Phase II Trial of Radiosurgery to Magnetic Resonance Spectroscopy–Defined High-Risk Tumor Volumes in Patients With Glioblastoma Multiforme

Abstract

Purpose To determine the efficacy of a Gamma Knife stereotactic radiosurgery (SRS) boost to areas of high risk determined by magnetic resonance spectroscopy (MRS) functional imaging in addition to standard radiotherapy for patients with glioblastoma (GBM). Methods and Materials Thirty-five patients in this prospective Phase II trial underwent surgical resection or biopsy for a GBM followed by SRS directed toward areas of MRS-determined high biological activity within 2 cm of the postoperative enhancing surgical bed. The MRS regions were determined by identifying those voxels within the postoperative T2 magnetic resonance imaging volume that contained an elevated choline/N-acetylaspartate ratio in excess of 2:1. These voxels were marked, digitally fused with the SRS planning magnetic resonance image, targeted with an 8-mm isocenter per voxel, and treated using Radiation Therapy Oncology Group SRS dose guidelines. All patients then received conformal radiotherapy to a total dose of 60 Gy in 2-Gy daily fractions. The primary endpoint was overall survival. Results The median survival for the entire cohort was 15.8 months. With 75% of recursive partitioning analysis (RPA) Class 3 patients still alive 18 months after treatment, the median survival for RPA Class 3 has not yet been reached. The median survivals for RPA Class 4, 5, and 6 patients were 18.7, 12.5, and 3.9 months, respectively, compared with Radiation Therapy Oncology Group radiotherapy-alone historical control survivals of 11.1, 8.9, and 4.6 months. For the 16 of 35 patients who received concurrent temozolomide in addition to protocol radiotherapeutic treatment, the median survival was 20.8 months, compared with European Organization for Research and Treatment of Cancer historical controls of 14.6 months using radiotherapy and temozolomide. Grade 3/4 toxicities possibly attributable to treatment were 11%. Conclusions This represents the first prospective trial using selective MRS-targeted functional SRS combined with radiotherapy for patients with GBM. This treatment is feasible, with acceptable toxicity and patient survivals higher than in historical controls. This study can form the basis for a multicenter, randomized trial.

Clinical Proton MR Spectroscopy in Central Nervous System Disorders

“…Delineation of tumor infiltration is an essential part of (a) preoperative decision making, (b) intraoperative MR imaging-guided resections, and (c) postoperative follow-up and application of additional therapies (postsurgery radiation and/or chemotherapy). MR spectroscopy was shown to spatially correlate with histologic type and grade and to reflect heterogeneity in brain tumors before surgery: A tCho/tNAA ratio greater than 2, a Lac/tNAA ratio greater than 0.25, and the presence of lipid at MR spectroscopic imaging with a long TE (144 msec) are characteristics of a highgrade tumor, allowing demarcation TE MR spectroscopic imaging has been used to identify regions of more aggressive phenotype within a heterogeneous gliobastoma multiforme to improve gamma knife radiosurgery (64). For neurosurgical treatment planning, MR spectroscopy plays a role in differentiating areas of tumor from benign processes and, together with other MR imaging methods, in establishing their relationship to key normal brain structures (56), particularly in gliomas.…”

“…Prognostic MR spectroscopy markers are important for treatment stratification and can help identify patients who need more intensive treatment from the outset for some tumor types (47,62,63). These include the detection of 2-hydroxyglutarate in isocitrate dehydrogenase-1 mutated gliomas (47), citrate in proliferating pediatric astrocytomas (62), and highly MR spectroscopy-visible saturated lipids with elevated scylloinositol and low glutamine in high-risk pediatric brain tumors (64). A tCho/ tNAA ratio of more than 2.1 at long (77).…”

Stereotactic Radiosurgery and Radiotherapy in the Management of High-Grade Gliomas

“…In a trial for newly diagnosed GBM patients, MRS was used to target a post-resection, pre-EBRT radiosurgery boost [ 66 ]. As a novel means of managing the large 10 × 10 × 15 mm MRS voxels, an 8 mm Gamma Knife "shot" was used to target each suspicious voxel.…”

Malignant Glioma: Viewpoint—Chemotherapy

“…The combination of stereotactic radiosurgery with TMZ in the frame of the standard chemoradiotherapy is likely feasible and should be properly studied in prospective randomized trials. The repeated reports on feasibility of this approach in uncontrolled phase II studies, and frequently with inappropriate historical comparators are misleading and a waste of the limited resources [ 120 ]. In vitro, temozolomide has been shown to inhibit tumor cell migration.…”