PURPOSE:Despite Tumor Treating Fields (TTF) being included in NCCN guidelines as standard treatment for GBM after improving overall survival in a prospective randomized trial, adoption has been limited. We sought to describe utilization, validate the efficacy, and compare patterns of failure after TTF for GBM patients in a real-world dataset. METHODS:We identified patients with newly diagnosed GBM between 2014-2023 who received standard fractionation external beam radiotherapy (EBRT). Data collected included extent of resection, radiotherapy dose fractionation and modality, utilization of tumor treating fields, and presence and location of progression based on radiographic findings. Kaplan-Meier (KM) curves were generated for progression-free and overall survival. Patient/disease characteristics in relation to TTF utilization were evaluated between the two groups. RESULTS:Three-hundred and ninety-three (393) patients were included in this study. 74 patients were treated with TTF (18.8 %). The adoption of TTF utilization increased in 2019 by 10 %. The rate of TTF utilization was approximately 20 % from 2019 to 2023. 2-year OS was improved with the addition of TTF after EBRT (58 % versus 41 %, p < 0.006). On multivariable adjustment, TTF use remained associated with improved OS (p = 0.038). There was a trend towards increased marginal failures and decreased in-field failures with the addition of TTF (p = 0.099). CONCLUSION:Widespread adoption of TTF in the treatment of GBM has been generally met with hesitation with less than one-fourth of modern patients receiving TTF. TTF was associated with improved OS, consistent with previously published prospective clinical trial results. Our results also suggest there may be an interplay between TTF and EBRT, affecting pattern of failure, with decreased rates of in-field failure among the TTF group.

Abstract BACKGROUND Pineoblastoma is an aggressive, rare tumor of the pineal gland. Due to rarity of pineoblastoma, no large-scale prospective clinical trial data is available to guide clinical practice. Patients often receive treatment based on approaches to other high-grade embryonal central nervous system (CNS) tumors such as medulloblastoma. Multimodality treatment typically consists of maximal surgical resection followed by radiation therapy and chemotherapy. Despite treatment, recurrence is common and five-year survival rate is 60-70%. Pineoblastoma can disseminate through the leptomeninges, which is associated with poor survival. No therapy is known to confer a survival benefit in the setting of leptomeningeal disease (LMD) related to pineoblastoma. MATERIAL AND METHODS We report radiographic response and longer than expected survival for a patient with LMD related to pineoblastoma treated with single-agent temozolomide chemotherapy. RESULTS A 22-year-old male with a history of pineoblastoma presented with periodic headaches and leptomeningeal enhancement on surveillance imaging. 5 years prior to presentation (age 17), he was initially diagnosed with pineoblastoma after gross total resection followed by treatment with proton craniospinal radiation and adjuvant carboplatin/vincristine chemotherapy. Surveillance craniospinal MRIs identified diffuse leptomeningeal enhancement involving the posterior fossa and diffusely throughout the spine and lumbosacral nerve roots. While cerebrospinal fluid (CSF) cytology was negative for tumor cells on three separate occasions, CSF cell-free DNA (cfDNA) analysis isolated tumor DNA. He was started on temozolomide chemotherapy with near complete resolution of leptomeningeal enhancement on MRI after 2 cycles and complete resolution after 6 cycles. Treatment was well-tolerated with grade 1 fatigue as the only toxicity. Patient remains alive 20 months after initial diagnosis of LMD with resolution of headaches and durable radiographic response. CONCLUSION This case highlights utility of CSF cfDNA as a companion tool for diagnosis of LMD. Durable clinical and radiographic response achieved suggests temozolomide can be considered as a salvage treatment option for recurrent pineoblastoma with LMD.

Purpose/Objective(s) Glioblastoma (GBM) is the most aggressive primary brain tumor, with inevitable recurrence despite trimodality therapy, and an overall survival of approximately 15 months. Historic series suggest local progression comprises approximately 80% of treatment failures with this disease, but little is known regarding patterns of failure in a modern cohort. In this large multicenter retrospective review, we sought to explore the modern patterns of failure of patients with GBM. Materials/Methods We obtained institutional review board approval for this retrospective study. We identified patients with newly diagnosed GBM between 2014-2023 who received external beam radiotherapy (EBRT) at a large multisite academic institution. Data collected included extent of resection, radiotherapy dose, radiotherapy modality, utilization of tumor treating fields (TTF), and presence and location of progression (in-field, marginal, or distant). In-field was defined as ≥80% recurrence volume within the 95% isodose volume, marginal as 20-80% recurrence volume within the 95% isodose volume, and distant as a recurrence <20% within the 95% isodose volume. Chi-square tests were performed to evaluate patient and disease characteristics in relation to location of failure. Results Six-hundred and seventy (670) patients were included in this retrospective study, with 447 demonstrating radiographic progression at the time of the analysis. Of the patients with progression, 393 (87.9%), 32 (7.2%), and 22 (4.9%) demonstrated in-field, marginal, and distant progression, respectively. Location of progression was not statistically associated with MGMT status (P = 0.65), resection extent (P = 0.16), IDH status (P = 0.32), concurrent TMZ (P = 0.20), adjuvant TMZ (P = 0.914), or radiation dose/fractionation [60Gy/30Fx, 40Gy/15Fx, 25Gy/5Fx, or >60Gy] (P = 0.51). Tumor treating fields (TTF) was associated with decreased in-field and increased marginal failures (P = 0.002). Proton treatment was associated with decreased marginal failures and increased distant failures as compared to photon treatment (P = 0.025). Temporal and parietal tumors were associated with lower rates of marginal and distant failure as compared to frontal and occipital tumors (P = 0.04). Conclusion In this large modern cohort, over 80% of tumor progression occurred locally, despite modern neurosurgical and radiotherapeutic techniques. In contrast to other published data, we found no association between pattern of progression and MGMT methylation. The relationship between pattern of progression and TTF suggests that may play a clinically significant role in DNA damage response. Despite modern aggressive therapy, these findings suggest that improvements in local therapy continue to be desperately needed in GBM.

Purpose/Objective(s) Meningioma is the most frequently encountered brain tumor and typically managed with surgery and/or radiotherapy. However, recurrence rates for WHO grade II and III meningioma are reported as high as 40-80%, respectively. With each recurrence, safe and effective salvage options are quickly exhausted, leading to significant morbidity and mortality. As nearly all meningiomas express somatostatin receptors, we evaluated the efficacy of lutetium-177 (177Lu)–Dotatate for refractory meningioma. Materials/Methods This is a single-arm, phase II clinical trial conducted at a single, large academic center. Eligible patients included those with surgery- and radiation-refractory meningioma with measurable disease and ≥ 15% growth over a 6-month period. 68Ga-DOTATATE PET/MRI was performed and a Krenning score of ≥ 2 was required. The 177Lu-Dotatate was delivered at a dose of 7.4 GBq (200 mCi) every 8 weeks for a total of 4 administrations. MRI brain was performed prior to each administration. The primary endpoint was progression-free survival at 6 months (PFS-6). Exceeding the established RANO historical benchmark of 26% for PFS-6 signaled a promising therapy. Secondary endpoints include PFS, overall survival (OS), and rates of adverse events (AEs) at least possibly related to the investigational agent. A separate WHO grade I cohort continues to enroll. Results From April 2020 to April 2023, 26 patients were screened and 20 met all eligibility requirements and were enrolled into the WHO grade II/III cohort. The median age was 66.8 years (range = 38.9-85.0) and 95% had WHO grade II meningioma. ECOG PS was 0, 1, and 2 in 55%, 35%, and 10% of patients, respectively. A total of 40% of patients had a history of seizures and 65% had a history of neurologic deficit related to the refractory tumor, although only 15% were receiving corticosteroids at the time of enrollment. A Krenning score of 2, 3 and 4 was observed in 45%, 45%, and 10% of patients, respectively. PFS-6 and median PFS was 77.8% (95% CI = 52-94) and 10.7 months, respectively. Median survival was not reached. 1-year OS was 88.5% (95% CI = 47-96). There was no grade 4 or 5 AE attributable to treatment. A total of 10 patients experienced grade 3 hematologic AE with two patients experiencing grade 3 hepatitis (n = 1) and grade 3 seizure (n = 1), at least possibly attributed to treatment. 5 patients did not complete all 4 administrations due to possible treatment related AE (n = 2), tumor progression (n = 2), and other comorbidities (n = 1). Conclusion This phase II clinical trial met the primary endpoint of PFS-6 and represents a significant milestone for surgery- and radiation-refractory meningioma as one of the first prospectively evaluated systemic agents to yield substantial clinical efficacy, surpassing established clinical benchmarks with reasonable safety profile. The 177Lu-Dotatate PFS appears as a safe and rational therapeutic choice with broad eligibility for the patient population under study, particularly as alternative therapy options are limited.

Purpose/Objective(s) Radiation therapy (RT) target volumes for oligodendroglioma (oligo) are typically defined using MRI T2 sequences, as these tumors are often non-enhancing. Because of the lack of specificity of T2 hyperintensity, this practice may result in target volumes larger or smaller than optimal for a patient. The amino acid radiotracer 18F-DOPA does not require breakdown of the blood-brain barrier for transport, and therefore demonstrates high uptake in glioma even beyond T1 contrast enhancement but low uptake in normal tissue. While 18F-DOPA PET has been prospectively utilized for glioblastoma, data on its utility in oligo is lacking. We hypothesized that 18F-DOPA PET would result in changes in RT target volumes for most patients with oligodendroglioma. Materials/Methods This is a single institution analysis of patients with WHO 2016 oligo who underwent 18F-DOPA PET prior to RT on two prospective clinical trials. MRI T2 and T1 contrast enhancement (when applicable) were compared with 18F-DOPA PET defined tumor volumes. Tumor maximum SUV (SUVmax) and tumor mean SUV (SUVmean) were calculated. Patients were followed for radiographic disease progression. Results Ten patients with IDH-mutant, 1p/19q co-deleted oligo (N = 8 newly diagnosed/2 recurrent; n = 8 WHO Grade II, n = 2 Grade III) were enrolled between November 2010 and June 2020. Median age was 46 (range = 30-61). Five patients were female. Median T/N ratio to define tumor volume on PET was 2.6 (2.1-3.3). Median MRI T2-defined tumor volume was 66.6 cc (range = 5.6-217.3), and 18F-DOPA volume was 19.83 cc (range = 5.6-121.2). WHO Grade 2 oligo median 18F-DOPA SUVmax and SUVmean were 4.2 (range = 2.2-8.6) and 2.1 (range = 1.7-3.3), respectively. In all 10 patients, 18F-DOPA imaging identified additional tumor volume outside the T2 volume (median 2.23 cc, range 0.1-6.6 cc). Two of the ten patients had contrast enhancing tumor. Median tumor volume outside of enhancement was 126.9cc (56.8-197.0) by T2 and 64.7cc (28.6-100.7) by 18F-DOPA. At last follow-up, 3 of 7 patients with long-term follow-up had experienced progression. Median progression-free survival was 80.7 months (range = 65.4 – not reached). Compared to patients without progression, patients with progression had a median SUVmax of 6.2 vs 4.2, SUVmean of 2.7 vs 2.1, and total volume of 37.6cc vs 25.4cc. Conclusion 18F-DOPA PET imaging in patients with low-grade oligo consistently demonstrated high tumor SUVmax and SUVmean with tumor identified both within and outside of the standard T2-hyperintensity defined tumor volume in all patients. 18F-DOPA PET has the potential to improve target delineation for patients with oligodendroglioma.

Abstract BACKGROUND Myxopapillary ependymomas (MPE) are slow-growing tumors of the spine typically involving the medullary conus and cauda equina. MPE is regularly managed with surgical resection with radiation therapy reserved for cases where gross total resection cannot be achieved. Management of inoperable cases represents a clinical challenge. No systemic therapy is approved for treatment of MPE. Addition of chemotherapy may improve outcomes for cases not amenable to resection. MATERIAL AND METHODS We report feasibility and preliminary efficacy of combination treatment with proton beam radiation therapy and temozolomide chemotherapy for a patient with large, unresectable MPE. RESULTS A 19-year-old female presented with one year of gradually worsening hip and back pain despite treatment with physical therapy. MRI Lumbar spine identified a destructive and expansile T2-heterogenous and hyperintense intraosseous mass (14 x 12 x 13 cm) with extraosseous expansion involving the sacrum, coccyx, and left SI joint with abnormal soft tissue enhancement extending along the posterior spine. No additional lesions were identified on neuro-axis imaging. Biopsy of the mass was consistent with a WHO grade 2 myxopapillary ependymoma. Standard treatment of care would include complete surgical resection. Unfortunately, this would require a morbid procedure in an en block fashion with immediate and permanent loss of bowel, bladder, sexual, and ambulatory function in a young patient whose primary symptom was pain and mild weakness. It was therefore elected to treat the patient in an unconventional approach and begin with proton beam radiation therapy (59.4 Gy in 33 fractions) with concurrent temozolomide followed by 6 cycles of adjuvant temozolomide. Mild clinical improvement and significant radiographic response were achieved (size reduced to 8 x 7 x 11 cm). CONCLUSION This case suggests a potential role for use of proton radiation therapy with concurrent and adjuvant temozolomide for management of myxopapillary ependymoma not amenable to surgical resection.

Purpose/Objective(s) Although gadolinium contrast-enhanced MRI is standardly used to identify the gross tumor volume (GTV) during target delineation for radiotherapy for glioblastoma, it has been established that biologically relevant, non-enhancing tumor extends beyond this volume. To identify non-enhancing tumor, advanced imaging techniques including 18F-DOPA PET/CT and advanced MRI (aMRI) utilizing dynamic contrast enhanced perfusion MRI and high b-value diffusion MRI have been employed at different institutions. This analysis is the first to compare these imaging modalities within the same patients and compare the tumor volumes identified to evaluate their impact on radiotherapy planning. We hypothesized advanced imaging would identify non-enhancing tumor in the majority of patients. Materials/Methods Patients enrolled on a prospective study underwent 18F-DOPA PET/CT and aMRI (perfusion and diffusion MRI) along with standard MRI sequences. GTV_PET was delineated using a predetermined threshold of mean SUV in normal contralateral brain. GTV_Diffusion was delineated by thresholding the FLAIR abnormality region on high b-value scans. GTV_Perfusion was delineated by thresholding the FLAIR abnormality region on the cerebral blood volume image obtained by fitting Tofts model to the perfusion data. A high dose GTV (HGTV) was then generated by adding GTV_PET, GTV_Diffusion, and GTV_Perfusion to the standard GTV (GTV_convMRI) comprised of T1 contrast enhancement and resection cavity. Isotropic 5- and 10-mm expansions were applied to the GTV_convMRI, and the volume of GTV_PET, GTV_Diffusion, and GTV_Perfusion outside of these expansions was quantified and compared. Results Of the 52 patients enrolled to-date, 4 had GTV_Perfusion unavailable due to technical difficulties, 2 did not undergo aMRI due to MRI related contraindications, and 2 withdrew consent. The median (inter-quartile range) volume, in cm3, of GTV_convMRI, GTV_Diffusion, GTV_Perfusion, and GTV_PET were 24.9 (13.7-40.5), 2.1 (0.8-5.8), 11.2 (4.2-19.4) and 5.8 (1.6-13.1), respectively. In the 44 subjects included in the analysis, the HGTV was outside the GTV_convMRI+5mm in 39 (89%), while the HGTV was outside the GTV_convMRI+10mm in 25 (57%) patients. GTV_Diffusion and GTV_Perfusion were found to be outside of GTV_PET in 93% and 95% of patients, respectively. Conclusion 18F-DOPA PET and advanced MRI techniques identify tumor over one centimeter beyond contrast enhancement in over half of cases. These imaging modalities appear to be complementary, rather than duplicative, with only partial overlap in the majority of patients. Additional prospective data is needed to demonstrate how altering target volumes impacts patient outcomes.

Abstract BACKGROUND Although glioblastoma (GBM) is the most common malignant primary brain tumor in adults, extracranial metastasis is rare, occurring in <2% of cases. This rarity has been attributed to the blood brain barrier, immunologic factors, lack of traditional lymphatics in the brain, and the poor prognosis of GBM, limiting its opportunity to metastasize. When GBM does metastasize, bone is the most common destination. GBM may spread hematogenously to bone, especially to vertebral bodies via the surrounding venous plexus. In this single-institution study, we review the clinical characteristics of GBM patients with osseous metastases and evaluate potential risk factors and prognostic significance. MATERIAL AND METHODS Using an institutional database, we identified and retrospectively analyzed 6 GBM patients with osseous metastases and studied their demographics, tumor genetics, clinical courses, and outcomes. RESULTS Five of 6 (83%) GBM patients with osseous metastases were male, with a median age of 46 years at GBM diagnosis (range: 20-84). All patients had IDH wild type and MGMT unmethylated GBM with mutations in TP53. Two patients (33%) were initially diagnosed with gliosarcoma. All patients were treated with surgical resection followed by radiation with concurrent and adjuvant temozolomide. Five patients (83%) received bevacizumab for vasogenic edema (n=4) or intracranial tumor progression (n=1) prior to bone metastasis diagnosis. Bone metastases were diagnosed a median of 12.2 months (range: 5.3-35.2) after GBM diagnosis and 4.8 months after starting bevacizumab (range: 3.5-13.2). Two patients (33%) received immune checkpoint inhibitor therapy and two patients (33%) received tumor-treating fields prior to bone metastasis discovery. Bone metastases were symptomatic in 2 patients, presenting with back pain (n=1) and leg weakness and urinary incontinence (n=1). Three patients (50%) had concurrent metastases to other organs. Osseous metastases were biopsy-confirmed in 3 (50%) cases, while the other 3 patients had no known alternative malignancy to explain their bone metastases. After osseous metastasis discovery, the median survival was 27 days (range: 13-225). CONCLUSION Most of our GBM patients with osseous metastases were male and most, but not all, were young at GBM diagnosis. Tumor genetics common to all patients included IDH wild type, MGMT unmethylated status, and TP53 mutation, which may be important for osseous metastasis. Most patients received bevacizumab, which may be associated with earlier metastasis. While rare, metastatic GBM should be within the differential for GBM patients with bone pain or progressive neurologic symptoms, as osseous metastases portend a dismal prognosis in an already aggressive malignancy.

Selecting the optimal SRS dose fractionation and planning parameters to minimize both LP and RN remains a challenge for large targets. In this analysis, 27 Gy in 3 fractions appeared to provide equivalent LP and RN compared to 30 Gy in 5 fractions, and may be more convenient for patients. Patients with PD-L1≥1% with large brain targets treated with SRS may be at increased risk of RN; corticosteroid prophylaxis may be considered in this population.