Exploratory Analysis of Serial (18)F-fluciclovine PET-CT and Multiparametric MRI during Chemoradiation for Glioblastoma

SIMPLE SUMMARY: Glioblastoma (GBM), the most common malignant adult primary brain tumour, has a prognosis of ~12–15 months. Poor prognosis is partly due to the inability to accurately define the extent of tumour infiltration; currently demarcated using magnetic resonance imaging (MRI) sequences (e.g., post-contrast T1-weighted (Gd-T1) and dynamic contrast-enhanced (DCE-MRI)). Anti-1-amino-3-(18)fluorine-fluorocyclobutane-1-carboxylic acid ((18)F-fluciclovine) positron emission tomography (PET) may depict GBM better than MRI. This prospective pilot study aimed to explore the relationship of (18)F-fluciclovine PET, DCE-MRI and Gd-T1 in patients with GBM undergoing standard-of-care adjuvant chemoradiotherapy. A parallel mouse glioma model was used to investigate the relationship between (18)F-fluciclovine PET, MRI and tumour biology. Clinical results showed that GBM volume on (18)F-fluciclovine PET tended to be larger than Gd-T1 and DCE-MRI in patients with shorter overall survival (OS) but smaller in patients with longer OS. The preclinical study confirmed that (18)F-fluciclovine uptake reflected biologically active tumour. Results suggest that (18)F-fluciclovine PET may better define GBM infiltration than MRI. ABSTRACT: Anti-1-amino-3-(18)fluorine-fluorocyclobutane-1-carboxylic acid ((18)F-fluciclovine) positron emission tomography (PET) shows preferential glioma uptake but there is little data on how uptake correlates with post-contrast T1-weighted (Gd-T1) and dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) activity during adjuvant treatment. This pilot study aimed to compare (18)F-fluciclovine PET, DCE-MRI and Gd-T1 in patients undergoing chemoradiotherapy for glioblastoma (GBM), and in a parallel pre-clinical GBM model, to investigate correlation between (18)F-fluciclovine uptake, MRI findings, and tumour biology. (18)F-fluciclovine-PET-computed tomography (PET-CT) and MRI including DCE-MRI were acquired before, during and after adjuvant chemoradiotherapy (60 Gy in 30 fractions with temozolomide) in GBM patients. MRI volumes were manually contoured; PET volumes were defined using semi-automatic thresholding. The similarity of the PET and DCE-MRI volumes outside the Gd-T1 volume boundary was measured using the Dice similarity coefficient (DSC). CT-2A tumour-bearing mice underwent MRI and (18)F-fluciclovine PET-CT. Post-mortem mice brains underwent immunohistochemistry staining for ASCT2 (amino acid transporter), nestin (stemness) and Ki-67 (proliferation) to assess for biologically active tumour. 6 patients were recruited (GBM 1–6) and grouped according to overall survival (OS)—short survival (GBM-SS, median OS 249 days) and long survival (GBM-LS, median 903 days). For GBM-SS, PET tumour volumes were greater than DCE-MRI, in turn greater than Gd-T1. For GBM-LS, Gd-T1 and DCE-MRI were greater than PET. Tumour-specific (18)F-fluciclovine uptake on pre-clinical PET-CT corresponded to immunostaining for Ki-67, nestin and ASCT2. Results suggest volumes of (18)F-fluciclovine-PET activity beyond that depicted by DCE-MRI and Gd-T1 are associated with poorer prognosis in patients undergoing chemoradiotherapy for GBM. The pre-clinical model confirmed (18)F-fluciclovine uptake reflected biologically active tumour.