Risk Of Radiation Necrosis Research Articles

RADT-02. PRE-OPERATIVE VERSUS POST-OPERATIVE FRACTIONATED STEREOTACTIC RADIOTHERAPY: A SINGLE-INSTITUTION ANALYSIS OF 534 RESECTED METASTASES

Abstract Patients with large or symptomatic brain metastases and limited intracranial disease typically have surgery followed by post-operative (post-op) stereotactic radiosurgery (SRS). However, SRS can lead to elevated rates of radiation necrosis (RN), meningeal disease (MD), and local failure (LF). Fractionated treatments can deliver a higher biological effective dose and may reduce the risk of LF, and pre-operative (pre-op) treatments may reduce the risk of RN and MD through treating smaller volumes and tumor sterilization. We hypothesize that pre-op fractionated stereotactic radiation therapy (FSRT) will reduce the incidence rate of RN, MD, and LF when compared to patients who receive post-op FSRT. A retrospective analysis was performed at a single institution and included patients who had surgical resection and radiation to at least one brain metastasis. Patients with multiple metastases resected, either during the same surgery or at different times in the disease course, were eligible for inclusion. Outcomes were evaluated on a per-lesion basis. The primary outcome was a composite endpoint defined by 1) LF, 2) MD, and/or 3) Grade 2 or higher (symptomatic) RN. 458 patients with 534 resected brain metastases were eligible for analysis. 235 metastases received pre-op FSRT, and 299 metastases received post-op FSRT. Overall, 15% of patients had multiple brain metastases resected. Overall, 6 (2.6%) pre-op and 13 (4.3%) post-op patients experienced LF. 21 (8.9%) pre-op and 38 (12.7%) post-op patients experienced symptomatic RN. 11 (4.7%) pre-op and 29 (9.7%) post-op patients were diagnosed with MD (p=0.031). 14% and 24% of metastases that received pre-op and post-op FSRT, respectively, experienced the composite endpoint (p=0.005). In our study, pre-op FSRT compares favorably to post-op FSRT primarily due to a 50% reduction in the incidence of MD. Differences in symptomatic RN or LF were small on adjusted analyses. Prospective validation of pre-op FSRT is needed.

BIOM-39. GENOMIC AND CLINICAL ASSOCIATIONS WITH RADIATION NECROSIS IN PATIENTS WITH DIFFUSE INFILTRATING GLIOMAS

Abstract BACKGROUND Radiation necrosis (RN) is a complication of radiotherapy (RT) that can significantly affect quality of life and outcomes in patients with gliomas. Clinical and molecular factors predisposing patients to RN are not clearly established. We hypothesize that clinicogenomic data can be leveraged to identify patients at high risk for RN. METHODS We identified patients from 2014-2024 with diffuse gliomas and RN diagnosed based on Advanced-Brain-Tumor-Imaging which includes conventional MRI, 3 perfusion parameters, spectroscopy and/or pathology at MD Anderson. Inclusion criteria included diagnosis of RN 12-weeks after RT and concordance of 4 ABTI parameters. For each case, we identified 2 controls who were gender-,diagnosis-, and age-matched using a nearest neighborhood algorithm. We evaluated the correlation between 15 most mutated genes in baseline tissue and occurance of RN. A logistic regression model was employed to assess the multivariable relationship between patient characteristics, gene mutations, and RN. RESULTS We identified 62 patients with RN; 50 glioblastoma (80.6%), 8 diffuse astrocytoma (12.9%) and 4 oligodendroglioma (6.5%). Time from RT to RN diagnosis was 254 days (IQR 154-483). 18(29%) of RN cases and 29(24.4%) of controls had received more than one course of RT. Patients treated with bevacizumab before RT had significantly lower odds of developing RN compared to those who did not receive bevacizumab (OR 0.103 [0.011 – 0.960], p=0.0459). BRAF mutations were more frequent in the RN cohort (8.1% vs. 2.4%) and patients with BRAF mutation were more likely to have RN than those without BRAF mutation (OR 6.842 [1.2, 39.01], p=0.0304). Age, gender, diagnosis, IDH, MGMT or 1p19q status were not associated with RN. CONCLUSION We found that bevacizumab administration was associated with a significant reduction in RN development. We also found a novel association between presence of BRAF mutations and increased risk of RN in glioma patients, which warrants further investigation.

Risk of late radiation necrosis more than 5 years after stereotactic radiosurgery.

Radiation necrosis (RN) is a well-recognized late complication most commonly occurring within 2 years of stereotactic radiosurgery (SRS); however, late RN (LRN), RN occurring or recurring > 5 years after SRS, has been poorly described. This study analyzes the incidence of and risk factors for LRN occurring > 5 years after SRS. This retrospective analysis included patients treated with linear accelerator-based SRS for tumors or arteriovenous malformations with > 5 years of clinical and serial MRI follow-up. LRN was defined as new neurological symptoms with neuroanatomically correlated imaging findings without disease recurrence. Univariate and multivariate analyses for LRN were performed using the Cox proportional hazards model. The authors identified a cumulative 297 lesions in 219 patients treated to a median dose of 17 Gy with a median follow-up of 7.4 years. In total, 290 (97.6%) lesions were treated in a single fraction, and 64 (21.5%) were treated after resection. The LRN occurred in 19 (8.7%) patients and in 23 (7.7%) lesions at a median of 6.1 years (range 5.1-13.9 years) after SRS. Fifteen of the 23 (65.2%) lesions were managed with steroids, bevacizumab, and/or antiepileptic drugs. The remaining 8 (34.8%) were resected; histopathology confirmed necrosis without disease recurrence in each. On multivariate analysis, only > 5-cm3 volume of the brain receiving 12 Gy (brain V12Gy) (HR 6.01, 95% CI 1.77-20.48; p = 0.004) and a history of early, previously resolved RN (HR 9.53, 95% CI 2.00-45.61; p = 0.005) remained significantly associated with LRN. RN risk persists well beyond 5 years after SRS, and recognizing LRN as an entity has important implications in managing these patients. LRN risk was highest in those with a brain V12Gy > 5 cm3 and a history of early RN after SRS, warranting close follow-up in perpetuity for select patients.

Surgically targeted radiation therapy versus stereotactic radiation therapy: A dosimetric comparison for brain metastasis resection cavities

BackgroundSurgically targeted radiation therapy (STaRT) with Cesium-131 seeds embedded in a collagen tile is a promising treatment for recurrent brain metastasis. In this study, the biological effective doses (BED) for normal and target tissues from STaRT plans were compared with those of external beam radiotherapy (EBRT) modalities. MethodsNine patients (n=9) with 12 resection cavities (RCs) who underwent STaRT (cumulative physical dose of 60 Gy to a depth of 5 mm from the RC edge) were replanned with CyberKnife® (CK), Gamma Knife® (GK), and intensity modulated proton therapy (IMPT) using an SRT approach (30 Gy in 5 fractions). Statistical significance comparing D95% and D90% in BED10Gy (BED10Gy95% and BED10Gy90%) and to RC + 0 to + 5 mm expansion margins, and parameters associated with radiation necrosis risk (V83Gy, V103Gy, V123Gy and V243Gy) to the normal brain were evaluated by a Wilcoxon-signed rank test. ResultsFor RC+0 mm, median BED10Gy90% for STaRT (90.1 Gy10, range: 64.1-140.9 Gy10) was significantly higher than CK (74.3 Gy10, range:59.3-80.4 Gy10, p=0.04), GK (69.4 Gy10, range: 59.8-77.1 Gy10, p=0.005), and IMPT (49.3 Gy10, range: 49.0-49.7 Gy10, p=0.003), respectively. However, for the RC+5 mm, the median BED10Gy90% for STaRT (34.1 Gy10, range: 22.2-59.7 Gy10) was significantly lower than CK (44.3 Gy10, range: 37.8-52.4 Gy10), and IMPT (46.6 Gy10, range: 45.1-48.5 Gy10), respectively but not significantly different from GK (34.1 Gy10, range: 22.8-47.0 Gy10). The median V243Gy was significantly higher in CK (11.7 cc, range: 4.7-20.1 cc), GK(6.2 cc, range: 2.3-11.9 cc) and IMPT (19.9 cc, range: 11.1-36.6 cc) compared to STaRT (1.1 cc, range: 0.0-7.8 cc) (p<0.01). ConclusionThis comparative analysis suggests the STaRT approach may treat recurrent brain tumors effectively via delivery of higher radiation doses with equivalent or greater BED up to at least 3 mm from the RC edge as compared to EBRT approaches.

Reirradiation of metastases of the central nervous system: part 1-brain metastasis.

Because of improved survival of cancer patients, more patients irradiated for brain metastases develop intracerebral recurrences requiring subsequent courses of radiotherapy. Five studies focused on reirradiation with whole-brain radiation therapy (WBRT) after initial WBRT for brain metastases. Following the second WBRT course, improvement of clinical symptoms was found in 31-68% of patients. Rates of neurotoxicity, such as encephalopathy or cognitive decline, were reported in two studies (1.4% and 32%). In another study, severe or unexpected adverse events were not observed. Survival following the second WBRT course was generally poor, with median survival times of 2.9-4.1 months. The survival prognosis of patients receiving two courses of WBRT can be estimated by a scoring tool considering five prognostic factors. Three studies investigated reirradiation with single-fraction stereotactic radiosurgery (SF-SRS) following primary WBRT. One-year local control rates were 74-91%, and median survival times ranged between 7.8 and 14 months. Rates of radiation necrosis (RN) after reirradiation were 0-6%. Seven studies were considered that investigated re-treatment with SF-SRS or fractionated stereotactic radiation therapy (FSRT) following initial SF-SRS or FSRT. One-year local control rates were 60-88%, and the median survival times ranged between 8.3 and 25 months. During follow-up after reirradiation, rates of overall (asymptomatic or symptomatic) RN ranged between 12.5% and 30.4%. Symptomatic RN occurred in 4.3% to 23.9% of cases (patients or lesions). The risk of RN associated with symptoms and/or requiring surgery or corticosteroids appears lower after reirradiation with FSRT when compared to SF-SRS. Other potential risk factors of RN include the volume of overlap of normal tissue receiving 12 Gy at the first course and 18 Gy at the second course of SF-SRS, maximum doses ≥40 Gy of the first or the second SF-SRS courses, V12 Gy >9 cm3 of the second course, initial treatment with SF-SRS, volume of normal brain receiving 5 Gy during reirradiation with FSRT, and systemic treatment. Cumulative EQD2 ≤100-120 Gy2 to brain, <100 Gy2 to brainstem, and <75 Gy2 to chiasm and optic nerves may be considered safe. Since most studies were retrospective in nature, prospective trials are required to better define safety and efficacy of reirradiation for recurrent or progressive brain metastases.

Is pulsed saturation transfer sufficient for differentiating radiation necrosis from tumor progression in brain metastases?

Stereotactic radiosurgery (SRS) for the treatment of brain metastases delivers a high dose of radiation with excellent local control but comes with the risk of radiation necrosis (RN), which can be difficult to distinguish from tumor progression (TP). Magnetization transfer (MT) and chemical exchange saturation transfer (CEST) are promising techniques for distinguishing RN from TP in brain metastases. Previous studies used a 2D continuous-wave (ie, block radiofrequency [RF] saturation) MT/CEST approach. The purpose of this study is to investigate a 3D pulsed saturation MT/CEST approach with perfusion MRI for distinguishing RN from TP in brain metastases. The study included 73 patients scanned with MT/CEST MRI previously treated with SRS or fractionated SRS who developed enhancing lesions with uncertain diagnoses of RN or TP. Perfusion MRI was acquired in 49 of 73 patients. Clinical outcomes were determined by at least 6 months of follow-up or via pathologic confirmation (in 20% of the lesions). Univariable logistic regression resulted in significant variables of the quantitative MT parameter 1/(RA·T2A), with 5.9 ± 2.7 for RN and 6.5 ± 2.9 for TP. The highest AUC of 75% was obtained using a multivariable logistic regression model for MT/CEST parameters, which included the CEST parameters of AREXAmide,0.625µT (P = .013), AREXNOE,0.625µT (P = .008), 1/(RA·T2A) (P = .004), and T1 (P = .004). The perfusion rCBV parameter did not reach significance. Pulsed saturation transfer was sufficient for achieving a multivariable AUC of 75% for differentiating between RN and TP in brain metastases, but had lower AUCs compared to previous studies that used a block RF approach.

The Impact of Immune Checkpoint Inhibition on the Risk of Radiation Necrosis Following Stereotactic Radiotherapy for Metastatic Brain Cancer.

Purpose/objective Forty percentof cancer patients develop brain metastases (BM) and are often treated with stereotactic radiation (SRS/SRT). Checkpoint inhibitor (CI) use is suspected of increasing the risk of radiation necrosis (RN). Our aim is to determine whether treatment with CI is associated with an increased risk of RN in BM patients treated with SRS/SRT. Methods We retrospectively identified the medical records of BM patients treated with SRS/SRT between 1/2017 and 12/2021 using an institutional database.RN was defined by MRI imaging read by neuroradiologists and/or surgical pathology. V12GY of patients with and without RN was compared using the Mann-Whitney test. The chi-square test was used to see if RN was associated with CI use, histology, particular CI agent used, > 1 course SRS/SRT, SRS/SRT dose, chemotherapy, whole brain radiotherapy (WBRT), age, or sex. Results Two hundred and fifty-ninepatients treated with 455 courses of SRS/SRT were analyzed. The most common primary histologies were lung 56% (N=146), breast 14% (N= 37), melanoma 9% (N=24), and renal cancer 7% (N=18). A total of 53.8% (N = no. of patients) were treated with CI. The overall rate of any RN was 21.8% (N=27) in the CI group compared to 14.8% (N=141) in the non-CI group (p=0.174). Mean V12Gy was 15.525 cc and 9.419 cc in patients with and without RN (p=0.02768). Mean number of SRS/SRT courses was 2 and 1.53 for patients with and without RN, and >1 course of SRS/SRT was a predictor of RN (p <0.01). Other features analyzed were not significant. Conclusion RN was higher in the BM patients treated with SRS/SRT receiving CI compared to non-CI patients (21.8%, N=27, versus 14.6%, N= 16), but failed to reach statistical significance. V12Gy and > 1 course of SRS/SRT was associated with RN. Caution should be taken in treating patients with SRS/SRT and CI there might be an increased risk of RN.

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.

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.

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.

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.

Stereotactic Radiosurgery for Small Intact Brain Metastasis: A Comparative Evaluation of 3 Different Single Fraction Prescription Doses

While single-fraction stereotactic radiosurgery (SRS) in the treatment of small brain metastases (SBM, ≤ 2 cm) is well established, prescription dosing varies considerably across institutions and clinical trials. The choice of prescription dose is a delicate balance between local failure (LF) and radiation necrosis (RN) risks. In the modern era, historically-established dosing thresholds may no longer be applicable. To evaluate the impact of prescription dose on outcomes, we performed a comparative analysis of patients with SBM treated with definitive SRS using three different prescriptions, at a single tertiary institution. Consecutive patients with intact SBM treated with SRS from January 2017 and December 2021 were analyzed. Baseline patient characteristics and dosing parameters were abstracted from the medical record. To limit the integral brain dose when treating multiple brain metastases, the institutional practice was to reduce prescription dose as the total number of lesions increased (i.e., 24 Gy for ≤10 lesions, 22 Gy for 11-20, and 20 Gy for >20). A per lesion analysis, where each lesion was followed from the date of SRS to the last follow-up, was conducted with primary endpoints of LF and RN. Gray's test was used to compare the cumulative incidence of the LF and RN, with death as a competing risk. Factors affecting LF were analyzed using Cox hazard regression analysis. A total of 1318 SBM in 250 patients received SRS and met the inclusion criteria. The median age was 62 years (range: 18-90), median KPS was 90 (range: 50-100) and 66% were female. The most common primary tumors were lung (55.5%) and breast cancers (26.4%). With a median follow-up of 12 months, 136 (11%) LF in 44 patients and 70 (5.7%) RN events in 46 patients occurred. The actuarial 1-year cumulative rate of LF was lower in lesions treated with 24 Gy (6.4%, 95% CI: 4.7-8.6%) or 22 Gy (5.8%, 95% CI: 3.7-8.7%) compared to 20 Gy (15.4%, 95% CI: 10.9-20.5%) (p<0.01). 22 Gy and 24 Gy prescription doses were associated with a 44% and 52% reduction in risk in LF compared to 20 Gy (HR: 0.56; 95% CI: 0.36-0.9; p = 0.01 and HR: 0.48; 95% CI: 0.31-0.74; p<0.01, respectively). In a subset analysis of radiosensitive tumors, 1-year LF rate was still lower with 24 Gy (7.4%, 95% CI: 5.3-9.9%) and 22 Gy (6.1%, 95% CI: 3.7-9.4%) than 20 Gy (15.7%, 95% CI: 11.2-21%) (p = 0.01). The cumulative 1-year RN rate numerically declined with dose, but was not statistically significantly different, with 3.6% (95% CI: 2.3-5.3%) for 24 Gy, 2.6% (95% CI: 1.3-4.8%) for 22 Gy and 1.4% (95% CI: 0.4-3.7%) for 20 Gy. Patients treated with single fraction SRS to intact SBM were at increased risk of LF with prescription doses of 20 Gy compared to 22-24 Gy, without an increased risk of RN. Even in patients with radiosensitive histologies, higher LF rates were still observed following 20 Gy compared to 22-24 Gy.

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.

Radiation Necrosis following SRS or FSRT with Higher BED for Brain Metastases >20 mm

In the RTOG 90-05 study, the maximum tolerated dose of single-fraction radiosurgery (SRS) for lesions 21-30 mm was 18 Gy (BED 45 Gy12). However, patients of the RTOG study were previously irradiated with median 60 Gy (brain tumors) or 30 Gy (brain metastasis). Thus, the max. tolerated BED for lesions not irradiated before may be >45 Gy12. This study investigated safety and efficacy of SRS or fractionated stereotactic radiotherapy (FSRT) with BED >49 Gy12 for radiotherapy-naive brain metastases >20 mm. Data of 169 patients who received SRS or FSRT alone with BED >49 Gy12 for 1-4 brain metastases (2011-2022) were retrospectively analyzed. Thirty-two patients had lesions >20 mm (21-30 mm, n = 27; 21-40 mm, n = 4; >40 mm, n = 1). SRS was performed with 20 Gy (n = 9; 53.3 Gy12) or 19 Gy (n = 2; 49.1 Gy12), prescribed to the 60-80% isodose line (PTV = GTV). FSRT was Linac-based delivering 3 x 10 Gy (n = 3; 55 Gy12), 3 x 11 Gy (n = 4; 63.3 Gy12), 7 x 6 Gy (n = 1; 63 Gy12), 9 x 5 Gy (n = 1; 63.8 Gy12), 10 x 4 Gy (n = 11; 53.3 Gy12), or 12 x 4 Gy (n = 1; 64 Gy12), prescribed to the 80% isodose line (PTV = GTV+1-2 mm). SRS and FSRT were compared for grade ≥2 radiation necrosis (RN), local control (LC) and survival (OS). Fractionation [SRS (n = 89) vs FSRT (n = 48)] and lesion size (≤20 vs >20 mm) were studied in terms of RN rates. Kaplan-Meier method and log-rank test were used for univariate analyses and the Cox proportional hazards model for multivariate analyses. In patients with lesions >20 mm, SRS and FSRT were compared (Fisher's exact/Chi square test) for age, gender, KPS, year of SRS/FSRT, primary tumor, number/site of lesions, systemic treatment, and extracranial metastases. In patients with lesions >20 mm, significantly more patients receiving SRS had a KPS >80 than patients treated with FSRT (91% vs 29%, p = 0.002); otherwise, distributions of patient characteristics were balanced. In patients with lesions >20 mm, SRS was associated with significantly higher RN rates at 1 year (50% vs 9%) and 2 years (50% vs 9%) on univariate analysis (p = 0.012), which remained on multivariate analysis (HR: 0.10; 95% CI: 0.01-0.94, p = 0.044). No significant differences were found for LC (p = 0.21) at 1 year (75% vs 70%) and 2 years (75% vs 53%), and OS (p = 0.09) at 1 year (36% vs 59%) and 2 years (27% vs 46%). In patients with lesions ≤20 mm, 1- and 2-year RN rates following SRS were both 4%, compared to 0% and 15% respectively after FSRT (p = 0.60). In the SRS group, RN rates were significantly higher with lesions >20 mm (vs ≤20 mm) on univariate (p<0.001) and multivariate (HR: 3.82, 95% CI: 1.70-8.58, p = 0.001) analyses. In the FSRT group, max. diameter had no significant impact on RN rates (p = 0.93). Given the limitations of this study, FSRT with BED >49 Gy12 appears associated with a low risk of RN when used for brain metastases >20 mm. SRS with 1x19-20 Gy may not be optimal for metastases >20 mm but appears safe for lesions ≤20 mm. Prospective trials are 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.

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.

Dose-Volume Tolerance of the Brain and Predictors of Radiation Necrosis After 3-Fraction Radiosurgery for Brain Metastases: A Large Single-Institutional Analysis

Stereotactic radiosurgery (SRS) is the current standard of care in patients with brain metastases and controlled extracranial disease. Radiation necrosis (RN) is the dose-limiting side effect of SRS, but the dose constraints especially for fractionated SRS remain poorly defined. We assessed the risk of RN after 3-fraction SRS with a goal to identify specific dose-volume constraints associated with grade 3 or higher RN (G3RN). A single-institutional retrospective review of patients treated with 3-fraction SRS was performed. The primary endpoint was G3RN, which was defined as severe symptoms with evidence of necrosis on magnetic resonance imaging with perfusion and/or biopsy confirmation. Tissue volume around each target lesion was contoured, and volumetric doses per lesion were recorded. Logistic regression models were used to estimate the relationship between RN and each volumetric dose, and normal tissue complication probability modeling was performed using a modified Lyman-Kutcher-Burman model. From 2015 to 2021, 434 patients underwent 539 courses of linear accelerator-based SRS; 2518 lesions were treated. Median SRS dose was 24 Gy. Median follow-up after SRS was 7.9 months, and the median overall survival was 9 months. A total of 93 patients (17.2%) and 123 lesions (4.9%) developed any RN. Forty-two patients (7.8%) and 57 lesions (2.3%) developed G3RN. On logistic regression, V20 and V23 were best predictors of any grade RN and G3RN, respectively, with cutoff values of 4 cc, 10 cc, and 20 cc associated with <5%, <7.5%, and <10% risk of any RN, respectively, and V23 < 15 cc associated with <5% risk of G3RN. With constrained optimization of the normal tissue complication probability Lyman-Kutcher-Burman model for G3RN, we obtained a TD50 (uniform dose resulting in a 50% complication risk) of 31.4 Gy (95% CI, 27.8-35.1 Gy). In patients receiving 3-fraction SRS, G3RN was seen in 7.8% of patients, and 2.3% of the lesions were treated. V20 and V23 were the most robust dosimetric parameters associated with RN. Further studies evaluating the outcomes and RN in patients treated with fractionated SRS compared with single-fraction SRS are warranted.