Radiation Necrosis In Patients Research Articles

Gadolinium Enhanced T2 FLAIR is an Imaging Biomarker of Radiation Necrosis and Tumor Progression in Patients with Brain Metastases.

Differentiating radiation necrosis (RN) from tumor progression (TP) after radiotherapy for brain metastases is an important clinical problem requiring advanced imaging techniques which may not be widely available and are challenging to perform at multiple time points. The ability to leverage conventional MRI for this problem, could have meaningful clinical impact. The purpose of this study was to explore contrast enhanced T2 FLAIR (T2FLAIRc) as a new imaging biomarker of RN and TP. This single-institution retrospective study included patients with treated brain metastases undergoing DSC-MRI between January 2021 and June 2023. Reference standard assessment was based on histopathology or serial follow-up including results of DSC-MRI for a minimum of 6 months from the first DSC-MRI. The index test was implemented as part of the institutional brain tumor MRI protocol and preceded the first DSC-MRI. T2FLAIRc and gadolinium enhanced T1 MPRAGE (T1c) signal were normalized against normal brain parenchyma and expressed as z-score. Mean signal intensity of enhancing disease for RN and TP groups were compared using unpaired t-test. Receiver operator characteristic (ROC) curves and area under the ROC curve (AUC) were derived by bootstrapping. DeLong test was used to compare AUC. 56 participants (mean age, 62 years +/-12.7 [SD]; 39 females); 28 RN, 28 TP were evaluated. The index MRI was performed on average 73 days +/-34 [SD] before the first DSC-MRI. Significantly higher z-scores were found for RN using T2FLAIRc (8.3 versus 5.8, p<0.001) and T1c (4.1 versus 3.5, p=0.02). AUC for T2FLAIRc (0.83, 95% CI, 0.72-0.92) was greater than T1c (0.70, 95% CI, 0.560.83) (p = 0.04). The AUC of DSC derived rCBV (0.82, 95% CI, 0.70-0.93) was not significantly different from T2FLAIRc (p = 0.9). A higher normalized T1c and T2FLAIRc signal intensity was found for RN. In a univariable test, mean T2FLAIRc signal intensity of enhancing voxels showed good discrimination performance for distinguishing RN from TP. The results of this work demonstrate the potential of T2FLAIRc as an imaging biomarker in the work-up of RN in patients with brain metastases. AUC = area under the receiver operating characteristic curve; RN = radiation necrosis; ROC = receiver operating characteristic; SRS = stereotactic radiosurgery; T1c = contrast enhanced T1; T2FLAIRc = contrast enhanced T2 FLAIR; TP = tumor progression.

Comparative analysis of bevacizumab and LITT for treating radiation necrosis in previously radiated CNS neoplasms: a systematic review and meta-analysis.

Radiation necrosis (RN) is a local inflammatory reaction that arises in response to radiation injury and may cause significant morbidity. This study aims to evaluate and compare the efficacy of bevacizumab and laser interstitial thermal therapy (LITT) in treating RN in patients with previously radiated central nervous system (CNS) neoplasms. PubMed, Cochrane, Scopus, and EMBASE databases were screened. Studies of patients with radiation necrosis from primary or secondary brain tumors were included. Indirect meta-analysis with random-effect modeling was performed to compare clinical and radiological outcomes. Twenty-four studies were included with 210 patients in the bevacizumab group and 337 patients in the LITT group. Bevacizumab demonstrated symptomatic improvement/stability in 87.7% of cases, radiological improvement/stability in 86.2%, and steroid wean-off in 45%. LITT exhibited symptomatic improvement/stability in 71.2%, radiological improvement/stability in 64.7%, and steroid wean-off in 62.4%. Comparative analysis revealed statistically significant differences favoring bevacizumab in symptomatic improvement/stability (p = 0.02), while no significant differences were observed in radiological improvement/stability (p = 0.27) or steroid wean-off (p = 0.90). The rates of adverse reactions were 11.2% for bevacizumab and 14.9% for LITT (p = 0.66), with the majority being grade 2 or lower (72.2% for bevacizumab and 62.5% for LITT). Both bevacizumab and LITT exhibited favorable clinical and radiological outcomes in managing RN. Bevacizumab was found to be associated with better symptomatic control compared to LITT. Patient-, diagnosis- and lesion-related factors should be considered when choosing the ideal treatment modality for RN to enhance overall patient outcomes.

154 Elucidating the Immune Landscape of Radiation Necrosis Through Single Cell Analysis of Recurrent Brain Lesions in Patients After Stereotactic Radio Surgery

INTRODUCTION: Radiation necrosis (RN), a common and morbid side effect of radiosurgical treatment of brain metastasis, is becoming more prevalent as immunotherapy options and patient survival improve. Thought to be immunologically driven, the pathophysiology of RN remains poorly defined. Further, RN is often indistinguishable from regrowing metastases after stereotactic radiosurgery (SRS), requiring invasive brain biopsy for diagnosis. METHODS: We collected 20 intraoperative samples from patients undergoing craniotomy for RN and/or metastatic tumor, as well as time-matched blood and CSF. We created a tissue bank, processed samples, and using fluorescence-activated cell sorting (FACS) and 10x Genomics single cell RNA sequencing, analyzed the cellular immune profile of lesional tissue, blood, and CSF. RESULTS: RN tissue demonstrates a robust, detectable expression of immune cells, including CD8+ and CD4+ T cells, natural killer (NK) and myeloid cells. Importantly, clustering of RN-derived immune cells (including T cells, myeloid cells, and NK cells) is reflected in the blood and CSF, with similar immune profiles. We demonstrate a subpopulation of myeloid cells with a microglia signature (CD14+, LYZ-, MS4A7+), and a separate population expressing interferon-stimulated gene (ISG). Supporting these findings, pathway analysis of top blood markers reveals pathways involved in innate and inflammatory immune responses in the blood of RN patients. CONCLUSIONS: These findings demonstrate the feasibility of extracting live cells from RN tissue for scRNAseq analysis and suggest that there are unique signatures of RN that can be detected in the blood and CSF of patients. This work has the potential to open new avenues for improved diagnostic and therapeutic approaches to allow earlier detection and more effective treatment of RN in patients with metastatic brain tumors.

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.

Multiparametric Analysis Combining DSC-MR Perfusion and [18F]FET-PET is Superior to aSingle Parameter Approach for Differentiation of Progressive Glioma from Radiation Necrosis.

Perfusion-weighted (PWI) magnetic resonance imaging (MRI) and O‑(2-[18F]fluoroethyl-)-l-tyrosine ([18F]FET) positron emission tomography (PET) are both useful for discrimination of progressive disease (PD) from radiation necrosis (RN) in patients with gliomas. Previous literature showed that the combined use of FET-PET and MRI-PWI is advantageous; hhowever the increased diagnostic performances were only modest compared to the use of asingle modality. Hence, the goal of this study was to further explore the benefit of combining MRI-PWI and [18F]FET-PET for differentiation of PD from RN. Secondarily, we evaluated the usefulness of cerebral blood flow (CBF), mean transit time (MTT) and time to peak (TTP) as previous studies mainly examined cerebral blood volume (CBV). In this single center study, we retrospectively identified patients with WHO gradesII-IV gliomas with suspected tumor recurrence, presenting with ambiguous findings on structural MRI. For differentiation of PD from RN we used both MRI-PWI and [18F]FET-PET. Dynamic susceptibility contrast MRI-PWI provided normalized parameters derived from perfusion maps (r(relative)CBV, rCBF, rMTT, rTTP). Static [18F]FET-PET parameters including mean and maximum tumor to brain ratios (TBRmean, TBRmax) were calculated. Based on histopathology and radioclinical follow-up we diagnosed PD in 27and RN in 10cases. Using the receiver operating characteristic (ROC) analysis, area under the curve (AUC) values were calculated for single and multiparametric models. The performances of single and multiparametric approaches were assessed with analysis of variance and cross-validation. After application of inclusion and exclusion criteria, we included 37patients in this study. Regarding the in-sample based approach, in single parameter analysis rTBRmean (AUC = 0.91, p < 0.001), rTBRmax (AUC = 0.89, p < 0.001), rTTP (AUC = 0.87, p < 0.001) and rCBVmean (AUC = 0.84, p < 0.001) were efficacious for discrimination of PD from RN. The rCBFmean and rMTT did not reach statistical significance. Aclassification model consisting of TBRmean, rCBVmean and rTTP achieved an AUC of 0.98 (p < 0.001), outperforming the use of rTBRmean alone, which was the single parametric approach with the highest AUC. Analysis of variance confirmed the superiority of the multiparametric approach over the single parameter one (p = 0.002). While cross-validation attributed the highest AUC value to the model consisting of TBRmean and rCBVmean, it also suggested that the addition of rTTP resulted in the highest accuracy. Overall, multiparametric models performed better than single parameter ones. Amultiparametric MRI-PWI and [18F]FET-PET model consisting of TBRmean, rCBVmean and PWI rTTP significantly outperformed the use of rTBRmean alone, which was the best single parameter approach. Secondarily, we firstly report the potential usefulness of PWI rTTP for discrimination of PD from RN in patients with glioma; however, for validation of our findings the prospective studies with larger patient samples are necessary.

RADT-08. IS THERE A CORRELATION BETWEEN ANEMIA AND RADIATION NECROSIS IN BREAST CANCER PATIENTS WITH BRAIN METASTASES UNDERGOING RADIOSURGERY? A PRELIMINARY SINGLE-INSTITUTION COHORT STUDY

Abstract INTRODUCTION Stereotactic radiosurgery (SRS) is a highly effective treatment for brain metastases. Radiation necrosis (RN) is a prominent dose-limiting toxicity, occurring in 5-10% of patients. Data on differences in RN incidence based on tumor molecular markers and the potential correlation with anemia have not been explored. The objective of this study was to 1) report our institutional rates of RN in patients with breast cancer brain metastases (BCBM) undergoing radiosurgery; and 2) investigate the correlation of anemia with RN rates. METHODS A retrospective review of patients with BCBM treated with SRS between May 2006 and October 2020 was conducted. To ensure homogeneity, only patients with oligometastatic disease (1-4 BM) and only 1 session of SRS were included. Hemoglobin (Hb) was assessed from 3 months before or 6 months post SRS, and diagnosis of anemia was made for Hb &amp;lt;13 g/dL in males and Hb &amp;lt;12 g/dL in females. Logistic regression was used to analyze correlation of anemia and RN. RESULTS 44 patients were included (82 total lesions treated by SRS, median 2). Seventy-seven lesions were treated with SRS to a median dose of 20 Gy (15-24 Gy). Five lesions were treated with fractionated SRS (30Gy, 3-5 fractions). Five patients (11.4%) developed RN based on imaging; two went on to biopsy with one having pathological confirmation of RN. Anemia was identified in twenty-eight (63.7%) patients; 1 was treated with iron supplementation. Although anemia was not significantly associated with RN, patients with anemia did have significantly lower OS than those without (p = 0.04). CONCLUSION Our institutional data suggest similar RN rates in BCBM patients as the literature. Our sample size was too small to investigate correlation between anemia and RN, though survival may be impacted. Larger, multi-institutional studies are underway to further study this possibility.

Safety and Efficacy of Stereotactic Radiosurgery with Concurrent Targeted Systemic Therapy for Brain Metastases

Data describing the safety and efficacy of central nervous system (CNS)-active targeted systemic therapies in combination with stereotactic radiosurgery (SRS, 1 fraction) and/or radiotherapy (SRT, 3-5 fractions) for brain metastases are emerging but limited. We report rates of local and intracranial failure and radiation necrosis in patients receiving CNS-active targeted systemic therapy and SRS/SRT. We retrospectively identified patients with intact brain metastases at two institutions from 2009-2022 who were treated with SRS/SRT and CNS-active targeted systemic therapy in any sequence. Patients were followed for a minimum of 3 months after SRS/SRT with brain MRI. Patients typically stopped the targeted agent 2-4 days prior to radiation and resumed 2-4 days after. Targeted therapies included inhibitors of ALK/ROS1 (Alectinib, Ceritinib, Crizotinib, Lorlatinib), EGFR (Afatinib, Erlotinib, Gefitinib, Osimertinib), BRAF (Dabrafenib, Encorafenib, Vemurafenib), MEK (Binimetinib, Trametinib), CDK 4/6 (Abemaciclib, Palbociclib, Ribociclib), HER2 (Afatinib, Lapatinib, Neratinib, Pertuzumab, Trastuzumab, T-DM1, T-DXd, Tucatinib), KRAS (Adagrasib and Sotorasib), PARP (Niraparib, Olaparib), VEGF(R) (Axitinib, Bevacizumab, Ramucirumab), and less-selective tyrosine (receptor) kinase inhibitors (Bosutinib, Brigatinib, Entrectinib, Lenvatinib, Pazopanib, Sorafenib, Sunitinib). Local failure (LF) and radiation necrosis were determined radiographically with clinical impression (grade 2 (symptomatic) or higher (G2+)) and compared between different systemic agents. The study included 95 patients with 310 metastases (SRS 246, SRT 64 metastases). Most common primary histologies were non-small cell lung cancer (36% 34/95), breast cancer (28% 27/95), and melanoma (16% 15/95). Overall survival at 1 and 2 years was 80% (76/95) and 55% (52/95), respectively. Median follow-up was 16.6 (range 3-91) months. Median tumor size was 7mm (range 1-75mm). Median number of brain metastases per patient was 2.5 (range 1-12). The G2+ radiation necrosis rate was 5.8% (18/310) while the LF rate was 9.7% (30/310) per metastasis. There was no significant difference in G2+ radiation necrosis by class of targeted therapy. Sixty-two percent (59/95) of patients experienced distant intracranial failure. Median intracranial progression free survival (PFS) was 8.0 (range 0.4-61.4) months. Although heterogeneous, patients treated with SRS/SRT and ongoing CNS-active targeted systemic therapies have on average >6 month intracranial PFS and little evidence of significant toxicity. We observed <6% G2+ radiation necrosis for this cohort, and no particular class of agent was associated with a significantly higher rate of G2+ radiation necrosis.

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.

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.

Transcriptional expression of radiation-induced early cortical morphological alterations and its association with radiation necrosis in patients with nasopharyngeal carcinoma

PurposeTo explore the effects of standard radiotherapy on cortical morphology and its potential transcriptional expression, and to determine the predictive power of cortical morphological measurement at the early stage for radiation necrosis (RN) occurrence within 3 years post-radiotherapy in patients with nasopharyngeal carcinoma (NPC). Methods185 NPC patients participated. Pre-treatment and post-radiotherapy (1–3 months) structural MRI were collected longitudinally and prospectively. Multiple cortical morphological indices were compared between pre-treatment and post-radiotherapy. Brain-wide gene expression was used to assess the transcriptional profiles associated with radiation-induced cortical morphological changes. Machine learning was used to construct predictive models for RN with cortical morphological alterations at the early stage. ResultsRelative to pre-treatment, NPC patients exhibited a widespread reduction in cortical volume (CV) and cortical thickness (CT) post-radiotherapy (p < 0.001). Partial least squares regression analysis revealed that radiotherapy-related cortical atrophy was closely related to transcriptional profiles (p < 0.001), with the most correlated genes enriched in ATPase Na+/K+ transporting alpha-1 and alpha-3 polypeptide and respiratory electron transport chain. Furthermore, models constructed with cortical morphological features at 1–3 months post-radiotherapy had favorable predictive power for RN occurrence in NPC patients within 3-year follow-up, the area under the curve was 0.854 and 0.843 for CV and CT, respectively. ConclusionsNPC patients exhibited widespread cortical atrophy at 1–3 months post-radiotherapy, which was closely correlated with dysfunction of the ATPase Na+/K+ transporting alpha-1 and alpha-3 polypeptide and respiratory electron transport chain. Cortical morphology at 1–3 months post-radiotherapy may serve as an early biomarker for identifying RN.

PO-1120 Radiation necrosis in patients treated with brain SRT: evaluation of clinical and dosimetric factors

PO-1120 Radiation necrosis in patients treated with brain SRT: evaluation of clinical and dosimetric factors

Novel Mechanisms and Future Opportunities for the Management of Radiation Necrosis in Patients Treated for Brain Metastases in the Era of Immunotherapy.

Radiation necrosis, also known as treatment-induced necrosis, has emerged as an important adverse effect following stereotactic radiotherapy (SRS) for brain metastases. The improved survival of patients with brain metastases and increased use of combined systemic therapy and SRS have contributed to a growing incidence of necrosis. The cyclic GMP-AMP (cGAMP) synthase (cGAS) and stimulator of interferon genes (STING) pathway (cGAS-STING) represents a key biological mechanism linking radiation-induced DNA damage to pro-inflammatory effects and innate immunity. By recognizing cytosolic double-stranded DNA, cGAS induces a signaling cascade that results in the upregulation of type 1 interferons and dendritic cell activation. This pathway could play a key role in the pathogenesis of necrosis and provides attractive targets for therapeutic development. Immunotherapy and other novel systemic agents may potentiate activation of cGAS-STING signaling following radiotherapy and increase necrosis risk. Advancements in dosimetric strategies, novel imaging modalities, artificial intelligence, and circulating biomarkers could improve the management of necrosis. This review provides new insights into the pathophysiology of necrosis and synthesizes our current understanding regarding the diagnosis, risk factors, and management options of necrosis while highlighting novel avenues for discovery.

Effect of Bevacizumab Treatment in Cerebral Radiation Necrosis : Investigation of Response Predictors in a Single-Center Experience.

Bevacizumab is a feasible option for treating cerebral radiation necrosis (RN). We investigated the clinical outcome of RN after treatment with bevacizumab and factors related to the initial response and the sustained effect. Clinical data of 45 patients treated for symptomatic RN between September 2019 and February 2021 were retrospectively collected. Bevacizumab (7.5 mg/kg) was administered at 3-week intervals with a maximum four-cycle schedule. Changes in the lesions magnetic resonance image (MRI) scans were examined for the response evaluation. The subgroup analysis was performed based on the initial response and the long-term maintenance of the effect. Of the 45 patients, 36 patients (80.0%) showed an initial response, and eight patients (17.8%) showed delayed worsening of the corresponding lesion. The non-responders showed a significantly higher incidence of diffusion restriction on MRI than the responders (100.0% vs. 25.0%, p<0.001). The delayed worsening group showed a significantly higher proportion of glioma pathology than the maintenance group (87.5% vs. 28.6%, p=0.005). Cumulative survival rates with sustained effect were significantly higher in the groups with non-glioma pathology (p=0.019) and the absence of diffusion restriction (p<0.001). Pathology of glioma and diffusion restriction in MRI were the independent risk factors for non-response or delayed worsening after initial response. The initial response of RN to bevacizumab was favorable, with improvement in four-fifths of the patients. However, a certain proportion of patients showed non-responsiveness or delayed exacerbations. Bevacizumab may be more effective in treating RN in patients with non-glioma pathology and without diffusion restriction in the MRI.

Clinical Outcomes of Stereotactic Radiosurgery-Related Radiation Necrosis in Patients with Intracranial Metastasis from Melanoma.

Radiation necrosis (RN) is a clinically relevant complication of stereotactic radiosurgery (SRS) for intracranial metastasis (ICM) treatments. Radiation necrosis development is variable following SRS. It remains unclear if risk factors for and clinical outcomes following RN may be different for melanoma patients. We reviewed patients with ICM from metastatic melanoma to understand the potential impact of RN in this patient population. Patients who received SRS for ICM from melanoma at Mayo Clinic Arizona between 2013 and 2018 were retrospectively reviewed. Data collected included demographics, tumor characteristics, radiation parameters, prior surgical and systemic treatments, and patient outcomes. Radiation necrosis was diagnosed by clinical evaluation including brain magnetic resonance imaging (MRI) and, in some cases, tissue evaluation. Radiation necrosis was diagnosed in 7 (27%) of 26 patients at 1.6 to 38 months following initial SRS. Almost 92% of all patients received systemic therapy and 35% had surgical resection prior to SRS. Patients with RN trended toward having larger ICM and a prior history of surgical resection, although statistical significance was not reached. Among patients with resection, those who developed RN had a longer period between surgery and SRS start (mean 44 vs 33 days). Clinical improvement following treatment for RN was noted in 2 (29%) patients. Radiation necrosis is relatively common following SRS for treatment of ICM from metastatic melanoma and clinical outcomes are poor. Further studies aimed at mitigating RN development and identifying novel approaches for treatment are warranted.

Radiation Necrosis Risk in NSCLC Patients Receiving EGFR TKIs or ALK Inhibitors

<h3>Purpose/Objective(s)</h3> Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs) and anaplastic lymphoma kinase (ALK) inhibitors have become commonplace in the treatment of locally advanced and metastatic NSCLC with activating mutations. The toxicity of stereotactic radiation therapy (SRT) when given concurrently with these drugs remains unclear. The purpose of this study was to determine the incidence of radiation necrosis (RN) in patients receiving these targeted therapies (TGT). <h3>Materials/Methods</h3> We retrospectively reviewed metastatic NSCLC patients who received EGFR TKI or ALK inhibitor at our institution. Patients with brain metastases treated with SRT with a minimum of 6 months post-SRT follow up were included for analysis, and demographic, oncologic, radiation and imaging records were reviewed. RN diagnosis was based upon the radiologist interpretation, radiation oncologist progress notes, or pathology reports after resection. Local recurrence was defined radiographically or histologically. Biologically effective dose was calculated using the linear quadratic equation using an α/β of 3 (BED3) and 10 (BED10). <h3>Results</h3> Thirty-nine patients with 161 treated brain lesions fit our inclusion criteria. Most patients were female (76.9%), with a median age of 60 (range 27-73), and were treated to a median of 3 (1-27) lesions per patient. EGFR TKI or ALK inhibitor was administered in the 2-week interval surrounding SRT (TGT+) for 116 of 161 lesions, and 28 of 116 (24.1%) developed evidence of RN (21 symptomatic, 18.1%). Among the 45 lesions where TKI or ALK inhibitor was not given in the 2-week interval surrounding SRT (TGT-), one case of RN (2.2%) was identified. Most symptomatic RN lesions (67%) resolved with therapy. Local control among TGT+ and TGT- lesions was 93.1% and 97.7% respectively (p=0.08). The odds for developing RN were higher for TGT+ than TGT- treatments (OR=14; 95%CI 1.8-106). In 19 out of 116 TGT+ lesions, TGT was either held during SRT or initiated within 2 weeks following SRT, and the RN rate was not lower than for SRT where TGT was administered concurrently (26.3% vs 23.7%, p=0.4). Among TGT+ lesions, there was no difference in number of TKIs received prior to, during, or after SRT for those with or without RN. There was no association of prescribed BED3 or BED10 with the development of RN. Lesions that developed RN were more likely to be treated with osimertinib than those without RN (46% vs 23%, p=0.02). <h3>Conclusion</h3> Patients receiving SRT with EGFR TKI or ALK therapy 2 weeks before or after SRT are at higher risk of RN. This risk does not appear to diminish when holding TGT during SRT or delaying TGT initiation until after SRT. Special attention should be given to patients receiving SRT with osimertinib therapy as our data suggest that they are at higher risk of developing RN. Future work will focus on identification of unique dosimetric and temporal factors that may be predictive of RN in patients taking these targeted agents.

Predictive Factors for Survival and Radiation Necrosis in Patients with Recurrent High-Grade Glioma Treated with Re-Irradiation

<h3>Purpose/Objective(s)</h3> To analyze the predictors of survival and radiation necrosis in adult patients (pts) with recurrent high-grade gliomas (rHGG) who have undergone re-irradiation (ReRT). <h3>Materials/Methods</h3> All adult pts with rHGG who had ReRT from 2009 to 2020 at one institution were retrospectively reviewed. Demographic, clinical, dosimetric, and radiological data were obtained from the electronic medical records. The primary outcome was to identify predictors of overall survival (OS) and radiation necrosis (RN). The secondary outcome was to identify patterns of failure after ReRT, which was defined as in-field, marginal or distant if >95% of the recurrence volume was in the 80% isodose line (IDL), between 80%-20% IDL, or outside 20% IDL, respectively. OS, progression-free survival (PFS), and RN were estimated by the Kaplan-Meier method. Toxicity was recorded according to CTCAE V5.0. <h3>Results</h3> Were included 79 pts with a median age of 52 yrs (range, 19-79), 62% were male, 85% had grade 4 glioma at presentation and 98% at ReRT. IDH was wildtype/mutated/unknown in 73%/11%/15% of pts. 92% had concurrent/adjuvant temozolamide at the primary treatment. 34% had re-resection prior to ReRT. 16% had concurrent bevacizumab at ReRT. The most common fractionation schedules at the primary treatment were 40 Gy/15Fx (9%) and 50-60 Gy/28-33Fx (91%), and at ReRT were 17-24 Gy/1Fx (9%), 20-35 Gy/5Fx (38%), 25-35 Gy/10Fx (48%) and 36-54 Gy/18-30Fx (5%). The median cumulative equivalent dose in 2 Gy fractions (EQD2, a/b=2) was 103 Gy (range, 81-216). The median OS and PFS were 9.9 (95% CI 8.3-11.6) and 4.1 mos (95% CI 3.6-5.4), respectively. The OS and PFS rate at 6/12 months were 69.6%/34.2% and 29.1%/7.5%, respectively. The prognostic factors for OS on multivariate analyses (MVA) were interval from initial treatment to first progression ≥16.3mos (HR=0.35, 95% CI 0.20-0.59, p<0.001), re-resection prior ReRT (HR=0.43, 95% CI 0.25-0.73, p=0.002), ECOG ≥1 at ReRT (HR=1.90, 95% CI 1.10-3.30, p=0.022) and PTV volume at ReRT ≥112cc (HR=2.63, 95% CI 1.55-4.44, p≤0.001). Toxicities G2 and G3 were 22% (8.8% RN) and 5% (2.5% RN), respectively. Concurrent use of bevacizumab (p<0.001) and EQD2 ≤98 Gy (p<0.001) were predictors for lower incidence of RN on MVA. Exploratory analysis suggested three risk groups for RNs based on cumulative EQD2: ≤100 Gy (RN = 4%), 100-111 Gy (RN = 13%), and ≥111 Gy (RN = 20%). The failures after ReRT were in-field, marginal or distant in 67%, 6%, and 27% of pts who had follow-up MRI, respectively. <h3>Conclusion</h3> Re-irradiation is a safe and effective treatment for GBM. We describe predictive factors for OS and RN to guide patient section. Focus on pts with the most favorable OS may aid in identifying pts most likely to benefit from ReRT.

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

<h3>Purpose/Objective(s)</h3> Stereotactic radiosurgery (SRS) or fractionated stereotactic radiotherapy (FSRT) 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 are poorly defined. FSRT can decrease risk of RN over SRS while maintaining or improving high rates of overall survival (OS). We assessed the survival and risk of RN after FSRT with a goal to identify specific dose/volume constraints associated with grade 3 or higher RN using NTCP modeling. <h3>Materials/Methods</h3> A single-institutional retrospective review of patients treated with 3-fraction FSRT from 2015 to 2020 was performed. Tissue volume (brain + target) around each target lesion was contoured in a consistent manner and volumetric doses per lesion were recorded. RN was defined using biopsy or MRI with perfusion as available and graded using CTCAE version 5.0. Our primary endpoint was grade 3 or higher RN. All statistical analyses were performed using statistical software. <h3>Results</h3> From 2015 to 2020, a total of 439 patients underwent 509 courses of 3-fraction Linac-based FSRT, treating a total of 2394 metastatic lesions (range 1-71, mean = 4.7 and median = 3 lesions per course). 61 patients had ≥10 and 31 patients had ≥15 lesions treated per course. Median RT dose per fraction was 8 Gy (range 5-9 Gy). 11.8% patients received prior whole brain radiation (WBRT). Median follow-up after RT was 8 months (IQR 3-18m). A total of 64 patients (78 lesions) developed RN with 17, 17, 29 and 1 patients developing grade 1, 2, 3 and 4 RN respectively. Grade 3 or higher RN was observed in 5.9% patients. On per lesion analysis, rate of any RN and grade 3 RN was 3.2% and 1.5% respectively. Median time to RN was 11.3m (range 0.7 – 38.4). Of 30 patients with grade 3 or higher RN, 7 (23%) received prior WBRT, 19 (63%) received post-op FSRT to the cavity and 1 (3%) received pre-op FSRT. Most of these patients were managed by steroids, while 25 underwent resection and 6 received bevacizumab. Tissue volume receiving 20 Gy (V20) of <20cc or >20 cc was associated with 2.5% and 10.2% risk of RN respectively, while a V23 of <20 cc or >20 cc was associated with 2.3% vs 12.1% risk of grade 3 or higher RN. Mean V20 in patients who developed Grade 3 or higher RN was statistically higher than the entire cohort (36.9cc vs 14.1cc, p=0.002). Median OS after RT was 10m (1yr and 2yr OS of 45.8% and 30.4%, respectively) while patients who developed RN survived longer compared to rest of the cohort (32m vs 8m, p <0.001). Patients with 15 or more lesions treated per course had similar survival compared to rest of the cohort (8m vs 10m, p = 0.136), after excluding those who received prior WBRT. <h3>Conclusion</h3> In patients receiving 3 fraction FSRT, grade 3 or higher RN was seen in 5.9% patients and 1.5% lesions treated. Risk of RN was significantly lower in patients with V23 of <20 cc. Further studies evaluating the outcomes and RN in patients treated with FSRT compared to SRS or hippocampal avoidance WBRT are warranted.

Stereotactic Radiotherapy with Immunotherapy for Treatment of Brain Metastases: Optimal Timing and Fractionation to Improve Disease Control and Minimize Toxicity

<h3>Purpose/Objective(s)</h3> Immune checkpoint inhibitors (ICI) are increasingly used to treat patients with brain metastases, while stereotactic radiosurgery (SRS, 1 fraction) and stereotactic radiotherapy (SRT, 3-5 fractions) are established modalities. Emerging data suggest that ICI and SRS/SRT may work synergistically, with reports of increased efficacy and toxicity. We characterized factors associated with intracranial control and radiation necrosis in patients receiving both ICI and SRS/SRT. <h3>Materials/Methods</h3> We retrospectively identified patients treated with ICI and SRS/SRT for intact brain metastases at two institutions from 2013-2020. Patients had diagnoses of non-small cell lung cancer, renal cell carcinoma, or melanoma and were followed for a minimum of 2 months after receipt of both SRS/SRT and ICI with brain MRI. The analysis was completed on a per-metastasis basis. Local failure (LF) and radiation necrosis (determined radiographically with clinical impression or pathologically; included grade 2 (symptomatic) or higher) were analyzed by univariate and multivariate logistic regression which included tumor diameter, timing of ICI relative to SRS/SRT, PD-L1 (positive defined as ≥ 1%), and SRT vs. SRS. Progression-free survival (PFS) was defined as time from SRS/SRT to local or distant brain failure, death, or last follow up for those without progression. <h3>Results</h3> There were 179 patients with 549 metastases, 492 metastases treated with SRS, and 57 metastases treated with SRT. Median follow up from the time of SRS/SRT was 14.7 months. Median tumor size was 7mm (< 5mm: 253, ≥ 5 & < 10mm: 159, ≥ 10 and < 20mm: 91, and ≥ 20mm: 46). Rates of LF and grade 2+ radiation necrosis for the entire cohort were 5.8% (32/549) and 6.9% (38/549), respectively (15.6% (28/179) rate of grade 2+ radiation necrosis per-patient). LF rates for those who received ICI outside +/- 3 months from SRS/SRT vs. within +/- 3 months from SRS/SRT were 9.0% and 4.4%, respectively. Rates of grade 2+ radiation necrosis for those with positive vs. negative PD-L1 were 9.2% vs. 1.6%, respectively. Positive PD-L1 status was associated with improved intracranial PFS (HR 0.53, p = 0.03). <h3>Conclusion</h3> Combination ICI and SRS/SRT is increasingly used to treat brain metastases. Our study showed improved local control when ICI is given within 3 months from time of SRS/SRT without an associated increase in radiation necrosis. Increasing tumor size was associated with LF and radiation necrosis. Positive PD-L1 was associated with improved intracranial PFS and increased radiation necrosis. We recommend further study, ideally prospectively, to better characterize this treatment combination.

Leveraging Serial MRI Radiomics and Machine Learning to Predict Risk of Radiation Necrosis in Patients with Brain Metastases Managed with Stereotactic Radiation and Immunotherapy

<h3>Purpose/Objective(s)</h3> Radiation necrosis (RN) is the primary dose-limiting toxicity of stereotactic radiotherapy (SRT) for brain metastases (BMs), especially in patients also receiving immunotherapy (IO). We investigated the utility of serial magnetic resonance imaging (MRI) radiomic features to develop predictive quantitative imaging biomarkers of brain metastases response to SRT and IO. <h3>Materials/Methods</h3> Using an IRB-approved single-institution database, we retrospectively identified adult patients with brain metastases managed with SRT and IO between 2006 and 2021. We collected per-lesion outcomes measures of RN (radiographic and/or symptomatic), progressive disease (PD), or neither (NA). Routine pre- and post-SRT contrast-enhanced T1-weighted MRIs were pushed to MIM Software (Beachwood, OH), where individual BMs were manually contoured. A total of 1061 radiomics features were extracted per lesion using a digital gene expression panel. They were selected from the following categories: shape, intensity, neighborhood intensity difference (NID), grey-level co-occurrence matrix (GLCM), and grey-level run-length matrix (GLRLM). Feature reduction followed using Spearman's correlation coefficient (0.3 cut-off). Features with non-significantly different mean ranks pre- and post-SRT (p<0.01) per Wilcoxon signed-rank test were also excluded. Simple then multiple nominal logistic regressions (SLR and MLR) with Bonferroni correction were used to model the risk of RN, PD, or NA based on pre- and post-SRT, and delta-radiomic ([post-pre]/pre) features. 95% CI of ROC AUC was obtained by 10,000 bootstrapping. Statistical analysis was performed using software. <h3>Results</h3> Our dataset encompassed 301 BMs from 92 patients with NSCLC, melanoma, and renal cell carcinoma, all treated with brain SRT and IO. 74 (24.6%), 75 (24.9%), and 152 developed RN, PD, or NA, respectively. The final radiomic feature set included 39 features that significantly changed post-SRT (p<0.01). MLR resulted in a 3-radiomic feature model that predicted risk of RN (ROC AUC 0.71). The model included post-SRT BM surface area and texture (GLCM 3D Homogeneity) and pre-RT BM roundness. Interestingly, another 5-radiomic feature MLR model predicted RN and PD (ROC AUC 0.71) based on pre-SRT GLCM 3D texture feature, 3 post-SRT shape features (surface area, mean breadth, and roundness), in addition to delta-volume. <h3>Conclusion</h3> Our analysis showed that static and serial MR radiomic features could potentially predict BMs response to SRT and IO. Model external validation, combination with clinical variables, and integration of other MRI sequences are warranted before the large-scale adoption of this novel diagnostic approach.

43: Predictive Factors for Survival and Radiation Necrosis in Patients with Recurrent High-Grade Glioma Treated with Re-Irradiation

43: Predictive Factors for Survival and Radiation Necrosis in Patients with Recurrent High-Grade Glioma Treated with Re-Irradiation