Purpose: Glioblastoma multiforme (GBM) is characterized by tissue hypoxia associated with resistance to radiotherapy and chemotherapy. To clarify the biological link between hypoxia and tumour-induced neovascularization and tumour aggressiveness, we analysed detailed volumetric and spatial information of viable hypoxic tissue assessed by (18)F-fluoromisonidazole (FMISO) PET relative to neovascularization in Gd-enhanced MRI and tumour aggressiveness by L-methyl-(11)C-methionine (MET) PET in newly diagnosed GBMs.
Methods: Ten patients with newly diagnosed GBMs were investigated with FMISO PET, MET PET and Gd-enhanced MRI before surgery. Tumour volumes were calculated by performing a three-dimensional threshold-based volume of interest (VOI) analysis for metabolically active volume on MET PET (MET uptake indices of ≥1.3 and ≥1.5) and Gd-enhanced volume on MRI. FMISO PET was scaled to the blood FMISO activity to create tumour to blood (T/B) images. The hypoxic volume (HV) was defined as the region with T/B greater than 1.2. PET and MR images of each patient were coregistered to analyse the spatial location of viable hypoxic tissue relative to neovascularization and active tumour extension.
Results: Metabolically active tumour volumes defined using MET uptake indices of ≥1.3 and ≥1.5 and the volumes of Gd enhancement showed a strong correlation (r = 0.86, p < 0.01 for an index of ≥1.3 and r = 0.77, p < 0.05 for an index of ≥1.5). The HVs were also excellently correlated with the volumes of Gd enhancement (r = 0.94, p < 0.01). The metabolically active tumour volumes as defined by a MET uptake index of ≥1.3 and the HVs exhibited a strong correlation (r = 0.87, p < 0.01). On superimposed images, the metabolically active area on MET PET defined by a MET uptake index of ≥1.3 was usually larger than the area of the Gd enhancement and about 20-30% of the MET area extended outside the area of the enhancement. On the other hand, the surface area of viable hypoxic tissue with a T/B cutoff of ≥1.2 on FMISO PET did not substantially differ from the area of the Gd enhancement.
Conclusion: The volumetric analysis demonstrates that the viable hypoxic tissue assessed by FMISO PET is related to the neovascularization in Gd-enhanced MRI and the tumour aggressiveness by MET PET in newly diagnosed GBMs. The spatial analysis shows that the metabolically active tumour may be substantially underestimated by Gd-enhanced MRI. Complementary use of MET and FMISO to Gd-enhanced MRI may improve the understanding of tumour biology and lead to the most efficient delineation of tumour volume and treatment strategy.