Serial analysis of 3D H-1 MRSI for patients with newly diagnosed GBM treated with combination therapy that includes bevacizumab

Abstract

Interpretation of changes in the T1- and T2-weighted MR images from patients with newly diagnosed glioblastoma (GBM) treated with standard of care in conjunction with anti-angiogenic agents is complicated by pseudoprogression and pseudoresponse. The hypothesis being tested in this study was that 3D H-1 magnetic resonance spectroscopic imaging (MRSI) provides estimates of levels of choline, creatine, N-acetylaspartate (NAA), lactate and lipid that change in response to treatment and that metrics describing these characteristics are associated with survival. Thirty-one patients with newly diagnosed GBM and being treated with radiation therapy (RT), temozolomide, erlotinib and bevacizumab were recruited to receive serial MR scans that included 3-D lactate edited MRSI at baseline, mid-RT, post-RT and at specific follow-up time points. The data were processed to provide estimates of metrics representing changes in metabolite levels relative to normal appearing brain. Cox proportional hazards analysis was applied to examine the relationship of these parameters with progression free survival (PFS) and overall survival (OS). There were significant reductions in parameters that describe relative levels of choline to NAA and creatine, indicating that the treatment caused a decrease in tumor cellularity. Changes in the levels of lactate and lipid relative to the NAA from contralateral brain were consistent with vascular normalization. Metabolic parameters from the first serial follow-up scan were associated with PFS and OS, when accounting for age and extent of resection. Integrating metabolic parameters into the assessment of patients with newly diagnosed GBM receiving therapies that include anti-angiogenic agents may be helpful for tracking changes in tumor burden, resolving ambiguities in anatomic images caused by non-specific treatment effects and for predicting outcome.

Keywords: Anti-angiogenic therapy; MRSI; Metabolic imaging; Newly diagnosed glioblastoma; Survival.

Fig. 1

Anatomic images, spectra and CNI color overlays from the Fup1 scan for a 47 year old female patient with a KPS of 90, sub-total resection, a low PFS of 159 days and a low OS of 206 days. The CNI maps were thresholded to show only values that were 2 or higher in order to highlight the metabolic lesion. The median and maximum CNI were 4.8 and 19.9. Note the high lipid peaks in the cavity, which are surrounded by areas with increased choline and decreased NAA that corresponded to the metabolic lesion. The residual CE volume was 3 cm³ is minimal and corresponds mainly to a thin rim around the resection. The volume of the T2 lesion at this time point is 29 cm³. As is shown from the FLAIR images and CNI overlays from the three lower slices, the metabolic lesion is relatively large and gives a clear picture of regions that are likely to reflect recurrent/residual tumor

Fig. 2

Changes in mean anatomic, choline, lactate and lipid parameters for patients with scans at all four time points (pre-, mid-, post-RT and Fup1). The asterisks denote time points at which the change from pre-RT in the relevant parameter was statistically significant. The sum values are integrals of the various parameters from voxels within the region with CNI >2. There were 21 subjects with anatomic data and 19 subjects with metabolic data at all 4 time points

Fig. 3

Serial post-Gad T1-weighted, FLAIR images and overlaid CNI maps for a male patient who was 47 years old, had a PFS of 330 days and OS of 706 days. The yellow boxes indicating PRESS selected volumes are oblique for follow-up scans because the 3D imaging and spectral data were post-processed to register them to the pre-RT exam in order to aid in making visual comparisons

Fig. 4

Serial post-Gad T1-weighted, FLAIR images and overlaid CNI maps for a female patients who was 38 years old, had a PFS = of 360 days and OS of 434 days. The yellow boxes indicating PRESS selected volumes are oblique for follow-up scans because the 3D imaging and spectral data were post-processed to register them to the pre-RT exam in order to aid in making visual comparisons