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BACKGROUND CONTEXT With improvements in adjuvant radiotherapy and minimally invasive surgical techniques, separation surgery has become the default surgical intervention for spine metastases at many centers. However, it is unclear if there is clinical benefit from anterior column resection in addition to simple epidural debulking prior to stereotactic body radiotherapy (SBRT). PURPOSE To examine the effect of anterior column debulking versus epidural disease resection alone in the local control of metastases to the bony spine. STUDY DESIGN Retrospective cohort study. PATIENT SAMPLE Ninety-seven patients who underwent open surgery followed by SBRT for spinal metastases at a single comprehensive cancer center. OUTCOME MEASURES Local tumor recurrence following surgery and SBRT. METHODS Data were collected regarding radiation dose, cancer histology, extent of anterior column resection, and recurrence. Tumor involvement was categorized using the International Spine Radiosurgery Consortium guidelines. Univariable analyses were conducted to determine predictors of local recurrence and time to local recurrence. RESULTS Among the 97 included patients, mean age was 60.5±11.4 years and 51% of patients were male. The most common primary tumor types were lung (20.6%), breast (17.5%), kidney (13.4%) and prostate (12.4%). Recurrence was seen in 17 patients (17.5%) and local control rates were: 85.5% (1-year), 81.1% (2-year), and 54.9% (5-year). Overall predictors of local recurrence were tumor pathology (p

In the management of symptomatic bone metastases, current practice guidelines do not provide clear methodology for selecting palliative radiotherapy (RT) regimens based on specific patient and disease features. Decision support aids may offer an effective means for translating the complex data needed to render individualised treatment decisions, yet no such tools are available for use in this setting. Thus, we describe the development of the Bone Metastases Ensemble Trees for Survival-Decision Support Platform (BMETS-DSP), which aims to optimise selection of evidence-based, individualised palliative RT regimens.The Ottawa Decision Support Framework was used as the theoretical basis for development of BMETS-DSP. First, we utilised stakeholder input and review of the literature to assess determinants underlying the provider decision. Based on this assessment and iterative stakeholder feedback, we developed the web-based, provider-facing BMETS-DSP. Consistent with the underlying theoretical framework, our design also included assessment of decision quality using the International Patient Decision Aids Standards (IPDAS) certification checklist.Stakeholder input and review of 54 evidence-based publications identified the following determinants of the provider decision: estimated prognosis, characteristics of the target symptomatic lesion and the primary cancer type, consideration of alternative interventions, access to patient-specific recommendations, and patient preferences. Based on these determinants, we developed the BMETS-DSP that (1) collects patient-specific data, (2) displays an individualised predicted survival curve, and (3) provides case-specific, evidence-based recommendations regarding RT, open surgery, systemic therapy, and hospice referral to aid in the decision-making process. The finalised tool met IPDAS quality requirements. Preliminary results of a pilot assessment suggest impact of clinical outcomes.We describe the successful development of a provider-facing decision support platform to aid in the provision of palliative RT in better alignment with patient and disease features. Impact of the BMETS-DSP on decision outcomes will be further assessed in a randomised, controlled study.

OBJECTIVE Non–small cell lung cancer (NSCLC) is the most common primary tumor to develop brain metastasis. Prognostic markers are needed to better determine survival after neurosurgical resection of intracranial disease. Given the importance of mutation subtyping in determining systemic therapy and overall prognosis of NSCLC, the authors examined the prognostic value of mutation status for postresection survival of patients with NSCLC brain metastasis. METHODS The authors retrospectively analyzed all cases of NSCLC brain metastasis with available molecular testing data that were resected by a single surgeon at a single academic center from January 2009 to February 2019. Mutation status, demographic characteristics, clinical factors, and treatments were analyzed. Association between predictive variables and overall survival after neurosurgery was determined with Cox regression. RESULTS Of the included patients (n = 84), 40% were male, 76% were smokers, the mean ± SD Karnofsky Performance Status was 85 ± 14, and the mean ± SD age at surgery was 63 ± 11 years. In total, 23%, 26%, and 4% of patients had EGFR, KRAS, and ALK/ROS1 alterations, respectively. On multivariate analysis, survival of patients with EGFR (HR 0.495, p = 0.0672) and KRAS (HR 1.380, p = 0.3617) mutations were not significantly different from survival of patients with wild-type (WT) tumor. However, the subgroup of patients with EGFR mutation who also received tyrosine kinase inhibitor (TKI) therapy had significantly prolonged survival (HR 0.421, p = 0.0471). In addition, postoperative stereotactic radiosurgery (HR 0.409, p = 0.0177) and resected tumor diameter < 3 cm (HR 0.431, p = 0.0146) were also significantly associated with prolonged survival, but Graded Prognostic Assessment score ≤ 1.0 (HR 2.269, p = 0.0364) was significantly associated with shortened survival. CONCLUSIONS Patients with EGFR mutation who receive TKI therapy may have better survival after resection of brain metastasis than patients with WT tumor. These results may inform counseling and decision-making regarding the appropriateness of resection of NSCLC brain metastasis.

PURPOSE The Bone Metastases Ensemble Trees for Survival Decision Support Platform (BMETS-DSP) provides patient-specific survival predictions and evidence-based recommendations to guide multidisciplinary management for symptomatic bone metastases. We assessed the clinical utility of the BMETS-DSP through a pilot prepost design in a simulated clinical environment. METHODS Ten Radiation Oncology physicians reviewed 55 patient cases at two time points: without and then with the use of BMETS-DSP. Assessment included 12-month survival estimate, confidence in and likelihood of sharing estimates with patients, and recommendations for open surgery, systemic therapy, hospice referral, and radiotherapy (RT) regimen. Paired statistics compared pre- versus post-DSP outcomes. Reported statistical significance is P < .05. RESULTS Pre- versus post-DSP, overestimation of true minus estimated survival time was significantly reduced (mean difference –2.1 [standard deviation 4.1] v –1 month [standard deviation 3.5]). Prediction accuracy was significantly improved at cut points of < 3 (72 v 79%), ≤ 6 (64 v 71%), and ≥ 12 months (70 v 81%). Median ratings of confidence in and likelihood of sharing prognosis significantly increased. Significantly greater concordance was seen in matching use of 1-fraction RT with the true survival < 3 months (70 v 76%) and < 10-fraction RT with the true survival < 12 months (55 v 62%) and appropriate use of open surgery (47% v 53%), without significant changes in selection of hospice referral or systemic therapy. CONCLUSION This pilot study demonstrates that BMETS-DSP significantly improved physician survival estimation accuracy, prognostic confidence, likelihood of sharing prognosis, and use of prognosis-appropriate RT regimens in the care of symptomatic bone metastases, supporting future multi-institutional validation of the platform.

Background: Tumor Treating Fields (TTFields) therapy is a loco-regional, noninvasive treatment approved for newly diagnosed (nd)/recurrent (r) glioblastoma (GBM) and mesothelioma. Approval for ndGBM was based on the pivotal phase 3 EF-14 study where TTFields therapy/temozolomide (TMZ), administered in the adjuvant setting, significantly improved PFS and OS vs TMZ monotherapy. TTFields therapy-related adverse events (AEs) were mostly mild-to-moderate skin reactions, with no evidence of TTFields therapy-related systemic toxicity. Radiotherapy (RT) concomitant with TTFields therapy demonstrated an increased therapeutic effect in preclinical models. Supplementary evidence from two pilot phase 2 studies demonstrated that concomitant administration of TTFields therapy with standard of care RT/TMZ was feasible and well-tolerated. Here we present a phase 3 study examining the efficacy and safety of TTFields therapy concomitant with RT/TMZ in patients with ndGBM. Materials and Methods: TRIDENT (EF-32; NCT04471844) is a global, randomized, phase 3 study of patients ≥18 years of age (≥22 years in the US) with histologically confirmed ndGBM, ≥3 months life expectancy, ≥70 Karnofsky Performance Status, and adequate organ function. Patients will be stratified by the extent of resection and methylation status of the MGMT promoter. Approximately 950 patients will be assigned 1:1 to continuous TTFields therapy (200 kHz, ≥18 h/day) concomitant with RT/TMZ (experimental arm) or RT/TMZ alone (control arm). Patients will first receive 6 weeks of experimental or control therapy, TTFields therapy will then be added to the control group and all patients will receive 6 cycles of maintenance TMZ and continuous TTFields therapy. Once initiated, TTFields therapy use will continue until second disease progression (PFS2) or until 24 months (if clinically able) from the time of randomization. The primary endpoint is median OS; secondary endpoints include 1- and 2- year OS rates, PFS, 6- and 12-month PFS rates, and PFS2 (all per Response Assessment in Neuro-Oncology [RANO]), overall radiological response (per RANO), severity and frequency of AEs, quality of life (QoL; per European Organisation for Research and Treatment of Cancer QoL Questionnaires), neurological function (per Neurological Assessment in Neuro-Oncology scale), and tumor pathology post study treatments (when available). The ability of TTFields therapy to prolong OS in a dose-dependent manner is an exploratory endpoint. The primary endpoint is based on the hypothesis that TTFields therapy/RT/TMZ can significantly improve OS (vs RT/TMZ) and will be tested using a stratified log-rank test. The sample size is calculated for a hazard ratio of Citation Format: Wenyin Shi, Lawrence Kleinberg, Suriya A. Jeyapalan, Samuel A. Goldlust, Seema Nagpal, Leonardo Lustgarten, Stephanie E. Combs, David Roberge, Ryo Nishikawa, David Reardon, Rachel Grossman, Martin Glas. TRIDENT phase 3 study (EF-32): First-line Tumor Treating Fields (TTFields; 200 kHz) therapy concomitant with chemo-radiation, followed by maintenance TTFields/temozolomide in newly diagnosed glioblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT061.

Study Design Retrospective Cohort Objective Antiresorptive drugs are often given to minimize fracture risk for bone metastases, but data regarding optimal time or ability to reduce stereotactic body radiotherapy (SBRT)-induced fracture risk is limited. This study examines the association between antiresorptive use surrounding spinal SBRT and vertebral compression fracture (VCF) incidence to provide information regarding effectiveness and optimal timing of use. Methods Patients treated with SBRT for spinal metastases at a single institution between 2009-2020 were included. Kaplan-Meier analysis was used to compare cumulative incidence of VCF for those taking antiresorptive drugs pre-SBRT, post-SBRT only, and none at all. Cox proportional hazards and Fine-Gray competing risk models were used to identify additional factors associated with VCF. Results Of the 234 patients (410 vertebrae) analyzed, 49 (20.9%) were taking bisphosphonates alone, 42 (17.9%) were taking denosumab alone, and 25 (10.7%) were taking both. Kaplan-Meier analysis revealed a statistically significant lower VCF incidence for patients initiating antiresorptive drugs before SBRT compared to those taking none at all (4% vs 12% at 1 year post-SBRT, P = .045; and 4% vs 23% at 2 years, P = .008). On multivariate analysis, denosumab duration (HR: .87, P = .378) or dose (HR: 1.00, P = .644) as well as bisphosphonate duration (HR: .98, P= .739) or dose (HR: .99, P= .741) did not have statistical significance on VCF incidence. Conclusion Initiating antiresorptive agents before SBRT may reduce the risk of treatment-induced VCF. Antiresorptive drugs are underutilized in patients with spine metastases and may represent a useful intervention to minimize toxicity and improve long-term outcomes.

Brain metastases are common in patients with breast cancer, and those with triple negative status have an even higher risk. Triple negative status is currently not considered when managing brain metastases. To determine whether triple negative breast cancer (TNBC) patients with brain metastases have a higher burden of intracranial disease and whether WBRT has a survival benefit in this cohort of patients. We conducted a retrospective cohort study with 85 patients meeting the inclusion criteria. 25% of patients had TNBC. 95% of the patients in this study received SRS and 48% received WBRT. The average number of new brain metastases from time of initial brain imaging to radiation therapy was 0.67 ± 1.1 in the non-TNBC status patients and 2.6 ± 3.7 in the triple negative status patients (p = 0.001). A cox proportional hazards model showed that WBRT does not significantly affect overall survival in patients with TNBC (HR 1.48; 95% CI 0.47–4.67; p = 0.50). Our findings highlight the highly aggressive intracranial nature of TNBC. The rate of new brain metastasis formation is higher in TNBC patients compared to non-TNBC patients. Furthermore, there is no survival benefit for WBRT in TNBC patients. These findings are relevant for clinicians planning brain radiation for TNBC patients as they may find more brain metastases at the time of brain radiation than they anticipated based on initial brain imaging.

BACKGROUND Tumor Treating Fields therapy (TTFields; 200 kHz) comprise alternating electric fields that disrupt cancer cell division, and is approved for newly diagnosed glioblastoma (ndGBM), recurrent GBM and mesothelioma. In the phase 3 EF-14 trial, TTFields/temozolomide (TMZ) significantly increased overall survival (OS) and progression-free survival (PFS) vs TMZ alone in patients with ndGBM. TTFields-related adverse events (AEs) were mainly dermatological with no increases in systemic toxicity. In preclinical models, the addition of TTFields to radiotherapy (RT) increased the therapeutic effect. Additionally, TTFields added to RT/TMZ was reported as feasible and well-tolerated in 2 clinical pilot phase 2 studies. MATERIALS AND METHODS TRIDENT (EF-32; NCT04471844) is an international, phase 3 randomized trial comparing TTFields (200 KHz, ≥18 h/day)/RT/TMZ vs RT/TMZ alone. Adult patients (N=950; ≥18 years of age [≥22 years of age; US]) with histologically confirmed ndGBM, Karnofsky Performance Status ≥70, life expectancy ≥3 months, adequate organ function and eligible for RT/TMZ will be enrolled. Patients will be stratified by extent-of-resection and MGMT promoter methylation status and randomized 1:1 to receive continuous TTFields/RT/TMZ or RT/TMZ during the investigational period. Subsequently, all patients will receive TTFields/6 cycles of maintenance TTFields/TMZ; TTFields will continue for 24 months or until second disease progression per Response Assessment in Neuro-Oncology (RANO). The primary endpoint is median OS. Secondary endpoints include median PFS (RANO), 1- and 2-year survival rates, overall radiological response (RANO), PFS6, PFS12, severity and frequency of AEs and quality-of-life, OS per TTFields duration-of-usage. The study is powered at 80% to detect a hazard ratio of

OBJECTIVE There has been limited research on the efficacy of multidisciplinary tumor boards (MDTBs) in improving the treatment of patients with tumors affecting the nervous system. The objective of the present study was to quantify the utility of MDTBs in providing alternative diagnostic interpretations and treatment plans for this patient population. METHODS The authors performed a prospective study of patients in 4 hospitals whose cases were discussed at MDTBs between July and November 2019. Patient demographic data, diagnoses, treatment plans, and eligibility for clinical trials were recorded, among other variables. RESULTS A total of 176 cases met eligibility criteria for study inclusion. The majority (53%) of patients were male, and the mean patient age was 52 years. The most frequent diagnosis was glioblastoma (32.4%). Among the evaluable cases, MDTBs led to 38 (21.6%) changes in image interpretation and 103 (58.2%) changes in patient management. Additionally, patients whose cases were discussed at MDTBs had significantly shorter referral times than patients whose cases were not discussed (p = 0.024). CONCLUSIONS MDTB discussions led to significant numbers of diagnostic and treatment plan changes as well as shortened referral times, highlighting the potential clinical impact of multidisciplinary care for patients with nervous system tumors.

Objective Stereotactic body radiotherapy (SBRT) for spine metastases is associated with post-treatment vertebral compression fracture (VCF). The purpose of this study is to identify clinical and radiation planning characteristics that predict post-SBRT VCF through a novel normal tissue complication probability (NTCP) analysis. Methods Patients with de novo spine metastases treated with SBRT between 2009 and 2018 at a single institution were included. Those who had surgical stabilization or radiation to the same site prior to SBRT were excluded. VCF was defined as new development or progression of existing vertebral body height loss not attributable to tumor growth. Probit NTCP models were constructed and fitted using a maximum likelihood approach. A multivariate proportional hazard model was used to estimate time to VCF using the Fine and Gray method. Results Three hundred and two vertebral segments from 193 patients were treated with a median dose of 24 Gy in 3 fractions (range 15–30 Gy in 1–5 fractions). With a median follow up of 13.9 months, local control was 89.3% at 1 year. A total of 26 SBRT-induced VCFs were observed, with 1 and 2-year cumulative incidences of 4.6% and 6.7%. NTCP modeling demonstrated a steep response of VCF risk to the dose to 80% and 50% volume of the planning target volume (PTV D80% and D50%), but not maximum dose or dose to 1 cc or 10% of PTV. D80% of 25 Gy and D50% of 28 Gy in 3 fractions corresponded to 10% VCF risk. On multivariate analysis, lower body mass index (HR 0.90 per unit increase, p = 0.04), total spinal instability neoplastic score (SINS, HR 2.44 unstable vs stable, p = 0.04), and PTV D80% (HR 1.11 for every Gy increase, p = 0.003) were associated with increased VCF risk. Conclusions SBRT provides excellent tumor control for spinal metastases and is associated with low rate of VCF in our cohort. NTCP modeling suggests that the larger volume of spine receiving lower doses are more closely associated with post-SBRT VCF than high dose regions. Under current target delineation methods, common SBRT regimens such as 24 Gy in 2 fractions or 27 Gy in 3 fractions may be inherently associated with VCF risk of 10% or greater. Consensus contouring guidelines should be reevaluated to minimize the volume of irradiated spine in light of these new data.

Background In treating glioblastoma, irradiation of the neural progenitor cell (NPC) niches is controversial. Lower hippocampal doses may limit neurocognitive toxicity, but higher doses to the subventricular zones (SVZ) may improve survival. Objective To prospectively evaluate the impact of limiting radiation dose to the NPC niches on tumor progression, survival, and cognition in patients with glioblastoma. Methods Patients with glioblastoma received resection followed by standard chemoradiation. Radiation dose to the NPC niches, including the bilateral hippocampi and SVZ, was minimized without compromising tumor coverage. The primary outcome was tumor progression in the spared NPC niches. Follow-up magnetic resonance imaging was obtained bimonthly. Neurocognitive testing was performed before treatment and at 6- and 12-mo follow-up. Cox regression evaluated predictors of overall and progression-free survival. Linear regression evaluated predictors of neurocognitive decline. Results A total of 30 patients enrolled prospectively. The median age was 58 yr. Median mean doses to the hippocampi and SVZ were 49.1 and 41.8 gray (Gy) ipsilaterally, and 16.5 and 19.9 Gy contralaterally. Median times to death and tumor progression were 16.0 and 7.6 mo, and were not significantly different compared to a matched historical control. No patients experienced tumor progression in the spared NPC-containing regions. Overall survival was associated with neurocognitive function (P ≤ .03) but not dose to the NPC niches. Higher doses to the hippocampi and SVZ predicted greater decline in verbal memory (P ≤ .01). Conclusion In treating glioblastoma, limiting dose to the NPC niches may reduce cognitive toxicity while maintaining clinical outcomes. Further studies are needed to confirm these results.

Purpose In patients with spinal instability, cord compression, or neurologic deficits, the standard of care is surgery followed by radiation therapy (RT). Recurrence rates after conventional RT remain high. The purpose of this study is to prospectively examine the efficacy of postoperative stereotactic body RT (SBRT) in patients who have undergone surgical intervention for spine metastases. We hypothesize that postoperative SBRT to the spine would be associated with higher local control than historical rates after conventional RT. Methods and Materials Thirty-five adult patients with a Karnofsky Performance Status score ≥40 and spine metastases from solid tumors with no prior overlapping RT and target volumes ≤3 consecutive vertebral levels were enrolled. Thirty-three patients were treated. Two patients underwent treatment to 2 target volumes for a total of 35 target volumes. All patients received SBRT 30 Gy in 5 fractions. Patients were followed with neurological examinations and computed tomography and/or magnetic resonance imaging every 3 months. Neurologic function was assessed at the same time points using the American Spinal Injury Association (ASIA) impairment score. Pain was rated according to the 10-point visual analogue scale and MD Anderson Cancer Center brief pain index. Toxicity was recorded according to National Cancer Institute Common Toxicity Criteria for Adverse Events Version 4. The primary objective was the rate of radiographic local recurrence at 12 months after completion of SBRT. Results Patient characteristics were as follows: 34.3% had radioresistant primaries; 71.4% were ASIA E and the remainder ASIA D; and the median baseline Karnofsky Performance Status score was 70 (range, 50-100). Radiographic and symptomatic local control at 1 year were 90% (95% confidence interval, 76%-98%). The median time to recurrence in these 3 patients was 3.5 months (range, 3.4-5.8 months), all had radiosensitive tumors, and all recurrences were epidural. No patients experienced wound dehiscence, hardware failure, or spinal cord myelopathy. The median time to return to systemic therapy was 0.5 months (range, 0-9.4 months). Conclusions This prospective study of postoperative spine SBRT demonstrates excellent local control with low toxicity. These data suggest superior rates of local control compared with conventional RT; however, a formal comparative study 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.

PurposeGlioblastoma (GBM) is highly aggressive with poor prognosis. Belinostat is a histone deacetylase inhibitor with blood–brain barrier permeability, anti-GBM activity, and potential to enhance chemoradiation. The purpose of this clinical trial was to assess the clinical efficacy of combining belinostat with standard-of-care therapy for GBMs. Methods13 patients were enrolled in each of the control and belinostat cohorts. The belinostat cohort was given a belinostat regimen (500-750 mg/m2 1x/day x 5 days) every 3 weeks (weeks 0, 3, and 6 of RT). All patients received temozolomide and radiation therapy (RT). RT margins of 5-10 mm were added to generate clinical tumor volumes and 3 mm added to create planning target volumes. Patient outcomes included progression-free survival, overall survival (OS), and recurrence pattern analysis of enhancing tumor (rGTV). ResultsMedian OS was 15.8 months for the control cohort and 18.5 months for the belinostat cohort (p=0.53). The rGTVs in the control cohort occurred in areas that received higher radiation doses than that in the belinostat cohort. For those belinostat patients who experienced out-of-the field recurrence, tumors were detectable by spectroscopic MRI before RT. ConclusionThe median OS was slightly longer for the belinostat cohort than the control cohort but not statistically significant. Recurrence analysis suggests better in-field control with belinostat, suggesting a radio-sensitizing effect. This study highlights the potential of belinostat as a synergistic therapeutic agent for GBM treatment. It may be particularly beneficial to combine this radio-sensitizing effect with spectroscopic MRI-guided radiation therapy.

PURPOSE/OBJECTIVE(S) To distinguish radionecrosis (RN) from true progression (TP) in brain metastases treated with stereotactic radiosurgery (SRS), we apply machine learning to create a multi-domain model that incorporates clinical factors, multiparametric radiomics(mpRads), and tumor connectomics, a novel MRI-based complex graph theory framework that describes the intricate network of relationships within the tumor and surrounding tissue. MATERIALS/METHODS Metastases treated with SRS that had pathologic confirmation of RN vs. TP after imaging progression were included from a single institution. Regions of interest were manually segmented using the single largest diameter of the T1 post-contrast(T1C) lesion plus the corresponding area of T2 FLAIR hyperintensity. We developed an Integrated Radiomics Informatics System (IRIS) based on an isomap support vector machine (IsoSVM) model to classify TP from RN using leave-one-out cross-validation (LOOCV). Class imbalance was resolved using differential misclassification weighting during model training using IRIS. Area under the receiver operating characteristic (AUC-ROC) and AUC-PR (precision recall) analysis were performed. RESULTS We analyzed 135 lesions in 110 patients. There were 43 cases (31.9%) of RN and 92 cases (68.1%) of TP. The top-performing connectomics features were degree centrality (increased with RN) and average path length (decreased with RN), suggesting greater “connectivity” and increased similarity in intralesional features between the T1C and FLAIR signal regions in RN cases. The top-performing radiomics feature was multidimensional entropy (increased in TP), demonstrating greater heterogeneity in TP cases. Finally, the top-performing clinical features were prior RT before SRS, histology, and treated lesion size. The LOOCV IsoSVM model successfully classified TP from RN with an AUC-ROC of 0.84 (95% CI: 0.77-0.90) and AUC-PR of 0.90 (95% CI: 0.82-0.95). The F1 score was 0.89. CONCLUSION Our novel machine-learning framework was able to efficiently combine features from multiple domains (i.e., radiomics, connectomics, and clinical factors) to distinguish pathologically-proven TP from RN with excellent discrimination.

Purpose: Tumor treating fields (TTFields) is a novel antimitotic treatment that was first proven effective for glioblastoma multiforme, now with trials for several extracranial indications underway. Several studies focused on concurrent TTFields therapy with radiation in the same time period, but were not given simultaneously. This study evaluates the targeting accuracy of simultaneous radiation therapy while TTFields arrays are in place and powered on, ensuring that radiation does not interfere with TTFields and TTFields does not interfere with radiation. This is one of several options to enable TTFields to begin several weeks sooner, and opens potential for synergistic effects of combined therapy. Methods: TTFields arrays were attached to a warm saline water bath and salt was added until the TTFields generator reached the maximal 2000 mA peak-to-peak current. A ball cube phantom containing 2 orthogonal films surrounded by fiducials was placed in the water phantom, CT scanned, and a radiation treatment plan with 58 isocentric beams was created using a 3 cm circular collimator. Fiducial tracking was used to deliver radiation, the films were scanned, and end-to-end targeting error was measured with vendor-supplied software. In addition, radiation effects on electric fields generated by the TTFields system were assessed by examining logfiles generated from the field generator. Results: With TTFields arrays in place and powered on, the robotic radiosurgery system achieved a final targeting result of 0.47 mm, which was well within the submillimeter specification. No discernible effects on TTFields current output beyond 0.3% were observed in the logfiles when the radiation beam pulsed on and off. Conclusion: A robotic radiosurgery system was used to verify that radiation targeting was not adversely affected when the TTFields arrays were in place and the TTFields delivery device was powered on. In addition, this study verified that radiation delivered simultaneously with TTFields did not interfere with the generation of the electric fields.

Background Glomus jugulare tumors are rare slow-growing hypervascular tumors that arise from the paraganglia of the chemoreceptor system within the jugulare foramen of the temporal lobe. The historical standard treatment has been surgical resection, but because of their high vascularity and involvement with cranial nerves (CNs), Gamma Knife radiosurgery (GKRS) has been advocated as an alternative. The goal of this study is to update and report long-term results of GKRS to achieve local control and symptomatic improvement and to reduce morbidity and mortality when treating glomus jugulare tumors. Materials and Methods This study retrospectively collected and reviewed clinical and radiographic data of 32 patients with glomus jugulare tumors treated with GKRS at the Miami Neuroscience Center, South Miami, FL, from 1995 to 2019. For the 32 patients, the mean volume treated was 13.9 cc (0.23 to 40.0 cc), with an average of 8.6 isocenters. The median prescription dose was 12.84 Gy ± 2.07 Gy (range: 10-20 Gy). Follow-up data were available for 29 out of 32 patients, with a median clinical follow-up time of 37.3 months (range: 4.3-169.1 months). At follow-up, patients were evaluated for neurological signs and symptoms and radiographic evidence of progression of disease. Results The median age of the cohort treated with GKRS was 60 years (range: 14-83 years). There were three males and 27 females. Presenting symptomatology was available for 30 out of 32 patients. The most common presenting symptom was hearing loss (21/30) and the most common CN deficit was in CN VIII (19/30). Out of 29 of the patients followed up, 28 patients had improvement (20/29) or resolution (8/29) of symptoms. At the most recent evaluation or contact, patients were without symptomatic progression of CN deficits. Radiographic tumor control was achieved in 28 out of 29 patients. One patient had a recurrence seven years after GKRS, which was treated with surgery. There were no complications, radionecrosis, or mortality reported from GKRS. Conclusion These data confirm that GKRS is a reasonable upfront treatment option for glomus jugulare tumors. GKRS should be considered more frequently given its excellent long-term local control with low morbidity and risk of complications.

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.

Esophageal cancer is the sixth leading cause of cancer-related deaths worldwide. Squamous cell carcinoma is the most common histology in Eastern Europe and Asia, and adenocarcinoma is most common in North America and Western Europe. Surgery is a major component of treatment of locally advanced resectable esophageal and esophagogastric junction (EGJ) cancer, and randomized trials have shown that the addition of preoperative chemoradiation or perioperative chemotherapy to surgery significantly improves survival. Targeted therapies including trastuzumab, ramucirumab, and pembrolizumab have produced encouraging results in the treatment of patients with advanced or metastatic disease. Multidisciplinary team management is essential for all patients with esophageal and EGJ cancers. This selection from the NCCN Guidelines for Esophageal and Esophagogastric Junction Cancers focuses on recommendations for the management of locally advanced and metastatic adenocarcinoma of the esophagus and EGJ.

Background Gliomas with 1p/19q-codeletion as well as mutation of isocitrate dehydrogenase (IDH) 1 are typically characterized as oligodendrogliomas with comparatively good response to treatment with radiation and chemotherapy. Case presentation We present the case of a 28-year-old man with an IDH1 and TP53 mutant high grade glioma with abnormalities in chromosomes 1 and 19 suggestive of anaplastic oligodendroglioma that rapidly progressed to widespread metastatic disease. Biopsy of a liver lesion confirmed metastasis of the patient’s known brain primary and chemotherapy with temozolomide was initiated. The patient’s rapidly growing tumor burden with fulminant liver failure and tumor lysis led to multisystem failure of which the patient died. Further molecular testing illustrated features more consistent with glioblastoma: multiple large chromosomal aberrations including loss of whole chromosome 1 and 2q; gain/amplification of MYCN, MET, and CDK4; loss of CDKN2A/B; and an ATRX mutation. Conclusion This case illustrates the importance of higher level molecular diagnostic testing for patients with particularly aggressive disease progression that is not concordant with standard prognoses. Additional data on cases with atypical alterations of 1p and 19q are needed to better understand the distinct biology of these cancers so that appropriate therapies can be developed. Electronic supplementary material The online version of this article (10.1186/s13000-019-0793-5) contains supplementary material, which is available to authorized users.

Spinal cord dose constraints are a critical feature for stereotactic body radiation therapy (SBRT). Spinal cord maximum point dose (Dmax) by Monte Carlo (MC) calculations is used as a critical cord tolerance limit for SBRT, but information is lacking about its reproducibility. This study examines uncertainty of MC dose calculations for small volumes in spine SBRT. Seven consecutive spine radiosurgery cases were randomly selected to measure precision of the Dmax calculation in comparison to other volumes. Each plan was calculated five times using MC with a 2% uncertainty objective, and variabilities in dose-volume histogram (DVH) parameters across recalculations were evaluated with coefficient of variation (standard deviation divided by mean). The average ratio of D0.03 cc/Dmax was calculated across a larger series of 130 cases. The variability of Dmax was twice as high for D0.03 cc and five times as high for D1 cc across recalculations for the seven cases. For larger volumes, the variability was lower. The standard deviation of Dmax was 0.1959 Gy, compared to 0.0931 Gy, 0.0569 Gy, and 0.0364 Gy for D0.03 cc, D0.1 cc, and D1 cc, respectively. The average D0.03 cc/Dmax among 130 cases was 0.93. Dmax has greater variability compared to D0.03 cc, D0.1 cc, and D1 cc, potentially creating risks when used for guidance for spinal cord. D0.03 cc may be an attractive alternative with higher reliability while its limits could be obtained by scaling the reported Dmax limit by a factor of 0.93. This may help guide treatment planning and aid in discovering true dose constraints for spine SBRT.

INTRODUCTION Tumor Treating Fields (TTFields; 200 kHz; non-invasive, loco-regional antimitotic treatment) is approved for newly-diagnosed glioblastoma (ndGBM). In the Phase 3 EF-14 trial, post-surgical radiotherapy/temozolomide, followed by maintenance TTFields/temozolomide significantly increased overall survival (OS) and progression-free survival (PFS) in patients with ndGBM versus TMZ alone. Addition of maintenance TTFields did not increase systemic toxicity; and related adverse events (AEs) were mainly dermatological. In preclinical models, addition of TTFields increased the benefit of radiotherapy. Two pilot studies showed that TTFields concomitant with radiotherapy/temozolomide is feasible and well-tolerated. The benefit of TTFields concomitant with radiotherapy/temozolomide will be investigated in the TRIDENT trial. METHODS TRIDENT (EF-32; NCT04471844) is an international, pivotal, phase 3 randomized trial comparing triple-combination of TTFields/radiotherapy/temozolomide versus standard radiotherapy/temozolomide. Patients in both arms will receive maintenance TTFields/TMZ. Arrays of the Optune® System will be used to deliver TTFields (200 KHz) for ≥18 hours/day concomitant with radiotherapy. TTFields treatment will be continued until second disease progression (RANO) or 24 months, whichever occurs first. Patients with pathologically-confirmed ndGBM, ≥ 18 years of age (≥ 22 years of age; US), KPS ≥ 70, post-surgery/biopsy, and amenable for radiotherapy/temozolomide will be stratified by extent-of-resection and MGMT promoter methylation status. The primary endpoint is median OS. Secondary endpoints include median PFS (RANO), 1-year and 2-year survival rates, overall radiological response (ORR; RANO), PFS (PFS-6M, PFS-12M, PFS-2Y), severity and frequency of AEs (CTCAE V5.0), pathological post-treatment changes in resected GBM tumors, quality-of-life (EORTC QLQ-C30), and OS correlation to TTFields duration-of-usage. The hypothesis is that first-line TTFields/RT/TMZ triple-combination will significantly improve OS compared to radiotherapy/temozolomide; each followed by maintenance TTFields/temozolomide. Sample size (N=950; 475/arm) was powered for a HR < 0.8 with 5% type I error. Survival will be measured from time-of-randomization. The TRIDENT trial is currently enrolling patients. RESULTS/CONCLUSIONS N/A TiP.

Purpose/Objective(s) Radiotherapy, especially high-dose radiation in the form of stereotactic body radiotherapy (SBRT), may stimulate the therapeutic effect of immune checkpoint inhibitors (ICIs). Both SBRT and ICIs play an increasingly important role in the management of spine metastasis. We hypothesize that SBRT and ICI may act synergistically to improve the outcomes of patients with spine metastasis. Materials/Methods We retrospectively reviewed patients with spine metastasis treated with SBRT at an academic center between 2009 and 2019. Patients who received ICI at any point during their disease course were compared to those with the same primary tumor types who did not receive ICI. Cox proportional hazard analyses were performed for overall survival (OS) and local control (LC), adjusting for primary tumor type, age, performance status, and prior spine surgery and/or radiation. Results 153 patients with 194 unique spine lesions were treated with SBRT. The most common primary tumor types were renal cell carcinoma (RCC), non-small cell lung cancer (N = 48, 31% each), colorectal cancer (N = 21, 14%), melanoma and liver cancer (N = 10, 6% each). 82 patients received at least one course of ICI. The most common type of ICI was single-agent anti-PD-1 (N = 71, 88%), followed by dual anti-CTLA-4/PD-1 inhibitors (N = 14, 17%). Of patients receiving ICI, 44 (53.6%) initiated ICI before SBRT, and 38 (46.4%) received ICI after SBRT. The median survival (MS) after SBRT was 14.8 months (95% confidence interval [CI] 11.4-19.6). On univariable analysis, MS was significantly longer for patients starting ICI after SBRT (27.3 months, 95% CI 16.0-33.9) than for those who did not receive any ICI (MS 11.3 months, 95% CI 8.9-15.8, P = 0.04). Patients with RCC (HR 0.67, 95% CI 0.45-1.00, P = 0.05) and higher body mass index (BMI, HR 0.97 as continuous variable, 95% CI 0.93-1.00, P = 0.05) trended toward longer OS. On multivariable analysis after adjusting for primary tumor type, performance status and BMI, only ICI treatment after SBRT was significantly associated with increased survival (HR 0.62, 95% CI 0.39-0.98, P = 0.04). LC after SBRT was numerically higher in patients receiving ICI (1-year LC 91.3%, 95% CI 82.4-95.8%; 2-year 79.7%, 95% CI 65.7-88.5%), than those who did not (1-year 81.5%, 95% CI 65.9-90.5%; 2-year LC 55.5%, 95% CI 35.6-71.4%), although this was not statistically significant (P = 0.18). ICI Initiation before SBRT trended toward superior LC compared to no ICI (multivariable HR 0.49, 95% CI 0.22-1.08, P = 0.08). Both epidural disease and paraspinal extension were associated with worse LC on univariable and multivariable analyses. Conclusion ICIs may enhance survival and tumor control after SBRT for patients with spine metastasis. Post-SBRT ICI may improve systemic disease control and survival, while pre-SBRT ICI may augment LC. Further research is needed to maximize the synergy between these two treatment modalities. Author Disclosure X. Chen: None. M.C. LeCompte: None. L.R. Kleinberg: Research Grant; Novartis, Novocure, Accuray, Arbor. Honoraria; Accuray. Advisory Board; Novocure. Travel Expenses; Accuray. R.K. Hales: Research Grant; Genentech. K. Voong: Research Grant; Radiation Oncology Institute, Lung Cancer Research Foundation, Canon, Inc. P. Forde: Research Grant; Bristol Myers-Squibb, AstraZeneca, Kyowa-Kirin, Novartis. Honoraria; Bristol Myers-Squibb, AstraZeneca, Novartis, Merck, AbbVie, EMD, Inivata. J.R. Brahmer: Research Grant; AstraZeneca, Bristol Myers Squibb, Genentech/Roche, Merck, RAPT Therapeutics, Revolution Medicines. Consultant; Amgen, Bristol Myers Squibb, Genentech, Eli Lilly, GlaxoSmithKline, Merck, Sanofi. M. Markowski: Honoraria; Clovis Oncology, Exelixis. D.M. Ryan II: None. L. Lo: None. D.M. Sciubba: Consultant; Medtronic, DePuy-Synthes, Baxter. K.J. Redmond: Research Grant; Elekta AB, Accuray. Honoraria; AstraZeneca, Accuray. Travel Expenses; Elekta AB, Accuray.

Stereotactic radiosurgery (SRS), stereotactic body radiotherapy (SBRT), and stereotactic ablative body radiotherapy (SABR) are commonly used in the treatment of central nervous system (CNS) disease. This study has refined the radiation toxicity estimates for some normal tissues of the CNS based on review and analysis of the clinical evidence for single fraction radiosurgery, hypofractionated SBRT, and conventionally fractionated radiation therapy. Published guidelines and protocols are reviewed. In the past, many normal tissue tolerances were compiled based on the experience of the investigators and publications in the literature. Some tolerances were determined by modeling or calculation using the existing biological formulas, in particular the linear quadratic (LQ) model. In the present study, the estimate of risk for each dose tolerance limit in some CNS tissues is provided exclusively with normal tissue complication probability (NTCP). The clinical outcomes are compared to understand the difference in biological effect between radiosurgery and radiotherapy. Normal tissue dose tolerances and the corresponding complication rates are provided for brainstem, optic nerves, cochlea, and spinal cord, including single fraction SRS, five-fraction SBRT, and conventional radiation therapy. Calculation of biologically effective dose (BED) or single fraction equivalent dose (SFED) alone using the LQ model conveys no consensus on the biological effect across different fractionations. Comparison of conventional radiation therapy to brain and spinal cord with single fraction equivalent dose leads to even conflicting clinical outcomes. Effective differences between single fraction SRS and conventional radiotherapy need to be better understood. The existing biological model might not be valid to predict the radiosurgical outcomes based on conventionally fractionated radiotherapy. However, application of the statistical dose response models of clinical SRS and SBRT outcomes data to selected current dose tolerance guidelines into simple tables can be a clinically useful resource.

Purpose In the treatment of resected metastatic brain disease, a recent phase 3 trial by the North Central Cancer Treatment Group (N107C/CEC.3) surprisingly found that the local control rate for whole-brain radiation therapy was better than that of stereotactic radiation surgery (SRS). To optimize target delineation, we performed a quantitative analysis of local failure patterns after postoperative SRS. Methods and materials Patients with brain metastases who were treated with surgery and SRS to the cavity were evaluated. Local failure was defined by pathologic confirmation or magnetic resonance imaging evidence of progression leading to further overlapping radiation therapy. T1 postgadolinium magnetic resonance imaging scans that were taken preoperatively and at recurrence were co-registered to the simulation computed tomography. Three volumes were compared: (1) Preoperative tumors, (2) resection cavities that were originally contoured as clinical target volumes for SRS, and (3) recurrent tumors. Overlap volume histograms quantified the proximity of the three volumes to the meninges. Results In the cohort of 173 patients, 18 patients experienced local failure in 19 resection cavities. The original SRS target volume overlapped with a median of 69.6% of the recurrent tumor. When the entire preoperative tumor was included, the overlap with the recurrent tumor increased to a median of 76.8%. Recurrent tumors were closer to the meninges than corresponding preoperative tumors (P = .03) but a median 8.2 mm expansion of the target volume from the meninges was needed to increase overlap with the recurrent tumor to 90%. Increases in overlap with the recurrent tumor were achieved most efficiently by uniformly expanding the contoured cavity and a median 2.8 mm expansion covered 90% of the recurrent tumor. Conclusions Our quantitative analysis of recurrence patterns suggests that a larger 3 mm uniform expansion of the SRS target volume substantially increases coverage of the volume that is later occupied by the recurrent tumor and may provide improved local control. The extent of the preoperative tumor in the target volume or expanding the target volume from the meninges provides little benefit.

PURPOSE The Bone Metastases Ensemble Trees for Survival (BMETS) model uses a machine learning algorithm to estimate survival time following consultation for palliative radiation therapy for symptomatic bone metastases (SBM). BMETS was developed at a tertiary-care, academic medical center, but its validity and stability when applied to external data sets are unknown. PATIENTS AND METHODS Patients treated with palliative radiation therapy for SBM from May 2013 to May 2016 at two hospital-based community radiation oncology clinics were included, and medical records were retrospectively reviewed to collect model covariates and survival time. The Kaplan-Meier method was used to estimate overall survival from consultation to death or last follow-up. Model discrimination was estimated using time-dependent area under the curve (tAUC), which was calculated using survival predictions from BMETS based on the initial training data set. RESULTS A total of 216 sites of SBM were treated in 182 patients. Most common histologies were breast (27%), lung (23%), and prostate (23%). Compared with the BMETS training set, the external validation population was older (mean age, 67 v 62 years; P < .001), had more primary breast (27% v 19%; P = .03) and prostate cancer (20% v 12%; P = .01), and survived longer (median, 10.7 v 6.4 months). When the BMETS model was applied to the external data set, tAUC values at 3, 6, and 12 months were 0.82, 0.77, and 0.77, respectively. When refit with data from the combined training and external validation sets, tAUC remained > 0.79. CONCLUSION BMETS maintained high discriminative ability when applied to an external validation set and when refit with new data, supporting its generalizability, stability, and the feasibility of dynamic modeling.

ObjectiveTo determine the long-term normal tissue complication probability with stereotactic body radiation therapy (SBRT) treatments for targets that move with respiration and its relation with the type of respiratory motion management (tracking vs. compression or gating).MethodsA PubMed search was performed for identifying literature regarding dose, volume, fractionation, and toxicity (grade 3 or higher) for SBRT treatments for tumors which move with respiration. From the identified papers logistic or probit dose-response models were fitted to the data using the maximum-likelihood technique and confidence intervals were based on the profile-likelihood method in the dose-volume histogram (DVH) Evaluator.ResultsPooled logistic and probit models for grade 3 or higher toxicity for aorta, chest wall, duodenum, and small bowel suggest a significant difference when live motion tracking was used for targeting tumors with move with respiration which was on the average 10 times lower, in the high dose range.ConclusionLive respiratory motion management appears to have a better toxicity outcome when treating targets which move with respiration with very steep peripheral dose gradients. This analysis is however limited by sparsity of rigorous data due to poor reporting in the literature.

PURPOSE Glioblastomas (GBMs) are highly aggressive brain tumors with poor prognosis. Belinostat is a histone deacetylase inhibitor with blood–brain barrier permeability, anti-GBM activity, and potential to enhance chemoradiation. This clinical trial sought to determine a tolerable dose of concurrent belinostat and assess the clinical efficacy of combining this drug with standard-of-care therapy. METHODS 13 patients each were enrolled in control and belinostat cohorts. The belinostat cohort was given a belinostat regimen (500-750mg/m2 1x/day x 5 days) every 3 weeks (weeks 0, 3, and 6 of RT). All patients received standard temozolomide and radiation therapy (RT). Patient outcomes included progression-free survival, overall survival (OS), and analysis of recurrence pattern of the recurrent gross tumor volume (rGTV). RESULTS Belinostat at 750 mg/m2 produce dose-limiting toxicities (DLTs) in 2 of 3 patients while belinostat at 500 mg/m2 did not result in DLTs. Median OS was 18.5 months for the belinostat cohort and 15.8 months for the control cohort (p=0.53). The rGTVs in the control cohort occurred in areas that received higher radiation doses than that in the belinostat cohort. For those belinostat patients that experienced out-of-field recurrences, tumors were detectable by spectroscopic MRI (sMRI) before RT. In particular, one belinostat patient had an IDH-mutant GBM that had an extraordinary response to therapy with significant shrinkage of enhancing tumor much greater than expected. CONCLUSION Belinostat given concurrently at 500 mg/m2 is well-tolerated. While median OS was not significantly increased for the belinostat cohort, recurrence analysis suggests better in-field control with belinostat, suggesting a radio-sensitizing effect. This study suggests that belinostat can act as a synergistic therapeutic agent for GBMs that may be further enhanced by sMRI-guided RT and may be particularly effective against IDH mutant tumors. A trial is currently in development using belinostat with sMRI-guided RT for IDH-mutant high-grade gliomas.

Objectives To describe toxicity and tumor outcome after resection and aggressive re-irradiation (stereotactic radiosurgery(SRS) or brachytherapy) of brain metastasis that have pathologically confirmed recurrence after prior radiosurgery. Methods A retrospective chart review identified 40 lesions in 35 patients that were initially treated with SRS, then demonstrated evidence of recurrence with pathologic confirmation and underwent re-irradiation either with radiosurgery (n=28, 70%) or intracavitary brachytherapy with Cesium-131 seeds (n=12, 30%). Toxicity was measured by: steroids initiated or increased within 3 months, imaging evidence of treatment effect vs disease progression at any time point, further intervention for local recurrence or necrosis, and any grade 3/4 neurologic events. Local control (with failure defined by sustained progression on imaging or pathologic confirmation of tumor) was measured from time of retreatment. Results Median follow-up from time of re-irradiation was 11.8 months (range 1 – 89.7 months). Dose for repeat radiosurgery was 18–25 Gy in 1–5 fractions, and brachytherapy dose was 55–65 Gy at 5 mm depth. Twelve lesions subsequently had imaging evidence of radionecrosis vs. progression. Of these, eight underwent repeat resection with pathology demonstrating radiation necrosis in five patients (n=4 with SRS, n=1 with brachy) and tumor recurrence in 3 (n=2 with brachy, and n=1 with SRS). Toxicities included: Steroids, 14(35%); imaging progression/necrosis 12(30%); grade 3/4 event, 3(20%); and surgically confirmed radionecrosis 5(12.5%). Local control of retreated lesions at 6 months is 85.5%, and at 12 months is 79.3%, OS at 1 year is 52.5% and at 2 years 46.6%. Local control at one year for repeat stereotactic treatment was 82.9% and for Cs131 brachytherapy was 80.8% Conclusions Aggressive re-irradiation after resection for pathologic confirmation appears to be appropriately safe and effective for the majority of patients after local failure of initial radiosurgery.

Background Stereotactic radiosurgery (SRS) may cause radiation necrosis (RN) that is difficult to distinguish from tumor progression (TP) by conventional MRI. We hypothesize that MRI-based multiparametric radiomics (mpRad) and machine learning (ML) can differentiate TP from RN in a multi-institutional cohort. Methods Patients with growing brain metastases after SRS at 2 institutions underwent surgery, and RN or TP were confirmed by histopathology. A radiomic tissue signature (RTS) was selected from mpRad, as well as single T1 post-contrast (T1c) and T2 fluid-attenuated inversion recovery (T2-FLAIR) radiomic features. Feature selection and supervised ML were performed in a randomly selected training cohort (N = 95) and validated in the remaining cases (N = 40) using surgical pathology as the gold standard. Results One hundred and thirty-five discrete lesions (37 RN, 98 TP) from 109 patients were included. Radiographic diagnoses by an experienced neuroradiologist were concordant with histopathology in 67% of cases (sensitivity 69%, specificity 59% for TP). Radiomic analysis indicated institutional origin as a significant confounding factor for diagnosis. A random forest model incorporating 1 mpRad, 4 T1c, and 4 T2-FLAIR features had an AUC of 0.77 (95% confidence interval [CI]: 0.66–0.88), sensitivity of 67% and specificity of 86% in the training cohort, and AUC of 0.71 (95% CI: 0.51–0.91), sensitivity of 52% and specificity of 90% in the validation cohort. Conclusions MRI-based mpRad and ML can distinguish TP from RN with high specificity, which may facilitate the triage of patients with growing brain metastases after SRS for repeat radiation versus surgical intervention.

OBJECTIVE Spinal chordoma is locally aggressive and has a high rate of recurrence, even after en bloc resection. Conventionally fractionated adjuvant radiation leads to suboptimal tumor control, and data regarding hypofractionated regimens are limited. The authors hypothesized that neoadjuvant stereotactic body radiotherapy (SBRT) may overcome its intrinsic radioresistance, improve surgical margins, and allow preservation of critical structures during surgery. The purpose of this study is to review the feasibility and early outcomes of high-dose hypofractionated SBRT, with a focus on neoadjuvant SBRT. METHODS Electronic medical records of patients with spinal chordoma treated using image-guided SBRT between 2009 and 2019 at a single institution were retrospectively reviewed. RESULTS Twenty-eight patients with 30 discrete lesions (24 in the mobile spine) were included. The median follow-up duration was 20.8 months (range 2.3–126.3 months). The median SBRT dose was 40 Gy (range 15–50 Gy) in 5 fractions (range 1–5 fractions). Seventeen patients (74% of those with newly diagnosed lesions) received neoadjuvant SBRT, of whom 15 (88%) underwent planned en bloc resection, all with negative margins. Two patients (12%) developed surgical wound-related complications after neoadjuvant SBRT and surgery, and 4 (two grade 3 and two grade 2) experienced postoperative complications unrelated to the surgical site. Of the remaining patients with newly diagnosed lesions, 5 received adjuvant SBRT for positive or close surgical margins, and 1 received SBRT alone. Seven recurrent lesions were treated with SBRT alone, including 2 after failure of prior conventional radiation. The 2-year overall survival rate was 92% (95% confidence interval [CI] 71%–98%). Patients with newly diagnosed chordoma had longer median survival (not reached) than those with recurrent lesions (27.7 months, p = 0.006). The 2-year local control rate was 96% (95% CI 74%–99%). Among patients with radiotherapy-naïve lesions, no local recurrence was observed with a biologically effective dose ≥ 140 Gy, maximum dose of the planning target volume (PTV) ≥ 47 Gy, mean dose of the PTV ≥ 39 Gy, or minimum dose to 80% of the PTV ≥ 36 Gy (5-fraction equivalent doses). All acute toxicities from SBRT were grade 1–2, and no myelopathy was observed. CONCLUSIONS Neoadjuvant high-dose, hypofractionated SBRT for spinal chordoma is safe and does not increase surgical morbidities. Early outcomes at 2 years are promising, although long-term follow-up is pending.

INTRODUCTION Glioblastoma (GBM) is highly aggressive with poor prognosis. Belinostat is a histone deacetylase inhibitor with blood–brain barrier permeability that has anti-GBM activity and may enhance effects of chemoradiation. Our institution conducted a clinical trial evaluating clinical efficacy of belinostat with standard-of-care therapy for GBMs. METHODS 13 and 14 patients were enrolled into cohort 1 (c1, control) or cohort 2 (c2, belinostat) with 12 in each group with sufficient follow-up MRIs for recurrence analysis. All patients received concurrent, adjuvant temozolomide and focal radiation therapy (RT). For c2 patients, the belinostat regimen (500-750mg/m2 1x/day x 5 days) was given over three cycles every 3 weeks (weeks -1, 2, and 5 of RT). RT margins of 5–10 mm and 3 mm were added to generate clinical tumor volumes and planning target volumes (PTVs). PTV1 (based on FLAIR MRI) and PTV2 (based on CE-T1w MRI) received 51 and 60 Gy, respectively, over 30 fractions. Volume at initial recurrence (rGTV) was contoured. RESULTS Mean age was 58.3 years for c1 and 51.1 years for c2. Patient/tumor characteristics were similar between cohorts. Median OS were 16.6 and 18.5 months for c1 and c2 (p=0.538), respectively. Average minimum, maximum and mean radiation dose to rGTV was 54.1 Gy, 64.2 Gy and 62 Gy, for c1, and 47.5 Gy, 57.6 Gy and 53.5 Gy, for c2 (p=0.322, 0.088 and 0.071), respectively. The mean overlap between rGTV and PTV1/PTV2 for c1 & c2 were 99.2% & 96.9%/99.8% & 78.7% (p=0.489/0.133), respectively. CONCLUSION Median OS was slightly longer for c2 though not statistically significant. rGTV in c1 received higher radiation doses and had more overlap with PTV2 than in c2. Out-of-field recurrence appears more likely in c2 suggesting better infield control with belinostat. This study highlights the potential of belinostat as a synergistic therapeutic agent for GBM treatment.

BACKGROUND There is limited research attempting to measure the efficacy of tumor boards (MDTBs) in the treatment of patients with tumors affecting the nervous system. OBJECTIVE The objective of the present study was to quantify the utility of a MDTB in providing alternative diagnostic interpretations and treatment plans for this patient population. METHODS A prospective study of patient cases discussed at four hospitals’ MDTBs between July and November 2019 was performed. Demographic data, diagnoses, treatment plans, and eligibility for clinical trials were recorded, among other variables. RESULTS A total of 176 patient cases met eligibility criteria. The majority of patients (53%) were male with a mean age of 52 years. The most frequent diagnosis was glioblastoma (32.4%). Among the evaluable cases, MDTBs led to 38 (21.6%) changes in image interpretation and 103 (58.2%) changes in patient management. Additionally, patients whose cases were discussed at MDTBs had significantly shorter referral times compared to patients whose cases were not discussed (p= 0.024). CONCLUSION MDTB discussions led to a significant number of diagnostic and treatment plan changes as well as shortened referral times, highlighting the potential clinical impact of multidisciplinary care for patients with nervous system tumors.

PURPOSE To test the effectiveness of machine learning algorithms in distinguishing radiation necrosis (RN) from tumor progression (TP) using MRI radiomic features. METHODS Brain metastases were treated with SRS to a median dose of 18Gy. Lesions that showed evidence of progression on follow-up MRI were sampled surgically, and diagnoses confirmed by histopathology. Cases from 2 institutions were combined and randomly assigned for training (70%) and testing (30%). T1 post-contrast (T1c) and T2 fluid attenuated inversion recovery (T2 FLAIR) MRI were used for radiomic feature extraction (50 features each). Three subsets of radiomic features were obtained and tested: Signature #1 included 10 previously published features that correlated with diagnosis on T test; signature #2 and #3 included 5 and 12 features obtained through recursive elimination using random forest (RF) and support vector machine (SVM), respectively. Supervised machine learning models were trained using RF, SVM (radial kernel) and regularized discriminant analysis (RDA) algorithms based on all three radiomics signatures. Receiver operator characteristics (ROC) were compared between signatures and algorithms. RESULTS A total of 135 individual lesions (37 RN and 98 TP) were included. Signature #3 demonstrated the highest area under the curve in the training set (average AUC=0.98, vs 0.95 and 0.92 for signature #1 and #2), as well as the testing set (average AUC=0.83, vs 0.74 and 0.79 for signature #1 and #2). RF and SVM demonstrated similar performance in both training (average AUC 0.99-1) and testing datasets (average AUC 0.79-0.80) among all three signatures. Both RF and SVM were superior to RDA in performance (average training AUC 0.83, testing AUC 0.77). The greatest sensitivity (83%) and specificity (100%) in the testing set were achieved using signature #3 and SVM. CONCLUSION RF and SVM are effective in distinguishing RN from TP in a multi-institution dataset using radiomic signatures.