Response Assessment of Bevacizumab for Treatment of Malignant Glioma by Neuroimaging

Abstract

  Since 2013, antiangiogenic therapy such as bevacizumab has been introduced in Japan for treatment of malignant gliomas, and previous studies have shown that a problem of pseudoresponse cannot be solved by evaluating images of the treatment. For rapidly reduced enhanced lesions after the initiation of bevacizumab, it would be mistaken to determine high response rate. The Response Assessment in Neuro-Oncology (RANO) group recommends fluid-attenuated inversion recovery (FLAIR) or T2 hyper-intensity to determine tumor progression during the bevacizumab therapy. However, since tumor-related edema, ischemia and radiation effects can all result in increased hyper-intensity area on FLAIR and T2WI, it is difficult to evaluate the activity of tumor. To this end, hypovascularized diffusion-weighted imaging (DWI), decreased relative cerebral blood volume (rCBV) on dynamic susceptibility contrast (DSC) perfusion weighted imaging (PWI) and increased ratio between N-acetyl-aspartate (NAA) and choline (Cho) on MR spectroscopy may represent imaging biomarkers for the improved outcome of the therapy. For assessment of treatment response to bevacizumab therapy, additional metabolic PET imaging provides an important and valuable addition to standard MRI. Amino acid PET tracers such as ¹¹C-methionine (MET), O-(2-¹⁸F-fluoroethyl)-L-tyrosine (FET) and L-3,4-dihydroxy-6-¹⁸F-fluoro-phenylalanine (FDOPA) have been evaluated for the assessment of treatment response to the therapy. Recent studies suggest that changes in FET and FDOPA PET parameters such as metabolically active tumor volume are useful for determining treatment failure at earlier time point than MRI-based RANO criteria and have also been used to predict a favorable outcome for responders to bevacizumab. ¹⁸F-fluoro-3’-deoxy-3’-L-fluorothymidine (FLT) is a helpful predictor of glioma progression. However, the assessment of treatment response to the therapy based on FLT needs careful interpretation because FLT is significantly dependent on blood brain barrier permeability. ¹⁸F-fluoromisonidazole (FMISO) could evaluate the dynamic biological effects between tissue hypoxia and vascular normalization occurring within recurrent high-grade glioma treated by bevacizumab. These multiple imaging modalities combining standard MRI with new physiological MRI and metabolic PET imaging may have a capacity to detect the susceptibility to bevacizumab therapy and will increasingly become important biomarkers in the future.