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The objective of this literature review was to develop International Stereotactic Radiosurgery Society (ISRS) consensus technical guidelines for the treatment of small, ≤1 cm in maximal diameter, intracranial metastases with stereotactic radiosurgery (SRS). Although different SRS technologies are available, most of them have similar treatment workflows and common technical challenges that are described. According to a systematic review of the literature, we present a summary of the latest evidence supporting our recommendations for best practice. In addition, several consensus statements from the ISRS guidelines committee are provided based on a patterns of practice questionnaire specifically focused on imaging specifications, target volume delineation and localisation practices, use of margins, treatment planning techniques and patient positioning.

OBJECTIVE With the incorporation of real-time image guidance on the Gamma Knife system allowing for mask-based immobilization (Gamma Knife Icon [GKI]), conventionally fully fractionated (1.8–3.0 Gy/day) GKI radiation can now be delivered to take advantage of an inherently minimal margin for delivery uncertainty, sharp dose falloff, and inhomogeneous dose distribution. This case series details the authors’ preliminary experience in re-irradiating 7 complex primary intracranial tumors, which were considered to have been previously maximally radiated and situated adjacent to critical organs at risk. METHODS The authors retrospectively reviewed all patients who received fractionated re-irradiation using GKI at the Sunnybrook Health Sciences Centre, University of Toronto, Ontario, Canada, between 2016 and 2021. Patients with brain metastases, and those who received radiotherapy courses in 5 or fewer fractions, were excluded. All radiotherapy doses were converted to the equivalent total dose in 2-Gy fractions (EQD2), with the assumption of an α/β ratio of 2 for late normal tissue toxicity and 10 for the tumor. RESULTS A total of 7 patients were included in this case series. Three patients had recurrent meningiomas, as well as 1 patient each with ependymoma, intracranial sarcoma, pituitary macroadenoma, and papillary pineal tumor. Six patients had undergone prior linear accelerator–based conventional fractionated radiotherapy and 1 patient had undergone prior proton therapy. Patients were re-irradiated with a median (range) total dose of 50.4 (30–63.4) Gy delivered in a median (range) of 28 (10–38) fractions with GKI. The median (range) target volume was 6.58 (0.2–46.3) cm3. The median (range) cumulative mean EQD2 administered to the tumor was 121.1 (107.9–181.3) Gy, and the median (range) maximum point EQD2 administered to the brainstem, optic nerves, and optic chiasm were 91.6 (74.0–111.5) Gy, 58.9 (6.3–102.9) Gy, and 59.9 (36.7–127.3) Gy, respectively. At a median (range) follow-up of 15 (6–42) months, 6 of 7 patients were alive with 4 having locally controlled disease. Only 3 patients experienced treatment-related toxicities, which were self-limited. CONCLUSIONS Fractionated radiotherapy using GKI may be a safe and effective method for the re-irradiation of complex progressive primary intracranial tumors, where the aim is to minimize the potential for serious late effects.

Introduction: Leptomeningeal disease (LMD) is a late complication of metastatic cancer that significantly limits patient survival. LMD is most prevalent in patients with melanoma, lung, and breast cancer, with incidence reaching 24.1% among those treated for brain metastases with both surgery and radiotherapy. As systemic treatment advances in oncology continue to improve patient survival, the incidence of LMD is expected to rise. This necessitates increased efforts to identify effective LMD therapies. Further, recent reporting of focal LMD in asymptomatic patients indicates that unique categories of LMD exist which may not necessarily portend a dismal prognosis. Unfortunately, exclusion of these patients from clinical trials has resulted in a paucity of high-quality evidence to guide management in this patient population. We therefore conducted a systematic review to determine the proportion and characteristics of phase III randomized clinical trials in breast cancer, lung cancer, and melanoma that included patients with LMD and/or included LMD-specific outcomes. Methods: The online ClinicalTrials.gov database was searched on December 22, 2020 for eligible phase III randomized control trials. No time limits were applied. The 1619 search results were screened by two independent reviewers for randomized, multi-arm therapeutic trials in advanced breast cancer, lung cancer, or melanoma. Results: 245 trials were included in this review, 75/245 (30.6%) of which included LMD-specific enrollment criteria. 67/245 (27.3%) trials explicitly excluded all patients with LMD, while 8 trials (3.3%) allowed conditional enrollment of patients with LMD; these stipulated that LMD must be asymptomatic/stable, and in some cases, treated. All 8 trials which conditionally allowed LMD patients to enroll were lung cancer trials. No temporal trend towards LMD inclusion was noted. CNS-specific outcomes, which did not include specific mention of LMD, were noted in 13/245 (5.4%) trials, 2 (15.4%) of which used standardized response criteria. No trials included LMD-specific outcomes. Conclusion: In this review, high rates of LMD exclusion and a complete lack of LMD-specific outcomes were noted in phase III trials for advanced breast cancer, lung cancer, and melanoma, despite these cancers carrying the highest risks of LMD. Lung cancer trials were most likely to include patients with LMD; this may be due to differences in tumor biology, drug penetration in the CNS and drug efficacy. Standardized and validated measures should be integrated into clinical trial design to facilitate inclusion of these patients when feasible and allow for meaningful assessment of LMD response to therapy. Table 1: Trial factors associated with exclusion of patients with leptomeningeal metastases a.based on study start date listed on clinicaltrials.gov, defined as “the actual date on which the first participant was enrolled in a clinical study.” b.based on studies with known location. Statistical test was between intercontinental versus single continent studies. Citation Format: Alisha Sharma, Kathryn Corbett, Maleeha Qazi, Hany Soliman, Arjun Sahgal, Sunit Das, Mary Jane Lim-Fat, Gregory R. Pond, Katarzyna Jerzak. Inclusion of Patients with Leptomeningeal Disease in Phase III Randomized Clinical Trials of Patients with Advanced Breast Cancer, Lung Cancer, and Melanoma: A Systematic Review [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P2-13-04.

OBJECTIVE Frailty has not been clearly defined in the context of spinal metastatic disease (SMD). Given this, the objective of this study was to better understand how members of the international AO Spine community conceptualize, define, and assess frailty in SMD. METHODS The AO Spine Knowledge Forum Tumor conducted an international cross-sectional survey of the AO Spine community. The survey was developed using a modified Delphi technique and was designed to capture preoperative surrogate markers of frailty and relevant postoperative clinical outcomes in the context of SMD. Responses were ranked using weighted averages. Consensus was defined as ≥ 70% agreement among respondents. RESULTS Results were analyzed for 359 respondents, with an 87% completion rate. Study participants represented 71 countries. In the clinical setting, most respondents informally assess frailty and cognition in patients with SMD by forming a general perception based on clinical condition and patient history. Consensus was attained among respondents regarding the association between 14 preoperative clinical variables and frailty. Severe comorbidities, extensive systemic disease burden, and poor performance status were most associated with frailty. Severe comorbidities associated with frailty included high-risk cardiopulmonary disease, renal failure, liver failure, and malnutrition. The most clinically relevant outcomes were major complications, neurological recovery, and change in performance status. CONCLUSIONS The respondents recognized that frailty is important, but they most commonly evaluate it based on general clinical impressions rather than using existing frailty tools. The authors identified numerous preoperative surrogate markers of frailty and postoperative clinical outcomes that spine surgeons perceived as most relevant in this population.

Background Bevacizumab (BEV), at a standard dose of 10 mg/kg every 2 weeks is associated with prolonged progression-free survival (PFS) but no improvement in overall survival (OS) in recurrent glioblastoma (rGBM). Few studies have examined the potential dose-dependent efficacy of BEV. In Ontario, reimbursement for the costs of BEV varies, and as a result, our practice began to routinely use lower dose regimens. The main aim of this study was to ensure that there was no harm to patients who received the low dose protocol. Methods A single-center retrospective study of patients given BEV for rGBM between 2015–2020 was performed. Clinical and treatment data including BEV dose regimen (SD [10 mg/kg every 2 weeks] vs LD [5 mg/kg every 2–3 weeks or 10 mg/kg every 3 weeks]) received at the time of rGBM diagnosis were captured. Overall survival (OS) and progression-free survival (PFS) on BEV were compared using the Kaplan-Meier product-limit method. Log-rank test was used to compare potential predictive factors. Cox regression model was performed for multivariable analysis of OS and PFS. Results A total of 96 patients were included with a median follow-up duration of 6.84 months (range 1.12–50.63 months) from the date of the first infusion. The LD group consisted of 55 of the 96 patients. By virtue of funding mechanisms for BEV, the median age in the LD group was significantly higher (62 vs 54 years p = 0.009). There was no difference in MGMT status between the 2 groups (p = 0.60). Eight patients received lomustine with BEV (3 from the SD and 5 from the LD. The LD group had prolonged median PFS (5.89 months versus 3.22 months; p = 0.0112) and OS (10.23 months versus 6.28 months; p = 0.0010). Multivariable analysis including the dose of BEV, the extent of resection, gender, and age revealed that standard dose of BEV, subtotal resection, and female sex were associated with worse overall survival. Nine patients in the SD group vs 18 patients in the LD group reported an adverse event related to BEV. Conclusions For patients with recurrent GBM, we found that a low dose regimen of BEV was associated with prolonged OS and PFS compared to the standard dose regimen. Lower dose schedules may be a better and more cost-effective option for patients with rGBM. Lower costs might provide more equitable access to this very important palliative drug.

A noticeable proportion of larger brain metastases (BMs) are not locally controlled after stereotactic radiotherapy, and it may take months before local progression is apparent on standard follow-up imaging. This work proposes and investigates new explainable deep-learning models to predict the radiotherapy outcome for BM. A novel self-attention-guided 3D residual network is introduced for predicting the outcome of local failure (LF) after radiotherapy using the baseline treatment-planning MRI. The 3D self-attention modules facilitate capturing long-range intra/inter slice dependencies which are often overlooked by convolution layers. The proposed model was compared to a vanilla 3D residual network and 3D residual network with CBAM attention in terms of performance in outcome prediction. A training recipe was adapted for the outcome prediction models during pretraining and training the down-stream task based on the recently proposed big transfer principles. A novel 3D visualization module was coupled with the model to demonstrate the impact of various intra/peri-lesion regions on volumetric multi-channel MRI upon the network's prediction. The proposed self-attention-guided 3D residual network outperforms the vanilla residual network and the residual network with CBAM attention in accuracy, F1-score, and AUC. The visualization results show the importance of peri-lesional characteristics on treatment-planning MRI in predicting local outcome after radiotherapy. This study demonstrates the potential of self-attention-guided deep-learning features derived from volumetric MRI in radiotherapy outcome prediction for BM. The insights obtained via the developed visualization module for individual lesions can possibly be applied during radiotherapy planning to decrease the chance of LF.

Stereotactic body radiation therapy (SBRT) improves complete pain response for painful spinal metastases compared with conventional external beam radiation therapy (cEBRT). We report mature local control and reirradiation rates in a large cohort of patients treated with SBRT versus cEBRT enrolled previously in the Canadian Clinical Trials Group Symptom Control 24 phase 2/3 trial.One hundred thirty-seven of 229 (60%) patients randomized to 24 Gy in 2 SBRT fractions or 20 Gy in 5 cEBRT fractions were retrospectively reviewed. By including all treated spinal segments, we report on 66 patients (119 spine segments) treated with SBRT and 71 patients (169 segments) treated with cEBRT. The primary outcomes were magnetic resonance-based local control and reirradiation rates for each treated spine segment.The median follow-up was 11.3 months (interquartile range, 5.3-27.7 months), and median overall survival in the SBRT and cEBRT cohorts were 21.6 (95% confidence interval [CI], 11.3, upper bound not reached) and 18.9 (95% CI, 12.2-29.1) months (P = .428), respectively. The cohorts were balanced with respect to radioresistant histology and presence of mass (paraspinal and/or epidural disease extension). Risk of local failure after SBRT versus cEBRT at 6, 12, and 24 months were 2.8% (95% CI, 0.8%-7.4%) versus 11.2% (95% CI, 6.9%-16.6%), 6.1% (95% CI, 2.5%-12.1%) versus 28.4% (95% CI, 21.3%-35.9%), and 14.8% (95% CI, 8.2-23.1%) versus 35.6% (95% CI, 27.8%-43.6%), respectively (P.001). cEBRT (hazard ratio [HR], 3.48; 95% CI, 1.94-6.25; P.001) and presence of mass (HR, 2.07; 95% CI, 1.29-3.31; P = .002) independently predicted local failure on multivariable analysis. The 1-year reirradiation rates and median times to reirradiation after SBRT versus cEBRT were 2.2% (95% CI, 0.4-7.0%) versus 15.8% (95% CI, 10.4%-22.3%) (P = .002) and 22.9 months versus 9.5 months, respectively. cEBRT (HR, 2.60; 95% CI, 1.27-5.30; P = .009) and radioresistant histology (HR, 2.00; 95% CI, 1.12-3.60; P = .020) independently predicted for reirradiation. Eight of 12 iatrogenic vertebral compression fractures were after SBRT and 4 of 12 after cEBRT; grade 3 adverse fracture effects were isolated to the SBRT cohort (5 of 12).Risk of local failure and reirradiation is lower with SBRT compared with cEBRT for spinal metastases. Although the iatrogenic vertebral compression fracture rates were within expectations, grade 3 vertebral compression fractures were isolated to the SBRT cohort.

Gamma Knife Icon-based hypofractionated stereotactic radiosurgery (GKI-HSRS) is a novel technical paradigm in the treatment of brain metastases that allows for both the dosimetric benefits of the GKI stereotactic radiosurgery (SRS) platform as well as the biologic benefits of fractionation. We report mature local control and adverse radiation effect (ARE) outcomes following 5 fraction GKI-HSRS for intact brain metastases.Patients with intact brain metastases treated with 5-fraction GKI-HSRS were retrospectively reviewed. Survival, local control, and adverse radiation effect rates were determined. Univariable and multivariable regression (MVA) were performed on potential predictive factors.Two hundred and ninety-nine metastases in 146 patients were identified. The median clinical follow-up was 10.7 months (range 0.5-47.6). The median total dose and prescription isodose was 27.5 Gy (range, 20-27.5) in 5 daily fractions and 52% (range, 45-93), respectively. The median overall survival (OS) was 12.7 months, and the 1-year local failure rate was 15.2%. MVA identified a total dose of 27.5 Gy vs. ≤ 25 Gy (hazard ratio [HR] 0.59, p = 0.042), and prior chemotherapy exposure (HR 1.99, p = 0.015), as significant predictors of LC. The 1-year ARE rate was 10.8% and the symptomatic ARE rate was 1.8%. MVA identified a gross tumor volume of ≥ 4.5 cc (HR 7.29, p 0.001) as a significant predictor of symptomatic ARE.Moderate total doses in 5 daily fractions of GKI-HSRS were associated with high rates of LC and a low incidence of symptomatic ARE.

A considerable proportion of metastatic brain tumors progress locally despite stereotactic radiation treatment, and it can take months before such local progression is evident on follow-up imaging. Prediction of radiotherapy outcome in terms of tumor local failure is crucial for these patients and can facilitate treatment adjustments or allow for early salvage therapies.In this work, a novel deep learning architecture is introduced to predict the outcome of local control/failure in brain metastasis treated with stereotactic radiation therapy using treatment-planning magnetic resonance imaging (MRI) and standard clinical attributes.At the core of the proposed architecture is an InceptionResentV2 network to extract distinct features from each MRI slice for local outcome prediction. A recurrent or transformer network is integrated into the architecture to incorporate spatial dependencies between MRI slices into the predictive modeling. A visualization method based on prediction difference analysis is coupled with the deep learning model to illustrate how different regions of each lesion on MRI contribute to the model's prediction. The model was trained and optimized using the data acquired from 99 patients (116 lesions) and evaluated on an independent test set of 25 patients (40 lesions).The results demonstrate the promising potential of the MRI deep learning features for outcome prediction, outperforming standard clinical variables. The prediction model with only clinical variables demonstrated an area under the receiver operating characteristic curve (AUC) of 0.68. The MRI deep learning models resulted in AUCs in the range of 0.72 to 0.83 depending on the mechanism to integrate information from MRI slices of each lesion. The best prediction performance (AUC = 0.86) was associated with the model that combined the MRI deep learning features with clinical variables and incorporated the inter-slice dependencies using a long short-term memory recurrent network. The visualization results highlighted the importance of tumor/lesion margins in local outcome prediction for brain metastasis.The promising results of this study show the possibility of early prediction of radiotherapy outcome for brain metastasis via deep learning of MRI and clinical attributes at pre-treatment and encourage future studies on larger groups of patients treated with other radiotherapy modalities.

Patients with small-cell lung cancer (SCLC) are at high risk for intracranial metastatic disease (IMD). Although stereotactic radiosurgery (SRS) has supplanted whole brain radiotherapy (WBRT) as first-line treatment for IMD in most solid cancers, WBRT remains first-line treatment for IMD in patients with SCLC. We aimed to evaluate the efficacy of SRS in comparison with WBRT and assess treatment outcomes following SRS.In this systematic review and meta-analysis, we searched MEDLINE, Embase, CENTRAL, and grey literature sources for controlled trials and cohort studies published in English reporting on SRS for IMD treatment in patients with SCLC from inception to March 23, 2022. Studies were excluded that did not report on SRS for IMD secondary to SCLC. Summary data were extracted. The primary outcome was overall survival, presented as pooled hazard ratios (HR) through random-effects meta-analysis for studies comparing SRS with WBRT with or without SRS boost, and as medians for single-arm SRS studies. This study is registered with the Open Science Framework, DOI 10.17605/OSF.IO/8M4HC, and PROSPERO, CRD42021258197.Of 3823 identified records, 31 were eligible for inclusion; seven were included in the meta-analysis. Overall survival following SRS was longer than following WBRT with or without SRS boost (HR 0·85; 95% CI 0·75-0·97; n=7 studies; n=18 130 patients), or WBRT alone (0·77; 0·72-0·83; n=7 studies; n=16 961 patients), but not WBRT plus SRS boost (1·17, 0·78-1·75; n=4 studies; n=1167 patients). Using single-arm studies, pooled median overall survival from SRS was 8·99 months (95% CI 7·86-10·16; n=14 studies; n=1682 patients). Between-study heterogeneity was considerable when pooled among all comparative studies (IThese results suggest survival outcomes are equitable following treatment with SRS compared with WBRT in patients with SCLC and IMD. Future prospective studies should focus on tumour burden and differences in local and distant intracranial progression between WBRT-treated and SRS-treated patients with SCLC.None.

Postoperative management of lower grade gliomas (grade 2 and 3) is heterogeneous. The American Radium Society's brain malignancies panel systematically reviewed and evaluated the literature to develop consensus guidelines addressing timing of postoperative therapy, monotherapy versus combined modality therapy, type of chemotherapy used with radiotherapy, and radiotherapy dose. Thirty-six studies were included. Using consensus methodology (modified Delphi), the panel voted upon representative case variants using a 9-point appropriateness scale to address key questions. Voting results were collated to develop summarized recommendations. Following gross-total surgical resection, close surveillance is appropriate for well-selected grade 2, IDH-mutant oligodendrogliomas or astrocytomas with low-risk features. For grade 2 gliomas with high-risk features or any grade 3 glioma, immediate adjuvant therapy is recommended. When postoperative therapy is administered, radiation and planned chemotherapy is strongly recommended over monotherapy. For grade 2 and 3 IDH-mutant oligodendrogliomas and astrocytomas, either adjunctive PCV (procarbazine, lomustine, vincristine) or temozolomide is appropriate. For grade 3 IDH-mutant astrocytomas, radiotherapy followed by temozolomide is strongly recommended. The recommended radiotherapy dose for grade 2 gliomas is 45-54 Gy/1.8-2.0 Gy, and for grade 3 gliomas is 59.4-60 Gy/1.8-2.0 Gy. While multiple appropriate treatment options exist, these consensus recommendations provide an evidence-based framework to approach postoperative management of lower grade gliomas.

Purpose: Mask-immobilized stereotactic radiosurgery (SRS) using a gating window is an emerging technology. However, the amount of intracranial tumor motion that can be tolerated during treatment while satisfying clinical dosimetric goals is unknown. The purpose of this study was to quantify the sensitivity of target dose to tumor motion. Methods and Materials: In clinical SRS plans, where a nose marker was tracked as surrogate for target motion, translational and rotational target movements were simulated using nose-marker displacements of ±0.5 mm, ±1.0 mm, or ±1.5 mm. The effect on minimum dose to 99% of the target (D99) and percent target coverage by prescription dose was quantified using mixed-effect modeling with variables: displacement, target volume, and location. Results: The effect on dose metrics is statistically larger for translational displacements compared with rotational displacements, and the effect of pitch rotations is statistically larger compared with yaw rotations. The mixed-effect model for translations showed that displacement and target volume are statistically significant variables, for rotation the variable target distance to rotation axis is additionally significant. For mean target volume (12.6 cc) and translational nose-marker displacements of 0.5 mm, 1.0 mm, and 1.5 mm, D99 decreased by 2.2%, 7.1%, and 13.0%, and coverage by 0.4%, 1.8%, and 4.4%, respectively. For mean target volume, mean distance midpoint-target to pitch axis (7.6cm), and rotational nose-marker displacement of 0.5 mm, 1.0 mm, and 1.5 mm, D99 decreased by 1.0%, 3.6%, and 6.9%, and coverage by 0.2%, 0.8%, and 1.9%, respectively. For rotational yaw axis displacement, mean distance midpoint-target axis (4.2cm), D99 decreased by 0.3%, 1.2%, and 2.5%, and coverage by 0.1%, 0.2%, and 0.5%, respectively. Conclusions: Simulated target displacements showed that sensitivity of tumor dose to motion depends on both target volume and target location. Suggesting that patient- and target-specific thresholds may be implemented for optimizing the balance between dosimetric plan accuracy and treatment prolongation caused by out-of-tolerance motion.

OBJECTIVE A systematic review was performed to provide objective evidence on the use of stereotactic radiosurgery (SRS) in the management of secretory pituitary adenomas and develop consensus recommendations. METHODS The authors performed a systematic review of the English-language literature up until June 2018 using the PRISMA guidelines. The PubMed (Medline), Embase, and Cochrane databases were searched. A total of 45 articles reporting single-institution outcomes of SRS for acromegaly, Cushing’s disease, and prolactinomas were selected and included in the analysis. RESULTS For acromegaly, random effects meta-analysis estimates for crude tumor control rate, crude endocrine remission rate, and any new hypopituitarism rates were 97.0% (95% CI 96.0%–98.0%), 44.0% (95% CI 35.0%–53.0%), and 17.0% (95% CI 13.0%–23.0%), respectively. For Cushing’s disease, random effects estimates for crude tumor control rate, crude endocrine remission rate, and any new hypopituitarism rate were 92.0% (95% CI 87.0%–95.0%), 48.0% (95% CI 35.0%–61.0%), and 21.0% (95% CI 13.0%–31.0%), respectively. For prolactinomas, random effects estimates for crude tumor control rate, crude endocrine remission rate, and any new hypopituitarism rate were 93.0% (95% CI 90.0%–95.0%), 28.0% (95% CI 19.0%–39.0%), and 12.0% (95% CI 6.0%–24.0%), respectively. Meta-regression analysis did not show a statistically significant association between mean margin dose with crude endocrine remission rate or mean margin dose with development of any new hypopituitarism rate for any of the secretory subtypes. CONCLUSIONS SRS offers effective tumor control of hormone-producing pituitary adenomas in the majority of patients but a lower rate of endocrine improvement or remission.

Background: The incidence of brain metastases (BrM) has steadily increased over time as women with metastatic breast cancer (MBC) live longer and survive to experience spread of cancer to the central nervous system (CNS). Women with triple negative and HER2+ MBC, which represent 30-40% of the MBC population, are at particularly high risk of BrM. At present, MBC patients are not screened for BrM; rather, they undergo imaging of the brain only after symptoms suggestive of CNS involvement develop. Unfortunately, by the time that patients experience potentially debilitating symptoms of BrM, they often have a significant burden of disease with limited treatment options and a poor prognosis. We hypothesize that early detection of BrM via magnetic resonance imaging (MRI)-based screening may allow for early intervention and, ultimately, improved outcomes for MBC patients. Methods: A multi-centre, open-label prospective phase II study, randomizing 50 women with triple negative or HER2+ MBC to either MRI-based BrM screening or symptom-directed surveillance. Randomization is stratified for tumor subtype. Intervention arm: Contrast-enhanced MRI of the brain at baseline, 4-, 8- and 12-months with concurrent chemical exchange saturation transfer (CEST) imaging, a new metabolic MRI sequence that may detect BrM even earlier than standard MRI. Control arm: Symptom-directed surveillance (brain imaging only if patients develop symptoms suggestive of BrM). All participants complete questionnaires at baseline, 6- and 15-months to assess overall (EORTC QLQ BN20) and neurologic-specific (FACT-BR tools) quality of life (QoL) as well as cancer-related anxiety (NCI PRO-CTCAE). A blood sample is collected for ctDNA analysis at baseline in all patients at diagnosis of BrM, if applicable. Key inclusion criteria: 1) Age ≥18; 2) Triple negative MBC, with metastatic disease diagnosed ≤12 weeks prior to study entry OR HER2+ MBC with no restrictions regarding timeline of diagnosis; 3) No symptoms of BrM or known asymptomatic BrM at study entry. Key exclusion criteria: 1) ECOG>2; 2) Inability to complete an MRI (e.g., claustrophobia). Analyses: The primary goal of this study is to determine the feasibility of a randomized trial of BrM screening versus symptom-directed surveillance in the proposed patient population. The pilot study will be considered “not feasible” if 50% of patients allocated to the control arm are screened for BrM with CT or MRI. Overall survival will be assessed as a secondary endpoint. We will also investigate how screening for BrM influences the detection rate of BrM and explore how subsequent intervention affects both overall and neurologic-specific QoL. Our data will enable a power calculation to determine a sample size for a future, larger trial. 28 of 50 planned patients have enrolled in the study to-date. Citation Format: Katarzyna J Jerzak, Arjun Sahgal, Gregory Pond, Priscilla K Brastianos, Orit Freedman, Gregory Stanisz, Ellen Warner. MRI screening versus symptom-directed surveillance for brain metastases among patients with triple negative or HER2+ metastatic breast cancer: A pilot study (nct03881605) [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr OT1-07-01.

Purpose Despite the increasing use of stereotactic body radiation therapy for non–spine bone metastases (NSBM), there is no established standard for target delineation. The objective of this study was to provide consensus recommendations on clinical target volume (CTV) delineation based on international expert contours. Methods and Materials Eleven cases of NSBM were contoured by 9 international radiation oncologists. For each case, the gross tumor volume was provided on the simulation computed tomography scans with accompanying magnetic resonance imaging. Participants contoured the CTV and completed a clinical survey. Agreement between CTV contours were analyzed with simultaneous truth and performance level estimation using the kappa coefficient and the Dice similarity coefficient (DSC) and summarized to establish contouring recommendations. A direction-dependent analysis was applied to the consensus contours to quantify margins. Results All CTV contours were completed. Six participants used a single-dose level, whereas 3 used a 2-dose level simultaneous integrated boost (SIB) technique. For the SIB cases, the largest volume receiving a stereotactic body radiation therapy (SBRT) dose was used for contour analysis. There was substantial agreement between contours across cases with a mean kappa of 0.72 (mean sensitivity 0.85, mean specificity 0.97). The mean DSC value was 0.77 (range, 0.67-0.87). Consensus CTV contouring recommendations were (1) an intraosseous CTV margin of 5 to 10 mm should be strongly considered within contiguous bone; (2) an extraosseous margin of 5 to 10 mm should be strongly considered where there is soft tissue disease or cortical bone disruption; (3) CTVs should be manually cropped to respect anatomic barriers to spread (eg, peritoneal cavity, pleura, uninvolved joint space and cortical bone). Conclusions CTV contouring recommendations for NSBM-SBRT were established based on analysis of international expert consensus contours with a high level of agreement. These principles may provide guidance to treating physicians and inform future study until prospective clinical data can provide further refinement.

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 (pConclusion: Imaging features extracted from the GTV and CTV regions can lead to risk-stratification of GBM undergoing biopsy, while it was redundant for patients with GTR and STR.

Table S1 highlights the inclusion/exclusion criteria for the PDT clinical trial in table format.

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/m2 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.

Figure S1 shows an overview of the PDT fiber set-up and placement for a kyphoplasty case.

Background Preclinical studies have demonstrated focused ultrasound (FUS) stimulated microbubble (MB) rupture leads to the activation of acid sphingomyelinase-ceramide pathway in the endothelial cells. When radiotherapy (RT) is delivered concurrently with FUS-MB, apoptotic pathway leads to increased cell death resulting in potent radiosensitization. Here we report the first human trial of using magnetic resonance imaging (MRI) guided FUS-MB treatment in the treatment of breast malignancies. Methods In the phase 1 prospective interventional study, patients with breast cancer were treated with fractionated RT (5 or 10 fractions) to the disease involving breast or chest wall. FUS-MB treatment was delivered before 1st and 5th fractions of RT (within 1 hour). Results 8 patients with 9 tumours were treated. All 7 evaluable patients with at least 3 months follow-up treated for 8 tumours had a complete response in the treated site. The maximum acute toxicity observed was grade 2 dermatitis in 1 site, and grade 1 in 8 treated sites, at one month post RT, which recovered at 3 months. No RT-related late effect or FUS-MB related toxicity was noted. Conclusions This study demonstrated safety of combined FUS-MB and RT treatment. Promising response rates suggest potential strong radiosensitization effects of the investigational modality. Trial registration: clinicaltrials.gov, identifier NCT04431674

Purpose Integrating magnetic resonance (MR) into radiotherapy planning has several advantages. This report details the clinical implementation of an MR simulation (MR-planning) program for external beam radiotherapy (EBRT) in one of North America's largest radiotherapy programs. Methods and materials An MR radiotherapy planning program was developed and implemented at Sunnybrook Health Sciences Center in 2016 with two dedicated wide-bore MR platforms (1.5 and 3.0 Tesla). Planning MR was sequentially implemented every 3 months for separate treatment sites, including the central nervous system (CNS), gynecologic (GYN), head and neck (HN), genitourinary (GU), gastrointestinal (GI), breast, and brachial plexus. Essential protocols and processes were detailed in this report, including clinical workflow, optimized MR-image acquisition protocols, MR-adapted patient setup, strategies to overcome risks and challenges, and an MR-planning quality assurance program. This study retrospectively reviewed simulation site data for all MR-planning sessions performed for EBRT over the past 5 years. Results From July 2016 to December 2021, 8798 MR-planning sessions were carried out, which corresponds to 25% of all computer tomography (CT) simulations (CT-planning) performed during the same period at our institution. There was a progressive rise from 80 MR-planning sessions in 2016 to 1126 in 2017, 1492 in 2018, 1824 in 2019, 2040 in 2020, and 2236 in 2021. As a result, the relative number of planning MR/CT increased from 3% of all planning sessions in 2016 to 36% in 2021. The most common site of MR-planning was CNS (49%), HN (13%), GYN (12%), GU (12%), and others (8%). Conclusion Detailed clinical processes and protocols of our MR-planning program were presented, which have been improved over more than 5 years of robust experience. Strategies to overcome risks and challenges in the implementation process are highlighted. Our work provides details that can be used by institutions interested in implementing an MR-planning program.

Background Despite the paucity of prospective evidence, stereotactic radiotherapy (SRT) is increasingly being considered in the setting of oligoprogression to delay the need to change systemic therapy. Objective To determine the local control (LC), progression-free survival (PFS), cumulative incidence of changing systemic therapy, and overall survival (OS) after SRT to oligoprogressive metastatic renal cell carcinoma (mRCC) lesions in patients who are on tyrosine kinase inhibitor (TKI) therapy. Design, setting, and participants A prospective multicenter study was performed to evaluate the use of SRT in oligoprogressive mRCC patients. Patients with mRCC who had previous stability or response after ≥3 mo of TKI therapy were eligible if they developed progression of five of fewer metastases. Thirty-seven patients with 57 oligoprogressive tumors were enrolled. Intervention Oligoprogressive tumors were treated with SRT, and the same TKI therapy was continued afterward. Outcome measurements and statistical analysis Competing risk analyses and the Kaplan-Meir methodology were used to report the outcomes of interest. Results and limitations The median duration of TKI therapy prior to study entry was 18.6 mo; 1-yr LC of the irradiated tumors was 93% (95% confidence interval [CI] 71–98%). The median PFS after SRT was 9.3 mo (95% CI 7.5–15.7 mo). The cumulative incidence of changing systemic therapy was 47% (95% CI 32–68%) at 1 yr, with a median time to change in systemic therapy of 12.6 mo (95% CI 9.6–17.4 mo). One-year OS was 92% (95% CI 82–100%). There were no grade 3–5 SRT-related toxicities. Conclusions LC of irradiated oligoprogressive mRCC tumors was high, and the need to change systemic therapy was delayed for a median of >1 yr. Patient summary The use of stereotactic radiotherapy in metastatic kidney cancer patients, who develop growth of a few tumors while on oral targeted therapy, can significantly delay the need to change to the next line of drug therapy.

Purpose: High-field magnetic resonance-linear accelerators (MR-Linacs), linear accelerators combined with a diagnostic magnetic resonance imaging (MRI) scanner and online adaptive workflow, potentially give rise to novel online anatomic and response adaptive radiation therapy paradigms. The first high-field (1.5T) MR-Linac received regulatory approval in late 2018, and little is known about clinical use, patient tolerability of daily high-field MRI, and toxicity of treatments. Herein we report the initial experience within the MOMENTUM Study (NCT04075305), a prospective international registry of the MRLinac Consortium. Methods and Materials: Patients were included between February 2019 and October 2020 at 7 institutions in 4 countries. We used descriptive statistics to describe the patterns of care, tolerability (the percentage of patients discontinuing their course early), and safety (grade 3-5 Common Terminology Criteria for Adverse Events v.5 acute toxicity within 3 months after the end of treatment). Results: A total 943 patients participated in the MOMENTUM Study, 702 of whom had complete baseline data at the time of this analysis. Patients were primarily male (79%) with a median age of 68 years (range, 22-93) and were treated for 39 different indications. The most frequent indications were prostate (40%), oligometastatic lymph node (17%), brain (12%), and rectal (10%) cancers. The median number of fractions was 5 (range, 1-35). Six patients discontinued MR-Linac treatments, but none due to an inability to tolerate repeated high-field MRI. Of the 415 patients with complete data on acute toxicity at 3 month follow-up, 18 (4%) patients experienced grade 3 acute toxicity related to radiation. No grade 4 or 5 acute toxicity related to radiation was observed. Conclusions: In the first 21 months of our study, patterns of care were diverse with respect to clinical utilization, body sites, and radiation prescriptions. No patient discontinued treatment due to inability to tolerate daily high-field MRI scans, and the acute radiation toxicity experience was encouraging. (c) 2021 Published by Elsevier Inc.

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.

Despite manifold advances in oncology, cancers of the central nervous system remain among the most lethal. Unique features of the brain, including distinct cellular composition, immunological privilege, and physical barriers to therapeutic delivery, likely contribute to the poor prognosis of patients with neuro-oncological disease. Focused ultrasound is an emerging technology that allows transcranial delivery of ultrasound energy to focal brain targets with great precision. A review of the clinical and preclinical focused ultrasound literature was performed to obtain data regarding the current state of the focused ultrasound in context of neuro-oncology. A narrative review was then constructed to provide an overview of current and future applications of this technology. Focused ultrasound can facilitate direct control of tumors by thermal or mechanical ablation, as well as enhance delivery of diverse therapeutics by disruption of the blood–brain barrier without local tissue damage. Indeed, ultrasound-sensitive drug formulations or sonosensitizers may be combined with ultrasound blood–brain barrier disruption to achieve high local drug concentration while limiting systemic exposure to therapeutics. Furthermore, focused ultrasound can induce radiosensitization, immunomodulation, and neuromodulation. Here we review applications of focused ultrasound with a focus on approaches currently under clinical investigation for the treatment of neuro-oncological disease, such as blood–brain barrier disruption for drug delivery and thermal ablation. We also discuss design of clinical trials, selection of patient cohorts, and emerging approaches to improve the efficacy of transcranial ultrasound, such as histotripsy, as well as combinatorial strategies to exploit synergistic biological effects of existing cancer therapies and ultrasound. Focused ultrasound is a promising and actively expanding therapeutic modality for diverse neuro-oncological diseases.

Brain metastases (BM) in metastatic renal cell carcinoma (mRCC) have been reported to be present in up to 25% of patients diagnosed with mRCC. There is limited published literature evaluating the role of routine intra-cranial imaging for the screening of asymptomatic BM in mRCC.To evaluate the potential utility of routine intra-cranial imaging, a retrospective cohort study was conducted to characterize the outcomes of mRCC patients who presented with asymptomatic BM, as compared to symptomatic BM.The Canadian Kidney Cancer Information System (CKCis) database was used to identify mRCC patients diagnosed with BM. This cohort was divided into two groups based on the presence or absence of BM symptoms. Details regarding patient demographics, disease characteristics, systemic treatments, BM characteristics and survival outcomes were extracted. Statistical analysis was through chi-square tests, analysis of variance, and Kaplan-Meier method to characterize survival outcomes. A p-value of0.05 was considered statistically significant for all analyses. A total of 267 mRCC patients with BM were identified of which 106 (40%) presented with asymptomatic disease. The majority of patients presented with multiple (i.e.,1) BM (75%) with no significant differences noted in number of BM or BM-directed therapy received in symptomatic, as compared to asymptomatic BM patients. Median [95% confidence interval (CI)] overall survival (OS) from mRCC diagnosis was 42 months (95% CI: 32-62) for patients with asymptomatic BM, and 39 months (95% CI: 29-48) with symptomatic BM (p = 0.10). OS from time of BM diagnosis was 28 months (95% CI: 18-42) for the asymptomatic BM group, as compared to 13 months (95% CI: 10-21) in the symptomatic BM group (p = 0.04).Given a substantial proportion of patients may present with asymptomatic BM, limiting intra-cranial imaging to patients with symptomatic BM, may be associated with a missed opportunity for timely diagnosis and treatment. The utility of routine intra-cranial imaging in patients with renal cell carcinoma, warrants further prospective evaluation.

PurposeThis study reports the workflow and initial clinical experience of high grade glioma (HGG) radiotherapy on the 1.5 T MR-Linac (MRL), with a focus on the temporal variations of the tumor and feasibility of multi-parametric image (mpMRI) acquisition during routine treatment workflow.Materials and methodsTen HGG patients treated with radiation within the first year of the MRL’s clinical operation, between October 2019 and August 2020, were identified from a prospective database. Workflow timings were recorded and online adaptive plans were generated using the Adapt-To-Position (ATP) workflow. Temporal variation within the FLAIR hyperintense region (FHR) was assessed by the relative FHR volumes (n = 281 contours) and migration distances (maximum linear displacement of the volume). Research mpMRIs were acquired on the MRL during radiation and changes in selected functional parameters were investigated within the FHR.ResultsAll patients completed radiotherapy to a median dose of 60 Gy (range, 54-60 Gy) in 30 fractions (range, 30-33), receiving a total of 287 fractions on the MRL. The mean in-room time per fraction with or without post-beam research imaging was 42.9 minutes (range, 25.0–69.0 minutes) and 37.3 minutes (range, 24.0–51.0 minutes), respectively. Three patients (30%) required re-planning between fractions 9 to 12 due to progression of tumor and/or edema identified on daily MRL imaging. At the 10, 20, and 30-day post-first fraction time points 3, 3, and 4 patients, respectively, had a FHR volume that changed by at least 20% relative to the first fraction. Research mpMRIs were successfully acquired on the MRL. The median apparent diffusion coefficient (ADC) within the FHR and the volumes of FLAIR were significantly correlated when data from all patients and time points were pooled (R=0.68, pConclusionWe report the first clinical series of HGG patients treated with radiotherapy on the MRL. The ATP workflow and treatment times were clinically acceptable, and daily online MRL imaging triggered adaptive re-planning for selected patients. Acquisition of mpMRIs was feasible on the MRL during routine treatment workflow. Prospective clinical outcomes data is anticipated from the ongoing UNITED phase 2 trial to further refine the role of MR-guided adaptive radiotherapy.

To evaluate the cumulative incidence of fracture and local failure and associated risk factors after stereotactic body radiation therapy (SBRT) for long bone metastases.Data from 111 patients with 114 metastases in the femur, humerus, and tibia treated with SBRT in 7 international centers between October 2011 and February 2021 were retrospectively reviewed and analyzed using a competing risk regression model.The median follow-up was 21 months (range, 6-91 months). All but 1 patient had a Karnofsky performance status ≥70. There were 84 femur (73.7%), 26 humerus (22.8%), and 4 tibia (3.5%) metastases from prostate (45 [39.5%]), breast (22 [19.3%]), lung (15 [13.2%]), kidney (13 [11.4%]), and other (19 [16.6%]) malignancies. Oligometastases accounted for 74.8% of metastases and 28.1% were osteolytic. The most common total doses were 30 to 50 Gy in 5 daily fractions (50.9%). Eight fractures (5 in the femur, 2 in the tibia, and 1 in the humerus) were observed with a median time to fracture of 12 months (range, 0.8-33 months). In 6 out of 8 patients, fracture was not associated with local failure. The cumulative incidence of fracture was 3.5%, 6.1%, and 9.8% at 1, 2, and 3 years, respectively. The cumulative incidence of local failure (9/110 metastases with imaging follow-up) was 5.7%, 7.2%, and 13.5% at 1, 2, and 3 years, respectively. On multivariate analysis, extraosseous disease extension was significantly associated with fracture (P = .001; subhazard ratio, 10.8; 95% confidence interval, 2.8-41.9) and local failure (P = .02; subhazard ratio, 7.9; 95% confidence interval, 1.4-44.7).SBRT for metastases in long bones achieved high rates of durable local metastasis control without an increased risk of fracture. Similar to spine SBRT, patients with extraosseous disease extension are at higher risk of local failure and fracture.

Background To evaluate the potential intracranial efficacy of immunotherapy among patients with breast cancer brain metastases (BrM), we analyzed the immunohistochemical expression of programmed death-ligand 1 (PD-L1), a predictive biomarker of response to immunotherapy. Methods In this single-center retrospective cohort study, consecutive patients with breast cancer BrM (immunotherapy naïve) who underwent surgery for BrM at Sunnybrook Health Sciences Center between July 1999 and June 2013 were identified. PD-L1 expression by immunohistochemistry (IHC) was assessed on BrM samples in triplicate; PD-L1 positive status was defined as PD-L1 expression ≥1% on tumor-infiltrating cells as a percentage of tumor area using the Ventana SP142 antibody. Estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor (HER2) status was determined using 2018 ASCO/CAP guidelines. Results The median patient age at the time of BrM diagnosis was 52 (range 32–85). PD-L1 expression using the SP42 antibody was identified in 9 out of 59 (15.3%) breast cancer BrM. The frequency of PD-L1 positive BrM by subtype is as follows: TNBC (n = 3/12, 25.0%), HER2+/HR- (n = 3/14, 21.4%), HR+/HER2- (n = 2/18, 11.1%), and HER2+/HR+ (n = 1/14, 7.1%). 24-month brain-specific progression-free survival was 66.7% (95% CI 37.9%–100%) among patients with PD-L1 positive BrM versus 42% (95% CI 26.6%–67.3%) among those with PD-L1 negative BrM (log-rank P-value .142). Conclusions One in 7 patients in our cohort had PD-L1 positive BrM; this proportion was highest (25%) among those with TNBC. Intracranial efficacy of immunotherapy warrants further study, particularly among patients with treatment-naïve metastatic TNBC, for whom extracranial efficacy has already been established.

Background This study was conducted in order to develop a model for predicting response to neoadjuvant chemotherapy (NAC) in patients with locally advanced breast cancer (LABC) using pretreatment quantitative ultrasound (QUS) radiomics. Methods This was a multicenter study involving four sites across North America, and appropriate approval was obtained from the individual ethics committees. Eighty‐two patients with LABC were included for final analysis. Primary tumors were scanned using a clinical ultrasound system before NAC was started. The tumors were contoured, and radiofrequency data were acquired and processed from whole tumor regions of interest. QUS spectral parameters were derived from the normalized power spectrum, and texture analysis was performed based on six QUS features using a gray level co‐occurrence matrix. Patients were divided into responder or nonresponder classes based on their clinical‐pathological response. Classification analysis was performed using machine learning algorithms, which were trained to optimize classification accuracy. Cross‐validation was performed using a leave‐one‐out cross‐validation method. Results Based on the clinical outcomes of NAC treatment, there were 48 responders and 34 nonresponders. A K‐nearest neighbors (K‐NN) approach resulted in the best classifier performance, with a sensitivity of 91%, a specificity of 83%, and an accuracy of 87%. Conclusion QUS‐based radiomics can predict response to NAC based on pretreatment features with acceptable accuracy., This multi‐institutional study investigated the role of radiomics from quantitative ultrasound (QUS) in predicting the final response to neoadjuvant chemotherapy (NAC) for 82 patients with locally advanced breast cancer (LABC). We had shown the QUS‐radiomics model can predict the response to treatment with an accuracy of 87% from spectroscopic features obtained before the start of NAC.

Background Breast cancer is the most common cancer among women worldwide and the second leading cause of brain metastases (BrM). We assessed the treatment patterns and outcomes of women treated for breast cancer BrM at our institution in the modern era of stereotactic radiosurgery (SRS). Materials and Methods We conducted a retrospective analysis of women (≥18 years of age) with metastatic breast cancer who were treated with surgery, whole brain radiotherapy (WBRT), or SRS to the brain at the Sunnybrook Odette Cancer Centre, Toronto, Canada, between 2008 and 2018. Patients with a history of other malignancies and those with an uncertain date of diagnosis of BrM were excluded. Descriptive statistics were generated and survival analyses were performed with subgroup analyses by breast cancer subtype. Results Among 683 eligible patients, 153 (22.4%) had triple-negative breast cancer, 188 (27.5%) had HER2+, 246 (36.0%) had hormone receptor (HR)+/HER2−, and 61 (13.3%) had breast cancer of an unknown subtype. The majority of patients received first-line WBRT (n = 459, 67.2%) or SRS (n = 126, 18.4%). The median brain-specific progression-free survival and median overall survival (OS) were 4.1 months (interquartile range [IQR] 1.0–9.6 months) and 5.1 months (IQR 2.0–11.7 months) in the overall patent population, respectively. Age >60 years, presence of neurological symptoms at BrM diagnosis, first-line WBRT, and HER2− subtype were independently prognostic for shorter OS. Conclusion Despite the use of SRS, outcomes among patients with breast cancer BrM remain poor. Strategies for early detection of BrM and central nervous system–active systemic therapies warrant further investigation. Implications for Practice Although triple-negative breast cancer and HER2+ breast cancer have a predilection for metastasis to the central nervous system (CNS), patients with hormone receptor–positive/HER2− breast cancer represent a high proportion of patients with breast cancer brain metastases (BrM). Hence, clinical trials should include patients with BrM and evaluate CNS-specific activity of novel systemic therapies when feasible, irrespective of breast cancer subtype. In addition, given that symptomatic BrM are associated with shorter survival, this study suggests that screening programs for the early detection and treatment of breast cancer BrM warrant further investigation in an era of minimally toxic stereotactic radiosurgery.

Background Stereotactic body radiotherapy (SBRT) is increasingly used to treat oligometastatic disease (OMD), but the effect of metastasis timing on patient outcomes remains uncertain. Methods An international database of patients with OMD treated with SBRT was assembled with rigorous quality assurance. Early versus late metastases were defined as those diagnosed ≤24 versus >24 months from the primary tumor. Overall survival (OS), progression‐free survival (PFS), and incidences of wide‐spread progression (WSP) were estimated using multivariable Cox proportional hazard models stratified by primary tumor types. Results The database consists of 1033 patients with median follow‐up of 24.1 months (0.3–104.7). Late metastatic presentation (N = 427) was associated with improved OS compared to early metastasis (median survival 53.6 vs. 33.0 months, hazard ratio [HR] 0.59, 95% confidence interval [CI]: 0.47–0.72, p, Despite the increasing utilization of stereotactic body radiotherapy (SBRT) for patients with oligometastasic disease (OMD), prognostic and predictive factors for this treatment modality are not well understood. In this analysis of a large, multi‐institutional database of SBRT for OMD, the timing of metastatic presentation is a significant prognostic factor, as patients with late metastasis (>24 months from cancer diagnosis) have lower risk of widespread progression and death after SBRT.

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 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.

Study design General population utility valuation study. Objective The aim of this study was to develop a technique for calculating utilities from the Spine Oncology Study Group Outcomes Questionnaire v2.0 (SOSGOQ2.0). Summary of background data The ability to calculate quality-adjusted life-years (QALYs) for metastatic spine disease would enhance treatment decision-making and facilitate economic analysis. QALYs are calculated using utilities. Methods Using a hybrid concept-retention and factorial analysis shortening approach, we first shortened the SOSGOQ2.0 to eight items (SOSGOQ-8D). This was done to lessen the cognitive burden of the utility valuation exercise. A general population sample of 2730 adults was then asked to evaluate 12 choice sets based on SOSGOQ-8D health states in a Discrete Choice Experiment. A utility scoring rubric was then developed using a mixed multinomial-logit regression model. Results We were able to reduce the SOSGOQ2.0 to an SOSGOQ-8D with a mean error of 0.003 and mean absolute error of 3.078 compared to the full questionnaire. The regression model demonstrated good predictive performance and was used to develop a utility scoring rubric. Regression results revealed that participants did not regard all SOSGOQ-8D items as equally important. Conclusion We provide a simple technique for converting the SOSGOQ2.0 to utilities. The ability to evaluate QALYs in metastatic spine disease will facilitate economic analysis and patient counseling. We also quantify the importance of individual SOSGOQ-8D items. Clinicians should heed these findings and offer treatments that maximize function in the most important items.Level of Evidence: 3.

Background: Radiomics involving quantitative analysis of imaging has shown promises in oncology to serve as non-invasive biomarkers. We investigated whether pre-treatment T2-weighted magnetic resonance imaging (MRI) can be used to predict response to neoadjuvant chemotherapy (NAC) in breast cancer. Materials and Methods: MRI scans were obtained for 102 patients with locally advanced breast cancer (LABC). All patients were treated with standard regimens of NAC as decided by the treating oncologist, followed by surgery and adjuvant treatment according to standard institutional practice. The primary tumor was segmented, and 11 texture features were extracted using the grey-level co-occurrence matrices analysis of the T2W-images from tumor cores and margins. Response assessment was done using clinical-pathological responses with patients classified into binary groups: responders and non-responders. Machine learning classifiers were used to develop a radiomics model, and a leave-one-out cross-validation technique was used to assess the performance. Results: 7 features were significantly (p < 0.05) different between the two response groups. The best classification accuracy was obtained using a k-nearest neighbor (kNN) model with sensitivity, specificity, accuracy, and area under curve of 63, 93, 87, and 0.78, respectively. Conclusions: Pre-treatment T2-weighted MRI texture features can predict NAC response with reasonable accuracy.

Summary Background Conventional external beam radiotherapy is the standard palliative treatment for spinal metastases; however, complete response rates for pain are as low as 10–20%. Stereotactic body radiotherapy delivers high-dose, ablative radiotherapy. We aimed to compare complete response rates for pain after stereotactic body radiotherapy or conventional external beam radiotherapy in patients with painful spinal metastasis. Methods This open-label, multicentre, randomised, controlled, phase 2/3 trial was done at 13 hospitals in Canada and five hospitals in Australia. Patients were eligible if they were aged 18 years and older, and had painful (defined as ≥2 points with the Brief Pain Inventory) MRI-confirmed spinal metastasis, no more than three consecutive vertebral segments to be included in the treatment volume, an Eastern Cooperative Oncology Group performance status of 0–2, a Spinal Instability Neoplasia Score of less than 12, and no neurologically symptomatic spinal cord or cauda equina compression. Patients were randomly assigned (1:1) with a web-based, computer-generated allocation sequence to receive either stereotactic body radiotherapy at a dose of 24 Gy in two daily fractions or conventional external beam radiotherapy at a dose of 20 Gy in five daily fractions using standard techniques. Treatment assignment was done centrally by use of a minimisation method to achieve balance for the stratification factors of radiosensitivity, the presence or absence of mass-type tumour (extraosseous or epidural disease extension, or both) on imaging, and centre. The primary endpoint was the proportion of patients with a complete response for pain at 3 months after radiotherapy. The primary endpoint was analysed in the intention-to-treat population and all safety and quality assurance analyses were done in the as-treated population (ie, all patients who received at least one fraction of radiotherapy). The trial is registered with ClinicalTrials.gov , NCT02512965 . Findings Between Jan 4, 2016, and Sept 27, 2019, 229 patients were enrolled and randomly assigned to receive conventional external beam radiotherapy (n=115) or stereotactic body radiotherapy (n=114). All 229 patients were included in the intention-to-treat analysis. The median follow-up was 6·7 months (IQR 6·3–6·9). At 3 months, 40 (35%) of 114 patients in the stereotactic body radiotherapy group, and 16 (14%) of 115 patients in the conventional external beam radiotherapy group had a complete response for pain (risk ratio 1·33, 95% CI 1·14–1·55; p=0·0002). This significant difference was maintained in multivariable-adjusted analyses (odds ratio 3·47, 95% CI 1·77–6·80; p=0·0003). The most common grade 3–4 adverse event was grade 3 pain (five [4%] of 115 patients in the conventional external beam radiotherapy group vs five (5%) of 110 patients in the stereotactic body radiotherapy group). No treatment-related deaths were observed. Interpretation Stereotactic body radiotherapy at a dose of 24 Gy in two daily fractions was superior to conventional external beam radiotherapy at a dose of 20 Gy in five daily fractions in improving the complete response rate for pain. These results suggest that use of conformal, image-guided, stereotactically dose-escalated radiotherapy is appropriate in the palliative setting for symptom control for selected patients with painful spinal metastases, and an increased awareness of the need for specialised and multidisciplinary involvement in the delivery of end-of-life care is needed. Funding Canadian Cancer Society and the Australian National Health and Medical Research Council.

PURPOSE: We sought to investigate the tumor control probability (TCP) of vestibular schwannomas (VS) following single-fraction stereotactic radiosurgery (SRS) or hypofractionated SRS over 2–5 fractions (fSRS). MATERIALS AND METHODS: Studies (PubMed Indexed from 1993 – 2017) were eligible for data extraction if they contained dosimetric details of SRS/fSRS correlated with local tumor control. The rate of tumor control at 5 years (or at 3 years if 5-year data were not available) were collated. Poisson modeling estimated the TCP per equivalent dose in 2 Gy per fraction (EQD2) and in 1, 3, and 5 fractions. RESULTS: Data were extracted from 35 publications containing a total of 5162 patients. TCP modeling was limited by the absence of analyzable data of