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Background Glioblastomas (GBMs) are aggressive brain tumors despite radiation therapy (RT) to 60 Gy and temozolomide (TMZ). Spectroscopic magnetic resonance imaging (sMRI), which measures levels of specific brain metabolites, can delineate regions at high risk for GBM recurrence not visualized on contrast-enhanced (CE) MRI. We conducted a clinical trial to assess the feasibility, safety, and efficacy of sMRI-guided RT dose escalation to 75 Gy for newly diagnosed GBMs. Methods Our pilot trial (NCT03137888) enrolled patients at 3 institutions (Emory University, University of Miami, Johns Hopkins University) from September 2017 to June 2019. For RT, standard tumor volumes based on T2-FLAIR and T1w-CE MRIs with margins were treated in 30 fractions to 50.1 and 60 Gy, respectively. An additional high-risk volume based on residual CE tumor and Cho/NAA (on sMRI) ≥2× normal was treated to 75 Gy. Survival curves were generated by the Kaplan–Meier method. Toxicities were assessed according to CTCAE v4.0. Results Thirty patients were treated in the study. The median age was 59 years. 30% were MGMT promoter hypermethylated; 7% harbored IDH1 mutation. With a median follow-up of 21.4 months for censored patients, median overall survival (OS) and progression-free survival were 23.0 and 16.6 months, respectively. This regimen appeared well-tolerated with 70% of grade 3 or greater toxicity ascribed to TMZ and 23% occurring at least 1 year after RT. Conclusion Dose-escalated RT to 75 Gy guided by sMRI appears feasible and safe for patients with newly diagnosed GBMs. OS outcome is promising and warrants additional testing. Based on these results, a randomized phase II trial is in development.

BACKGROUND WHO grade II (atypical) meningiomas are treated with surgical resection, often followed by adjuvant fractionated radiation therapy (FRT). The increased availability of frameless stereotactic radiosurgery (SRS) presents an opportunity to offer patients a high biological effective dose over fewer fractions. Here we study the patterns of care and outcomes of these two forms of adjuvant RT. METHODS Patients with atypical meningioma were abstracted from the National Cancer Database (NCDB). Descriptive statistics were reported, and differences between treatment groups were assessed using either a chi-square test or ANOVA. Patients were grouped by treatment type and Kaplan Meier (KM) analysis was performed to compare overall survival (OS) using a log rank test. Univariable (UVA) and multivariable (MVA) cox regression analyses were completed. RESULTS Of 10,015 cases diagnosed from 2004-2016, 7,153 received surgery alone, 2,059 received surgery and adjuvant FRT (S+RT), and 362 received adjuvant SRS (S+SRS). The use of adjuvant RT increased by 71.8% for S+RT and 97.8% for S+SRS. In 2004, 15.1% of 443 registered patients received S+RT and 2.26% received S+SRS, while in 2016 these figures were 26.0% and 4.47%, respectively, for the 1051 registered patients (p< 0.001 and 0.022, respectively). For the 8,636 patients with survival data there was no significant difference in median OS between S+RT and S+SRS (130 months vs. 125 months, log rank p=0.935). On UVA, S+RT conferred better survival compared to surgery alone (HR 0.81 [0.72-0.91], p< 0.001) while S+SRS trended towards better survival (HR 0.82 [0.64-1.06], p=0.124). On MVA, no significant OS benefit was seen with S+RT (HR 0.96 [0.85-1.08], p=0.491) or S+SRS (HR 0.90 [0.69-1.16], p=0.413) versus surgery alone. CONCLUSIONS While the use of adjuvant RT for atypical meningioma has increased substantially since 2004, OS is comparable between FRT and SRS. The data presented here support further prospective investigation of adjuvant SRS.

Radiation therapy (RT) targeted by conventional MRI may not fully identify the tumor profile of (GBM), which may in part account for high recurrence rates. Identifying the extent of GBM margins remains a challenging task due to the infiltrative nature of these tumors and limitations in current standard imaging methods. Multiple studies have demonstrated that MR spectroscopic imaging, or spectroscopic MRI (sMRI), can detect areas of infiltrating tumor with a high degree of sensitivity, and could be an essential tool in targeting tumor margins. sMRI enables the identification of non-enhancing, infiltrating cells that are marked by increased Choline/N-Acetylaspartate ratio (Cho/NAA), including regions undetected by standard MRI and therefore left untreated. sMRI shows considerable promise for improving the efficacy of RT and may delay recurrence. In this study, we correlated pre-treatment sMRI metabolite maps with recurrence patterns to validate that sMRI could provide coverage for untreated regions that later recurred, and provide support for its adjunctive use in tumor contouring for RT planning. In an ongoing NCI-funded trial (U01CA172027), metabolite and their ratio maps were obtained pre-chemoradiation and normalized to the patient’s normal-appearing contralateral white matter (NAWM) and then compared to contrast-enhancing recurrence patterns with at least 6 months follow-up. A Cho/NAA ratio of twice the NAWM mean was used to identify regions of potential infiltration in our patients, and the resulting planning target volumes were compared with actual treated target volumes based on conventional MRI. For 9 out of 11 cases, the addition of sMRI data expanded RT volumes to better encompass regions of tumor recurrence, which were not completely covered by the CTV60. Thus, RT planning for GBMs augmented by sMRI could reduce recurrence rates. A multi-institutional clinical trial has been initiated to prospectively assess potential for sMRI to guide RT and assess treatment response (R01CA214557).

PURPOSE: Bevacizumab is a monoclonal antibody targeting vascular endothelial growth factor (VEGF) approved for treatment of recurrent glioblastoma (GBM). Previous studies have demonstrated differential outcomes for patients treated with this agent for other tumors based on whether hypertension developed as a side effect. We conducted a single-institutional retrospective study analyzing survival outcomes for patients with recurrent GBM treated with bevacizumab based on whether patients developed drug-induced hypertension. PATIENTS AND METHODS: All GBM patients treated within Emory Healthcare from 2007-2012 were reviewed. 82 patients were identified that received bevacizumab for recurrent GBM and were included on study. Patients were classified as normotensive or hypertensive depending on whether hypertension developed secondary to therapy. Progression free survival (PFS) and overall survival (OS) were graphed by the Kaplan-Meier method and normotensive versus hypertensive groups were compared by log rank tests. Univariate and multivariate analysis were performed using the Cox proportional hazard method assessing for potential patient, treatment and tumor factors that may predict outcome. RESULTS: Median followup time was 7 months. Of the 82 recurrent GBM patients treated with bevacizumab, 30 developed drug-induced hypertension. Median time to development of hypertension was 21 days. Median PFS for the normotensive and hypertensive groups was 2.5 months (95% CI: 1.6-3.0) and 6.7 months (95% CI: 4.6-10.0), respectively (p