Radiation Necrosis Research Articles

Refractory seizures secondary to radiation-induced focal cortical dysplasia/neuronal gigantism: illustrative case.

Focal cortical dysplasia is a structural cause of drug-resistant epilepsy commonly identified in childhood. In rare cases, radiation-induced injury has led to radiation-induced cortical dysplasia, also known as "focal neuronal gigantism." The authors present a 53-year-old woman with recurrent status epilepticus events after she had radiation therapy and surgery for a left frontal meningioma several years prior. Imaging revealed findings consistent with radiation necrosis and possible recurrence. The patient's status epilepticus events required escalating therapies to manage. Scalp electroencephalography indicated that the seizure's origin was in the left hemisphere. A craniotomy was performed to remove the left frontal lesion, and histopathology was consistent with radiation-induced focal cortical dysplasia/neuronal gigantism. The patient's seizures ceased following the surgery, and she remains on maintenance antiseizure medications. Radiation-induced focal cortical dysplasia/neuronal gigantism is an incredibly rare complication of therapy. However, it warrants consideration in the context of radiation necrosis and intractable epilepsy.

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 <13 g/dL in males and Hb <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.

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

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

CTNI-14. NEOADJUVANT STEREOTACTIC RADIOSURGERY (NASRS) FOR LARGE BRAIN METASTASES (BRM): RESULTS OF AN INTERNATIONAL MULTICENTER PHASE II TRIAL

Abstract BACKGROUND We conducted an international multi-center phase II trial evaluating NASRS for BrM. We hypothesized that radiation necrosis (RN) would be lower than post-operative cavity radiotherapy since the tissues receiving the highest radiation dose are resected in NASRS. METHODS BrM patients with 1 index lesion ( >2 and <5 cm in greatest diameter) suitable for resection, and 9 or less additional BrM (< 3 cm in greatest diameter, not requiring resection) were recruited across 3 centres. SRS was administered a median 3 (range: 2-21) days prior to surgical resection. A single fraction of 15-21 Gy was delivered, targeting the index tumor with a 2mm margin. From a sample of 30 patients, the primary endpoint was the 1-year rate of grade 2+ (G2+) RN from the index lesion. Secondary endpoints included local failure (LF), leptomeningeal disease (LMD) and overall survival (OS). RESULTS We enrolled 35 patients [Mean age (SD): 58.9 (12.9) years, 46% female] between 2018 and 2022. The most common primary histologies were lung (40%), and gastrointestinal (20%) cancers. The median BrM volume prior to surgery was 16.6 cc (range 3.2 -38.0); median index lesion size was 3.2 (range: 1.9-4.5) cm. All participants received planned protocol treatment; n = 30 are currently available for 1 year outcomes. No patients developed G2+ RN; 5 had a LF (1-year rate 38%) at 5-12-months following surgery, all of whom had an en-bloc resection. One patient each developed classic LMD and pachymeningeal failure 3 and 11 months after surgery, respectively. Median OS was 11.5 months. CONCLUSION No patients in our study experienced G2+ RN. The 1-year rate of LF was higher than anticipated, indicating the potential benefit of considering a higher radiation dose or larger margins for improved outcomes.

SURG-32. EFFICACY OF LASER INTERSTITIAL THERMAL THERAPY (LITT) FOR BIOPSY-PROVEN RADIATION NECROSIS IN RADIOGRAPHICALLY RECURRENT BRAIN METASTASES

Abstract BACKGROUND Evidence is growing for the efficacy of laser interstitial thermal therapy (LITT) for radiation necrosis (RN) following stereotactic radiosurgery (SRS) for patients with brain metastases. Questions remain regarding local control, symptom control, and concurrent use of therapies. METHODS Demographics, intraprocedural data, safety, Karnofsky performance status (KPS) and survival data were prospectively collected from the LAANTERN multi-center registry (NCT02392078) then analyzed on patients consented between 2016-2020 and who were undergoing LITT for biopsy-proven RN at one of 14 U.S. centers. Data was monitored for accuracy. Statistical analysis included individual variable summaries, multivariable Fine and Gray analysis, and Kaplan Meier estimated survival. RESULTS Ninety patients met inclusion criteria. Median hospitalization time was 32.5hrs. Median time to corticosteroid cessation after LITT was 13 days (range 0 - 1229) and cumulative incidence of lesional progression was 19% at 1-year. Median post-procedure overall-survival was 2.6 years [1.7, NR] and 77% at one year as estimated by Kaplan Meier. Median KPS remained 80 through 2-year follow-up. Seizure prevalence improved from 34.4% pre-procedure to 12% 1-month post-LITT and 7.9% at 3-months. There was no significant difference in risk of radiographic progression in total and near-total ablations (91% or greater ablative coverage) versus sub-total ablations (< 90%). Lesion size was not a significant predictor of future radiographic progression. CONCLUSIONS LITT is an effective, minimally invasive, safe treatment for RN, in terms of both local control and symptom management. LITT is effective in the management of lesion-related seizures in addition to averting expected neurological death. LITT facilitates ongoing systemic therapy (particularly immunotherapy) by enabling the rapid cessation of corticosteroids. Effective management options for RN could facilitate the more aggressive use of combined systemic and radiotherapeutic treatment options for brain metastases patients in order to avoid failure due to tumor recurrence and extend survival.

RADT-09. CLINICAL OUTCOMES OF FRACTIONATED STEREOTACTIC RADIOTHERAPY FOR INTACT AND POSTOPERATIVE RADIORESISTANT RENAL CELL CARCINOMA AND MELANOMA BRAIN METASTASES

Abstract PURPOSE Fractionated Stereotactic Radiotherapy (FSRT) may be an optimal strategy for radioresistant renal cell carcinoma (RCC) and melanoma brain metastases (BM). We reviewed our institutional experience of FSRT to intact BM and postoperative cavities for patients with melanoma and RCC. METHODS We retrospectively identified consecutive patients with melanoma and renal cell carcinoma with unresected or resected BM treated with FSRT at our institution from 1/2018 to 1/2021. Time to event outcomes were estimated using the Kaplan-Meier method with log-rank tests and multivariable Cox regression analyses. RESULTS We identified 44 patients with a total of 64 BM: 31 intact (48.4%) and 33 resected BMs (51.6%). Thirty-six (81.8%) were melanoma and eight (18.2%) were RCC. The majority of intact BM (n = 22/31; 71%) and cavities (n = 21/33; 64%) were treated to 30 Gy (24-30) in 5 fractions and 25 Gy (24-35), respectively. Median PTV volume for intact BM was 5.04 cc (1.2-19.8) and for resected BM was 16.7 cc (4.8-89.1). Median interval from planning MRI to FSRT was 10 days (3-28). Median time from surgery to FSRT was 37 days (9-90). At 18.6 months median follow-up, local and intracranial distant failures were observed in 4 and 20 patients, respectively. Our cohort had a local recurrence-free survival (LRFS) of 83% and overall survival (OS) of 57% at 12 months; no difference between primary FSRT versus surgery followed by FSRT (p = 0.93 and p = 0.52, respectively). On MVA, higher FSRT dose was associated with better local control (p = 0.01). Radiation Necrosis (RN) was observed in eight treatment areas (12.5%). Neither resection status (p = 0.99) nor PTV volume (p = 0.61) were associated with RN. CONCLUSION FSRT is associated with low rates of toxicity and clinically significant disease control for both intact and resected melanoma and RCC BM, with higher FSRT dose being correlated with improved control.

RADT-20. STEREOTACTIC RADIOSURGERY FOR 15 OR MORE BRAIN METASTASES

Abstract BACKGROUND Patients with ≥ 15 brain metastases(BM) continue to be treated with whole brain radiation therapy(WBRT), despite poor neurocognitive outcomes. We analyzed our institutional experience of treating these patients with stereotactic radiosurgery(SRS), with the aim of evaluating safety, cognitive outcomes, and survival. METHODS Patients who received SRS for ≥ 15 BMs in 1-5 fractions from 2014-2022 using the previously described single isocenter multi-target technique were included. Cognitive outcomes were objectively evaluated using serial Patient-Reported Outcome Measurement Information System(PROMIS) scores. RESULTS A total of 124 patients treated with LINAC-based SRS were included. The mean and median number of lesions treated per patient was 24.8 and 20, respectively (range 15 – 94). Most common primary histologies were lung(47.6%), melanoma(21.0%), and breast(14.5%). The median SRS dose was 24 Gy(range 18 – 30 Gy). The rate of any grade radiation necrosis (RN) and ≥ grade 3 RN were 15.3% and 3.2% respectively. New onset seizures were seen in 2.4% and alopecia in 2.4%. Median follow-up was 5.1 months(m). When cognitive data were available, 25 of 31 patients had a stable or improved PROMIS score. The 12m local control was 97.6% while overall intracranial control was 20.8%. One-year freedom from neurological death, leptomeningeal disease, and salvage WBRT were 85.6%, 87.6% and 71.7% respectively. Median overall survival(OS) from brain metastases diagnosis was 11.3m(95% CI 7.2m – 15.3m). On univariate analysis, no prior WBRT(p = 0.038), higher KPS(p = 0.002) and systemic therapy after SRS(p < 0.001) predicted for improved OS. CONCLUSIONS We present here the largest study evaluating SRS for patients with ≥ 15 BMs. We found that SRS was safe, had favorable cognitive outcomes, and comparable survival outcomes to contemporary studies evaluating WBRT in this patient population. Our study supports further randomized studies comparing SRS and memory avoidance WBRT approaches for patients with ≥ 15 BMs.

CTNI-48. SURVIVAL, TOXICITY, AND PATIENT REPORTED QOL OUTCOMES FOLLOWING PULSED REDUCED DOSE RATE RE-IRRADIATION WITH CONCURRENT BEVACIZUMAB FOR RECURRENT GRADE 4 GLIOMAS: RESULTS OF A PHASE II STUDY

Abstract Grade 4 gliomas are aggressive primary brain tumors with dismal prognosis despite maximal treatment. Recurrent disease is typically found within the prior radiation treatment field, complicating reirradiation. Pulsed reduced dose rate (PRDR) radiation is a treatment technique that reduces effective dose rate and increases treatment time allowing for intrafraction repair. Bevacizumab is a systemic VEGF inhibitor with efficacy in treating gliomas. We conducted a phase 2 prospective trial combining PRDR radiation with biweekly bevacizumab (10 mg/kg) in patients with recurrent grade 4 gliomas. Radiation was delivered with reduced dose rate delivered in 20 cGy pulses every 3 minutes in 2 Gy daily fractions to a total dose of 54 Gy. Kaplan Meier analysis was utilized to calculate progression free survival (PFS) and overall survival (OS). Toxicities were evaluated based on Common Terminology Criteria for Adverse Event v5.0 criteria. Mini Mental Status Examination (MMSE), as well as FACT-Brain, and FACIT-Fatigue patient reported quality of life (QoL) surveys were collected at baseline and follow up visits. Minimal important difference scores were calculated using by ½ standard deviation method. A total of 36 patients were enrolled, with 77% having previously received additional therapy for recurrent disease prior to study enrollment. Median PFS was 4.9 months and median OS was 6.9 months. No grade 4+ toxicity was observed. Two patients had grade 3 treatment related toxicity (seizure and radiation necrosis, both PRDR related). Treatment related grade 2 toxicity was seen in 44% of patients, primarily fatigue (30%). Clinically significant decrease in mean MMSE score, and FACT-BR QoL metrics across all sub-domains were noted in follow up. No clinically significant difference in mean FACIT-Fatigue QoL metric was observed. In this prospective phase 2 trial, PRDR with concurrent bevacizumab resulted in encouraging survival outcomes with acceptable toxicity in patients with recurrent grade 4 gliomas.

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 (< 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 < 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 < 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 < 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.

NIMG-30. DEEP LEARNING SEGMENTATION OF INFILTRATIVE AND ENHANCING CELLULAR TUMOR IN POST-TREATMENT GLIOBLASTOMA PATIENTS WITH MULTI-SHELL DIFFUSION MRI

Abstract Multimodal MRI is used for the evaluation of tumor burden in glioblastoma (GBM) patients after surgical resection, radiation, and chemotherapy. However, it can be challenging to identify non-enhancing infiltrative tumor and differentiate recurrent enhancing tumor from post-treatment changes. Restriction spectrum imaging (RSI), an advanced multishell diffusion technique, has shown promise in distinguishing cellular tumor from edema and enhancing post-treatment changes including pseudoprogression and radiation necrosis. We developed a convolutional network (nnUNet) that incorporates traditional multimodal MRI with DSC perfusion and RSI to detect and quantify enhancing and nonenhancing cellular tumor in post-treatment glioblastoma patients. This cellular tumor segmentation network was evaluated in a cohort of 186 post-treatment GBM patients (55.5 +/- 13.7 years, 158 male) with 243 timepoints using 5-fold cross validation. Cellular tumor volumes were then used to predict overall survival (OS) and progression free survival (PFS) in 94 patients with imaging within 3 months of initial surgery. Accuracy for segmenting cellular tumor as measured by the Dice-similarity coefficient was 0.77 (IQR 0.55-0.87) and the AUC of the ROC curve for detecting residual/recurrent tumor compared to post-treatment changes was 0.86. The predicted cellular tumor volumes were an independent hazard over age, sex, GTR status and conventional enhancing residual tumor for both OS (p=0.0003) and PFS (p=0.0004). The tumor segmentation network was validated in an external dataset of 22 GBM patients (55 timepoints) with a median Dice of 0.73 and AUC of 0.91. Survival prediction was validated in a different external dataset of 70 post-treatment GBM patients, with cellular tumor volumes being an independent predictor of OS (p=0.03). In conclusion, deep learning models incorporating advanced imaging can accurately segment enhancing and nonenhancing cellular tumor, which can help distinguish recurrent/residual tumor from post-treatment changes and predict OS and PFS.

RADT-40. FINAL RESULTS OF THE PROSPECTIVE PHASE 2 MARCIE TRIAL: EFFICACY AND TOXICITY OF POSTOPERATIVE BIMODAL RADIOTHERAPY WITH C12-BOOST IN PATIENTS WITH ATYPICAL MENINGIOMAS FOLLOWING SUBTOTAL RESECTION

Abstract Radiotherapy is recommended by current EANO guidelines for patients with atypical meningiomas (WHO grade 2) following subtotal resection. While meningiomas are generally considered radioresistant, novel radiotherapeutic modalities using carbon ions present an increased relative biological effectiveness (RBE) compared to photons, while reducing the radiation exposure for adjacent organs at risk by exploiting the Bragg peak. Our prospective phase 2 trial investigated bimodal radiotherapy using a carbon-ion boost in patients with atypical meningiomas following subtotal resection. A total of 33 patients were enrolled from 07/2012 until 07/2020. The study was prematurely terminated in 07/2020 after recruiting 33 of the initially planned 40 patients due to one grade 5 toxicity. Study treatment comprised a carbon ion boost (18 Gy [RBE] in 6 fractions) targeted to the macroscopic tumor in combination with photon radiotherapy (50 Gy in 25 fractions). The primary endpoint was progression-free survival, and secondary endpoints included overall survival, safety and toxicities. With a median follow-up of 42 months, the 3-year estimates of progression-free survival (PFS), local PFS and overall survival were 80.3%, 86.7% and 89.8%, respectively. Radiation-induced contrast enhancements (RICE) was encountered in 45%, particularly in cases of periventricularly-located meningiomas. Patients exhibiting (transient) RICE were either asymptomatic (40%) or presented immediate improvement (47%) after the administration of corticosteroids or/and bevacizumab. Treatment-associated complications were encountered in 2 patients with radiation necrosis: 1 patient died due to postoperative complications in an external center after resection of radiation necrosis, and the other received an aggregated 21 cycles of bevacizumab. As a result, the study was prematurely terminated. Post-hoc integrated molecular-morphologic scoring identified patients at risk of tumor progression. Study treatment may be considered for selected patients with molecular high-risk meningiomas to achieve high tumor control rates. Patients’ risk to develop radiation-induced side effects depends on the location of the treatment volume.

INNV-24. MACHINE LEARNING-BASED SPECTROSCOPIC TISSUE DIFFERENTIATION IN FLUORESCENCE-GUIDED NEUROSURGERY

Abstract Maximal resection of malignant gliomas is hindered by difficulty in distinguishing tumor margins. Fluorescence-guided resection with 5-ALA assists in reaching this goal. Previously, we characterized five fluorophore emissions that accurately represent any spectrum measured from human brain tumor biopsies with a wide-field hyperspectral device. In this study, the effectiveness of these five spectra was explored for different tumor classification tasks in 891 hyperspectral widefield measurements of 184 patients harboring low- (n=30) and high-grade gliomas (n=115), non-glial primary brain tumors (n=19), radiation necrosis (n=2), miscellaneous (n=10) and metastases (n=8), which corresponds to up to 15000 spectra for a given test. The statistical differences in fluorophore abundances between classes were determined and visualized using dimensionality reduction techniques, including principal component analysis (PCA) and t-distributed stochastic neighbor embedding (t-SNE). Three machine-learning models were trained to classify tumor type (12 classes), grade (3 classes), and glioma margins (3 classes). Five algorithms were tested with varying hyperparameters for each classification task. We explored whether PCA projection onto five different axes than fluorophore abundances can provide more information for visualization and classification. The abundances of the five a priori fluorophore spectra matched or outperformed the five optimal PCA components for all classification tasks. These five axes capture 96-99% of the variance in the dataset. Using random forests and multilayer perceptrons, the classifiers achieved average test accuracies of 74-82%, 79%, and 81%, respectively. All five fluorophore abundances varied between tumor margin type as well as between grades (p < 0.01). For tissue type, at least four of five fluorophore abundances were found to be significantly different (p < 0.01) between all classes. These results demonstrate the differing contribution of fluorophores in different tissue classes tissue, as well as the five fluorophores value as potential optical biomarkers, opening new opportunities for intraoperative classification systems in fluorescence-guided neurosurgery.

QLTI-03. FRACTIONATED PREOPERATIVE VS POSTOPERATIVE STEREOTACTIC RADIOTHERAPY FOR PATIENTS WITH MELANOMA BRAIN METASTASES: A COST UTILITY ANALYSIS

Abstract INTRODUCTION Stereotactic radiosurgery (SRS) followed by surgical resection is an emerging treatment paradigm for brain metastases. Preoperative SRS may improve outcomes such as rates of radiation necrosis (RN) and leptomeningeal disease (LMD) compared to postoperative SRS. However, the impact of this paradigm shift on metrics such as cost of care and hospital length of stay is unclear. In this study, we sought to categorize these metrics for melanoma metastases, specifically. METHODS A retrospective analysis identified patients who underwent surgical resection and fractionated stereotactic radiation therapy (FSRT) for melanoma brain metastases. Demographics, medical history, systemic and local treatment modalities, imaging, and postoperative course were collected. Perioperative cost of care was analyzed beginning two weeks preoperatively and concluded at four-weeks postoperatively. Continuous variables were analyzed via non-parametric two-sided t-tests and ANOVAs. Categorical variables were analyzed via Chi-squared tests. RESULTS Forty-two patients underwent 43 craniotomies for melanoma metastases. The mean age at surgery was 59.6 years-old and the male predominance was 65.1%. Total cost of perioperative care was more expensive among those treated with neoadjuvant (n = 11) FSRT compared to those who underwent postoperative (n = 32) FSRT ($262,072 vs $174,646; p = 0.0254). Mean length of stay for craniotomies was similar between groups (p = 0.1674), although trending down among the neoadjuvant FSRT group (4.5 days) among the neoadjuvant FSRT group versus the postoperative FSRT group (7.0 days). CONCLUSIONS In this study, neoadjuvant FSRT had an increased cost of care in the perioperative period, and similar lengths of hospital stay for craniotomy. Preoperative FSRT for melanoma metastases may result in shorter LOS, however, comes with an increased cost of care. Further investigation of itemization of healthcare costs to identify areas of improvement for neoadjuvant therapy is warranted.

IMMU-54. PNEUMOCYSTIS JIROVECII PNEUMONIA INFECTION IN A PATIENT WITH ANAPLASTIC ASTROCYTOMA AND RADIATION NECROSIS IN THE SETTING OF CORTICOSTEROID AND PEMBROLIZUMAB USE

Abstract We present a case with anaplastic astrocytoma and radiation-induced brain necrosis, diagnosed with pneumocystis jirovecii pneumonia(PJP) while receiving corticosteroid and pembrolizumab, an immune checkpoint inhibitor(ICI). ICIs have significantly changed management of many cancer types and are known to be associated with immune related adverse events(irAEs). Recently, concerns have emerged regarding the potential relationship between ICI use and infection risks, and PJP, a rare opportunistic infection, has been reported in patients with ICI treatments with or without corticosteroid use. A 40-year-old man with anaplastic astrocytoma and radiation-induced brain necrosis on corticosteroid and pembrolizumab presented with high fever and tachycardia over three days, and the patient later developed hypoxia and cough. The patient was on dexamethasone for brain radiation necrosis for two months and he received one dose of pembrolizumab two weeks prior to his symptom onset, based on genetic information that showed hypermutated tumor and abnormal DNA mismatch repair protein expression. Chest CT showed abnormal findings from infectious or inflammatory process. Bronchoalveolar lavage sample confirmed positive pneumocystis jiroveci PCR test, confirmed PJP, and he was treated with clindamycin, primaquine, and prednisone. To the best of our knowledge, this is the first reported case of PJP in a patient with primary brain tumor receiving corticosteroid and pembrolizumab. ICIs are being investigated in patients with primary brain tumors and wildly used in patients with malignancies with frequent central nervous system involvements, such as malignant melanomas and non-small cell lung cancers. Awareness of risk for infectious conditions including PJP in patients on ICI treatment, especially with corticosteroid use is crucial for implementing appropriate prophylactic measures and prompt diagnosis and treatment interventions.

CTNI-42. PHASE I CLINICAL TRIAL OF PEPOSERTIB PLUS RADIATION IN NEWLY DIAGNOSED MGMT-UNMETHYLATED GLIOBLASTOMA

Abstract BACKGROUND DNA-dependent protein kinase (DNA-PK) is a pivotal component of DNA damage repair (DDR) pathways and is an attractive target in glioblastoma because its expression renders tumors less vulnerable to radiotherapy. Peposertib is a small molecule DNA-PK inhibitor that has been shown to potentiate radiotherapy and regress glioblastoma tumors pre-clinically. We conducted a two-stage phase I trial of peposertib plus radiation in newly-diagnosed MGMT-unmethylated glioblastoma (NCT04555577). Method: In stage 1, patients received peposertib plus standard-of-care radiotherapy to determine the maximum-tolerated dose (MTD) based on the Bayesian Optimal Interval design (maximum n = 24). Stage 2 is a window-of-opportunity expansion cohort and will include 5 surgical patients to evaluate tumor drug concentration. Both groups receive adjuvant temozolomide for 6-cycles. RESULTS Fifteen completed the 10-week dose-limiting toxicity (DLT) period; 3-50mg, 3-100mg, 3-200mg, 6-300mg. One DLT (G3 radiation necrosis [RN] at 300mg) was observed. Most notable toxicity was 3 patients with transient G3 dermatitis of the scalp (not DLT per protocol) (2-200mg, 1-300mg). Therefore, radiation dose constrains to the skin were incorporated and subsequent patients did not experience this toxicity. Next-generation sequencing (NGS) was available for 13 archival tissue. Two patients had pathology-proven RN (one within and one outside of the DLT period). Both tumors had mutations in DDR genes (i.e. ATRX, DICER1). Recurrent tissue was available for one patient after treatment with peposertib showed gain of two ATM mutations. CONCLUSION The initial safety data of peposertib plus radiation in newly-diagnosed MGMT unmethylated glioblastoma is favorable. The cases with RN in tumors with DDR mutations, the gain of two ATM mutations in a recurrent tumor and the cases of scalp dermatitis suggest that peposertib is active and possibly potentiates the effect of radiation. Safety and survival data and correlations with genomics will be presented. The study was supported by EMD Serono (CrossRef Funder ID: 10.13039/100004755).

CTNI-56. FEASIBILITY AND EFFICACY OF AI-GUIDED PERSONALIZED PRECISION RADIATION THERAPY IN NEWLY DIAGNOSED GLIOBLASTOMA: A MATCHED-CONTROL STUDY

Abstract PURPOSE The aim of this study was to evaluate the feasibility and efficacy of AI-guided personalized precision radiation therapy (PPRT) in improving outcomes for patients with newly diagnosed glioblastoma. METHODS In an open-label trial conducted at the University of Pennsylvania (NCT03477513), between August 2018 and April 2021, 17 patients with IDH-wildtype glioblastoma who underwent maximal safe resection were enrolled. They were matched with a cohort of glioblastoma patients based on age, sex, extent of resection (EOR), O6-methylguanine-DNA methyltransferase promoter (MGMTp) methylation status, and IDH status. Propensity Score Matching (PSM) was employed to assess the impact of the intervention on the likelihood of survival, using logistic regression to estimate the propensity score. Four patients were disqualified based on exclusion criteria. The PPRT group received personalized radiation dose escalation guided by AI-based predictive modeling of recurrence, along with concomitant and maintenance temozolomide chemotherapy. The control group received standard-of-care chemoradiotherapy between 2012 and 2020. In this study, we utilized a previously published and evaluated (retrospectively and prospectively) predictive AI model, which accurately estimated neoplastic cell infiltration and predicted future tumor recurrence using preoperative, multi-parametric MRIs. RESULTS Median overall survival was 24.4 months in the PPRT-temozolomide group and 17.9 months in the standard-of-care treatment group (hazard ratio, 0.34; 95% CI: 0.15-0.77; p = 0.009). PPRT was well-tolerated, with low-grade adverse events during radiation. Radiation necrosis occurred in 54% of the PPRT-temozolomide group and 36% of the standard-of-care group. CONCLUSION AI-guided PPRT in newly diagnosed glioblastoma patients demonstrated feasibility in routine clinical practice and led to a statistically significant improvement in overall survival compared to matched controls receiving standard-of-care treatment. These findings highlight the potential of personalized precision radiation therapy, with focused dose escalation, in enhancing outcomes for glioblastoma patients and emphasize the need for prospective validation in a randomized controlled clinical trial.

A Potential Risk of Radiation-Induced Cavernous Malformations Following Adjuvant Gamma Knife Radiosurgery for Mesial Temporal Lobe Epilepsy.

Several clinical studies have explored the feasibility and efficacy of radiosurgical treatment for mesial temporal lobe epilepsy, but the long-term safety of this treatment has not been fully characterized. This study aims to report and describe radiation-induced cavernous malformation as a delayed complication of radiosurgery in epilepsy patients. The series includes 20 patients with mesial temporal lobe epilepsy who underwent Gamma Knife radiosurgery (GKRS). The majority received a prescribed isodose of 24 Gy as an adjuvant treatment after anterior temporal lobectomy. In this series, we identified radiation-induced cavernous malformation in three patients, resulting in a cumulative incidence of 18.4% (95% confidence interval, 6.3% to 47.0%) at an 8-year follow-up. These late sequelae of vascular malformation occurred between 6.9 and 7.6 years after GKRS, manifesting later than other delayed radiation-induced changes, such as radiation necrosis. Neurological symptoms attributed to intracranial hypertension were present in those three cases involving cavernous malformation. Of these, two cases, which initially exhibited an insufficient response to radiosurgery, ultimately demonstrated seizure remission following the successful microsurgical resection of the cavernous malformation. All things considered, the development of radiation-induced cavernous malformation is not uncommon in this population and should be acknowledged as a potential long-term complication. Microsurgical resection of cavernous malformation can be preferentially considered in cases where the initial seizure outcome after GKRS is unsatisfactory.

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

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

Hyperarc Vmat and Vmat planning for stereotactic radiosurgery in multiple brain metastases

Automated treatment planning systems are available for linear accelerator (LINAC) based single and more isocenter multitarget stereotactic radiosurgery (SRS) of brain metastases. HyperArc Volumetric Modulated Arc Therapy (HA-VMAT) is a relatively new isocentric Volumetric Modulated Arc Therapy (VMAT) technique developed specifically for non-coplanar, multileaf collimator (MLC)-based stereotactic radiotherapy with automatic treatment optimization and dose delivery. The HA-VMAT planning approach was developed to accommodate dosing procedures for brain metastases stereotactic radiosurgery. In this study, it was aimed to compare the dosimetric parameters of treatment plans created with single and multi-isocenter retrospectively VMAT and HA-VMAT techniques in patients with lung cancer and multiple brain metastases (4–7) who received single and multi-fraction stereotactic radiosurgery (SRS). Using VMAT and HA-VMAT techniques, two separate treatment plans were created for each case, and tumor target coverage (homogeneity index (HI); conformity index (CI); gradient index (GI)) and organ at risk (OAR) were evaluated dosimetrically. Physical properties and Monitor unit (MU) values of both treatment approaches were compared. Treatment plans were created for study purposes and patients were not treated with these plans. In the study, HI (p = 0.000), CI (p = 0.000) and GI (p = 0.002) values calculated with the HA-VMAT technique are superior to the VMAT technique. Medium-low dose spreads (V4Gy-V16Gy) were significantly reduced in HA-VMAT plans compared to plans with VMAT. HA-VMAT plans result in lower MU than VMAT plans. HA-VMAT planning has significantly less radiation necrosis indicator (V8Gy-V16Gy) compared to VMAT plans. However, there are few studies investigating the ability of the HA-VMAT technique to create high-quality treatment plans for extracranial lesions. HA-VMAT may constitute one of the new options for SRS dose delivery for both single target and multiple targets.

Stereotactic Radiosurgery for Cranial and Spinal Hemangioblastomas: A Single-Institution Retrospective Series.

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. 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 of 18 Gy to the 77% median isodose line. 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 rate was 91.3% for all hemangioblastomas, 91.7% among the sporadic lesions, and 92.9% in patients with VHL. 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. 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.