A multi-institutional pilot clinical trial of spectroscopic MRI-guided radiation dose escalation for newly diagnosed glioblastoma

Abstract

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 U, U Miami, Johns Hopkins U) from 9/2017 to 6/2019. 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) ≥ 2x 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 on study. 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 OS and PFS 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 one 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.

Final Report on Clinical Outcomes and Tumor Recurrence Patterns of a Pilot Study Assessing Efficacy of Belinostat (PXD-101) with Chemoradiation for Newly Diagnosed Glioblastoma

“…The choice to use two radiation target volumes is common practice for participating institutions in this trial and recognized by organizations such as RTOG and ASCO [ 14 , 15 ]. Further, a two-target regimen has been conducted in other clinical trials to success [ 3 , 14 , 15 , 16 , 17 , 18 ]. Enhancing lesions in T1w-CE imaging are highly specific for tumor as those regions of the brain have experienced a breakdown of the BBB, justifying a higher radiation dose of 60 Gy.…”

Imaging of GBM in the Age of Molecular Markers and MRI Guided Adaptive Radiation Therapy

“…The median overall survival was 23.0 months. While there was an increased risk of radiation necrosis, it was clinically manageable and did not result in grade 3 or higher toxicity [ 99 ]. These promising findings and manageable toxicity may revive dose escalation that is guided by advanced imaging findings such as those detected on spectroscopic MRI.…”

A Novel Approach to Determining Tumor Progression Using a Three-Site Pilot Clinical Trial of Spectroscopic MRI-Guided Radiation Dose Escalation in Glioblastoma

“…However, these techniques may not adequately target tumor, and imaging methods that detect tumor with high specificity while preserving normal brain may improve outcomes for GBM patients. We have been developing a high-resolution, 3D magnetic resonance spectroscopic imaging (MRSI) sequence with whole brain coverage that we have termed spectroscopic MRI (sMRI) [ 7 ]. sMRI is a non-invasive metabolic imaging technique that can non-invasively detect tumor without contrast agents by detecting areas of metabolically abnormal tumor which have elevation of choline (Cho) due to high cell turnover and decreased N-acetylaspartate (NAA) due to displacement of normal neurons and axons by tumor [ 8 , 9 , 10 ].…”

“…We recently completed a multi-institutional, single-arm pilot clinical trial for newly-diagnosed GBM patients where brain regions with a Cho/NAA ≥ 2x normal were treated with an escalated radiation dose of 75 Gy [ 7 ]. Patients had a median overall survival (OS) of 23.0 months, seven months longer than that in historical controls [ 2 , 15 , 16 , 17 ].…”

“…RANO, or the Response Assessment in Neuro-Oncology criteria, has found success in clinical trial applications but is less commonly used in general clinical practice. While we previously reported the (PFS) from our clinical trial, we did not provide details as to how we determined tumor progression, especially when considering the high rates of pseudo-progression and radiation necrosis [ 7 ]. In this study, we demonstrate how we determined progression for these patients by applying the Brain Tumor Reporting and Data System (BT-RADS) framework of structured imaging classification to imaging obtained as part of our clinical trial [ 25 , 26 , 27 ].…”