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Background: Quantitative image analysis using pre-operative magnetic resonance imaging (MRI) has been able to predict survival in patients with glioblastoma (GBM). The study explored the role of postoperative radiation (RT) planning MRI-based radiomics to predict the outcomes, with features extracted from the gross tumor volume (GTV) and clinical target volume (CTV)., Methods: Patients with IDH-wildtype GBM treated with adjuvant RT having MRI as a part of RT planning process were included in the study. 546 features were extracted from each GTV and CTV. A LASSO Cox model was applied, and internal validation was performed using leave-one-out cross-validation with overall survival as endpoint. Cross-validated time-dependent area under curve (AUC) was constructed to test the efficacy of the radiomics model, and clinical features were used to generate a combined model. Analysis was done for the entire group and in individual surgical groups-gross total excision (GTR), subtotal resection (STR), and biopsy., Results: 235 patients were included in the study with 57, 118, and 60 in the GTR, STR, and biopsy subgroup, respectively. Using the radiomics model, binary risk groups were feasible in the entire cohort (p < 0.01) and biopsy group (p = 0.04), but not in the other two surgical groups individually. The integrated AUC (iAUC) was 0.613 for radiomics-based classification in the biopsy subgroup, which improved to 0.632 with the inclusion of clinical features., Conclusion: Imaging features extracted from the GTV and CTV regions can lead to risk-stratification of GBM undergoing biopsy, while the utility in other individual subgroups needs to be further explored., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Purpose/objective(s): This study examined changes in the clinical target volume (CTV) and associated clinical implications on a magnetic resonance imaging linear accelerator (MR LINAC) during hypofractionated stereotactic radiotherapy (HSRT) to resected brain metastases. In addition, the suitability of using T2/FLAIR (T2f) sequence to define CTV was explored by assessing contouring variability between gadolinium-enhanced T1 (T1c) and T2f sequences., Materials/methods: Fifteen patients treated to either 27.5 or 30 Gy with five fraction HSRT were imaged with T1c and T2f sequences during treatment; T1c was acquired at planning (FxSim), and fraction 3 (Fx3), and T2f was acquired at FxSim and all five fractions. The CTV were contoured on all acquired images. Inter-fraction cavity dynamics and CTV contouring variability were quantified using absolute volume, Dice similarity coefficient (DSC), and Hausdorff distance (HD) metrics., Results: The median CTV on T1c and T2f sequences at FxSim were 12.0cm 3 (range, 1.2-30.1) and 10.2cm 3 (range, 2.9-27.9), respectively. At Fx3, the median CTV decreased in both sequences to 9.3cm 3 (range, 3.7-25.9) and 8.6cm 3 (range, 3.3-22.5), translating to a median % relative reduction of - 11.4% on T1c (p = 0.009) and - 8.4% on T2f (p = 0.032). We observed a median % relative reduction in CTV between T1c and T2f at FxSim of - 6.0% (p = 0.040). The mean DSC was 0.85 ± 0.10, and the mean HD was 5.3 ± 2.7 mm when comparing CTV on T1c and T2f at FxSim., Conclusion: Statistically significant reductions in cavity CTV was observed during HSRT, supporting the use of MR image guided radiation therapy and treatment adaptation to mitigate toxicity. Significant CTV contouring variability was seen between T1c and T2f sequences. Trial registration NCT04075305 - August 30, 2019., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Purpose: Multileaf collimator (MLC) linear accelerator (Linac)-based hypofractionated stereotactic radiation therapy (HSRT) is increasingly used not only for large brain metastases or those adjacent to critical structures but also for those metastases that would otherwise be considered for single-fraction radiosurgery (SRS). However, data on outcomes in general are limited, and there is a lack of understanding regarding optimal dosing. Our aim was to report mature image-based outcomes for MLC-Linac HSRT with a focus on clinical and dosimetric factors associated with local failure (LF)., Methods and Materials: A total of 220 patients with 334 brain metastases treated with HSRT were identified. All patients were treated using a 5-fraction daily regimen and were followed with clinical evaluation and volumetric magnetic resonance imaging every 2 to 3 months. Overall survival and progression-free survival were calculated using the Kaplan-Meier method, with LF determined using Fine and Gray's competing risk method. Predictive factors were identified using Cox regression multivariate analysis., Results: Median follow-up was 10.8 months. Median size of treated metastasis was 1.9 cm; 60% of metastases were <2 cm in size. The median total dose was 30 Gy in 5 fractions; 36% of the cohort received <30 Gy. The median time to LF and 12-month cumulative incidence of LF was 8.5 months and 23.8%, respectively. Median time to death and 12-month overall survival rates were 11.8 months and 48.2%, respectively. Fifty-two metastases (15.6%) had an adverse radiation effect, of which 32 (9.5%) were symptomatic necrosis. Multivariable analysis identified worse LF in patients who received a total dose of <30 Gy (hazard ratio, 1.62; P = .03), with LF at 6 and 12 months of 13% and 33% for patients treated with <30 Gy versus 5% and 19% for patients treated with >30 Gy. Exploratory analysis demonstrated a dose-response effect observed in all histologic types, including among breast cancer subtypes., Conclusion: Optimal local control is achieved with HSRT of ≥30 Gy in 5 daily fractions, independent of tumor volume and histology, with an acceptable risk of radiation necrosis., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background and Purpose: To quantitatively compare the recurrence patterns of glioblastoma (isocitrate dehydrogenase-wild type) versus grade 4 isocitrate dehydrogenase-mutant astrocytoma (wild type isocitrate dehydrogenase and mutant isocitrate dehydrogenase, respectively) following primary chemoradiation. Materials and Methods: A retrospective matched cohort of 22 wild type isocitrate dehydrogenase and 22 mutant isocitrate dehydrogenase patients were matched by sex, extent of resection, and corpus callosum involvement. The recurrent gross tumor volume was compared to the original gross tumor volume and clinical target volume contours from radiotherapy planning. Failure patterns were quantified by the incidence and volume of the recurrent gross tumor volume outside the gross tumor volume and clinical target volume, and positional differences of the recurrent gross tumor volume centroid from the gross tumor volume and clinical target volume. Results: The gross tumor volume was smaller for wild type isocitrate dehydrogenase patients compared to the mutant isocitrate dehydrogenase cohort (mean ± SD: 46.5 ± 26.0 cm 3 vs 72.2 ± 45.4 cm 3 , P  = .026). The recurrent gross tumor volume was 10.7 ± 26.9 cm 3 and 46.9 ± 55.0 cm 3 smaller than the gross tumor volume for the same groups ( P  = .018). The recurrent gross tumor volume extended outside the gross tumor volume in 22 (100%) and 15 (68%) ( P = .009) of wild type isocitrate dehydrogenase and mutant isocitrate dehydrogenase patients, respectively; however, the volume of recurrent gross tumor volume outside the gross tumor volume was not significantly different (12.4 ± 16.1 cm 3 vs 8.4 ± 14.2 cm 3 , P  = .443). The recurrent gross tumor volume centroid was within 5.7 mm of the closest gross tumor volume edge for 21 (95%) and 22 (100%) of wild type isocitrate dehydrogenase and mutant isocitrate dehydrogenase patients, respectively. Conclusion: The recurrent gross tumor volume extended beyond the gross tumor volume less often in mutant isocitrate dehydrogenase patients possibly implying a differential response to chemoradiotherapy and suggesting isocitrate dehydrogenase status might be used to personalize radiotherapy. The results require validation in prospective randomized trials.

Introduction: Magnetic resonance imaging-linear accelerator radiotherapy is an innovative technology that requires special consideration for secondary electron interactions within the magnetic field, which can alter dose deposition at air-tissue interfaces. As part of ongoing quality assurance and quality improvement of new radiotherapy technologies, the purpose of this study was to evaluate skin dose modelled from the treatment planning systems of a magnetic resonance imaging-linear accelerator and a conventional linear accelerator, and then correlate with in vivo measurements of delivered skin dose from each linear accelerator. Methods: In this prospective cohort study, 37 consecutive glioma patients had treatment planning completed and approved prior to radiotherapy initiation using commercial treatment planning systems: a Monte Carlo-based algorithm for magnetic resonance imaging-linear accelerator or a convolution-based algorithm for conventional linear accelerator. In vivo skin dose was measured using an optically stimulated luminescent dosimeter. Results: Monte Carlo-based magnetic resonance imaging-linear accelerator plans and convolution-based conventional linear accelerator plans had similar dosimetric parameters for target volumes and organs-at-risk. However, magnetic resonance imaging-linear accelerator plans had 1.52 Gy higher mean dose to air cavities ( P  < .0001) and 1.10 Gy higher mean dose to skin ( P  < .0001). In vivo skin dose was 14.5% greater for magnetic resonance imaging-linear accelerator treatments ( P  = .0027), and was more accurately predicted by Monte Carlo-based calculation ( ρ  = 0.95, P  < .0001) versus convolution-based ( ρ  = 0.80, P  = .0096). Conclusion: This is the first prospective dosimetric comparison of glioma patients clinically treated on both magnetic resonance imaging-linear accelerator and conventional linear accelerator. Our findings suggest that skin doses were significantly greater with magnetic resonance imaging-linear accelerator plans but correlated better with in vivo measurements of actual skin dose from delivered treatments. Future magnetic resonance imaging-linear accelerator planning processes are being designed to account for skin dosimetry and treatment delivery.

Background: The peritumoral region (PTR) of glioblastoma (GBM) appears as a T2W-hyperintensity and is composed of microscopic tumor and edema. Infiltrative low grade glioma (LGG) comprises tumor cells that seem similar to GBM PTR on MRI. The work here explored if a radiomics-based approach can distinguish between the two groups (tumor and edema versus tumor alone)., Methods: Patients with GBM and LGG imaged using a 1.5 T MRI were included in the study. Image data from cases of GBM PTR, and LGG were manually segmented guided by T2W hyperintensity. A set of 91 first-order and texture features were determined from each of T1W-contrast, and T2W-FLAIR, diffusion-weighted imaging sequences. Applying filtration techniques, a total of 3822 features were obtained. Different feature reduction techniques were employed, and a subsequent model was constructed using four machine learning classifiers. Leave-one-out cross-validation was used to assess classifier performance., Results: The analysis included 42 GBM and 36 LGG. The best performance was obtained using AdaBoost classifier using all the features with a sensitivity, specificity, accuracy, and area of curve (AUC) of 91%, 86%, 89%, and 0.96, respectively. Amongst the feature selection techniques, the recursive feature elimination technique had the best results, with an AUC ranging from 0.87 to 0.92. Evaluation with the F-test resulted in the most consistent feature selection with 3 T1W-contrast texture features chosen in over 90% of instances., Conclusions: Quantitative analysis of conventional MRI sequences can effectively demarcate GBM PTR from LGG, which is otherwise indistinguishable on visual estimation., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background and Purpose: MRI linear accelerators (MR-Linacs) may allow treatment adaptation to be guided by quantitative MRI including diffusion-weighted imaging (DWI). The aim of this study was to evaluate the accuracy and precision of apparent diffusion coefficient (ADC) measurements from DWI on a 1.5 T MR-Linac in patients with central nervous system (CNS) tumours through comparison with a diagnostic scanner., Materials and Methods: CNS patients were treated using a 1.5 T Elekta Unity MR-Linac. DWI was acquired during MR-Linac treatment and on a Philips Ingenia 1.5 T. The agreement between the two scanners on median ADC over the gross tumour/clinical target volumes (GTV/CTV) and in brain regions (white/grey matter, cerebrospinal fluid (CSF)) was computed. Repeated scans were used to estimate ADC repeatability. Daily changes in ADC over the GTV of high-grade gliomas were characterized from MR-Linac scans., Results: DWI from 59 patients was analyzed. MR-Linac ADC measurements showed a small bias relative to Ingenia measurements in white matter, grey matter, GTV, and CTV (bias: -0.05 ± 0.03, -0.08 ± 0.05, -0.1 ± 0.1, -0.08 ± 0.07 μm 2 /ms). ADC differed substantially in CSF (bias: -0.5 ± 0.3 μm 2 /ms). The repeatability of MR-Linac ADC over white/grey matter was similar to previous reports (coefficients of variation for median ADC: 1.4%/1.8%). MR-Linac ADC changes in the GTV were detectable., Conclusions: It is possible to obtain ADC measurements in the brain on a 1.5 T MR-Linac that are comparable to those of diagnostic-quality scanners. This technical validation study adds to the foundation for future studies that will correlate brain tumour ADC with clinical outcomes., Competing Interests: Conflicts of Interest Dr. Arjun Sahgal: Advisor/consultant with Abbvie, Merck, Roche, Varian (Medical Advisory Group), Elekta (Gamma Knife Icon), BrainLAB, and VieCure (Medical Advisory Board); Past educational seminars with Elekta AB, Accuray Inc., Varian (CNS Teaching Faculty), BrainLAB, Medtronic Kyphon; Research grant with Elekta AB; Travel accommodations/expenses by Elekta, Varian, BrainLAB. Dr. Chia-Lin Tseng: Travel accommodations/expenses & honoraria for past educational seminars by Elekta; belongs to the Elekta MR-Linac Research Consortium; advisor/consultant with Sanofi. Dr. Sten Myrehaug: Received research support from Novartis AG, honoraria from Novartis AG and Ipsen and travel support from Elekta. None related to this work. Dr. Mark Ruschin: Co‐inventor of and owns associated intellectual property specific to the image‐guidance system on the Gamma Knife Icon. None related to this work. Mrs. Mikki Campbell: Received honorarium for past educational seminars with Elekta AB; received research grants with Elekta AB; and travel accommodations/expenses by Elekta; belongs to the Elekta MR Linac Research Consortium. Dr. Brige Chugh: Previously held an industry partnership grant with Modus QA., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Background: There are no established threshold values regarding the degree of growth on imaging when assessing response of spinal metastases treated with stereotactic body radiation therapy (SBRT)., Objective: To determine a magnetic resonance imaging-based minimum detectable difference (MDD) in gross tumor volume (GTV) and its association with 1-yr radiation site-specific (RSS) progression-free survival (PFS)., Methods: GTVs at baseline and first 2 post-SBRT scans (Post1 and Post2, respectively) for 142 spinal segments were contoured, and percentage volume change between scans calculated. One-year RSS PFS was acquired from medical records. The MDD was determined. The MDD was compared against optimal thresholds of GTV changes associated with 1-yr RSS PFS using Youden's J index, and receiver operating characteristic curves between timepoints compared to determine which timeframe had the best association., Results: A total of 17 of the 142 segments demonstrated progression. The MDD was 10.9%. Baseline-Post2 demonstrated the best performance (area under the curve [AUC] 0.90). Only Baseline-Post2 had an optimal threshold > MDD at 14.7%. Due to large distribution of GTVs, volumes were split into tertiles. Small tumors (GTV < 2 cc) had optimal thresholds of 42.0%, 71.3%, and 37.2% at Baseline-Post1 (AUC 0.81), Baseline-Post2 (AUC 0.89), and Post1-Post2 (AUC 0.77), respectively. Medium tumors (2 ≤ GTV ≤ 8.3 cc) all demonstrated optimal thresholds < MDD, with AUCs ranging from 0.65 to 0.84. Large tumors (GTV > 8.3 cc) had 2 timepoints where optimal thresholds > MDD: Baseline-Post2 (13.3%; AUC 0.97) and Post1-Post2 (11.8%; AUC 0.66). Baseline-Post2 had the best association with RSS PFS for all tertiles., Conclusion: Given a MDD of 10.9%, for small GTVs, larger (>37%) changes were required before local failure could be determined, compared to 11% to 13% for medium/large tumors., (© Congress of Neurological Surgeons 2021.)

Purpose: To describe the implementation and initial results of using Chemical Exchange Saturation Transfer (CEST) for monitoring patients with central nervous system (CNS) tumours treated using a 1.5 tesla MR-guided radiotherapy system., Methods: CNS patients were treated with up to 30 fractions (total dose up to 60 Gy) using a 1.5 T Elekta Unity MR-Linac. CEST scans were obtained in 54 subjects at one or more time points during treatment. CEST metrics, including the amide magnetization transfer ratio (MTR Amide ), nuclear Overhauser effect (NOE) MTR (MTR NOE ) and asymmetry, were quantified in phantoms and CNS patients. The signal was investigated between tumour and white matter, across time, and across disease categories including high- and low-grade tumours., Results: The gross tumour volume (GTV) exhibited lower MTR Amide and MTR NOE and higher asymmetry compared to contralateral normal appearing white matter. Signal changes in the GTV during fractionated radiotherapy were observed. There were differences between high- and low-grade tumours, with higher CEST asymmetry associated with higher grade disease., Conclusion: CEST MRI using a 1.5 T MR-Linac was demonstrated to be feasible for in vivo imaging of CNS tumours. CEST images showed tumour/white-matter contrast, temporal CEST signal changes, and associations with tumour grade. These results show promise for the eventual goal of using metabolic imaging to inform the design of adaptive radiotherapy protocols., (Copyright © 2021 The Author(s). Published by Elsevier B.V. All rights reserved.)

Purpose: The peritumoral region (PTR) in glioblastoma (GBM) represents a combination of infiltrative tumor and vasogenic edema, which are indistinguishable on magnetic resonance imaging (MRI). We developed a radiomic signature by using imaging data from low grade glioma (LGG) (marker of tumor) and PTR of brain metastasis (BM) (marker of edema) and applied it on the GBM PTR to generate probabilistic maps., Methods: 270 features were extracted from T1-weighted, T2-weighted, and apparent diffusion coefficient maps in over 3.5 million voxels of LGG (36 segments) and BM (45 segments) scanned in a 1.5T MRI. A support vector machine classifier was used to develop the radiomics model from approximately 50% voxels (downsampled to 10%) and validated with the remaining. The model was applied to over 575,000 voxels of the PTR of 10 patients with GBM to generate a quantitative map using Platt scaling (infiltrative tumor vs. edema)., Results: The radiomics model had an accuracy of 0.92 and 0.79 in the training and test set, respectively (LGG vs. BM). When extrapolated on the GBM PTR, 9 of 10 patients had a higher percentage of voxels with a tumor-like signature over radiological recurrence areas. In 7 of 10 patients, the areas under curves (AUC) were > 0.50 confirming a positive correlation. Including all the voxels from the GBM patients, the infiltration signature had an AUC of 0.61 to predict recurrence., Conclusion: A radiomic signature can demarcate areas of microscopic tumors from edema in the PTR of GBM, which correlates with areas of future recurrence.

Background: Patient selection is critical for spine stereotactic body radiotherapy (SBRT) given potential for serious adverse effects and the associated costs., Objective: To identify prognostic factors associated with dying within 3 mo, or living greater than 3 yr, following spine SBRT, to better inform patient selection., Methods: Patients living ≤3 mo after spine SBRT and >3 yr after spine SBRT were identified, and multivariable regression analyses were performed. We report serious late toxicities observed, including vertebral compression fractures (VCF) and plexopathy., Results: A total of 605 patients (1406 spine segments) were treated from 2009 to 2018. A total of 51 patients (8.4%) lived ≤3 mo, and 79 patients (13%) survived >3 yr. Significant differences in baseline features were observed. On multivariable analysis, nonbreast/prostate primaries (odds ratio [ORs]: 28.8-104.2, P = .0004), eastern cooperative oncology group (ECOG) ≥2 (OR: 23.7, 95% CI: 3.2-177, P = .0020), polymetastatic disease (OR: 6.715, 95% CI: 1.89-23.85, P = .0032), painful lesions (OR: 3.833-8.898, P = .0118), and paraspinal disease (OR: 2.874, 95% CI: 1.118-7.393, P = .0288) were prognostic for ≤3 mo survival. The 3- and 5-yr rates of VCF were 10.4% and 14.4%, respectively, and 3- and 5-yr rates of plexopathy were 2.2% and 5.1%, respectively. A single duodenal perforation was observed, and there was no radiation myelopathy events., Conclusion: Shorter survival after spine SBRT was seen in patients with less radiosensitive histologies (ie, not breast or prostate), ECOG ≥2, and polymetastatic disease. Pain and paraspinal disease were also associated with poor survival. Fractionated spine SBRT confers a low risk of late serious adverse events., (© Congress of Neurological Surgeons 2021.)

Patients undergoing standard chemoradiation post-resection had MRIs at radiation planning and fractions 10 and 20 of chemoradiation. MRIs were 1.5T and 3D T2-FLAIR, pre- and post-contrast 3D T1-weighted (T1) and echo planar DWI with three b-values (0, 500, and 1000s/mm 2 ) were acquired. T2-FLAIR was coregistered to T1C images. Non-overlapping T1 contrast-enhancing (T1C) and nonenhancing T2-FLAIR hyperintense regions were segmented, with necrotic/cystic regions, the surgical cavity, and large vessels excluded. The simplified IVIM model was used to calculate voxelwise diffusion coefficient ( D ) and perfusion fraction ( f ) maps; ADC was calculated using the natural logarithm of b  = 1000 over b  = 0 images. T1C and T2-FLAIR segmentations were brought into this space, and medians calculated. MGMT promoter methylation status (MGMT PMS ), age at diagnosis, and Eastern Cooperative Oncology Group (ECOG) performance status were extracted from electronic medical records. The data were presented, analyzed, and described in the article, "Intravoxel incoherent motion (IVIM) modeling of diffusion MRI during chemoradiation predicts therapeutic response in IDH wildtype Glioblastoma", published in Radiotherapy and Oncology [1]., Competing Interests: Arjun Sahgal: Advisor/consultant: AbbVie, Merck, Roche, Varian, Elekta, BrainLAB, VieCure Board Member: International Stereotactic Radiosurgery Society Co-Chair: AO Spine Knowledge Forum Tumor Past educational seminars: Elekta AB, Accuray Inc., Varian, BrainLAB, Medtronic Kyphon Research support: Elekta AB Travel support: Elekta, Varian, BrainLAB Consortia: Elekta MR Linac Research Consortium, Elekta Spine, Oligometastases and Linac Based SRS Consortia. Sten Myrehaug: Research support: Novartis AG Honoraria: Novartis AG, Ipsen Travel support: Elekta Chia-Lin Tseng: Honoraria: Elekta Travel support: Elekta Consortia: Elekta MR Linac Research Consortium Hany Soliman: Horaria: Elekta AB Travel support: Elekta AB Sunit Das: Advisor/consultant: AbbVie, Xpan Medical, Synaptive Board member: Subcortical Surgery Group Past educational seminars: AbbVie, Congress of Neurological Surgeons, American Association of Neurological Surgeons, Society for NeuroOncology Research supports: Alkerme, Medicenna Travel support: Subcortical Surgery Group, Congress of Neurological Surgeons, American Association of Neurological Surgeons, Society for NeuroOncology, Integra All other authors declare that they have no known competing financial interests or personal relationships which have, or could be perceived to have, influenced the work reported in this article., (© 2021 The Author(s). Published by Elsevier Inc.)

Background: Prediction of early progression in glioblastoma may provide an opportunity to personalize treatment. Simplified intravoxel incoherent motion (IVIM) MRI offers quantitative estimates of diffusion and perfusion metrics. We investigated whether these metrics, during chemoradiation, could predict treatment outcome., Methods: 38 patients with newly diagnosed IDH-wildtype glioblastoma undergoing 6-week/30-fraction chemoradiation had standardized post-operative MRIs at baseline (radiation planning), and at the 10th and 20th fractions. Non-overlapping T1-enhancing (T1C) and non-enhancing T2-FLAIR hyperintense regions were independently segmented. Apparent diffusion coefficient (ADC T1C , ADC T2-FLAIR ) and perfusion fraction (f T1C , f T2-FLAIR ) maps were generated with simplified IVIM modelling. Parameters associated with progression before or after 6.9 months (early vs late progression, respectively), overall survival (OS) and progression-free survival (PFS) were investigated., Results: Higher ADC T2-FLAIR at baseline [Odds Ratio (OR) = 1.06, 95% CI 1.01-1.15, p = 0.025], lower f T2-FLAIR at fraction 10 (OR = 2.11, 95% CI 1.04-4.27, p = 0.018), and lack of increase in ADC T2-FLAIR at fraction 20 compared to baseline (OR = 1.12, 95% CI 1.02-1.22, p = 0.02) were associated with early progression. Combining ADC T2-FLAIR at baseline, f T2-FLAIR at fraction 10, ECOG and MGMT promoter methylation status significantly improved AUC to 90.3% compared to a model with only ECOG and MGMT promoter methylation status (p = 0.001). Using multivariable analysis, neither IVIM metrics were associated with OS but higher f T2-FLAIR at fraction 10 (HR = 0.72, 95% CI 0.56-0.95, p = 0.018) was associated with longer PFS., Conclusion: ADC T2-FLAIR at baseline, its lack of increase from baseline to fraction 20, or f T2-FLAIR at fraction 10 significantly predicted early progression. f T2-FLAIR at fraction 10 was associated with PFS., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)

Purpose: The concept of a radioresistant (RR) phenotype has been challenged with use of stereotactic body radiotherapy (SBRT). We compared outcomes following SBRT to RR spinal metastases to a radiosensitive cohort., Methods: Renal cell, melanoma, sarcoma, gastro-intestinal, and thyroid spinal metastases were identified as RR and prostate cancer (PCA) as radiosensitive. The primary endpoint was MRI-based local failure (LF). Secondary endpoints included overall survival (OS) and vertebral compression fracture (VCF)., Results: From a prospectively maintained database of 1394 spinal segments in 605 patients treated with spine SBRT, 173 patients/395 RR spinal segments were compared to 94 patients/185 PCA segments. Most received 24-28 Gy in 2 fractions (68.9%) and median follow-up was 15.5 months (range, 1.4-84.2 months). 1- and 2-year LF rates were 19.2% and 22.4% for RR metastases, respectively, which were significantly greater (p < 0.001) than PCA (3.2% and 8.4%, respectively). Epidural disease (HR: 2.47, 95% CI 1.65-3.71, p < 0.001) and RR histology (HR: 2.41, 95% CI 1.45-3.99, p < 0.001) predicted for greater LF. Median OS was 17.4 and 61.0 months for RR and PCA cohorts, respectively. Lung/liver metastases, polymetastatic disease and epidural disease predicted for worse OS. 2-year VCF rates were ~ 13% in both cohorts. Coverage of the CTV V90 (clinical target volume receiving 90% of prescription dose) by ≥ 87% (HR: 2.32, 95% CI 1.29-4.18, p = 0.005), no prior spine radiotherapy (HR: 1.96, 95% CI 1.09-3.55, p = 0.025), and a greater Spinal Instability Neoplasia Score (p = 0.013) predicted for VCF., Conclusions: Higher rates of LF were observed after spine SBRT in RR metastases. Optimization strategies include dose escalation and aggressive management of epidural disease.

Purpose: Magnetic resonance image (MRI) guided radiation therapy has the potential to improve outcomes for glioblastoma by adapting to tumor changes during radiation therapy. This study quantifies interfraction dynamics (tumor size, position, and geometry) based on sequential magnetic resonance imaging scans obtained during standard 6-week chemoradiation., Methods and Materials: Sixty-one patients were prospectively imaged with gadolinium-enhanced T1 (T1c) and T2/FLAIR axial sequences at planning (Fx0), fraction 10 (Fx10), fraction 20 (Fx20), and 1 month after the final fraction of chemoradiation therapy (P1M). Gross tumor volumes (GTVs) and clinical target volumes (CTVs) were contoured at all time points. Target dynamics were quantified by absolute volume (V), volume relative to Fx0 (V rel ), and the migration distance (d migrate ; the linear displacement of the GTV or CTV relative to Fx0). Temporal changes were assessed using a linear mixed-effects model., Results: Median volumes at Fx0, Fx10, Fx20, and P1M for the GTV were 18.4 cm 3 (range, 1.1-110.5 cm 3 ), 14.7 cm 3 (range, 0.9-115.1 cm 3 ), 13.7 cm 3 (range, 0.6-174.2 cm 3 ), and 13.0 cm 3 (range, 0.9-76.3 cm 3 ), respectively, with corresponding median V rel of 0.88 at Fx10, 0.77 at Fx20, and 0.71 at P1M relative to Fx0 (P < .001 for all). The GTV (CTV) migration distances were greater than 5 mm in 46% (54%) of patients at Fx10, 50% (58%) of patients at Fx20, and 52% (57%) of patients at P1M. Dynamic tumor morphologic changes were observed, with 40% of patients exhibiting a decreased GTV (V rel ≤1) with a d migrate >5 mm during chemoradiation therapy., Conclusions: Clinically meaningful tumor dynamics were observed during chemoradiation therapy for glioblastoma, supporting evaluation of daily MRI guided radiation therapy and treatment plan adaptation., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Glioblastoma in the elderly (>65 years of age) is associated with shorter overall survival (OS) than in younger patients. Best practice recommendations for elderly patients, especially those with borderline or poor performance status, remain a subject of debate amongst clinicians despite recent randomized trials. This review provides an updated evidence-based summary to inform the modern management of elderly patients with glioblastoma. Based on evidence from the CE.6 randomized controlled trial, hypofractionated radiation therapy administered over a three-week course (40 Gy in 15 fractions) concomitantly with temozolomide (TMZ) followed by adjuvant TMZ has been found to be superior to radiation therapy alone with mean OS of 9.3 vs. 7.6 months and progression-free survival (PFS) of 5.3 vs. 3.9 months. This regimen should be offered to newly-diagnosed elderly patients with glioblastoma with preserved functional status, and was not associated with a negative impact on health-related quality of life (QOL). Management of elderly patients with glioblastoma can be challenging and requires a patient-centered strategy. Personalized decisions accounting for clinical, psychosocial, molecular and treatment factors are critical for realistic decision making. The importance of discussing goals-of-care with patients and their caregivers early in the disease trajectory, and establishing capacity for decision-making and advanced care planning, is also reviewed.

Background: Local response prediction for brain metastases (BM) after stereotactic radiosurgery (SRS) is challenging, particularly for smaller BM, as existing criteria are based solely on unidimensional measurements. This investigation sought to determine whether radiomic features provide additional value to routinely available clinical and dosimetric variables to predict local recurrence following SRS., Methods: Analyzed were 408 BM in 87 patients treated with SRS. A total of 440 radiomic features were extracted from the tumor core and the peritumoral regions, using the baseline pretreatment volumetric post-contrast T1 (T1c) and volumetric T2 fluid-attenuated inversion recovery (FLAIR) MRI sequences. Local tumor progression was determined based on Response Assessment in Neuro-Oncology‒BM criteria, with a maximum axial diameter growth of >20% on the follow-up T1c indicating local failure. The top radiomic features were determined based on resampled random forest (RF) feature importance. An RF classifier was trained using each set of features and evaluated using the area under the receiver operating characteristic curve (AUC)., Results: The addition of any one of the top 10 radiomic features to the set of clinical features resulted in a statistically significant (P < 0.001) increase in the AUC. An optimized combination of radiomic and clinical features resulted in a 19% higher resampled AUC (mean = 0.793; 95% CI = 0.792-0.795) than clinical features alone (0.669, 0.668-0.671)., Conclusions: The increase in AUC of the RF classifier, after incorporating radiomic features, suggests that quantitative characterization of tumor appearance on pretreatment T1c and FLAIR adds value to known clinical and dosimetric variables for predicting local failure., (© The Author(s) 2020. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: The objective was to evaluate the risk and predictors of developing leptomeningeal disease (LMD) in patients with brain metastases treated with 5-fraction hypofractionated stereotactic radiotherapy (HSRT)., Methods: Patients treated with HSRT for intact brain metastases and/or surgical cavities were reviewed from a prospectively maintained database. Radiographic patterns of LMD were classified as focal classical, diffuse classical, focal nodular, and diffuse nodular., Results: HSRT was delivered, most commonly 30 Gy in 5 fractions, to 320 intracranial lesions (57% intact and 43% surgical cavities) in 235 patients. The median follow-up was 13.4 months (range, 0.8 to 60 mo). LMD developed in 19% of patients with a 1-year LMD rate of 12%. From the diagnosis of LMD, the median overall survival (OS) was 3.8 months (range, 2-20.8 mo). The most common LMD pattern was diffuse nodular (44%). No difference in OS was observed between LMD patterns (P = 0.203). Multivariable analysis identified surgical cavities at significantly higher risk of LMD compared with intact lesions (odds ratio [OR] = 2.30, 95% CI: 1.24, 4.29, P = 0.008). For cavities, radiosensitive tumors (OR = 2.35, 95% CI: 1.04, 5.35, P = 0.041) predicted for LMD, while, for intact metastases, patients receiving treatment with targeted agents or immunotherapy (TA/I) were at lower risk (OR = 0.178, 95% CI: 0.04, 0.79, P = 0.023)., Conclusions: Patients who had a brain metastasis resected were at an increased risk of LMD. OS was poor despite treatment of LMD, and no differences in OS based on the pattern of LMD was observed. Treatment with TA/I was observed to be protective against LMD and requires further study., (© The Author(s) 2019. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Purpose: Vertebroplasty (VP) and balloon kyphoplasty (KP) are minimally invasive stabilization procedures for pathologic vertebral compression fractures (VCF). Concurrent administration of photodynamic therapy (PDT) as a tumor-ablative modality has yet to be studied in humans as a potential complement to improved mechanical stability that is afforded by vertebral cement augmentation (VCA)., Patients and Methods: This first-in-human trial used a single 6 mg/m 2 dose of the clinical photosensitizer Visudyne with escalating laser light doses. Following a cohort of light-only controls ( n = 6), the drug and light treatment groups ( n = 6 each) were 50, 100, 150, and 200 J/cm. VCA was performed within 15 minutes following PDT. Patients were clinically reviewed at 1 and 6 weeks. The primary outcome measure was safety from a neurologic perspective., Results: Thirty patients comprising a variety of primary tumors were treated with PDT and either KP or VP. Vertebral PDT was technically feasible and delivered in all study patients. No dose groups showed significant increases in pain as defined by the generic SF-36 as well as disease-specific EORTC-QLQ-BM22 and EORTC-QLQ-C15-PAL questionnaires. The 50 and 100 J/cm groups showed the most significant pain reduction ( P < 0.05). Twelve (40%) patients experienced complications during the study including 3 patients with further vertebral fracture progression by 6 weeks despite VCA. No complications were directly attributed to PDT., Conclusions: Using the parameters described, vertebral PDT as an adjunct to VCA is safe from a pharmaceutical and neurologic perspective. The results of this trial motivate scale-up study evaluating potential PDT efficacy in vertebral metastatic treatment., (©2019 American Association for Cancer Research.)

Purpose: To compare normal tissue dosimetry between hippocampal-avoidance whole brain radiation therapy (HA-WBRT) and stereotactic radiosurgery (SRS) in patients with 10 to 30 brain metastases, and to describe a novel SRS strategy we term Spatially Partitioned Adaptive RadiosurgEry (SPARE)., Methods and Materials: A retrospective review identified SRS treatment plans with >10 brain metastases located >5 mm from the hippocampi. Our Gamma Knife Icon (GKI) SPARE (GKI-Spr) technique treats multiple metastases with single-fraction SRS partitioned over consecutive days while limiting the total treatment time to ≤60 minutes per day. Hippocampal and normal brain dosimetry were compared among GKI-Spr, single-fraction single-day GKI (GKI-Sfr), and 30 Gy in 10 fractions HA-WBRT. Dose metrics were converted to equivalent dose in 2 Gy fractions., Results: Ten cases were analyzed. Compared with HA-WBRT, GKI-Spr significantly reduced the median equivalent dose in 2 Gy fractions hippocampal maximum point dose, mean dose, and dose to 40% of the hippocampi (D40%) by 86%, 93%, and 93%, respectively, and similarly for GKI-Sfr by 81%, 92%, and 91%, respectively. The normal brain median mean dose was reduced by 95% with GKI-Spr and 94% with GKI-Sfr. Compared with GKI-Sfr, GKI-Spr further reduced all normal brain and hippocampal dose metrics (P ≤ .014)., Conclusions: GKI yields superior hippocampal and normal brain dosimetry compared with HA-WBRT, and GKI-Spr results in further dosimetric advantages., (Copyright © 2019 The Author(s). Published by Elsevier Inc. All rights reserved.)

Purpose: Radiation-induced pseudoprogression is a subacute clinical entity that is distinct from radiation necrosis and mimics tumor progression. Bevacizumab is a well-described treatment option for radiation necrosis, but its role in pseudoprogression is not clearly defined., Methods: We report a case of radiation-induced pseudoprogression rescued with bevacizumab in a 20-year-old man with a biopsy-proven low-grade astrocytoma of the tectum. A review of the literature was also conducted specific to bevacizumab as a treatment for symptomatic pseudoprogression after radiotherapy for CNS tumors., Results: This patient was treated with definitive intensity modulated stereotactic radiotherapy at a total dose of 54 Gy delivered in 30 daily fractions. Six weeks after radiotherapy the patient developed progressive headache, weakness and a documented deterioration in vision, which was accompanied by worsening of radiographic findings. A diagnosis of pseudoprogression was made and after limited benefit from a trial of dexamethasone, four cycles of bevacizumab were administered which resulted in rapid clinical and radiographic improvement., Conclusions: Our findings support the potential use of bevacizumab as a rescue agent for symptomatic pseudoprogression.

Brain metastases are the most common intracranial tumors and occur in 20-40% of all cancer patients. Lung cancer, breast cancer, and melanoma are the most frequent primary cancers to develop brain metastases. Treatment options include surgical resection, whole brain radiotherapy, stereotactic radiosurgery, and systemic treatment such as targeted or immune therapy. Anatomical magnetic resonance imaging (MRI) of the tumor (in particular post-Gadolinium T 1 -weighted and T 2 -weighted FLAIR) provide information about lesion morphology and structure, and are routinely used in clinical practice for both detection and treatment response evaluation for brain metastases. Advanced MRI biomarkers that characterize the cellular, biophysical, micro-structural and metabolic features of tumors have the potential to improve the management of brain metastases from early detection and diagnosis, to evaluating treatment response. Magnetic resonance spectroscopy (MRS), chemical exchange saturation transfer (CEST), quantitative magnetization transfer (qMT), diffusion-based tissue microstructure imaging, trans-membrane water exchange mapping, and magnetic susceptibility weighted imaging (SWI) are advanced MRI techniques that will be reviewed in this article as they pertain to brain metastases.

The use of radiotherapy, either in the form of stereotactic radiosurgery (SRS) or whole-brain radiotherapy (WBRT), remains the cornerstone for the treatment of brain metastases (BM). As the survival of patients with BM is being prolonged, due to improved systemic therapy (i.e., for better extra-cranial control) and increased use of SRS (i.e., for improved intra-cranial control), patients are clinically manifesting late effects of radiotherapy. One of these late effects is radiation necrosis (RN). Unfortunately, symptomatic RN is notoriously hard to diagnose and manage. The features of RN overlap considerably with tumor recurrence, and misdiagnosing RN as tumor recurrence may lead to deleterious treatment which may cause detrimental effects to the patient. In this review, we will explore the pathophysiology of RN, risk factors for its development, and the strategies to evaluate and manage RN.

Pain flare is a well-recognized side-effect of palliative radiotherapy for the treatment of painful bone metastases, with recent randomized data showing incidence rates up to 35%. The impact of pain flare has been associated with worsening immobility, anxiety, depression and quality of life. The use of dexamethasone has recently been supported as an effective option in reducing radiation-induced pain flare based on the NCIC Clinical Trials Group (NCIC CTG) Symptom Control 23 (SC.23) randomized double-blind placebo-controlled trial. Despite this, conflicting opinions exist, and standard clinical use of dexamethasone to prevent pain flare continues to be debated among clinicians. Given this controversy, two sides of the debate are presented. Although consensus has not been achieved, the choice to use dexamethasone in the prophylactic setting to reduce pain flare incidence should be a shared decision between the oncologist and patient. Factors including symptom burden, comorbidities, performance status, quality of life and radiation dose and fractionation should be taken into account on an individualized level.

We hypothesized that multicontrast late-enhancement (MCLE) MRI would improve the identification of papillary muscle involvement (PM-MI) in patients with myocardial infarction (MI), compared with conventional late gadolinium enhancement (LGE) MRI using the inversion recovery fast gradient echo (IR-FGRE) technique. Cardiac LGE-MRI studies using both MCLE and IR-FGRE pulse sequences were performed on a 1.5 Tesla (T) MRI system in 23 patients following MI. In all patients, PM-MI was confirmed by the diagnostic criteria as outlined below: (a) the increased signal intensity of PM was the same or similar to that of adjacent hyper-enhanced left ventricular (LV) infarct segments; and (b) the hyper-enhanced PM region was limited to the PM area defined by precontrast cine images of steady-state free precession (SSFP). Visual contrast score was rated according to the differentiation between LV blood pool and hyper-enhanced infarct myocardium. Quantitative contrast-noise ratios (CNR) of infarct relative to blood pool and viable myocardium were also measured on MCLE and IR-FGRE images. Of these 23 patients, 13 studies demonstrated primarily involvement of the territories of the right coronary (RCA, 8 patients) and/or left circumflex (LCX, 5 patients) arteries and 10 involved the territories of left anterior descending artery (LAD) with some LCX involvement. Although both IR-FGRE and MCLE determined the presence and extent of LV MI, better visual contrast scores were achieved in MCLE (2.9 ± 0.3) compared with IR-FGRE (1.6 ± 0.8, P < 0.001). The CNRs of infarct relative to LV blood pool showed a significant statistical difference (n = 23, P < 0.00001) between MCLE (16.2 ± 7.2) and IR-FGRE images (4.8 ± 4.1), which is consistent with the result of visual contrast scores between infarct and LV blood pool. The CNRs of infarct versus viable myocardium did not demonstrate a significant statistical difference (n = 23, P = 0.61) between MCLE (14.4 ± 7.0) and IR-FGRE images (13.6 ± 6.1). MCLE clearly demonstrated PM-MI in all cases (100%, 23/23) while only 39% (9/23) could be visualized on the corresponding IR-FGRE images. In conclusion, MCLE imaging provides better contrast between blood pool and infarct myocardium, thus improving the determination of PM-MI., (Copyright © 2010 Wiley-Liss, Inc.)

The arrhythmogenic substrate in patients with prior myocardial infarct (MI) is located at the border zone, BZ. In this study we correlated the BZ identified by two methods: electro-anatomical voltage mapping (EAVM) and a novel MRI method, multi-contrast late enhancement (MCLE). A pre-clinical porcine model with chronic MI was used to characterize BZ via MRI and EAVM. Results focus on the comparison between scar percentage and BZ percentage identified by each method. The correlation coefficient for BZ percentage between the two methods was 0.74 with a p-value of less the 0.0001. Bland-Altman plots were also used to compare between the two methods (slope of 0.83 ± 0.045). For a case of subtle infarct, there was only 1.3% infarct identified on EAVM compared to 22.2% on the corresponding slice on MCLE. The percentage of infarct on MCLE in subtle infarct does not relate to percentage of infarct in EAVM. Future registration between T(1) maps and EAVM will permit a quantitative comparison of MRI and EAVM measures.