Radiation Necrosis Research Articles

Leveraging Quantitative Imaging and Machine Learning to Differentiate Radionecrosis from Disease Recurrence in Patients with Brain Metastases

Radiation necrosis can be difficult to non-invasively discern from tumor progression after stereotactic radiosurgery (SRS). In this work, we investigate the utility of radiomics (computerized features) and machine learning to capture per-voxel lesion heterogeneity on routine MRI scans, to differentiate radionecrosis from tumor recurrence in patients with brain metastases treated with SRS. A retrospective analysis was conducted of patients with brain metastases treated with SRS. Eighty-three lesions (n = 56 intact; n = 27 surgical cavity) from 69 patients were identified with median age 68.8 years (range 40.2 - 91.0), of whom 53.6% were male and 33.3% received prior whole-brain radiotherapy (WBRT). Lesion histology included lung (60.2%), renal cell (15.7%), melanoma (10.8%), breast (9.6%), and other (3.6%). Pathologic confirmation was available in 73.5% of lesions. Both intact and resection cavity lesions were included and individually segmented. Image preprocessing and radiomic feature extraction were done using ANTsPy and open-source software. A total of 210 features were extracted from post-contrast T1-weighted (T1w) and T2/FLAIR MRIs. Highly correlated features were removed. Univariate logistic regression was conducted on the remaining T1w and T2/FLAIR features as well as on clinical variables. Multivariate analysis was implemented with various classifiers (Random Forest, Ridge, Lasso, Support Vector Machine [SVM]) on the top-performing features found on univariate logistic regression. Models were assessed using cross-validation to select the best model by area under ROC curve (AUC). Specificity and sensitivity were calculated. On univariate analysis, the top 10 radiomics features consisted of 6 T1w features and 4 T2/FLAIR features (4 GLCM, 3 first order, 1 GLSZM, 1 GLRLM, and 1 shape feature). Age, gender, disease site, prior WBRT, prior fractionated SRS, planning tumor volume, brain-GTV V12 Gy, and immunotherapy before or after SRS were not predictive (AUC less than 62.0%) on univariate analysis compared to radiomic features. Multivariate analysis of top performing radiomic features on both intact and surgical cavities yielded an AUC of 72.0% (standard deviation [SD] ±8.8%). Multivariate analysis of top features on intact lesions alone improved the AUC to 80.5% (SD ±10.8%), with sensitivity of 77.8%, specificity of 72.4%, and positive likelihood ratio of 2.82 in differentiating radionecrosis from recurrence. Radiomics and machine learning tools may improve diagnostic ability of distinguishing radiation necrosis from tumor recurrence after SRS. Further work is needed to deploy this in a larger multi-institutional cohort and prospectively evaluate its efficacy as a decision-support tool to personalize care in patients with brain metastases.

Stereotactic Radiosurgery (SRS) vs. Hypofractionated Stereotactic Radiotherapy (SRT) in Brain Metastases: Kinetic Responses

To evaluate the treatment responses of patients with brain metastases treated with SRS or SRT. Specifically, we intend to assess the differences in the kinetic response of SRS versus SRT. Brain metastasis patients who underwent SRS/SRT were collected consecutively between January 2014 and March 2021. The prescribed dose varied according to the tumor size. For SRS, the dose prescription followed the RTOG 90-05 protocol with 15 Gy, 18 Gy, and 24 Gy to the PTV for tumor diameters of 3.1-4 cm, 2.1-3 cm, and ≤ 2 cm, respectively. SRT was commonly used to treat larger lesions (3 cm in diameter) or those close to critical organs. The most common doses prescribed for SRT were 27 Gy in 3 fractions and 30 Gy in 5 fractions. All patients must have at least one imaging after treatment. If the tumor volume increased after the first imaging, which could be due to radiation necrosis or tumor progression, the following images would be excluded from the analysis. Multilevel linear regression was used to compare the kinetic response of SRS and SRT. The initial tumor volumes were adjusted in the model. Fifty-five patients with 128 brain metastases were treated with SRS (n = 85 lesions) or SRT (n = 42 lesions) between January 2014 and March 2021. At the time of analysis, 285 follow-up MRI scans were evaluated. Most patients had non-small cell lung cancer (75 lesions with SRS vs 20 lesions with SRT), followed by breast cancer (6 lesions with SRS vs 13 lesions with SRT). The median of the total dose (IQR) was 24 Gy (21-26 Gy) for SRS and 34 Gy (26-37 Gy) for SRT. For plan quality metrics in SRS/SRT, the median of Paddick's conformity index was 0.76 (IQR = 0.57-0.89) in SRS vs 0.84 (IQR = 0.69-9) in SRT with no statistically significant difference (p-value = 0.095). Likewise, the median homogeneity index in SRS was 1.34 (IQR = 1.22-1.43), compared to 1.36 (IQR = 1.21-1.57) in SRT, with no statistically significant difference (p-value = 0.21). The mean (range) of the initial tumor volume of SRS and SRT was 1 cc (0.01-13.7 cc) and 4 cc (0.02-17.70 cc), respectively. All tumors decreased in volume after treatment. The rate of tumor shrinkage in SRS was 0.13 cc per month (0.004 to 0.25, p-value 0.043). Compared to SRS, SRT made the tumors smaller at an additional rate of 0.45 cc per month (0.24 to 0.66, p-value < 0.001), even after adjusting for initial tumor volume. Most tumor progression or radiation necrosis appeared between 9 and 12 months after treatment. Following treatment, SRT exhibits better kinetic responses than SRS.

Post-Operative Stereotactic Radiotherapy for Resected Brain Metastases: Results of the Multicenter Analysis (AURORA) of the German Working Group "Stereotactic Radiotherapy"

While the results of prospective studies support the use of postoperative stereotactic radiotherapy (RT) to the resection cavity (RC) as the standard of care after surgery, there are several issues that need to be investigated such as factors for improving local control, risk of leptomeningeal disease and radiation necrosis. Further, the optimal dose and fractionation is still under debate. The working group "Stereotactic Radiotherapy" of the German Society of Radiation Oncology (DEGRO) analyzed its multi-institutional database with 661 patients who received postoperative stereotactic RT to the RC. Treatment was performed at 13 centers between 2008 and 2021. Patient characteristics, treatment details, and follow-up data including overall survival (OS), local control (LC) were evaluated. Cox Regression and Kaplan-Meier curves with Log-rank Tests were calculated for selected variables. In this retrospective study, overall survival was 61.5% at 1 year, 47.6% at 2 years, and 35.5% at 3 years, and local control was 84.6% at 1 year, 74.8% at 2 years, and 72.8% at 3 years. 96% of patients were treated with hypofractionated stereotactic radiotherapy (HSRT), only 26 patients received single fraction radiosurgery (4%). Prognostic factors associated with overall survival were Karnofsky Performance Status, RPA and GPA class, controlled primary tumor and absence of extracranial metastases, whereas prognostic factor associated with local control was planning target volume (23 mL or less). HSRT is the most common fractionation form in the treatment of RCs in this multicenter analysis. This approach results in excellent OS and LC outcomes. OS in patients with resected brain metastases is mainly influenced by performance status. In regard to local control, RT of large cavities remain a challenge with significantly worse outcome.

Outcomes Following Dose Escalated Radiotherapy for High Grade Meningioma

Conventionally fractionated radiotherapy (RT) is a defined treatment following surgery for atypical and malignant meningioma. However, the optimal radiotherapeutic approach is not well defined. We present the results of our dose-escalation strategy. Consecutive patients with a histopathologic grade 2 or 3 meningioma treated with RT were retrospectively reviewed. The primary outcome was progression-free survival (PFS), and secondary outcomes included cause-specific survival (CSS), overall survival (OS), local failure and incidence of radiation necrosis. We specifically compared the dose-escalation cohort, defined as those treated with ≥66 Gy EQD2 (equivalent dose in 2 Gy fractions, a/b = 10), to the standard dose cohort receiving <66 Gy EQD2. We defined adjuvant as RT delivered within 6 months of surgery otherwise the treatment was salvage. A total of 118 patients with Grade 2 (111/118) or 3 (7/118) meningioma were identified. 54/118 (45.8%) received dose-escalation and 64/118 (54.2%) standard dosing. 34/54 (63.0%) dose-escalated and 45/64 (70.3%) standardly dosed were treated adjuvantly. The median follow-up was 45.4 months (IQR: 24.0-80.0 months) and median OS was 9.7 years. Post-operative residual disease was present in all dose-escalated patients, as compared to 65.6% in the standard dose cohort. PFS at 3-, 4- and 5-years in the dose-escalated vs. standard dose cohort were 78.9%, 72.2% and 64.6% vs. 57.2%, 49.1% and 40.8%, respectively, (p = 0.030). On multivariable (MVA) analysis, dose-escalation (HR: 0.544, 95% CI: 0.303-0.977, p = 0.042) was associated with improved PFS, whereas ≥2 surgeries (HR: 1.989, 95% CI: 1.049-3.773, p = 0.035) and older age (HR: 1.035, 95% CI:1.015-1.056, p<0.001) associated with worse PFS. The cumulative risk of local failure at 3-, 4- and 5-years in the dose-escalated vs. standard dose cohort were 16.9%, 23.8% and 31.8% vs. 39.6%, 45.6% and 53.9%, respectively, favoring dose-escalation (p = 0.016). MVA confirmed dose-escalation as predictive of a lower risk of LF (HR: 0.483, 95% CI: 0.263-0.887, p = 0.019), while ≥2 surgeries prior to RT predicted for greater LF rates (HR:2.145, 95% CI:1.220-3.771, p = 0.008). A trend was observed for prolonged CSS and OS in the dose escalation cohort (p = <0.1). Seven patients (5.9%) developed symptomatic radiation necrosis (RN) with no significant difference between the two cohorts. Dose-escalated radiotherapy for high grade meningioma to at least 66 Gy is associated with significantly improved rates of local control and PFS with an acceptable risk of RN.

Outcomes of a Single Isocenter Brain Multi-Metastases Linear Accelerator Delivered Stereotactic Radiosurgery (SRS)

The management of brain metastases has evolved from using 2D whole brain radiotherapy (WBRT) to more complex techniques like stereotactic radiosurgery (SRS) for patients with limited disease. Long-term control of lesions is challenging with WBRT techniques but treating multiple lesions with traditional SRS, where each lesion is treated on its own isocenter, can be time-consuming and difficult on patients, especially those with claustrophobia. Single Isocenter Multiple Metastases (SIMM) SRS has emerged as an option to deliver ablative SRS doses simultaneously to multiple brain metastases using a single isocenter, thereby limiting the duration of treatments for patients. Though appealing, SIMM SRS adds technical complexity and could potentially lead to worse outcomes or more complications relative to traditional SRS treatments. Given the current paucity of clinical evidence supporting SIMM SRS, we sought to retrospectively review our institution's outcomes and complications for patients treated with SIMM SRS to determine the efficacy and safety of this approach in our hands. Patients treated at our institution with SIMM SRS with at least one post-treatment brain MRI were identified. Date on patient clinical characteristics, planning, and treatment characteristics, and outcomes were retrospectively collected. Post-treatment tumor control was evaluated with follow-up MRI imaging based on RANO criteria. Correlation between tumor control and toxicity was done by assessing radiation doses, PTV coverage, and normal brain V12 constraints. A total of 27 patients received SIMM SRS from January 2015 to February 2022. The median age at first SIMM SRS was 61 (range: 38-87). The most common disease sites were lung (63.0%), breast (18.5%), and GI (7.4%). The 27 patients had 47 SIMM SRS treatments of 163 lesions total. The median number of lesions treated per isocenter was 3 (range: 2-9). 5 patients had 2 SIMM SRS isocenters treated on the same day, treating clusters of lesions (ranging from 5-11 lesions treated on that day). The most common locations involved were frontal, cerebellar, and parietal lobes (32.52%, 21.47%, and 15.34%). The modal dose was 22 Gy (range: 18-24 Gy). Median OS from initial primary diagnosis was 23.23 months, and 9.92 months after the first SIMM SRS treatment. The median imaging follow-up was 9.8 months per lesion, and the local control rate was 95.03%. 2 lesions (1.23%) developed radiation necrosis and the median time to RT necrosis among those lesions was 5.7 months after treatment. The utilization of SIMM SRS demonstrates acceptable efficacy and safety as it has been implemented at our institution. Further studies to evaluate this planning modality are warranted to establish suitable candidates for SIMM SRS as well as evaluate the long-term outcomes for these patients.

Stereotactic Radiotherapy or Whole Brain Radiotherapy Combined with Pyrotinib and Capecitabine in HER2-Positive Advanced Breast Cancer Patients with Brain Metastases (BROPTIMA): A Prospective, Phase Ib/II Single-Arm Clinical Study

Approximately half of patients with advanced HER2-positive breast cancer (BC) will develop brain metastases (BM) over time. Local therapy including stereotactic radiotherapy (SRT) and whole brain radiotherapy (WBRT) is the main initial treatment in malignant tumor patients with BM. However, more than 50% patients after radiotherapy in one year suffered intracranial recurrence. Pyrotinib, a small molecule, irreversible, pan-ErbB receptor tyrosine kinase inhibitor (TKI), has a high potency for controlling BM and reducing the occurrence of brain metastases in advanced HER2-positive BC patients. We hypothesized that SRT or WBRT combined with pyrotinib and capecitabine could decrease intracranial progression in HER2 positive BC with newly diagnosed BM. In this prospective single-arm phase Ib/II trial (NCT04582968), eligible patients were assigned to either fractionated stereotactic radiotherapy (FSRT) or whole-brain radiation therapy (WBRT), combined with pyrotinib and capecitabine. The primary endpoint was one-year CNS progression-free survival (PFS) rate. Secondary endpoints included intracranial objective response rate (IC-ORR) according to RANO-BM criteria, progression-free survival (PFS), overall survival (OS) and evaluation of safety and neurocognitive function. From January 2020 to August 2022, 40 patients were enrolled. Twenty-nine patients were treated with FSRT in 8 Gy per fraction with 3 to 5 fractions and 11 were treated with WBRT in 3 Gy per fraction with 10 fractions, and then received chemotherapy in a time frame starting from 0 to 7 days after radiotherapy. At a median follow-up of 17.3 months, 1-year CNS-PFS rate was 74.9% (95% CI 61.9-90.7%) and median CNS-PFS was 18 months (95% CI, 15.5 to NA months). One-year PFS rate was 66.9% (53.1-84.2%) and median PFS time was 17.6 months (95% CI 12.8-34.1 months). The best intracranial response rate (IC-ORR: complete response and partial response) was 92.5% (37/40). The most common grade 3 or worse toxicity was diarrhea (7.5%) and asymptomatic radiation necrosis was detected in 4 of 67(6.0%) lesions treated with FSRT. No differences of neurocognitive function evaluated by MMSE (Mini-Mental State Exam) were observed between different groups at any time point. Radiotherapy combined with pyrotinib and capecitabine resulted in a promising efficacy that crossed the pre-specified boundary in patients with HER2-positive advanced breast cancer with brain metastases. This is the first prospective study showing the efficacy and safety of CNS radiotherapy concurrent with pyrotinib and capecitabine in patients with BM from HER2-positive breast cancer. Further investigation in a randomized controlled study is warranted.

Surgically Targeted Radiation Therapy (STaRT) for Brain Metastases: Initial Experience from a Prospective Multi-Institutional Registry

Resection and intraoperative brachytherapy for patients with large, operable brain metastasis allows for both relief of mass effect and the delivery of radiotherapy (RT) to the resection cavity with a favorable dosimetric profile. The objective of this study was to analyze early patterns-of-care and treatment-related toxicity outcomes for brain metastasis patients treated with surgically targeted radiation therapy (STaRT) using a novel brachytherapy carrier. Patients with brain metastasis, de novo and recurrent disease, who enrolled onto a prospective multi-institutional observational study (NCT04427384) were the subject of this analysis. Patients underwent resection and immediate implantation of bioresorbable, conformable, 20 mm x 20 mm x 4 mm collagen tile brachytherapy device(s) containing four uniform-intensity Cesium-131 sources. Toxicities were categorized using the CTCAE v5.0 adverse event (AE) criteria. From 10/2020 to 01/2023, 13 participating sites enrolled and treated 48 patients with 51 metastases (13 with de novo and 35 patients with recurrent brain metastases), and 3 patients had 2 lesions implanted at the same procedure. Median age was 61 years (range: 28-80), 52% were female, and the most common primary types were lung (56%) and breast (13%). The median maximum pre-operative dimension was 3.4 cm (range: 1.7-5.7) and median pre-operative tumor volume 13.7cm3 (range: 1.7-132). 64% had received prior RT with a median time from last RT to STaRT of 14.6 months range: 3.5-57.3). Median KPS at screening was 80 (range: 50-100), and remained stable at post op visit (80, range: 50-100), and at 3-months following treatment (80, range 50-100), respectively (p>0.05). The median time for implantation was 3 minutes (range: 0.4-30). At a median follow-up of 4 months (range: <1-18), no patient experienced a radiation-attributed AE, and only 1 attributable Gr >3 AE was noted (Gr 5 intracerebral hemorrhage deemed probably related to surgery and unrelated to the implanted device). Early results from this prospective multi-center trial demonstrate the feasibility and safety of STaRT. The lack of radiation-related AE, even with short follow-up, is intriguing given the relatively large lesion size and proportion of patients treated for recurrent, previously irradiated disease. Additional follow-up will provide data on tumor control outcomes and radiation necrosis rates using this novel technique.

Stereotactic Radiotherapy (SRT) in Combination with Aumolertinib to Treat Intracranial Oligometastatic Non-Small Cell Lung Cancer (NSCLC): An Update of a Phase II, Prospective Study

Stereotactic radiotherapy (SRT) is highly effective and less toxic for limited intracranial metastases. Aumolertinib is a tolerable third-generation epidermal growth factor receptor tyrosine kinase inhibitor that has CNS efficacy in patients with EGFR-mutant NSCLC. We aim to investigate the efficacy and safety of aumolertinib followed by SRT in patients with intracranial oligometastatic NSCLC. Intracranial oligometastatic Patients with EGFR sensitive mutations (EGFR-TKIs naive) were enrolled and received aumolertinib 110mg daily until intracranial disease progression. Then SRT (32-40 Gy total, 8 Gy/f) was given to intracranial oligo-progression disease if possible. The primary endpoint was intracranial objective response rate (iORR). Secondary endpoints included intracranial progression-free survival (iPFS), intracranial duration of response (iDOR)according to RECIST 1.1, cerebral radiation necrosis rate (CRNR) and overall survival (OS). Safety was evaluated according to Common Terminology Criteria for Adverse Events version 5.0 (CTCAE v5.0). This trial is registered with ClinicalTrials.gov, NCT04519983. To February 10, 2023, a total of 38 patients were enrolled and 35 patients were assessable followed for 3 months to 18 months. All patients received 110mg aumolertinib daily and received at least one independent imaging evaluation by a radiologist. After oral administration of aumolertinib, the best response of 94% patients in intracranial and extracranial lesions was partial response (PR). Two patients had stable intracranial disease. At data cut-off, one patient developed intracranial primary lesion progression at 12 months after oral administration of aumolertinib but stable in extracranial lesions. SRT treatment was given to this patient. No grade ≥3 adverse events occurred after continued oral administration of aumolertinib. The most common adverse reactions were rash and abnormal liver enzymes, 1 patient had grade 2 CK elevation. This report showed pronounced intracranial objective response benefit in patients with intracranial oligometastatic disease followed by SRT after intracranial oligo-progression and no new safety signals. Aumolertinib has promising efficacy and good tolerability in intracranial oligometastatic EGFR mutated NSCLC. [Keywords] Non-small cell lung cancer; epidermal growth factor receptor tyrosine kinase inhibitor; Aumolertinib; Stereotactic radiotherapy.

Outcomes of 30 Gy/5 Fr Hypofractionated Stereotactic Radiation Therapy for Small Brain Metastases (≤2 cm).

Stereotactic radiosurgery (SRS)-used for brain metastases (BMs) with a tumor diameter of ≤2 cm-has a high local control rate, however, it can cause symptomatic radiation-induced brain necrosis. Hypofractionated stereotactic radiation therapy (HFSRT) is not commonly used for such lesions and its effectiveness remains unknown. Herein, the efficacy of 30 Gy 5-fraction HFSRT for treating BMs of <2 cm was retrospectively evaluated. Patients who received HFSRT and had a gross tumor volume (GTV) of ≤2 cm in maximum diameter were included in the study (49 patients; 179 BMs; median follow-up period, 11.9 months). The mean GTV Peripheral Dose (D95) was 36.2 Gy. The local control (LC) rates at 1 and 2 years were 93.0% and 81.5%, respectively, for all lesions. The 1-year LC rates were 93.6% and 92.0% for ≤1.0-cm and 1.0-2.0-cm lesions, respectively. Multivariate analysis revealed that the only significant difference was in GTV maximal tumor diameter (HR=1.961, p=0.0002). Notably, only one patient had asymptomatic radiation necrosis. Owing to the high toxicity of SRS, 5-fraction HFSRT can be an effective treatment strategy for BMs of <2 cm.

Multi-Institutional Study of Stereotactic Radiosurgery for Recurrent WHO Grade 2/3 Meningiomas: An Interim Analysis

Meningiomas are the most common tumors of the central nervous system (CNS). Approximately 80% are classified as World Health Organization (WHO) grade 1, while 20% correspond to grade 2 or grade 3. In those with grade 2/3 disease, local recurrence is not uncommon. Salvage treatment options vary widely and include resection, external beam radiation therapy (EBRT), stereotactic radiosurgery (SRS), and/or clinical trials. Although retrospective studies have reported on the use of upfront SRS in grade 2/3 meningiomas, large-scale outcomes with SRS in the recurrent setting are lacking. The objective of this study was to report on oncologic outcomes for patients with recurrent grade 2/3 meningioma treated with SRS. This is an ongoing multi-institutional retrospective cohort study. Eligibility criteria include patients >18 years old with pathologically confirmed WHO grade 2 or 3 meningioma treated with SRS monotherapy at the time of first recurrence. Patients require pathologic confirmation only at time of diagnosis; those with upfront grade 1 disease must have pathologic confirmation of grade 2/3 disease at time of first recurrence. Patients with multifocal disease upfront were excluded from this study. A total of 60 patients met eligibility criteria. Baseline demographics at time of initial diagnosis are shown in table 1. At the time of first recurrence, 57 (95%) were WHO grade 2, and 3 (5%) were grade 3. Median follow up time from first recurrence was 5.02 years. Median marginal SRS dose was 16 Gy (IQR 14-17) to a 2.67cc planning treatment volume (IQR 1.4-5.1). 92% of patients received single fraction SRS. Median time to second recurrence was 5.92 years. 1, 3, and 5-year progression-free survival (PFS) was 95%, 68%, and 51%, respectively. 1, 3, and 5-year overall survival (OS) was 100%, 98%, and 96%, respectively. On multivariate analysis, grade 3 disease was independently associated with worse PFS (HR 15.7, p = 0.03). Median SRS dose and treatment volume did not correlate with PFS. 1 patient (1.7%) experienced symptomatic radiation necrosis requiring steroids, 3 (5.0%) experienced new seizure activity, and 2 (3.3%) additional patients showed clinical evidence of post-treatment neurocognitive decline. Based on this interim analysis, primary SRS for recurrent grade 2/3 meningioma appears safe and feasible, with outcomes comparable to prospective data on high-risk grade 2/3 patients treated with post-operative fractionated EBRT. We look forward to further analysis with a larger cohort which may help guide further prospective studies.

Characterization of Large Brain Metastases with 18F-Fluciclovine PET/CT Treated with Staged Stereotactic Radiosurgery (SSRS): Phase 1 Proof-of-Concept Interim Analysis

Single-session stereotactic radiosurgery (SRS) for large brain metastases (>2cm) results in modest local control. Temporally staged SRS (SSRS), whereby 2 stages of SRS are delivered over a time interval of several weeks, is a novel strategy associated with improved control rates and acceptable radiation necrosis rates. Biomarkers for response are lacking. Here, we report interim results of a phase 1, proof-of-concept study (NCT04689048) to assess the potential clinical utility of amino acid radiotracer 18F-fluciclovine PET/CT as a functional integral biomarker for patients with large brain metastases treated with SSRS. Patients with previously untreated large brain metastases (≥1 lesion; >2cm) underwent a baseline (pre-treatment) 18F-fluciclovine PET/CT and contrast-enhanced treatment planning brain MRI immediately before first SSRS (15 Gy), an interim PET/CT + MRI (4 weeks after the 1st SSRS, immediately prior the 2nd SSRS [15 Gy]), and post-treatment PET/CT + MRI (8 weeks after 2nd SSRS). This interim analysis reviewed the imaging characteristics from static PET images acquired 10-25 minutes after 18F-fluciclovine injection, for the first 7 enrolled patients who completed baseline imaging and 5 who completed the entire treatment course. Seven patients completed baseline imaging and were treated with SSRS for 9 protocol-eligible target lesions, and an additional 25 bystander lesions were treated with SRS. The median age was 72 years and 57% were female. All lesions > 5 mm exhibited baseline increased 18F-fluciclovine uptake compared to the normal contralateral brain. The median baseline target lesion diameters and volumes were 2.16 cm (1.76-3.22 cm) and 4.71cc (2.24-10.21 cc). The median baseline SUVmax, SUVpeak, and SUVmean values were 5.78 (2.16-8.79), 3.33 (0.5-2.72), and 1.75 (1.22-5.16), respectively. The median relative reduction in diameter and volume were both 2% (-13% to 23% and -30% to 60%, respectively) at the interim scans, and at the first follow-up were 30% (-0.2% to 44%) and 43% (-13% to 94%), respectively. Corresponding median relative reduction values for SUVmax, SUVpeak, and SUVmean at interim scans were 20% (-174%-73%), 9% (-99% to 75%), and 14% (-36% to 69%), and at first follow-up 59% (21% to 87%), 41% (-11% to 86%), and 21% (-44% to 79%), respectively. Bystander lesions (< 2 cm) treated with SRS had a median baseline lesion diameter and volume of 0.5 cm (Range: 0.20-1.64 cm) and 0.06 cc (Range: 0.01-1.94 cc). Corresponding median reductions for SUVmax were 5% at interim and 63% at follow-up scans. This proof-of-concept interim study reports baseline 18F-fluciclovine metrics for patients with brain metastases of varying lesion diameters and volumes. Target lesions appear to demonstrate interval reduction in PET metrics after SSRS, more than dimensional measurements alone.

Changes in Target Coverage and Dose to the Normal Brain during Fractionated Stereotactic Radiotherapy for Metastatic Brain Tumors

Fractionated stereotactic radiotherapy (SRT) has been applied to large brain metastases to reduce the risk of radiation necrosis. For fractionated SRT, potential of interfractional tumor changes during the treatment period, such as tumor size, shape, and geometry, must be considered to improve the tumor local control. Our center performs adaptive re-planning for large brain metastases based on repeat MRI verification with a contrast agent in the middle of the treatment period. Purpose of this study is to evaluate the dosimetric impact of the changes in tumor size, shape, and geometry on the doses to the targets and normal brain in patients with brain metastases undergoing fractionated SRT. Fifteen solitary large intracranial metastatic lesions treated with fractionated SRT were investigated. Standardized planning MRI (MRI-1) and repeat verification MRI (MRI-2) were performed during the middle of the irradiation period. The GTV on the MRI-1 and MRI-2 scans was contoured by the same oncologist. The PTV was created by adding an isotropic margin of 1 mm from the GTV in all directions. Volumetric modulated arc therapy (VMAT) with beam energies of 6 MV (flattening filter-free mode) was used and plans were normalized such that PTV D95% or D98% was equal to the prescribed dose. Beam configuration and intensity on the initial VMAT plan were used to evaluate the dose to the tumor and the normal brain on MRI-2. We evaluated the impact of D98% on the GTV using the plans on the MRI-1 and MRI-2 scans. For the normal brain, the V90%, V80%, and V50% were investigated. The median GTV changed from 9.8 cc (range of 3.2-33.0 cc) to 9.7 cc (range of 2.8-36.5 cc) (p = 0.482). Three and four tumors exhibited volume shrinkage and enlargement changes of >10%. Five tumors exhibited volume shrinkage and enlargement changes of <10%. Three tumors showed no volume changes. Of the 15 large brain metastases, 12 tumors required treatment plan modification. The dosimetric parameters of the GTV, PTV, and normal brain did not significantly differ between the MRI-1 and MRI-2 scans. Regarding the tumor dose, the D98% to the GTV increased in patients with tumor shrinkage because of dose inhomogeneity and decreased in patients with tumor enlargement. The V90%, V80%, and V50% increase with decreasing tumor volumes and were linearly related to the tumor volume difference, with a coefficient of determination of 0.97, 0.98, and 0.97, respectively. Our study demonstrated the usefulness of repeat verification MRI for adaptive radiotherapy in the middle of the treatment period due to changes in tumor size, shape, and geometry in patients with brain metastases. Repeated MRI should be considered to evaluate the dose to the target and normal brain, which improves tumor local control and reduces brain necrosis, to reduce the magnitude of underdosing to the target or overdosing to the normal brain during the treatment period.

Characterization of Radiographic and Molecular Changes in Mouse Brain after FLASH Irradiation

Despite refinements in treatment platforms such as incorporation of high-resolution imaging and real time motion tracking, the amount of radiation dose delivered safely to a particular tissue type is limited by both tissue intrinsic and extrinsic factors. FLASH radiotherapy (RT), delivery of relatively high radiation dose at dose rates several orders of magnitude higher than that of conventional (CONV) dose-rates, may change that paradigm due to normal tissue sparing characteristics of FLASH RT. Our Radiation Oncology Physics division developed a novel FLASH kV x-ray cabinet system for preclinical laboratory research. Here we utilize this technology to establish optimal radiation parameters for FLASH effect in brain tissue of a murine model. A range of total radiation dose and dose rates that are considered to be within the window for FLASH effect are being investigated. We have identified several measurable and clinically meaningful toxicity outcomes, including radiation necrosis and blood brain barrier integrity, to assess FLASH effects in brain tissue. A high-capacity rotating anode x-ray tube was implemented for FLASH irradiation, operating at 150 kVp with 0.025 mm Cu added filtration. A custom 3D printed immobilization tool was designed to reproducibly position animals for stereotactic irradiation of the brain. Dose and dose rate measurements were performed with calibrated radiographic film in kV solid water. Conventional dose rate irradiations were delivered using a standard laboratory irradiator (SARRP) operating at the same kVp and filtration. The depth-dose gradients in solid water were compared between the irradiators. Healthy 8-week-old C57BL6J mice were then irradiated with graded doses of FLASH and CONV x-rays (10- 60 Gy) using a single 1-cm wide AP field. Dose was prescribed to the center of the brain, at a depth of 3.25 mm. RT-induced necrosis is being monitored by serial biweekly MR imaging using a 7-T preclinical MRI machine. Histopathological changes will be assessed through H&E staining of harvested brain at 3-months post-irradiation (n = 5 per arm). FITC-Dextran infusion will be performed prior to necropsy to assess blood-brain barrier integrity. Animal setup for stereotactic FLASH brain irradiation was reproducible to within 0.5mm. Measured dose rates were 75.6 Gy/s for FLASH and 3.8 Gy/min for conventional irradiations. At 5-mm depth in solid water, the PDDs agreed to within 4% between SARRP and FLASH Irradiator. Biweekly T1 post and T2 weighted image acquisition is currently underway. Histology and FITC-Dextran data will be presented when available. We have successfully designed a high-precision platform to study x-ray FLASH effects in mice brain model. Evaluation of dose window for brain FLASH effect and molecular mechanisms of this phenomenon is an important step in the potential translation of FLASH RT for brain irradiation.

Tumor Location Impacts the Development of Radiation Necrosis in Benign Intracranial Tumors.

Radiation necrosis (RN) is a possible late complication of stereotactic radiosurgery (SRS), but only a few risk factors are known. The aim of this study was to assess tumor location in correlation to the development of radiation necrosis for skull base (SB) and non-skull base tumors. All patients treated with radiosurgery for benign neoplasms (2004-2020) were retrospectively evaluated. The clinical, imaging and medication data were obtained and the largest axial tumor diameter was determined using MRI scans in T1-weighted imaging with gadolinium. The diagnosis of RN was established using imaging parameters. Patients with tumors located at the skull base were compared to patients with tumors in non-skull base locations. 205 patients could be included. Overall, 157 tumors (76.6%) were located at the SB and compared to 48 (23.4%) non-SB tumors. Among SB tumors, the most common were vestibular schwannomas (125 cases) and meningiomas (21 cases). In total, 32 (15.6%) patients developed RN after a median of 10 (IqR 5-12) months. Moreover, 62 patients (30.2%) had already undergone at least one surgical resection. In multivariate Cox regression, SB tumors showed a significantly lower risk of radiation necrosis with a Hazard Ratio (HR) of 0.252, p < 0.001, independently of the applied radiation dose. Furthermore, higher radiation doses had a significant impact on the occurrence of RN (HR 1.372, p = 0.002). The risk for the development of RN for SB tumors appears to be low but should not be underestimated. No difference was found between recurrent tumors and newly diagnosed tumors, which may support the value of radiosurgical treatment for patients with recurrent SB tumors.

Factors associated with radiation necrosis and intracranial control in patients treated with immune checkpoint inhibitors and stereotactic radiotherapy

Background and PurposeEmerging data suggest immune checkpoint inhibitors (ICI) and stereotactic radiosurgery (SRS) or radiotherapy (SRT) may work synergistically, potentially increasing both efficacy and toxicity. This manuscript characterizes factors associated with intracranial control and radiation necrosis in this group. Materials and MethodsAll patients had non-small cell lung cancer, renal cell carcinoma, or melanoma and were treated from 2013 to 2021 at two institutions with ICI and SRS/SRT. Univariate and multivariate analysis were used to analyze factors associated with local failure (LF) and grade 2+ (G2 + ) radiation necrosis. ResultsThere were 179 patients with 549 metastases. The median follow up from SRS/SRT was 14.7 months and the median tumor size was 7 mm (46 tumors ≥ 20 mm). Rates of LF and G2 + radiation necrosis per metastasis were 5.8% (32/549) and 6.9% (38/549), respectively. LF rates for ICI +/- 1 month from time of radiation versus not were 3% (8/264) and 8% (24/285) (p = 0.01), respectively. G2 + radiation necrosis rates for PD-L1 ≥ 50% versus < 50% were 17% (11/65) and 3% (5/203) (p=<0.001), respectively. PD-L1 ≥ 50% remained significantly associated with G2 + radiation necrosis on multivariate analysis (p = 0.03). Rates of intracranial failure were 54% (80/147) and 17% (4/23) (p = 0.001) for those without and with G2 + radiation necrosis, respectively. ConclusionsPD-L1 expression (≥50%) may be associated with higher rates of G2 + radiation necrosis, and there may be improved intracranial control following the development of radiation necrosis. Administration of ICIs with SRS/SRT is overall safe, and there may be some local control benefit to delivering these concurrently.

The Safety and Efficacy of Concurrent Immune Checkpoint Blockade and Stereotactic Radiosurgery Therapy with Practitioner and Researcher Recommendations

Immune checkpoint inhibitors (ICIs) have shown growing promise in the treatment of brain metastases, especially combined with stereotactic radiosurgery (SRS). The combination of ICIs with SRS has been studied for efficacy as well as increasing radiation necrosis risks. In this review, we compare clinical outcomes of radiation necrosis, intracranial control, and overall survival between patients with brain metastases treated with either SRS alone or SRS-ICI combination therapy. A literature search of PubMed, Scopus, Embase, Web of Science, and Cochrane was performed in May 2023 for articles comparing the safety and efficacy of SRS/ICI versus SRS-alone for treating brain metastases. The search criteria identified 1961 articles, of which 48 met inclusion criteria. Combination therapy with SRS and ICI does not lead to significant increases in incidence of radiation necrosis either radiographically or symptomatically. Overall, no difference was found in intracranial control between SRS-alone and SRS-ICI combination therapy. Combination therapy is associated with increased median overall survival. Notably, some comparative studies observed decreased neurologic deaths, challenging presumptions that improved survival is due to greater systemic control. The literature supports SRS-ICI administration within 4 weeks of another for survival but remains inconclusive, requiring further study for other outcome measures. Combination SRS-ICI therapy is associated with significant overall survival benefit for patients with brain metastases without significantly increasing radiation necrosis risks compared to SRS alone. Although intracranial control rates appear to be similar between the 2 groups, timing of treatment delivery may improve control rates and demands further study attention.

Presence of Activated (Phosphorylated) STAT3 in Radiation Necrosis Following Stereotactic Radiosurgery for Brain Metastases.

Brain radiation necrosis (RN) is a subacute or late adverse event following radiotherapy, involving an exacerbated inflammatory response of the brain tissue. The risk of symptomatic RN associated with stereotactic radiosurgery (SRS) as part of the treatment of brain metastases (BMs) has been a subject of recent investigation. The activation of the signal transducer and activator of transcription 3 (STAT3) was shown in reactive astrocytes (RA) associated with BMs. Given that the pathophysiological mechanisms behind RN are not fully understood, we sought to investigate the role of STAT3 among other inflammatory markers in RN development. A mouse model of RN using clinical LINAC-based SRS was designed to induce brain necrosis with the administration of 50 Gy in a single fraction to the left hemisphere using a circular collimator of 5 mm diameter. Immunohistochemistry and multiplex staining for CD4, CD8, CD68, GFAP, and STAT3 were performed. For validation, eleven patients with BMs treated with SRS who developed symptomatic RN and required surgery were identified to perform staining for CD68, GFAP, and STAT3. In the mouse model, the RN and perinecrotic areas showed significantly higher staining for F4/80+ and GFAP+ cells, with a high infiltration of CD4 and CD8 T-lymphocytes, when compared to the non-irradiated cerebral hemisphere. A high number of GFAP+pSTAT3+ and F4/80+pSTAT3+ cells was found in the RN areas and the rest of the irradiated hemisphere. The analysis of human brain specimens showed that astrocytes and microglia were actively phosphorylating STAT3 in the areas of RN and gliosis. Phosphorylated STAT3 is highly expressed in the microglia and RA pertaining to the areas of brain RN. Targeting STAT3 via inhibition represents a promising strategy to ameliorate symptomatic RN in BM patients undergoing SRS.

X-ray features and diagnostics of purulent-necrotic lesions of the jaws

X-ray data of 750 patients with odontogenic and non-odontogenic osteomyelitis of the jaws aged 18 to 65 years were studied. The results of orthopantomography, panoramic zonography of facial bones, telerentgenography of the skull, intraoral radiography, computed tomography of the maxillofacial region are analyzed.&#x0D; The radiological characteristics of odontogenic acute, subacute, chronic and primary chronic osteomyelitis, hematogenic and posttraumatic osteomyelitis, radiation, bisphosphonate and phosphorus necrosis of the jaws are presented, taking into account differential diagnosis.&#x0D; The radiological semiotics of osteomyelitis of the jaws is diverse, since the features of the manifestation of osteomyelitis depend on the etiology, stage of the course and form of the bone inflammatory process.&#x0D; Orthopantomography is a method of primary diagnosis of osteomyelitis of the jaws. The use of computed tomography contributes to the accurate identification of the structure of the affected area, the magnitude of the destruction of anatomical details of the jaws and the boundaries of the spread of the purulent-necrotic process.

Surgically targeted radiation therapy (STaRT) for recurrent brain metastases: Initial clinical experience

PURPOSEThis study evaluates the outcomes of recurrent brain metastasis treated with resection and brachytherapy using a novel Cesium-131 carrier, termed surgically targeted radiation therapy (STaRT), and compares them to the first course of external beam radiotherapy (EBRT). METHODSConsecutive patients who underwent STaRT between August 2020 and June 2022 were included. All patients underwent maximal safe resection with pathologic confirmation of viable disease prior to STaRT to 60 Gy to a 5-mm depth from the surface of the resection cavity. Complications were assessed using CTCAE version 5.0. RESULTSTen patients with 12 recurrent brain metastases after EBRT (median 15.5 months, range: 4.9–44.7) met the inclusion criteria. The median BED10Gy90% and 95% were 132.2 Gy (113.9–265.1 Gy) and 116.0 Gy (96.8–250.6 Gy), respectively. The median maximum point dose BED10Gy for the target was 1076.0 Gy (range: 120.7–1478.3 Gy). The 6-month and 1-year local control rates were 66.7% and 33.3% for the prior EBRT course; these rates were 100% and 100% for STaRT, respectively (p < 0.001). At a median follow-up of 14.5 months, there was one instance of grade two radiation necrosis. Surgery-attributed complications were observed in two patients including pseudomeningocele and minor headache. CONCLUSIONSSTaRT with Cs-131 presents an alternative approach for operable recurrent brain metastases and was associated with superior local control than the first course of EBRT in this series. Our initial clinical experience shows that STaRT is associated with a high local control rate, modest surgical complication rate, and low radiation necrosis risk in the reirradiation setting.

P02.07.A IMMUNOLOGICAL AND EPIGENETIC FEATURES OF RADIATION NECROSIS IN GLIOBLASTOMA PATIENTS

Abstract BACKGROUND Radiation necrosis is a rare but highly relevant complication after radiotherapy in glioblastoma patients. Immunological and epigenetic features of these delayed tissue changes are not yet understood and no reliable biomarker to identify patients at risk of developing radiation necrosis is available. AIM To assess methylation patterns, T cell receptor repertoires and immune cell infiltration in patients with radiation necrosis and identify possible predictive epigenetic and immunological features. METHODS 405 glioblastoma patients who underwent tumor resection between 2008 and 2018 were retrospectively screened for histology-proven or MR-spectroscopy/FET-PET-diagnosed radiation necrosis (RN). After identifying patients with RN, a control cohort matched for age, sex and MGMT-status was established. For both cohorts, epigenetic profiles of primary tumor tissues were assessed via DNA methylation arrays. Immunohistochemistry was performed for CD3, CD8, CD68 and CD163. For patients with histology-proven RN, additional TCRß-bulk sequencing of DNA extracted from FFPE tissue of primary tumor and RN was performed. RESULTS 14/405 (3.5%) patients were identified with RN. The MGMT-promotor was hypermethylated in 50% of patients. The most prominent methylation subclasses of primary tumor tissue of patients in the RN cohort were GBM RTK I and GBM RTK II (5/8). None of these tumors was classified as GBM MES, which in contrast was the most prominent subclass in the control cohort (4/8). T cell infiltration and microglia/macrophage density did not differ between RN cohort and control cohort (CD3: 15.04 vs 20.28 counts/ROI, p= 0.55; CD8: 7.32 vs 8.3, p= 0.82; CD68: 7.42 vs 11.86, p=0.13; CD163: 14.29 vs 16.2, p= 0.73). In total, 1762 unique productive TCRß sequences were identified, overall productive clonality was low (0.2, range 0.06-0.4). A clonal expansion of specific TCRs from primary tumor to RN was identified in 2 patients. A more clonal repertoire in RN was observed in 50% of patients. 2 TCRß sequences were shared between 2 different patients, no sequences were shared between more than 2 patients. CONCLUSION Our data indicate that the methylation subclasses RTK I and RTK II may constitute a risk factor for RN whereas a MES subclass may be protective. Immune cell profiles in primary tumors of GBM patients that develop radiation necrosis during their treatment do not differ from primary tumors of control patients. TCR repertoire shows an overall low abundance of TCRs with polyclonal repertoires, but clonal expansion could be detected in a subset of patients, suggesting antigen-specific T cell responses to RN. Further analysis and validation of these findings in a larger cohort is ongoing.