A multisite clinical trial of spectroscopic MRI-guided radiation dose escalation for newly-diagnosed glioblastomas.
Authors: Shu Hui-Kuo George , Mellon Eric Albert , Kleinberg Lawrence , Gurbani Saumya S , Ramesh Karthik K , Goryawala Mohammed , Sheriff Sulaiman Ahmed , Huang Vicki , Barker Peter B , Maudsley Andrew , Schreibmann Eduard , Weinberg Brent D , Shim Hyunsuk 
Published: June 2021

2018 Background: Glioblastoma (GBM) is the most common adult primary malignant brain tumor. These pts have poor outcomes [median overall survival (OS) ̃ 16 months] despite radiation therapy (RT) to 60 Gy and temozolomide (TMZ). Magnetic resonance spectroscopy (MRS) measures levels of specific metabolites in the brain including choline (Cho) and N-acetyl aspartate (NAA). Previously, we found that high Cho/NAA ratios can aid in localizing regions of brain at high risk for GBM recurrence that may not be appreciated on standard contrast-enhanced (CE) MRI. Based on this finding, we conducted a clinical trial to assess the feasibility and safety of using an advanced volumetric MRS technique termed spectroscopic MRI (sMRI) to guide RT dose escalation for newly-diagnosed GBMs. Methods: Our clinical trial (NCT03137888) funded by the NCI (RO1CA214557) enrolled pts at 3 institutions (Emory U, U Miami, Johns Hopkins U) from 5/2017 to 4/2019. This study was approved by the IRB at each respective institution. Eligibility criteria included newly-diagnosed GBM pts ≥ 18 years of age with a tumor site that could be adequately imaged by sMRI. Cho/NAA ratio was normalized to the contralateral normal appearing white matter (NAWM). For RT planning, standard gross tumor volumes (GTV1 & 2) were defined based on T2-FLAIR and T1 CE MRIs and 5 mm margins were added to generate clinical tumor volumes (CTV1 & 2). GTV3 ( = CTV3, sMRI-defined) was generated by the union of residual CE tumor and Cho/NAA ≥ 2x NAWM. To remain eligible, CTV3 was required to be ≤ 65 cc. Planning target volumes (PTVs) were generated by applying a 3 mm margin around CTVs. 50.1, 60 and 75 Gy in 30 fractions were prescribed to PTV1, PTV2 and PTV3, respectively. All pts received standard concurrent/adjuvant TMZ. Survival curves were generated by the Kaplan-Meier method. Toxicities were assessed according to CTCAE v4.0. Results: 30 pts met eligibility and were treated on study. Mean/median ages were 56.4/58.9 years. 9 pts (30%) were MGMT methylated; 2 pts (6.7%) harbored an IDH1 mutation. With median followup of 21.4 months in censored pts, median OS was 23.0 months. 11 of 30 pts were documented to have experienced grade 3 or greater toxicities that were at least possibly due to their treatment. Of the 7 pts who experienced these by 9 months post-RT, most were attributable to TMZ (thrombocytopenia x 4, thrombocytopenia/neutropenia x 1, transaminitis x 1) and only one case (headaches/fatigue x 1) could potentially be ascribed to RT. Increased risk of pseudoprogression or radiation necrosis, especially beyond 3 months post-RT, was noted but these were clinically manageable and did not result in toxicity ≥ grade 3. Conclusions: Dose-escalated RT to 75 Gy guided by sMRI appears feasible and safe for pts with newly-diagnosed GBMs. OS outcome is also quite promising and warrants additional testing. Based on these results, a phase II randomized trial is planned at ECOG-ACRIN (EAF211). Clinical trial information: NCT03137888.