Symptomatic Radiation Necrosis Research Articles

Impact of concurrent antibody-drug conjugates and radiotherapy on symptomatic radiation necrosis in breast cancer patients with brain metastases: a multicenter retrospective study.

We aimed to investigate the impact of concurrent antibody-drug conjugates (ADC) and radiotherapy on symptomatic radiation necrosis (SRN) in breast cancer patients with brain metastases (BM). This multicenter retrospective study uses four institutional data. Eligibility criteria were histologically proven breast cancer, diagnosed BM with gadolinium-enhanced MRI, a Karnofsky performance status of 60 or higher, and radiotherapy for all BM lesions between 2017 and 2022. Patients with leptomeningeal dissemination were excluded. Concurrent ADC was defined as using ADC within four weeks before or after radiotherapy. The cumulative incidence of SRN until December 2023 with death as a competing event was compared between the groups with and without concurrent ADC. Multivariable analysis was performed using the Fine-Gray model. Among the 168 patients enrolled, 48 (29%) received ADC, and 19 (11%) had concurrent ADC. Of all, 36% were HER2-positive, 62% had symptomatic BM, and 33% had previous BM radiation histories. In a median follow-up of 31months, 18 SRNs (11%) were registered (11 in grade 2 and 7 in grade 3). The groups with and without concurrent ADC had 5 SRNs in 19 patients and 13 SRNs in 149, and the two-year cumulative incidence of SRN was 27% vs. 7% (P = 0.014). Concurrent ADC was associated with a higher risk of SRN on multivariable analysis (subdistribution hazard ratio, 3.0 [95% confidence interval: 1.1-8.3], P = 0.030). This study suggests that concurrent ADC and radiotherapy are associated with a higher risk of SRN in HER2-positive breast cancer patients.

The 5-factor modified frailty index as a prognostic factor of stereotactic radiosurgery for metastatic disease to the brain.

Frailty, a state of increased vulnerability to adverse health outcomes, is associated with poor neurosurgical outcomes. The relationship between frailty and stereotactic radiosurgery (SRS) for brain metastases (BMs), however, has not been adequately described. In this study, the authors attempted to examine the connection between frailty and outcomes for patients receiving SRS for BMs. A single-center retrospective cohort study was performed. The 5-factor modified frailty index (mFI-5) was used to stratify patients into pre-frail (mFI-5 score 0-1), frail (mFI-5 score 2), and severely frail (mFI-5 score ≥ 3) cohorts at the time of SRS treatment. Both overall survival (OS) and progression-free survival (PFS) were evaluated. Factors associated with OS/PFS were assessed using Kaplan-Meier analysis and a Cox proportional hazards model. Two hundred three patients met the inclusion criteria and received SRS to one or more BMs. Fifty-six patients (27.6%) received SRS as an adjuvant treatment. The 12-month OS and PFS rates were 58.6% and 45.5%, respectively. One hundred twenty-six patients (62.1%) were classified as pre-frail, 58 (28.6%) as frail, and 19 (9.4%) as severely frail. Significantly less OS was demonstrated in frailer groups (frail hazard ratio [HR] 3.14, p < 0.005; severely frail HR 3.13, p < 0.005). Compared with pre-frail patients, frail patients had shorter intervals of PFS (frail HR 2.05, p < 0.005). Five patients (2.5%) had symptomatic radiation necrosis (RN) and 60 (29.6%) required repeat radiation. Higher frailty scores at the time of SRS treatment were predictive of shorter OS and PFS intervals.

Treatment Plan Optimization Following Laser Interstitial Thermal Therapy (LITT) for Recurrent Metastasis Using Cleveland Clinic Scaling System (CCSS)

INTRODUCTION: Laser interstitial thermal therapy (LITT) is an effective treatment option for recurrent metastasis (RM). However, determining the best treatment approach for each patient following LITT remains challenging due to mixed pathology and lack of consensus. The Cleveland Clinic Scaling System (CCSS) has been proposed to facilitate decision-making in patients with radiation necrosis (RN) and/or RM following LITT. METHODS: We conducted a retrospective analysis of data from 20 patients who underwent LITT for RN and/or RM between 2019 and 2022 at Cleveland Clinic. Based on the symptomatic RN and/or RM which was confirmed by MRI, LITT, and biopsy were carried out. Three samples were acquired from the superficial, middle, and deep parts of each patient’s lesion. The samples were then classified into three main categories: RN, RM, or a mixture of the two, based on pathological results. Patient management was guided by our novel CCSS. According to CCSS, patients with 100% RN underwent continued observation with a 3-month MRI, individuals with &gt;20% tumor component received a low-dose or standard-dose radiation therapy ± CNS-penetrating targeted therapy, while those with &lt;20% tumor underwent short-term observation with 6-week MRIs ± CNS-penetrating targeted therapy. RESULTS: Among the patients, 57% were females, lung cancer was the most prevalent malignancy (61.4%), and the median age was 52 years (ranging from 25 to 83 years). Our analysis demonstrated that the application of the CCSS protocol significantly improved treatment outcomes after LITT, resulting in 93% lesion control at the 10-month follow-up. CONCLUSIONS: The use of the CCSS protocol can refine the treatment plan for patients with RN and/or RM following LITT. This approach has the potential to enhance patient safety by improving tumor control and minimizing unnecessary radiation.

High Radiation Dose to the Fornix Causes Symptomatic Radiation Necrosis in Patients with Anaplastic Oligodendroglioma.

Surgery, radiotherapy (RT), and chemotherapy have prolonged the survival of patients with anaplastic oligodendroglioma. However, whether RT induces long-term toxicity remains unknown. We analyzed the relationship between the RT dose to the fornix and symptomatic radiation necrosis (SRN). A total of 67 patients treated between 2009 and 2019 were analyzed. SRN was defined according to the following three criteria: 1) radiographic findings, 2) symptoms attributable to the lesion, and 3) treatment resulting in symptom improvement. Various contours, including the fornix, were delineated. Univariate and multivariate analyses of the relationship between RT dose and SRN, as well as receiver operating characteristic curve analysis for cut-off values, were performed. The most common location was the frontal lobe (n=40, 60%). Gross total resection was performed in 38 patients (57%), and 42 patients (63%) received procarbazine, lomustine, and vincristine chemotherapy. With a median follow-up of 42 months, the median overall and progression-free survival was 74 months. Sixteen patients (24%) developed SRN. In multivariate analysis, age and maximum dose to the fornix were associated with the development of SRN. The cut-off values for the maximum dose to the fornix and age were 59 Gy (equivalent dose delivered in 2 Gy fractions) and 46 years, respectively. The rate of SRN was higher in patients whose maximum dose to the fornix was >59 Gy (13% vs. 43%, p=0.005). The maximum dose to the fornix was a significant factor for SRN development. While fornix sparing may help maintain neurocognitive function, additional studies are needed.

Dosimetric feasibility analysis and presentation of an isotoxic dose-escalated radiation therapy concept for glioblastoma used in the PRIDE trial (NOA-28; ARO-2022-12)

Background and purposeThe PRIDE trial (NOA-28; ARO-2022-12; NCT05871021) is scheduled to start recruitment in October 2023. Its primary objective is to enhance median overall survival (OS), compared to historical median OS rates, in patients with methylguanine methlyltransferase (MGMT) promotor unmethylated glioblastoma by incorporating isotoxic dose escalation to 75 Gy in 30 fractions. To achieve isotoxicity and counteract the elevated risk of radiation necrosis (RN) associated with dose-escalated regimens, the addition of protective concurrent bevacizumab (BEV) serves as an innovative approach. The current study aims to assess the dosimetric feasibility of the proposed concept. Materials and methodsA total of ten patients diagnosed with glioblastoma were included in this dosimetric analysis. Delineation of target volumes for the reference plans adhered to the ESTRO-EANO 2023 guideline. The experimental plans included an additional volume for the integrated boost. Additionally, the 60 Gy-volume was reduced by using a margin of 1.0 cm instead of 1.5 cm. To assess the risk of symptomatic RN, the Normal Tissue Complication Probability (NTCP) was calculated and compared between the reference and experimental plans. ResultsMedian NTCP of the reference plan (NTCPref) and of the experimental plan (NTCPex) were 0.24 (range 0.11–0.29) and 0.42 (range 0.18–0.54), respectively. NTCPex was a median of 1.77 (range 1.60–1.99) times as high as the NTXPref. In a logarithmic comparison, the risk of RN is enhanced by a factor of median 2.00 (range 1.66–2.35). The defined constraints for the organs at risk were feasible. ConclusionWhen considering the potential protective effect of BEV, which we hypothesized might reduce the risk of RN by approximately two-fold, achieving isotoxicity with the proposed dose-escalated experimental plan for the PRIDE trial seems feasible.

RADT-38. DOSE ESCALATED RADIOTHERAPY IS ASSOCIATED WITH IMPROVED OUTCOMES FOR HIGH GRADE MENINGIOMA

Abstract BACKGROUND The optimal modern radiotherapy (RT) approach after surgery for atypical and malignant meningioma is unclear. We present results of dose-escalation. METHODS Consecutive patients with histopathologic grade 2 or 3 meningioma treated with RT were reviewed. A dose-escalation cohort [≥ 66Gy equivalent dose in 2 Gy fractions using an a/b = 10 (EQD2)], was compared to a standard dose cohort (&amp;lt; 66Gy). Outcomes were progression-free survival (PFS), cause-specific survival (CSS), overall survival (OS), local failure (LF) and radiation necrosis. RESULTS 118 patients (111 Grade 2, 94.1%) were identified; 54/118 (45.8%) received dose-escalation and 64/118 (54.2%) standard dose. Median follow-up was 45.4 months (IQR: 24.0 - 80.0 months) and median OS was 9.7 years (Q1: 4.6 years, Q3: not reached). All dose-escalated patients had residual disease vs. 65.6% in the standard dose cohort (p &amp;lt; 0.001). 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,p = 0.042) was associated with improved PFS, whereas ≥ 2 surgeries (HR: 1.989, p = 0.035) and older age (HR: 1.035, p &amp;lt; 0.001) were associated with worse PFS. The cumulative risk of LF was reduced with dose-escalation (p = 0.016). MVA confirmed dose-escalation protective for LF (HR: 0.483, p = 0.019), whereas ≥ 2 surgeries prior to RT predicted for LF (HR: 2.145, p = 0.008). A trend was observed for improved CSS and OS in the dose-escalation cohort (p &amp;lt; 0.1). Seven patients (5.9%) developed symptomatic radiation necrosis (RN) with no significant difference between the two cohorts. CONCLUSIONS Dose-escalated radiotherapy with ≥ 66Gy for high grade meningioma is associated with improved local control and PFS with an acceptable risk of RN.

INNV-05. OUTCOMES OF RECURRENT GLIOBLASTOMA PATIENTS WITH RADIATION NECROSIS FOLLOWING GAMMATILE BRACHYTHERAPY IMPLANTATION

Abstract Implantation of collagen tile brachytherapy GammaTile (GT Medical Technologies Tempe, AZ) allows for targeting of radiation to residual malignancy following surgical resection of gross disease. Radiation necrosis (RN) can develop after radiotherapy or brachytherapy. We sought to determine outcomes in recurrent glioblastoma patients with RN after treatment with Gammatile. All patients were previously treated with surgical resection followed Stupp protocol chemoradiation. At recurrence, patients underwent repeat surgical resection and implantation of GammaTile. Subsequent MRIs were assessed for stability, presumed RN or progression. Symptomatic RN patients were treated with corticosteroids or bevacizumab. From December 2020 to February 2023, 19 patients were treated. Median time from initial radiation to GammaTile therapy was 270 days. A total of 8 patients (42%) developed RN at a median time of 81 days from GammaTile. In RN patients vs those that did not develop RN, pathological tumor viability was lower (20% vs 50%, p=0.3), age was lower (54 vs 63, p=0.06), tumor volume was lower (10.8 cc vs 51.9 cc, p=0.02), time from initial surgery was longer (470 days vs 299 days, p=0.46), number of GammaTiles placed was lower (5 vs 8, p=0.045), rate of gross total resection (GTR) was higher (100% vs 64%, p=0.04), and MGMT methylation rate was higher (63% vs 11%, p=0.03). No patients in the RN group experienced radiographic progression (0% vs 45%, p=0.009) and 3 (38%) required bevacizumab therapy. Median overall survival from GammaTile surgery in the RN group was 325 days vs 188 days (p=0.03). Our series demonstrates a significant survival benefit in patients who develop RN following GammaTile implantation after glioblastoma recurrence. RN developed in younger patients with smaller tumor volumes, lower pathological tumor viability, and higher rates of GTR and MGMT methylation status.

Symptomatic Necrosis With Antibody-Drug Conjugates and Concurrent Stereotactic Radiotherapy for Brain Metastases

This cohort study investigates whether brain metastases that manifest after stereotactic radiotherapy with concurrent antibody-drug conjugates are associated with an increased risk of symptomatic radiation necrosis.

Dose-Escalated Radiation Therapy Is Associated With Improved Outcomes for High-Grade Meningioma

The optimal modern radiation therapy (RT) approach after surgery for atypical and malignant meningioma is unclear. We present results of dose escalation in a single-institution cohort spanning 2000 to 2021. Consecutive patients with histopathologic grade 2 or 3 meningioma treated with RT were reviewed. A dose-escalation cohort (≥66 Gy equivalent dose in 2-Gy fractions using an α/β=10) was compared with a standard-dose cohort (<66 Gy). Outcomes were progression-free survival (PFS), cause-specific survival, overall survival (OS), local failure (LF), and radiation necrosis. One hundred eighteen patients (111 grade 2, 94.1%) were identified; 54 (45.8%) received dose escalation and 64 (54.2%) standard dose. Median follow-up was 45.4 months (IQR, 24.0-80.0 months) and median OS was 9.7 years (Q1: 4.6 years, Q3: not reached). All dose-escalated patients had residual disease versus 65.6% in the standard-dose cohort (P < .001). PFS at 3, 4, and 5 years in the dose-escalated versus standard-dose cohort was 78.9%, 72.2%, and 64.6% versus 57.2%, 49.1%, and 40.8%, respectively, (P=.030). On multivariable analysis, dose escalation (hazard ratio [HR], 0.544; P=.042) was associated with improved PFS, whereas ≥2 surgeries (HR, 1.989; P=.035) and older age (HR, 1.035; P < .001) were associated with worse PFS. The cumulative risk of LF was reduced with dose escalation (P=.016). Multivariable analysis confirmed that dose escalation was protective for LF (HR, 0.483; P=.019), whereas ≥2 surgeries before RT predicted for LF (HR, 2.145; P=.008). A trend was observed for improved cause-specific survival and OS in the dose-escalation cohort (P < .1). Seven patients (5.9%) developed symptomatic radiation necrosis with no significant difference between the 2 cohorts. Dose-escalated RT with ≥66 Gy for high-grade meningioma is associated with improved local control and PFS with an acceptable risk of radiation necrosis.

Immune checkpoint inhibition and single fraction stereotactic radiosurgery in brain metastases from non-small cell lung cancer: an international multicenter study of 395 patients.

Approximately 80% of brain metastases originate from non-small cell lung cancer (NSCLC). Immune checkpoint inhibitors (ICI) and stereotactic radiosurgery (SRS) are frequently utilized in this setting. However, concerns remain regarding the risk of radiation necrosis (RN) when SRS and ICI are administered concurrently. A retrospective study was conducted through the International Radiosurgery Research Foundation. Logistic regression models and competing risks analyses were utilized to identify predictors of any grade RN and symptomatic RN (SRN). The study included 395 patients with 2,540 brain metastases treated with single fraction SRS and ICI across 11 institutions in four countries with a median follow-up of 14.2months. The median age was 67years. The median margin SRS dose was 19Gy; 36.5% of patients had a V12 Gy ≥ 10 cm3. On multivariable analysis, V12 Gy ≥ 10 cm3 was a significant predictor of developing any grade RN (OR: 2.18) and SRN (OR: 3.95). At 1-year, the cumulative incidence of any grade and SRN for all patients was 4.8% and 3.8%, respectively. For concurrent and non-concurrent groups, the cumulative incidence of any grade RN was 3.8% versus 5.3%, respectively (p = 0.35); and for SRN was 3.8% vs. 3.6%, respectively (p = 0.95). The risk of any grade RN and symptomatic RN following single fraction SRS and ICI for NSCLC brain metastases increases as V12 Gy exceeds 10 cm3. Concurrent ICI and SRS do not appear to increase this risk. Radiosurgical planning techniques should aim to minimize V12 Gy.

Immune Checkpoint Inhibition and Single Fraction Stereotactic Radiosurgery in Non-Small Cell Lung Cancer Brain Metastases: An International Multicenter Study of 395 Patients

Brain metastases most commonly arise from non-small cell lung cancer (NSCLC). In recent years, immune checkpoint inhibitors (ICI) have demonstrated improvements in overall survival (OS) in NSCLC. However, concerns remain about the risk of radiation necrosis (RN) when ICI are administered with stereotactic radiosurgery (SRS). Logistic regression was used to evaluate prognostic factors associated with the development of any grade RN and symptomatic RN. Cumulative incidence of RN was evaluated using competing risks analysis and the Fine and Gray model, where the null hypothesis was rejected for p < 0.05. There were 395 patients with 2,513 brain metastases treated across 11 international institutions included in the analysis. The median follow-up was 14.2 months. Median patient age was 67 years (Interquartile Range [IQR]: 61-73), 53.4% were male, the median Karnofsky Performance Status was 80 (IQR: 80-90), and 88.6% has active extracranial disease at the time of SRS. The median margin dose was 19 Gy (IQR: 18-20), 97.5% of patients were treated on the Gamma Knife ®, 3.8% underwent prior whole brain radiation therapy (WBRT). The median V12 Gy was 5.2 cm3 and 36.5% of patients had a V12 Gy ≥ 10 cm3, anti-PD-1 agents were administered in 91.6% of patients. A V12 Gy ³ 10 cm3 was associated with an increased risk of developing any grade RN; odds ratio (OR): 2.12, p = 0.04 and OR: 2.18; p = 0.03 on univariable and multivariable analysis, respectively. Similarly, a V12 Gy ≥ 10 cm3 was associated with an increased risk of developing symptomatic RN; OR: 3.80, p = 0.003 and OR: 3.95; p = 0.003 on univariable and multivariable analysis, respectively. Receipt of concurrent ICI and prior WBRT were not statistically significant. At 1-year, the cumulative incidence of any grade and symptomatic RN was 4.8% and 3.8%, respectively. The cumulative incidence of any grade RN was 3.8% vs. 5.3% for the concurrent and non-concurrent groups at 1-year, respectively (p = 0.35). The cumulative incidence of symptomatic RN was 3.8% vs. 3.6% for the concurrent and non-concurrent groups at 1-year, respectively (p = 0.95). The risk of any grade and symptomatic RN following SRS and ICI administration for NSCLC brain metastases increases as the V12 Gy exceeds 10 cm3. Concurrent ICI and SRS does not appear to increase this risk. Radiosurgical planning techniques should aim to minimize the V12 Gy.

Radiosurgery Dose Reduction for Brain Metastases on Immunotherapy (RADREMI): One-Year Safety and Efficacy Outcomes from a Multicenter Phase I Trial

The combination of immunotherapy and single-fraction stereotactic radiosurgery (SRS) for treatment of metastatic brain disease has yielded symptomatic radiation necrosis rates as high as 20% (PMID: 29327059). Consequently, the Radiosurgery Dose Reduction for Brain Metastases on Immunotherapy (RADREMI) multicenter phase I trial (registered at clinicaltrials.gov, NCT04047602) was created to address whether reduced-dose SRS can improve morbidity without compromising efficacy. In this report we present our one-year findings. Eligibility for RADREMI enrollment required brain metastases patients with: a) Histologically-confirmed primary malignancy, b) Receipt of immunotherapy within 30 days of SRS, c) 1-10 MRI-visible brain metastases, d) Estimated median survival of at least 6 months (via disease-specific graded prognostic assessment), and e) No history of whole brain radiation therapy. Reduced-dose SRS utilized 18 Gy for lesions 0-2 cm, 14 Gy for lesions 2.1-3 cm, and 12 Gy for lesions 3.1-4 cm. Symptomatic radiation necrosis was defined as imaging findings consistent with radiation necrosis combined with clinical symptoms requiring steroid administration and/or operative intervention. Local control was defined by Response Assessment in Neuro-Oncology (RANO) criteria. From December 18, 2019 to June 30, 2022, 54 lesions in 17 patients were treated on RADREMI with at least one-year of follow-up. One-year local control occurred in 52 of 54 lesions and in 15 of 17 patients, yielding control rates of 96% per lesion and 88% per patient. Radiographic radiation necrosis occurred in 2 of 54 lesions (4%). No symptomatic radiation necrosis occurred. Our findings of concurrent immunotherapy + reduced-dose SRS at one-year post-treatment revealed excellent local control (96%) with no symptomatic radiation necrosis, and minimal radiographic radiation necrosis. These results attest to the durability of the safety and efficacy of reduced-dose SRS with immunotherapy for metastatic brain disease.

Initial Report of Boswellia Serrata for Management of Cerebral Radiation Necrosis after Stereotactic Radiosurgery for Brain Metastases

Radiation necrosis (RN) is a concerning late toxicity after radiation therapy (RT) for brain metastases. Oral corticosteroids are the mainstay of management; however, they are not optimal for long-term use given multiple side effects and drug interactions, particularly with the emergence of immunotherapy for several cancers. Boswellia serrata (BS) is an over-the-counter supplement used for its anti-inflammatory properties and has been recently shown to reduce cerebral edema after brain RT. We evaluated the response rates with BS in a series of patients with brain metastases treated with stereotactic radiosurgery (SRS) who developed RN. We included patients who developed RN after SRS for brain metastases at our institution from 2020-2022 and were treated with BS. Patients were prescribed over the counter BS 4.2-4.5g daily in divided doses. Follow-up MRI imaging was obtained every 2-3 months after starting BS. Response was assessed using Response Assessment in Neuro-Oncology (RANO) criteria. Primary endpoint was ≥25% decrease in edema volume on T2-FLAIR MRI from baseline. Patients were censored if they had tumor progression or repeat RT to necrotic area, or death. Kaplan-Meier curves were used for survival estimates. A total of 50 patients received BS for Grade 1-3 CTCAE v5.0 RN (G1 = 11, G2 = 36, and G3 = 3). Median age was 62.8 years (range 36.9 - 50) and median RT dose was 24 Gy in 3 fractions. Median time to RN after SRS was 10 months(m). Median follow-up after starting BS was 6m and 40 patients had at least 1 follow up MRI available to evaluate response. The best response was complete response (CR) in 15% patients and partial response (PR) in 40% while 35% had stable disease (SD) and 10% had progressive disease. Median time to CR was 9m (6-12m) and PR was 6m (3-12m). Percentage of patients who had any response (CR or PR) at 3, 6, 9 and 12 months was 25%, 60%, 43% and 50%, respectively. 56% patients had symptomatic RN, of which 35.7% had improvement in symptoms with BS alone, while 64% required steroid use. Overall, median duration of response in patients with CR, PR or SD was 7.5m(range 2-31m). Salvage treatment for RN was steroids (33), surgery (4), Bevacizumab (5) or hyperbaric oxygen therapy (1). No patients had any CTCAE grade 3 or higher toxicities. 3 patients (6%) had any side-effects all of whom had Grade 1-2 gastrointestinal intolerance or diarrhea. 2 patients stopped treatment due to enrolment on an immunotherapy clinical trial. Overall, 39 patients remained on BS at last follow-up or death. We observed >50% response rates with use of BS in our cohort of patients with Grade 1-3 RN after SRS. More than 1/3rd patients with symptomatic RN were able to avoid long-term steroid use. BS is an easily available over-the-counter drug that appears to be a safe and promising treatment option for RN, and can potentially decrease steroid dependence in these patients, reducing the risk of several side-effects. Further prospective studies to compare Boswellia with placebo is warranted.

A Comparison of Local Failure and Necrosis Following Different Radiosurgery Strategies for Large Brain Metastases

Large brain metastases (LBMs) are associated with poor local control with single-fraction stereotactic radiosurgery (SRS) alone. Various alternative strategies have been developed, including fractionated SRS (FSRS) and staged SRS (SSRS) for intact LBMs, and resection with postoperative-SRS (postop-SRS) or preoperative-SRS (preop-SRS) for operable LBMs. The objective of this study is to compare local failure (LF) and radiation necrosis (RN) outcomes among these four management strategies to determine the optimal treatment paradigm. Consecutive patients diagnosed with LBM (≥2 cm in maximum dimension) between July 2017 and January 2022 and treated with one of the aforementioned strategies at a single tertiary institution were evaluated. All immobilization, target contouring, margins, dose- and prescription selection followed pre-defined institutional guidelines. Primary endpoints included LF, symptomatic RN, or a composite endpoint of these two variables. Gray's test was used to compare the cumulative incidence of the LF and the composite endpoint, with death as a competing risk. A total of 234 LBMs in 188 consecutive patients met the inclusion criteria. The median age was 65 years (range: 31-98), the median KPS was 80 (range: 50-100), and 58% were female. The most common primary tumors were lung (48%) and breast cancer (17%). The median maximum tumor diameter was 3.0 cm (range: 2.0-5.6). 47 (20%) lesions were treated with FSRS, 66 (28%) with SSRS, 74 (32%) with postop-SRS, and 47 (20%) with preop-SRS. With a median follow-up of 12 months, 22 (9%) LF and 11 (5%) RN events occurred. The 6-month and 1-year cumulative incidences of LF for the entire cohort were 5% (95% CI: 3%-9%) and 8% (95% CI: 5%-12%), respectively. The 6-month and 1-year LF rates were 4% (95% CI: 1%-13%) and 8% (95% CI: 3%-20%) for FSRS; 8% (95% CI: 3%-20%) and 8% (95% CI: 3%-20%) for SSRS; 7% (95% CI: 3%-15%) and 8% (95% CI: 3%-16%) for postop-SRS; 0 and 7% (95% CI: 2%-20%) for preop-SRS (p>0.05). The 1-year OS rates were favorable in resected patients (61% for postop-SRS and 82% for preop-SRS) compared to SRS alone strategies (45% for FSRS and 56% for SSRS) (p = 0.004). Similarly, RN events were significantly lower in resected patients treated with either bimodality approach (0 for postop-SRS and 4% for preop-SRS) than SRS standalone strategies (9% for FSRS and 8% SSRS) (p = 0.024). At 12 months, the cumulative probabilities of the composite endpoint were 13% (95% CI: 5%-25%) for FSRS, 15% (95% CI: 7%-25%) for SSRS, 9% (95% CI: 3%-17%) for postop-SRS, and 12% (95% CI: 4%-24%) for preop-SRS and not significantly different between the groups. For medically operable patients with surgically resectable LBMs, a strategy of surgery and SRS, regardless of timing, is associated with favorable local control and reduced risk for RN. For unresected patients, either SSRS or FSRS is associated with similar local control, but slightly higher RN risk. Prospective comparative evaluation is warranted.

Development of an RPA for Prediction of Radiation Necrosis Following Single Fraction Gamma Knife Radiosurgery for Brain Metastases

Radiation necrosis (RN) is a potential complication following treatment of brain metastases with stereotactic radiosurgery (SRS). Several risk factors for RN have been reported, but to our knowledge there are no recursive partitioning analysis (RPA) models to identify patients at highest risk for RN. We therefore sought to develop a predictive tool to identify patients at highest risk for the development of RN following single fraction SRS. Patients who underwent single fraction SRS for brain metastases from 2017-2021 were identified from a single institutional IRB-approved database. Patients with concern for RN were discussed in a multi-disciplinary setting and a diagnosis of RN was made based on pathologic or radiographic findings. Cox proportional hazards regression was done to identify factors associated with RN. RPA was performed to categorize patients into distinct risk groups for RN. Variables with p<0.1 on univariate analysis from the Cox regression analysis were included in the RPA. Patients with staged SRS, incomplete treatment records, or < 3 months radiographic follow-up were excluded from the analysis. The study population comprised 1,011 lesions from 283 patients with a median follow-up of 9.7 months. The majority of lesions had non-small cell lung cancer (NSCLC) (49%) as the primary site followed by breast (12%) and melanoma (11%). The median prescription dose was 24 Gy (range: 12-24 Gy). RN was diagnosed in 12.2% of lesions, of which 28% (35/123) were symptomatic RN. The median time to RN was 4.9 months. Variables identified for inclusion in the RPA included primary tumor site, use of targeted therapy, tumor location, pre-SRS hemorrhage, post-SRS hemorrhage, prior SRS to other lesions, number of SRS targets, maximum dose, maximum lesion diameter, 70% isodose line, heterogeneity index, conformality index, and gradient index. RPA identified four distinct groups. Group 1 was defined as maximum lesion diameter (MLD) <0.8 cm with primary tumor site other than breast, colorectal (CRC) or NSCLC (n = 174); group 2 was MLD <0.8 cm with breast, CRC, or NSCLC (n = 372). Group 3 was defined as MLD ≥ 0.8 cm without post-SRS hemorrhage (n = 336) and group 4 was MLD ≥0.8 cm with post-SRS hemorrhage (n = 129). Two-year RN free survival for all lesions was 82%, 100% for group 1, 89% for group 2, 76% for group 3, and 58% for group 4. We created the first RPA predictive model for RN following single fraction SRS and identified a subgroup of patients at highest risk. This RPA can help guide clinicians when educating patients on RN risk for brain metastases.

Impact of Concurrent Targeted Therapy and Immunotherapy on the Incidence of Radiation Necrosis Following Stereotactic Radiosurgery for Brain Metastases

The management of metastatic disease has evolved with the advent of immunotherapy (IT) and targeted therapies (TT). Yet, there is limited understanding of the toxicity associated with combining these agents with stereotactic radiosurgery (SRS). We retrospectively evaluated the impact of concurrent systemic therapy (ST) on the risk of radiation necrosis (RN) following LINAC-based SRS for brain metastases (BM). A retrospective study was conducted within an integrated health care system from March 2017 to December 2021 of 313 patients who underwent SRS or fractionated SRS in 3 or 5 treatments to a total of 1,644 intact BM. Post-operative cavity SRS and re-irradiated lesions were excluded. RN was diagnosed using perfusion MRI, contrast clearance MRI, or serial standard MRI and graded using CTCAE (v.5). Concurrent ST was defined as administration within 1 month preceding or following SRS. Overall survival (OS) and risk of RN were estimated by the Kaplan-Meier method. Logistics regression analyses were performed to compare risk of RN in patients who received concurrent systemic therapy to those who did not, adjusted for PTV volume and receipt of whole brain radiotherapy (WBRT). Median follow-up was 12.2 months. Median age was 64 years (range: 24-92). Primary sites per patient included lung (48.9%), breast (18.2%), melanoma (11.5%), kidney (6.1%), and other (15.3%). Median total lesions treated was 3 (range: 1-44); 65.9% of patients underwent 1 course of SRS, 23.4% underwent 2 courses, 6.2% underwent 3 courses, 4.5% underwent >4 courses. Seventy-six (24.2%) patients received WBRT. Overall, 70.6% of lesions received concurrent ST including chemotherapy (CT) (32.5%), IT (26.8%), and TT (27.6%); 16.4% received a combination of ST. Median OS was 12.9 months (95% CI: 10.4-15.5). RN was observed in 50 (3.0%) lesions in 42 (13.4%) patients. The 1-year risk of RN was 4.0% per lesion and 15.4% per patient. Symptomatic RN (SRN) was observed in 31 (1.9%) lesions in 24 (7.7%) patients. The 1-year risk of SRN was 2.7% per lesion and 10.1% per patient. When compared to lesions treated without concurrent systemic therapy, there was no increased risk of RN observed in lesions treated with concurrent CT (adjusted OR = 0.86 (95% CI: 0.43-1.73) p = 0.68), concurrent IT (adjusted OR = 0.84 (95% CI: 0.41-1.71) p = 0.84), or concurrent TT (adjusted OR = 0.57 (95% CI: 0.25-1.30) p = 0.18). Treatments of SRN included dexamethasone (96.8%), bevacizumab (22.6%), and laser interstitial thermal therapy (6.5%). Concurrent IT and TT appears well-tolerated in patients who undergo SRS for treatment of BM. No increased risk of RN was observed in lesions treated with concurrent IT or TT compared to lesions treated in the absence of concurrent ST. Further prospective and agent-specific evaluation is necessary to confirm these findings.

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.

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.

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.

P03.12.A PHASE III RANDOMIZED TRIAL COMPARING PREOPERATIVE HYPOFRACTIONATED RADIOSURGERY (HSRS) TO POSTOPERATIVE HYPOFRACTIONATED RADIOSURGERY (HSRS) FOR PATIENTS WITH LARGE BRAIN METASTASES SUITABLE FOR SURGICAL RESECTION SUPPORT TRIAL

Abstract BACKGROUND Standard of care for patients with large brain metastases (BMs) suitable for surgery is surgical resection followed by radiosurgery in single or multifractions (SRS/HSRS) on tumor bed. Although a satisfactory local control is obtained, an increasing rates of leptomeningeal disease (LMD) related to surgery, and symptomatic radionecrosis related to SRS/HSRS have been observed. In the last years the employ of preoperative SRS/HSRS has been investigated in retrospective studies. Advantages seem to be: better target delineation to intact lesion, reduction of normal brain irradiated considering useless of margins, potential prevention of any cells spilled during resection, greater oxygenation ratio of intact region, sterilization effect, and resection of majority of irradiated tissues. Preoperative HSRS versus postoperative ones will be investigated in multicentric randomized phase III trial. Primary endpoint is rate of leptmeningeal disease secondary endpoints, local control, symptomatic radiation necrosis, surgical morbidity, quality of life (QoL) and neurocognitive functions assessment between the two modalities; brain distant progression (BDP), and overall survival (OS) will be evaluated too. MATERIAL AND METHODS Inclusion criteria are: patients aged 18-80 years, diagnosed malignant primary tumor, KPS≥70, oligometastatic disease, limited brain metastases (up to 4), large BM suitable for surgery. Exclusion criteria are: prior WBRT, SCLC, or germinal cell tumour or Lymphoproliferative disease, prior neurosurgery, and incompatibility to perform MRI. Stratification factors will be: histology of primary tumor (Breast, NSCLC, Melanoma, Other) and BMs location (sovra-or infra-tentorial). In Arm A (experimental) patients undergo preoperative HSRS, 27 Gy in 3 fractions, followed by surgery. In Arm B (control): patients undergo surgical resection followed by postoperative HSRS at the same doses. Outcome evaluation will be assess using MRI, total body CT scan and/or CTPET, neuropsychological and Quality of life assessment before and after treatments. For distinguish RN occurrence and disease progression delayed-contrastMRI, and perfusion MRI will be employed. Considering that estimated 1 year LMD is 10% for postoperative HSRS, and ≤ 2% for preoperative enrolment of 146 patients is expected (73 per Arm). RESULTS Enrollment started at April 2023 and among first patients included the treatment has proven to be safe. CONCLUSION Preoperative HSRS in large BMs suitable for surgical resection need prospective evaluation aiming to improve outcome, and reduced treatments side effects.