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

Abstract

Anti-1-amino-3-18fluorine-fluorocyclobutane-1-carboxylic acid (18F-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 18F-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 18F-fluciclovine uptake, MRI findings, and tumour biology. 18F-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 18F-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 18F-fluciclovine uptake on pre-clinical PET-CT corresponded to immunostaining for Ki-67, nestin and ASCT2. Results suggest volumes of 18F-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 18F-fluciclovine uptake reflected biologically active tumour.

Diagnostic Accuracy of PET with 18F-Fluciclovine ([18F]FACBC) in Detecting High-Grade Gliomas: A Systematic Review and Meta-Analysis

“…However, sensitivity achieved 100% when [ 18 F]FACBC PET and MRI were combined [20]. In our review, tumor volumes defined by [ 18 F]FACBC uptake, were significantly larger than those defined by contrast-enhanced MRI [19][20][21]26,27]. On the other hand, only Michaud et al [22] showed a substantial volume overlap between [ 18 F]FACBC and MRI.…”

“…Only one study showed a correlation between areas of tumor proliferation (i.e., Ki-67) by immunohistochemistry staining and amino acid transporter in a pre-clinical model, suggesting that uptake occurred in biologically active tumors [19].…”

“…According to our predefined eligibility criteria, these 52 records were evaluated, excluding 42 of them (11 as not in the field of interest, 13 as reviews, editorials, or letters, 6 as case reports, and 12 as pre-clinical studies). After full-text assessment, the 10 remaining articles were judged as eligible for inclusion in our systematic review (qualitative synthesis) [18][19][20][21][22][23][24][25][26][27]. No further studies were considered eligible for inclusion after screening the references of these articles.…”

“…No further studies were considered eligible for inclusion after screening the references of these articles. Eight out of ten articles were included in the meta-analysis (quantitative synthesis) [18][19][20][21][22][23][24][25], while two studies included in the systematic review were excluded from the meta-analysis [26,27], since these reports did not contain sufficient data to evaluate the accuracy of [ 18 F]FACBC for differentiating between HGG and LGG. The study selection process is summarized in Figure 1.…”

“…Eight studies including 113 patients with gliomas were selected for the bivariate patient-based meta-analysis [18][19][20][21][22][23][24][25]. The sensitivity of [ 18 F]FACBC PET/CT or PET/MRI for detecting HGG ranged from 85.7% to 100%, with a pooled estimate of 92.9% (95% CI: 84.4-96.9%).…”