Spectroscopic MRI Detects Occult Glioblastoma Invasion during Chemoradiation

Abstract

The standard of care for glioblastoma (GBM) includes surgical resection followed by adjuvant chemoradiation (chemoRT). Treatment margins are controversial since conventional imaging does not define the extent of infiltrating tumor cells. Whole-brain spectroscopic MRI (sMRI) allows for visualization of native metabolites in normal brain and tumor cells, and the relative choline to N-acetyl-aspartate ratio greater than 2 (rChoNAA>2) strongly correlates with the presence of occult GBM cells in otherwise normal-appearing brain. With an MRI-Linac, we are performing studies of adaptive radiotherapy to measure changes in cavity size, edema, and enhancement during chemoRT. We questioned whether rChoNAA>2 would change along with anatomical changes to inform clinical target volumes for adaptive chemoRT trials. In a prospective study, 18 patients with primary GBM underwent daily MRI-guided chemoRT with standalone 3T sMRI generation of rChoNAA>2 maps at three timepoints before, during, and after chemoradiation. Conventional treatment volumes of T1 post-contrast and cavity (GTV2, i.e., boost) with or without FLAIR hyperintensity (GTV1) were compared to rChoNAA>2 volumes. DICE similarity coefficients were calculated to assess the spatial similarity of these volumes. Hausdorff distances were calculated to identify rChoNAA>2 extending beyond GTVs throughout the course of chemoradiation. The mean GTV1 was 58.1 cc (range 0-251.4 cc), the mean GTV2 was 47.9 cc (range 0-139.9 cc), and the mean rChoNAA>2 volume was 31.1 cc (range 0-103.2 cc). rChoNAA>2 volumes did not significantly change over the course of chemoRT or correlate with measurement timepoint. The mean DICE similarity coefficient between GTV1 and rChoNAA>2 volumes was 0.39 (range 0-0.80), and the mean DICE similarity coefficient between GTV2 and rChoNAA>2 volumes was 0.29 (range 0-0.77). DICE similarity coefficients were significantly different from unity indicating spatial differences between rChoNAA>2 and conventional MRI volumes. The mean Hausdorff distances of rChoNAA>2 extending beyond GTV1 was 1.3 cm (range 0.7-2.1 cm), and the mean Hausdorff distances of rChoNAA>2 extending beyond GTV2 was 1.9 cm (range 0.8-2.9 cm), suggesting high-risk disease invading beyond what is visible on conventional MRI sequences. Whole-brain sMRI with generation of rChoNAA>2 maps suggest conventional MRI does not fully capture the extent of disease in primary GBM throughout the course of chemoradiation. rChoNAA>2 maps often extend up to approximately 2 cm beyond conventional boost radiotherapy volumes. Further studies are ongoing to determine how sMRI can be used to adapt radiation target volumes during chemoradiation and escalate dose to occult disease.