Radiation Necrosis Research Articles

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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.

P03.02.B VIABLE TUMOR RECURRENCE IS A MAJOR CAUSE OF LOCAL FAILURE AFTER BEVACIZUMAB THERAPY FOR RADIATION NECROSIS IN BRAIN METASTASES TREATED WITH STEREOTACTIC RADIOSURGERY

Abstract BACKGROUND Bevacizumab (BVZ) is known to be effective to control radiation necrosis (RN) following stereotactic radiosurgery (SRS) for brain metastases (BMs), although treatment failure may occur. Here, we investigated the incidence and pattern of local failure after BVZ therapy for RN and its underlying biological mechanism. MATERIAL AND METHODS We conducted a retrospective analysis on 17 patients who had been treated with BVZ for RN following SRS for BMs between 2016 and 2021. In each patient, the diagnosis of RN was made based on the conventional and advanced MR with or without positron emission tomography. Median 5 cycles (range, 2-10 cycles) of BVZ (5 mg/kg) were administered at 2-week intervals. Treatment response was assessed by volumetric changes of the lesions on MR and patients’ neurological status. RESULTS Treatment response was typically brisk and substantial. Best MR response was seen at median 13 weeks (range, 3-56 weeks) after the start of BVZ with a median volume decrease of 84.5% (range, 38.7-100%) of perilesional brain edema on T2WI and of 54% (range, 2.9-100%) of contrast enhancing lesions on T1WI. Patients’ neurological status improved in 16 patients (94.1%) and was stationary in 1 (5.9%). During the median follow-up of 12 months (range, 2-60 months), delayed local failure was observed in 6 patients (35.3%) at median 10 months (range, 6-14 months) after starting BVZ treatment, where viable tumor recurrence was demonstrated in all of them. No reconstitution of RN without viable tumor was observed during the follow-up. CONCLUSION Although BVZ was highly effective to control RN following SRS for BMs, delayed local failure frequently occurs owing to viable tumor recurrence. This may imply that much predominant vascular stabilizing effect of BVZ over anti-tumor effect transiently obscures the presence of potential viable tumor cells but does not prevent them from eventual recurrence.

P03.06.A FRAMELESS FRACTIONATED STEREOTACTIC RADIOSURGERY FOR BRAIN METASTASES: AN INSTITUTIONAL SERIES OF 145 CASES

Abstract BACKGROUND Cobalt-60 stereotactic radiosurgery (SRS) typically involves single fraction treatment with frame immobilization. However, large tumor size, proximity to critical structures, and prior radiation treatment sometimes necessitate fractionated SRS with mask immobilization. We present a large institutional experience with fractionated mask-based SRS for brain metastases. MATERIAL AND METHODS In this single-institution, IRB-approved study, all patients treated with mask-based fractionated SRS for brain metastases from March 2017 to January 2023 were identified. The primary outcomes were 1- and 2-year local control (LC) by Kaplan-Meier method. RESULTS 118 patients with a total of 145 metastases were treated. The median follow-up time was seven months. The median age at treatment was 64.1 years (range: 26-95 years). 55.9% of patients were female. The most common primary tumors were breast (25.5%), non-small cell lung (23.4%), small-cell lung (8.3%), and melanoma (8.3%). For most cases (59.3%), the indication for fractionation was retreatment. Large size (28.3%), critical location (9.7%), and medical comorbidity (2.1%) were other indications. For all cases, the mean maximal linear size was 34.9 mm and mean target volume was 15.6 cc. For cases fractionated due to size, the mean size was 43.9 mm and mean target volume was 23.8 cc. Median total dose was 2,700 cGy (range: 1,620-3,000), and median dose per fraction (fx) was 600 cGy (range: 405-900). The most common prescriptions were 3,000 cGy/5 fx (40.0% of patients) and 2500 cGy in 500 cGy per fraction (37.2% of patients). Mean maximum dose was 4,833 cGy (range: 2,920-7,500). For 75.2% of treatments, the prescription isodose line was 50 to 59% (mean, 56.9%). Target coverage was 100% in all but one case (99%). For lesions near the brainstem, mean brainstem maximum point dose (MPD) was 9.3 Gy ± 9.8 Gy and brainstem mean dose was 3.3 Gy ± 3.3 Gy. For lesions near the optic pathway, mean optic nerve MPD was 14.4 Gy ± 9.2, optic nerve mean dose was 6.4 Gy ± 5.4 Gy, mean optic chiasm MPD was 11.7 Gy ± 7.9 Gy, and optic chiasm mean dose was 5.4 Gy ± 4.7 Gy. 1-year LC was 88.2% and 2-year LC was 80.4%. When retreatments were excluded, 1-year LC was 98.0% and 2-year LC was 98.0%. 18% of patients had acute grade 1-2 toxicities (fatigue, headache, nausea, and/or alopecia), and one patient had acute grade 3 fatigue. There were no other grade 3+ acute toxicities. 14% of patients had grade 1-2 radiation necrosis (RN); there were no cases of grade 3+ RN. CONCLUSION Cobalt-60 frameless fractionated SRS for brain metastases offers excellent local control, rigorous sparing of critical structures, and minimal toxicity. Frameless fractionated SRS should be considered for large, retreated, or critically located metastases.

P17.10.B VOLUMETRIC DIFFERENCES IN TARGET DEFINITON OF RECURRENT HIGH-GRADE GLIOMAS USING CONTRAST ENHANCED MRI VS.[18F] FDOPA PET IN RADIOSURGICAL PLANNING

Abstract BACKGROUND Radiosurgical treatment of high-grade gliomas usually bases target definition on contrast-enhanced T1-weighted MRI images. Despite advances in several MRI techniques, a number of limitations exist, primarily due to the disruption of the blood-brain barrier, making the target delineation less accurate, particularly when treating recurrences. Several studies support the use of amino acid PET/MRI in distinguishing progression from post-operative/post-radiation inflammation. However, no established guidelines define the biological target volume when using amino acid PET/MRI in radiosurgical treatment planning. We aimed to explore the volumetric differences in target volumes obtained with standard contrast-enhanced MRI versus [18F]FDOPA PET in patients with recurrent high-grade gliomas (rHGG). MATERIAL AND METHODS Ten patients obtained [18F]FDOPA PET/MRI within 1 week before radiosurgical treatment. We co-registered these images with the 3D MPRAGE-MRI typically used for stereotactic target definition and performed a follow-up PET/MRI scan 4-6 weeks after treatment. We reviewed and compared the method of tumor delineation, target volumes, and stereotactic accuracy in both modalities. RESULTS Radiosurgical treatment delivers high radiation doses to defined targets. The target volume and the proximity to eloquent structures limit the dose, thus depending on high-accuracy imaging. The invasive nature of malignant brain tumors makes anatomical delineation insufficient, particularly when treating recurrences. In such cases, amino acid PET supplies additional information. However, the spatial resolution afforded by [18F]FDOPA uptake alone is insufficient for stereotactic definition, which to a large degree is based on contrast-enhanced T1-weighted MRI images in order to achieve the sub-millimeter resolution needed for radiosurgical planning. Hybrid PET/MRI allows the combination of metabolic information of [18F]FDOPA-PET with the anatomical precision of stereotactic MRI. In the recurrent setting, [18F]FDOPA-PET supplies the necessary information for targeting the biologically active tumour, differentiating it from radiation necrosis, thus limiting the target volumes. This enables us to treat the recurrent tumours more efficiently. CONCLUSION [18F]FDOPA-PET is a useful supplement in radiosurgical planning and treatment of rHGG. It is helpful in the delineation of the biologically active tumor, thus limiting the target volume significantly. This enables higher radiation doses and potentially more efficient treatment. Further results will be presented.

JS09.5.A18F-FLUCICLOVINE PET FOR DETECTION OF RECURRENT BRAIN METASTASES AFTER RADIATION THERAPY: IMAGE INTERPRETATION CRITERIA RESULTS FROM PURSUE, A PROSPECTIVE PHASE 2 TRIAL

Abstract BACKGROUND Differentiating radiation necrosis from tumour progression after radiation therapy (RT) for brain metastases (BM) remains clinically challenging, and accurate imaging is crucial to prevent unnecessary surgery or unwarranted changes in therapy. 18F-Fluciclovine is a PET radiopharmaceutical with low background uptake in the brain and increased uptake in BM. The PURSUE study (NCT04410367) aimed to establish image interpretation criteria (IIC) for detecting suspected recurrent BM after RT using 18F-fluciclovine PET, based on several measures of lesion uptake. MATERIAL AND METHODS Across 7 US sites, 23 patients with solid tumour BM and a previously irradiated ‘reference’ lesion equivocal for recurrence on MRI who were scheduled for craniotomy underwent 18F-fluciclovine PET (185 MBq) &amp;lt;42 days post-MRI and 1-21 days pre-craniotomy. Three independent, blinded readers qualitatively rated lesion 18F-fluciclovine uptake as ‘mild’ (up to blood pool), ‘moderate’ (above blood pool to parotid gland), or ‘marked’ (above parotid gland). The primary endpoint was the diagnostic performance of different thresholds of lesion uptake on qualitative (visual) reads vs central histopathology. Secondary endpoints included diagnostic performance, based on different thresholds, of quantitative (e.g., lesion standardized uptake value [SUV]), and dynamic measures. A committee, including two independent imaging physicians, reviewed all data to establish the IIC, which were subsequently used to evaluate the diagnostic performance of 18F-fluciclovine. RESULTS All 23 reference lesions underwent histopathological analysis, with 10 (43%) being pathologically confirmed BM recurrence. The highest performing qualitative measure of 18F-fluciclovine lesion uptake was ‘marked’, rendering 92-100% and variable (40-80%) across readers. SUVmax was a reader-independent, high-performing quantitative metric (AUC 0.87, SUVmax threshold 4.8, 80% sensitivity, 85% specificity). Dynamic measures did not add diagnostic value. Thus, the committee established IIC as: "Lesions with 18F-fluciclovine uptake of a SUVmax equal to or greater than 4.8, or visually greater than the parotid gland, should be considered suspicious for recurrence. Otherwise, recurrence should be considered unlikely." Application of these IIC resulted in 80% sensitivity, 77-85% specificity, 73-80% positive predictive value, and 83-85% negative predictive value across readers. CONCLUSION PURSUE is the first prospective, multicentre study to define IIC for 18F-fluciclovine PET for accurate identification of suspected recurrent BM after RT, verified by histopathology. In this initial cohort, the IIC convey excellent diagnostic performance for 18F-fluciclovine and will help evaluate 18F-fluciclovine PET in future studies. This study was sponsored by Blue Earth Diagnostics Ltd.

P11.50.A STEREOTACTIC RADIOSURGERY FOR RECURRENT MEDULLOBLASTOMA IN PEDIATRIC AND ADULT PATIENTS: A SINGLE-INSTITUTION EXPERIENCE

Abstract BACKGROUND Medulloblastoma is the most common malignant brain tumor in children. In recent decades, the therapeutic landscape has undergone significant changes, with stereotactic radiosurgery (SRS) emerging as a promising modality for the treatment of recurrent medulloblastoma. Our study aims to provide a comprehensive long-term analysis of the efficacy and safety of SRS for both pediatric and adult patients with recurrent medulloblastomas at a single institution. MATERIAL AND METHODS In our study, we retrospectively reviewed the clinical and radiological records of patients who underwent CyberKnife SRS for medulloblastoma at our institution between 1998 and 2023. Clinical and radiographic follow-up data were available for a total of 15 medulloblastomas in 10 patients. The study population consisted of 8 pediatric patients (ages 3-18) and 2 adult patients (ages 19-75). The median age at the time of SRS was 13 years and the median tumor volume accounted for 1.88 cc. The median biologically equivalent dose (BED) and single-fraction equivalent dose (SFED) were 126 Gy and 18 Gy, respectively. The SRS was administered at the 75% of the median isodose line. RESULTS Following a median follow-up of 39 months (range: 6-78) post-treatment, 8 (53.3%) of the medulloblastomas progressed, 2 (13.3%) showed radiographic regression, and 5 (33.3%) remained stable in volume. The 3-year local tumor control rate for all medulloblastomas was 65.2%, with lower rates observed in the adult cohort (50%) and higher rates in pediatric patients (67.3%). The 3-year overall survival rate was 70%, with significantly higher rates in pediatric patients (75%) compared to adult patients (50%). The 3-year progression-free survival rate was 58.3%, with higher rates in pediatric patients (60%) compared to adult patients (50%). Two pediatric patients developed radiation-induced edema, while two adult patients experienced radiation necrosis at the latest follow-up, with both adult patients passing away. CONCLUSION SRS is a safe and effective long-term treatment option for recurrent medulloblastoma in both pediatric and adult patients, resulting in improved patient outcomes. Although rare, radiation-induced edema and necrosis were observed as adverse events but were manageable. Overall, our findings provide optimistic evidence for the use of SRS as a viable treatment modality for medulloblastoma.

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.

P11.18.B AIMING TOWARDS DIFFERENTIATING GLIOBLASTOMA PROGRESSION FROM PSEUDO PROGRESSION -PATIENTS COHORT ESTABLISHMENT AND PRELIMINARY RESULTS

Abstract BACKGROUND Longitudinal follow-up of glioblastoma patients includes advanced imaging modalities to identify tumor progression, which is of limited certainty and occasionally necessitates additional tissue sampling that has potential morbidity. Lately, the possibility of tumor-associated protein markers detection in patients' blood samples - liquid biopsies - has shown useful for this purpose in other cancers and has also gained significant interest in glioblastoma. METHODS This study presents data collected from 36histopathology-confirmed IDH-WT glioblastoma patientstreated in Sheba Medical Center between the years 2009 to 2021. Following their diagnosis, these patients were treated with radiation according to the Stupp protocol and subjected to repeated resection due to suspected tumor progressionbased on imaging studies. The data retrieved from patients' medical files include demographics, clinical outcomes, imaging characteristics, tumor molecular, andhistopathological markers. Notably, patients' selection and data retrieval were accomplished using a novel institutional AI algorithm software followed by complementary manual data retrieval of selected patients' medical files. RESULTS Patients demographics analysis showed that patientmedian age-at-diagnosis was 55.4 years (range, 21-82), and the male-to-female ratio was 3.5:1. The median overall survival (OS) was 25.1 months (range, 5.2-80.3) and the median follow-up duration was 23.1 months (range, 4.8-80.2).27 out of 36 patients had pathologically confirmed tumor progression while the remaining patients had post-radiation changes along with viable tumor or merely radiation necrosis identification. Pre-surgical resection blood samples were available for 27 out of 37 patients and will be used for a comprehensive glioblastoma-related proteins search using mass spectroscopy. In cases of patients' blood samples available both from the initial diagnosis surgical resection procedure and tumor progression surgical resection, a comparative analysis of those samples will be performed. The preliminary proteomics analysis and clinical outcomes measurements and volumetric tumor data will be presented. CONCLUSION s: Here, we present a glioblastoma patient cohort that was meticulously selected with the aim to examine our hypothesis that measuring glioblastoma-related proteins in patients' blood can be achieved and serve as a tool to distinguish between disease phases and monitor disease progression. Our comprehensive preliminary clinical, as well as proteomics data analysis, will be presented and discussed.

P11.49.B STEREOTACTIC RADIOSURGERY FOR CRANIAL AND SPINAL HEMANGIOBLASTOMAS: A SINGLE-INSTITUTION SERIES

Abstract BACKGROUND Stereotactic radiosurgery (SRS) has been an attractive treatment modality for both cranial and spinal hemangioblastomas, especially for multiple lesions commonly associated with von Hippel-Lindau (VHL) disease. This study aims to provide the largest long-term analysis of treatment efficacy and adverse effects of SRS for cranial and spinal hemangioblastomas at a single institution. MATERIAL AND METHODS We evaluated the clinical and radiological outcomes of patients with hemangioblastomas treated with CyberKnife SRS at our institute from 1998 to 2022. The follow-up data were available for 135 hemangioblastomas in 35 patients. Twenty-eight patients had 123 hemangioblastomas associated with VHL and 7 had 12 sporadic hemangioblastomas. The median age was 36 years and the median tumor volume accounted for 0.4 cc. The SRS was administered with the median single-fraction equivalent dose (SFED) of 18 Gy to the 77% median isodose line. RESULTS At a median follow-up of 57 months (range: 3-260), only 20 (16.2%) of the VHL-associated and 1 (8.3%) sporadic hemangioblastomas progressed. The 5-year local tumor control (LTC) rate was 91.3% for all hemangioblastomas, 91.7% among the sporadic lesions, and 92.9% in VHL patients. SRS improved tumor-associated symptoms of 98 (74.8%) of 131 symptomatic hemangioblastomas, including headache, neck pain, dizziness, visual disturbances, dysesthesia, ataxia, motor impairment, seizures, and dysphagia. Two patients developed radiation necrosis (5.7%) and 1 of them required surgical resection. CONCLUSION SRS is a safe and effective treatment option for patients with hemangioblastomas in critical locations such as the brainstem, cervicomedullary junction, and spinal cord, and in patients with multiple hemangioblastomas associated with VHL disease.

Pentoxifylline and Vitamin E Can Restrict Radiation Necrosis via Vascular Pathways, Experimental Study in an Animal Model

Radiation necrosis (RN) is a long-term side effect of Gamma Knife stereotactic radiosurgery that may require surgical intervention. Pentoxifylline and vitamin E have previously been shown to be effective in the treatment of RN in the published literature, but there are no data on the prophylactic use of these molecules or, more importantly, whether prophylaxis is required. The iatrogenic RN model included 50 Sprague-Dawley rats of both sexes. There were 7 treatment subgroups established. Gamma-Plan 8.32 was used to plan after magnetic resonance scans were performed in a specially designed frame. The injection doses used in the treatment groups were vitamin E (30mg/kg/day in a single dose) and pentoxifylline (50mg/kg/day in 2 doses). Control magnetic resonance scans were performed at the end of a 16-week treatment, and the subjects were decapitated for pathological evaluations. The intensity of hypoxia - inducible factor 1α immunoreactivity is statistically significantly lower in the therapeutic vitamin E, prophylactic pentoxifylline and vitamin E, and therapeutic pentoxifylline and vitamin E groups than in the other groups. Similarly, the intensity of vascular endothelial growth factor immunoreactivity was reduced in the therapeutic vitamin E and prophylactic pentoxifylline and vitamin E treatment modality groups.When compared with other groups, the therapeutic pentoxifylline group had significantly fewer vascular endothelial growth factor-immunoreactive cells in the perinecrotic area, with an accompanying decreased contrast enhancement pattern. Both vitamin E and pentoxifylline are effective for the treatment and/or restriction of RN, either alone or in combination. The use of these molecules as a preventive measure did not outperform the therapeutic treatment.

To promote the clinical application of PET/MRI in oncology

PET/MRI integrates anatomical, functional and metabolic information, and is increasingly used in the field of clinical oncology, including early diagnosis of disease, local staging, detection of systemic metastases, evaluation of treatment efficacy and prognosis. In addition to fine anatomical structure, MRI multiparametric imaging can also provide functional information of the lesion. Combined with metabolic information of PET, MRI multiparametric imaging can better evaluate the benign and maligant lesions, tumor grade and extent of invasion, and identify tumor recurrence and radiation necrosis. The development of new PET tracers, optimization of MRI sequences and examination paths, combined with high-throughput image quantitative analysis methods, radiomics, artificial intelligence and other new technologies will further promote the application of PET/MRI in oncology.

Clinically Driven Alpha/Beta Ratios for Melanoma Brain Metastases and Investigation of Biologically Effective Dose as a Predictor for Local Control After Radiosurgery: A Proof of Concept in a Retrospective Longitudinal Series of 274 Consecutive Lesions.

Brain metastases (BM) develop in nearly half of the patients with advanced melanoma. The aim of this retrospective historical cohort study was to analyze radiological response of melanoma BM to single-fraction Gamma Knife radiosurgery (GKRS), in relation to biologically effective dose (BED) for various alpha/beta ratios. Included in the study were 274 lesions. Primary outcome was local control (LC). Mean marginal dose was 21.6 Gy (median 22, range 15-25). Biologically effective dose was calculated for an alpha/beta ratio of 3 (Gy 3 ), 5 (Gy 10 ), 10 (Gy 10 ), and 15 (Gy 15 ). Receiver operating characteristic value for LC and BED was 85% (most statistically significant odds ratio 1.14 for BED Gy 15 , P = .006), while for LC and physical dose was 79% ( P = .02). When comparing equality of 2 receiver operating characteristic areas, this was statistically significant ( P = .02 and .03). Fractional polynomial regression revealed BED (Gy 10 and Gy 15 ) as statistically significant ( P = .05) with BED of more than 63 Gy 10 or 49 Gy 15 as relevant, also for higher probability of quick decrease in volume first month after GKRS and lower probability of radiation necrosis. Shorter irradiation time was associated with better LC ( P = .001), particularly less than 40 minutes (LC below 90%, P = .05). BED Gy 10 and particularly Gy 15 were more statistically significant than physical dose for LC after GKRS for radioresistant melanoma BM. Irradiation time (per lesion) longer than 40 minutes was predictive for lower rates of LC. Such results need to be validated in larger cohorts.

Outcomes of Isocitrate Dehydrogenase Wild Type Glioblastoma after Re-irradiation.

Glioblastomas (GBM) are the most common malignant primary brain tumors in adults and have a dismal prognosis. Patients frequently suffer from local tumor recurrences, with limited therapeutic options. Re-irradiation represents a possible intervention, but given the recent 5th edition of the World Health Organization classification of central nervous system tumors, studies in isocitrate dehydrogenase wild type (IDH-wt) cohorts undergoing a second course of radiotherapy remain limited. Herein, we sought to describe our institutional experience and outcomes after GBM IDH-wt re-irradiation. GBM patients with confirmed IDH-wt status undergoing re-irradiation were included in this single-center, retrospective analysis. A total of 88 patients were analyzed. The median clinical and radiographic follow-up periods were 4.6months and 4.4months, respectively. Most patients had a Karnofsky performance status of at least 80% (n=57). The median biologically effective dose and 2Gy equivalent dose (EQD2) for re-irradiations, assuming an α/β ratio of 10Gy for GBM, were 51.4 and 42.8Gy, respectively. In total, 71 deaths were recorded. The median overall survival (OS) was 8.0months. Multivariable Cox regression of OS revealed a positive influence of gross total resection vs. biopsy or no resection (hazard ratio: 0.43, p=0.02). The median progression-free survival (PFS) was 5.9months. The multivariable Cox regression for PFS did not detect any significant factors. No clear evidence of radiation necrosis was recorded during the available follow-up. However, only a minority (n=4) of patients underwent surgery after re-irradiation, none showing histopathological proof of radiation necrosis. The prognosis for recurrent IDH-wt GBM after re-irradiation is poor. Patients who are amenable and able to undergo re-resection may have a favorable OS. A second course of radiotherapy with a moderate cumulative EQD2 and small- to medium-sized planning target volumes appeared safe regarding the occurrence of radiation necrosis.