recommendations are updated noting ideal timing of boost delivery likely to be before or early during WBRT given equal cosmesis and less documented treatment discomfort.

Objective: Our objective was to report safety and efficacy of stereotactic radiosurgery (SRS) to the surgical bed following resection of brain metastases. Methods: Eighty-seven consecutive patients who underwent cavity-directed SRS to the operative bed for the treatment of brain metastases between 2002 and 2010 were evaluated. SRS required a gadolinium-enhanced, high-resolution, T1-weighted magnetic resonance imaging for tumor targeting and delivered a median dose of 18 Gy (14-22 Gy) prescribed to encompass the entire resection cavity. Whole brain irradiation was reserved for salvage. Patients were followed every 3 months with clinical examination and magnetic resonance imaging. Overall survival, local and regional recurrence, and factors affecting these outcomes were evaluated using Kaplan-Meier and log-rank analyses. Results: The median imaging follow-up was 7.1 months, with >40% of patients having imaging for ≥1 year. Local control at 1 and 2 years was 82% and 75%, respectively. Cavity recurrence was more common with a tumor diameter >3 cm (P < .020) or resection cavity volume >14 mL (P 3 cm were 100%, 86%, and 72%, respectively. Neither subtotal resection nor target margins >2 mm to 3 mm affected local control. The median overall survival was 14.3 months with actuarial 5-year survival of 20%. Actuarial regional central nervous system recurrence was 44% at 1 year. On univariate analysis, only the presence of extracranial disease was associated with survival (P < .001) and central nervous system failure (P < .030). Conclusions: Excellent local control is achievable with cavity-directed SRS in well-selected patients, particularly for lesions with diameter

To improve efficiency, convenience, and cost, a prospective phase II trial was initiated to evaluate accelerated partial breast irradiation delivered with noninvasive image-guided breast brachytherapy (NIBB) via five once-daily fractions.Women ≥50 years old with early-stage breast cancer undergoing breast conserving surgery were enrolled. Eligibility criteria included invasive carcinoma ≤2.0 cm or ductal carcinoma in situ ≤3.0 cm, ER positive (if invasive), lymph node negative, LVI absent, and margins negative by 2 mm. Patients received a total dose of 28.5 Gy in five daily fractions. NIBB was delivered using two orthogonal axes for each fraction. Applicators were selected to encompass the lumpectomy cavity with a 1.0 cm clinical target volume margin and 0 to 0.5 cm planning target volume margin. Acute and late toxicity was assessed based on CTCAE v3.0.Forty patients with a mean age of 67 years underwent protocol treatment. Mean tumor size was 1.0 cm (0.3-2.0 cm). Eighty percent had invasive carcinoma and the remainder had ductal carcinoma in situ. Mean tumor bed volume was 21 cc (5-79 cc) and mean breast volume was 1319 cc (499-3044 cc). Mean breast separation with compression was 6.7 cm (3.5-8.9 cm). All patients tolerated well. Median discomfort with compression was 1 (range: 0-7) on a 10-point pain scale. Acute skin reaction was Grade 0-1 in 70%, Grade 2 in 28%, and Grade 3 in 3%. Acute skin toxicity was not associated with breast size but was associated with larger breast separation with compression (p0.01) and larger applicator size (p0.01). No Grade 3+ late toxicity or local recurrences have been observed at a median followup of 14 months.Accelerated partial breast irradiation delivered using NIBB over five daily fractions is a convenient treatment option that is feasible and well tolerated.

PURPOSE: Noninvasive image-guided breast brachytherapy (NIBB) is an attractive novel approach to deliver accelerated partial breast irradiation (APBI). Calculations of equivalent uniform dose (EUD) were performed to identify the appropriate APBI dose for this technique. METHODS AND MATERIALS: APBI plans were developed for 15 patients: five with three- dimensional conformal APBI (3D-CRT), five with multi-lumen intracavitary balloons (m-IBB), and five simulating NIBB treatment. Prescription doses of 34.0 and 38.5 Gy were delivered in 10 fractions for m-IBB and 3D-CRT, respectively. Prescription doses ranging from 34.0 to 38.5 Gy were considered for NIBB. Dose-volume histogram data from all 3D-CRT, m-IBB, and NIBB plans were used to calculate the biologically effective EUD and corresponding EUD to the PTV_eval using the following equation: EUD 5 EUBED/(n (1 þ EUD/a/b)). An a/b value of 4.6 Gy was assumed for breast tumor. EUD for varying NIBB prescription doses were compared with EUD values for the other APBI techniques. RESULTS: Mean PTV_eval volume was largest for 3D-CRT (372.9 cm 3 ) and was similar for NIBB and m-IBB (88.7 and 87.2 cm 3 , respectively). The EUD value obtained by prescribing 38.5 Gy with 3D-CRT APBI was 38.6 Gy. The EUD value of 34.0 Gy prescribed with m-IBB was 34.4 Gy. EUD values for NIBB ranged from 33.9 to 38.2 Gy for prescription doses ranging from 34.0 to 38.5 Gy. CONCLUSIONS: Using EUD calculations to compare APBI techniques and treatment doses, a prescription dose of 36.0 Gy in 10 fractions using NIBB has a comparable biologic equivalent dose to other established brachytherapy techniques. 2015 American Brachytherapy Society. Published

Stereotactic radiosurgery (SRS) represents a treatment option for patients with brain metastases from small cell lung cancer (SCLC) following prior cranial radiation. Inferior local control has been described. We reviewed our failure patterns following SRS treatment to evaluate this concern.Individuals with SCLC who received SRS for brain metastases from 2004 to 2011 were identified. Central nervous system (CNS) disease was detected and followed by gadolinium-enhanced, high-resolution magnetic resonance (MR) imaging. SRS dose was prescribed to the tumor periphery. Local recurrence was defined by increasing lesion size or enhancement, MR-spectroscopy, and perfusion changes consistent with recurrent disease or pathologic confirmation. Any new enhancing lesion not identified on the SRS planning scan was considered a regional failure. Overall survival (OS) and CNS control were evaluated using the Kaplan-Meier method. Factors predicted to influence outcome were tested by univariate log-rank analysis and Cox regression.Fifteen males and 25 females (median age of 61 years [range, 36-79]) of which 39 received prior brain irradiation were identified. In all, 132 lesions (3.3 per patient) between 0.4 and 4.7 cm received a median dose of 16 Gy (12-22 Gy). Thirteen metastases (10%) ultimately recurred locally with 6- and 12-month control rates of 81% and 69%, respectively. Only 1 of 110 metastases2 cm recurred. Local failure was more likely for size2 cm (P.001) and dose16 Gy (P.001). The median OS was 6.5 months, and the time to regional CNS recurrence was 5.2 months. For patients with single brain metastases, both OS (P = .037) and regional CNS recurrence (P = .003) were improved. CNS control (P = .001), and survival (P = .057), were also longer for patients with controlled systemic disease.Local control following SRS for SCLC metastases is achievable for lesions2 cm. For metastases2 cm, local failure is more common than expected. Patients with controlled systemic disease and limited CNS involvement would benefit most from aggressive treatment.

PURPOSE: Noninvasive image-guided breast brachytherapy delivers conformal HDR (192)Ir brachytherapy treatments with the breast compressed, and treated in the cranial-caudal and medial-lateral directions. This technique subjects breast tissue to extreme deformations not observed for other disease sites. Given that, commercially-available software for deformable image registration cannot accurately co-register image sets obtained in these two states, a finite element analysis based on a biomechanical model was developed to deform dose distributions for each compression circumstance for dose summation. MATERIAL AND METHODS: The model assumed the breast was under planar stress with values of 30 kPa for Young's modulus and 0.3 for Poisson's ratio. Dose distributions from round and skin-dose optimized applicators in cranial-caudal and medial-lateral compressions were deformed using 0.1 cm planar resolution. Dose distributions, skin doses, and dose-volume histograms were generated. Results were examined as a function of breast thickness, applicator size, target size, and offset distance from the center. RESULTS: Over the range of examined thicknesses, target size increased several millimeters as compression thickness decreased. This trend increased with increasing offset distances. Applicator size minimally affected target coverage, until applicator size was less than the compressed target size. In all cases, with an applicator larger or equal to the compressed target size, > 90% of the target covered by > 90% of the prescription dose. In all cases, dose coverage became less uniform as offset distance increased and average dose increased. This effect was more pronounced for smaller target-applicator combinations. CONCLUSIONS: The model exhibited skin dose trends that matched MC-generated benchmarking results within 2% and clinical observations over a similar range of breast thicknesses and target sizes. The model provided quantitative insight on dosimetric treatment variables over a range of clinical circumstances. These findings highlight the need for careful target localization and accurate identification of compression thickness and target offset.

In this study, we use a competing risks analysis to assess factors predictive of early-salvage whole brain radiotherapy (WBRT) and early death after upfront stereotactic radiosurgery (SRS) alone for brain metastases in an attempt to identify populations that benefit less from upfront SRS.Patients from eight academic centers were treated with SRS for brain metastasis. Competing risks analysis was carried out for distant brain failure (DBF) versus death prior to DBF as well as for salvage SRS versus salvage WBRT versus death prior to salvage. Linear regression was used to determine predictors of the number of brain metastases at initial DBF (nDBF).A total of 2657 patients were treated with upfront SRS alone. Multivariate analysis (MVA) identified an increased hazard of DBF associated with increasing number of brain metastases (P 0.001), lowest SRS dose received (P 0.001), and melanoma histology (P 0.001), while there was a decreased hazard of DBF associated with increasing age (P 0.001), KPS 70 (P 0.001), and progressive systemic disease (P = 0.004). MVA for first salvage SRS versus WBRT versus death prior to salvage revealed an increased hazard of first salvage WBRT seen with increasing number of brain metastases (P 0.001) and a decreased hazard with widespread systemic disease (P = 0.002) and increasing age (P 0.001). Variables associated with nDBF included age (P = 0.02), systemic disease status (P = 0.03), melanoma histology (P = 0.05), and initial number of brain metastases (P 0.001).Patients with a higher initial number of brain metastases were more likely to experience DBF, have a higher nDBF, and receive early-salvage WBRT, while patients who were older, had lower KPS, or had more systemic disease were more likely to experience death prior to DBF or salvage WBRT.

Stereotactic radiosurgery (SRS) without whole brain radiotherapy (WBRT) for brain metastases can avoid WBRT toxicities, but with risk of subsequent distant brain failure (DBF). Sole use of number of metastases to triage patients may be an unrefined method. Data on 1354 patients treated with SRS monotherapy from 2000 to 2013 for new brain metastases was collected across eight academic centers. The cohort was divided into training and validation datasets and a prognostic model was developed for time to DBF. We then evaluated the discrimination and calibration of the model within the validation dataset, and confirmed its performance with an independent contemporary cohort. Number of metastases (≥8, HR 3.53 p = 0.0001), minimum margin dose (HR 1.07 p = 0.0033), and melanoma histology (HR 1.45, p = 0.0187) were associated with DBF. A prognostic index derived from the training dataset exhibited ability to discriminate patients' DBF risk within the validation dataset (c-index = 0.631) and Heller's explained relative risk (HERR) = 0.173 (SE = 0.048). Absolute number of metastases was evaluated for its ability to predict DBF in the derivation and validation datasets, and was inferior to the nomogram. A nomogram high-risk threshold yielding a 2.1-fold increased need for early WBRT was identified. Nomogram values also correlated to number of brain metastases at time of failure (r = 0.38, p

There has been significant progress and innovation in the treatment of patients with metastatic spinal tumors over the last two to three decades that has impacted our ability to provide individualized care that improves a patient's quality of life and degree of neurologic impairment. Advances in surgical techniques and radiation delivery modalities have dramatically improved our ability to decrease local tumor recurrence rates, improve pain control, and provide more durable spinal stability. Modern day spine tumor resection and reconstruction techniques have been shown to improve and prolong patients' ability to ambulate, maintain continence, and reduce the need for pain medications. Spinal radiosurgery, the focused delivery of radiation to a target in the spine, has significantly enhanced the ability to provide a high degree of local tumor control in a non-invasive manner, even for tumors that are deemed radioresistant by conventional radiation therapy standards. In most patients, a combination of treatment modalities, including both surgery and radiation, is the mainstay of any comprehensive treatment plan for metastatic spinal tumors. [Full article available at http://rimed.org/rimedicaljournal-2017-06.asp].

Introduction Tumor bed boost improves local control and is an important part of breast-conserving therapy. Data on the use of a hypofractioned tumor bed boost are needed. We performed a retrospective analysis of patients treated with hypofractionated whole breast irradiation (WBI) and hypofractionated boost to examine acute and delayed outcomes. Materials and Methods We examined the records of patients treated with hypofractionated WBI and tumor bed boost after lumpectomy for Stage 0 to II breast cancer. Local control, toxicity, and cosmetic outcome were evaluated. Patient, tumor, and treatment characteristics were evaluated including excision volume, surgical technique, surgical complications, chemotherapy, endocrine therapy administration, radiation dose, fractionation, and technique. Results A total of 143 patients received hypofractionated WBI with hypofractionated boost between 2010 and 2015. The median follow-up was 16.8 months. The median patient age was 65 years. Patient stage was 0, I, and II in 25%, 68%, and 7%, respectively. All patients received hypofractionated WBI with 42.5 Gy in 16 fractions. Sixty-one percent of women received a boost regimen of 2.66 Gy/fraction for 3 fractions. Boost techniques included noninvasive breast brachytherapy, electrons, 3-dimensional conformal radiation therapy, or a combination of techniques. Acute skin reaction was grade 1 in 65% and grade 2 in 32%. Good or excellent cosmetic outcome was achieved in 94% of patients. Subcutaneous fibrosis was the most common delayed toxicity in 19%, of which 86% was grade 1. There were no local recurrences. Conclusions Hypofractionated tumor bed boost is well-tolerated with a low rate of toxicity and high rate of good-to-excellent cosmetic outcome.

We present two cases of biopsy-proven neoplastic lumbosacral plexopathy from perineural spread of bladder cancer: one patient presented with predominantly sciatic nerve involvement and the second predominantly with obturator nerve involvement. These two patterns of perineural spread from bladder cancer were supported by imaging in our cases and solidified by review of the literature. Based on the innervation of the bladder, we provide an anatomic explanation for this observation. To our best knowledge, such an anatomic, mechanistic basis for perineural tumor spread in bladder cancer has not yet been described.

PURPOSE: Utilization of stereotactic radiosurgery (SRS) for brainstem metastases (BSM) is increasing. Multi-fraction SRS (MF-SRS) is a potential means of obtaining therapeutic gain while limiting toxicity. However, most available data assesses only single-fraction SRS (SF-SRS). This study aims to evaluate the efficacy and safety of SF-SRS and MF-SRS for BSM. METHODS: Data was retrospectively collected for patients with BSM treated with SRS between 2003–2018 at a single institution. Kaplan-Meier method was used to evaluate overall survival (OS) and local control (LC). Independent t-test was used for correlations between groups. RESULTS: 29 patients (31 lesions) were identified; 13 patients (15 lesions) underwent SF-SRS and 16 patients (16 lesions) underwent MF-SRS. Median follow-up was 6.8 months (1–80.8 months). Post-SRS MRI was available for 78% of patients. Median dose was 16Gy (12–18 Gy) for SF-SRS and 24 Gy (18–30 Gy) for MF-SRS. MF-SRS was delivered in a median of 3 fractions (3–5). There was a trend toward larger mean tumor volume with MF-SRS (1.297 vs 0.302mL, p=0.055). OS was 64.8% at 6 months and 49.3% at 12 months. LC was 90.9% at 6 months and 69.9% at 12 months. LC was similar between SF-SRS and MF-SRS at 6 months (100% vs 79.5%, p=0.143) and 12 months (50.0% vs 79.5%, p=0.812). Among the 4 patients who experienced local recurrence, 3 received salvage whole brain radiation and median OS was 8.1 months after LF. Distant CNS failures occurred in 40.3% of patients at 6 months and 72.4% at 12 months. Tumor volume >0.5 mL was associated with worse LC at 6 months (64.3% vs 100%, p=0.022). One patient developed symptomatic radiation necrosis (1/29 lesions, 3.4%) after MF-SRS. CONCLUSION: SRS is a safe and effective treatment for small BSM. Outcomes were not different between SF-SRS and MF-SRS but analysis is limited by small sample size.

INTRODUCTION: Brain metastasis velocity (BMV) is a prognostic metric that describes the recurrence rate of new brain metastases after initial treatment with radiosurgery (SRS). We have previously risk stratified patients into high, intermediate, and low-risk BMV groups, which correlates with overall survival (OS). We sought to externally validate BMV in a multi-institutional setting. METHODS: Patients from nine academic centers were treated with upfront SRS; the validation cohort consisted of data from eight institutions not previously used to define BMV. Patients were classified by BMV into low (< 4 BMV), intermediate (4–13 BMV), and high-risk groups (>13 BMV). Time-to-event outcomes were estimated using the Kaplan-Meier method. Cox proportional hazards methods were used to estimate the effect of BMV and salvage modality on OS. RESULTS: Of 2829 patients, 2092 patients were included in the validation dataset. Of these, 921 (44.0%) experienced distant brain failure (DBF). Median OS from initial SRS was 11.2 mo. Median OS for BMV < 4, BMV 4–13, and BMV > 13 were 12.5 mo, 7.0 mo, and 4.6 mo (p < 0.0001). Compared to initial salvage with WBRT, salvage SRS was associated with improved OS following DBF for BMV < 4 (p = 0.05), BMV 4–13 (p = 0.002) and BMV > 13 (p = 0.0001). CONCLUSIONS: This multi-institutional dataset validates BMV as a predictor of OS following initial SRS. BMV is being utilized in upcoming multi-institutional randomized controlled trials as a stratification variable for salvage whole brain radiation vs salvage SRS after DBF.

Background To compare clinical outcomes and toxicity in patients treated with NIBB boost with those in patients treated with external beam (EB) boost. Patients and Methods Women with early stage breast cancer treated with WBI and NIBB boost were identified. Control subjects treated with EB boost identified as the best possible match with respect to age, stage, chemotherapy use, and fractionation were chosen for a 2:1 comparison. Acute toxicity, late toxicity, and oncologic outcomes were reviewed. The McNemar nonparametric test was used to evaluate marginal homogeneity between matched pairs. Results One hundred forty-one patients were included in the analysis: 47 patients treated with NIBB boost and 94 matched control subjects treated with EB boost (electron, n = 93) or 3-D conformal radiation (n = 1). Grade 2+ desquamation developed in 18 patients (39%) treated with NIBB boost and in 49 patients (52%) treated with EB boost ( P = .07). Breast size, electron energy, and fractionation predicted for acute desquamation ( P P P = .006). Median follow-up was 13.6 months. One patient (2%) who received NIBB had Grade 2+ skin/subcutaneous fibrosis 15 months after completion of treatment. Among those treated with EB, 9 patients (9.5%) developed Grade 2+ subcutaneous fibrosis, and 1 patient had recurrent cellulitis. There was statistically significantly less combined skin/subcutaneous toxicity in those treated with NIBB than in those treated with EB ( P = .046). Conclusion NIBB boost is associated with favorable short-term clinical outcomes compared with EB.

Object The goal of this study was to evaluate outcomes in patients with ≥ 10 CNS metastases treated with Gamma Knife stereotactic radiosurgery (GK-SRS). Methods Patients with ≥ 10 brain metastases treated using GK-SRS during the period between 2004 and 2010 were identified. Overall survival and local and regional control as well as necrosis rates were determined. The influence of age, sex, histological type, extracranial metastases, whole-brain radiation therapy, and number of brain metastases was analyzed using the Kaplan-Meier method. Univariate (log-rank) analyses were performed, with a p value of < 0.05 considered significant. Results Fifty-three patients with ≥ 10 brain metastases were treated between 2004 and 2010. All had a Karnofsky Performance Status score of ≥ 70. Seventy-two percent had either non–small cell lung cancer (38%) or breast cancer (34%); melanoma, small cell lung cancer, renal cell carcinoma, and testicular, colon, and ovarian cancer contributed the remaining 28%. On average, 10.9 lesions were treated in a single session. Sixty-four percent of patients received prior whole-brain radiation therapy. The median survival was 6.5 months. One-year overall survival was 42% versus 14% when comparing breast cancer and other histological types, respectively (p = 0.074). Age, extracranial metastases, number of brain metastases, and previous CNS radiation therapy were not significant prognostic factors. Although the median time to local failure was not reached, the median time to regional failure was 3 months. Female sex was associated with longer time to regional failure (p = 0.004), as was breast cancer histological type (p = 0.089). No patient experienced symptomatic necrosis. Conclusions Patients with ≥ 10 brain metastases who received prior CNS radiation can safely undergo repeat treatment with GK-SRS. With median survival exceeding 6 months, aggressive local treatment remains an option; however, rapid CNS failure is to be expected. Although numbers are limited, patients with breast cancer represent one group of individuals who would benefit most, with prolonged survival and extended time to CNS recurrence.