Diagnostic and Prognostic Potential of 18F-FET PET in the Differential Diagnosis of Glioma Recurrence and Treatment-Induced Changes After Chemoradiation Therapy

Abstract

Background: MRI-based differential diagnosis of glioma recurrence (GR) and treatment-induced changes (TICs) remain elusive in up to 30% of treated glioma patients. We aimed to determine ¹⁸F-FET PET diagnostic performance in this clinical scenario, its outcome dependency on established prognostic factors, optimal ¹⁸F-FET semi-quantitative thresholds, and whether ¹⁸F-FET parameters may instantly predict progression-free survival (PFS) and overall survival (OS).

Methods: We retrospectively analyzed 45 glioma patients treated with chemoradiation therapy (32 males; mean age: 51 years, glioma grade: n=26 WHO4; n=15 WHO3; n=4 WHO2) who underwent ¹⁸F-FET PET to resolve differential diagnosis of GR and TICs raised by MRI performed in the preceding 2 weeks and depicting any of the following changes in their radiation field: volumetric increase of contrast-enhancing lesions; new contrast-enhancing lesion; significant increase in T2/FLAIR non-enhancing lesion without reducing corticosteroids. ¹⁸F-FET PET outcome relied on evaluation of maximum tumor-to-brain ratio (TBRmax), time-to-peak (TTP), and time-activity curve pattern (TAC). Metabolic tumor volume (MTV) and total tumor metabolism (TTM) were calculated for prognostic purposes. Standard of reference was repeat MRI performed 4-6 weeks after the previous MRI. Non-parametric statistics tested ¹⁸F-FET-based parameters for dependency on established prognostic markers. ROC curve analysis determined optimal cutoff values for ¹⁸F-FET semi-quantitative parameters. ¹⁸F-FET parameters and prognostic factors were evaluated for PFS and OS by Kaplan-Meier, univariate, and multivariate analyses.

Results: ¹⁸F-FET PET sensitivity, specificity, positive predictive value, negative predictive value were 86.2, 81.3, 89.3, 76.5%, respectively; higher diagnostic accuracy was yielded in IDH-wild-type glioma patients compared to IDH-mutant glioma patients (sensitivity: 81.8 versus 88.9%; specificity: 80.8 versus 81.8%). KPS was the only prognostic factor differing according to ¹⁸F-FET PET outcome (negative versus positive). Optimal ¹⁸F-FET cutoff values for GR were TBRmax ≥ 2.1, SUVmax ≥ 3.5, and TTP ≤ 29 min. PFS differed based on ¹⁸F-FET outcome and related metrics and according to KPS; a different OS was observed according to KPS only. On multivariate analysis, ¹⁸F-FET PET outcome was the only significant PFS factor; KPS and age the only significant OS factors.

Conclusion: ¹⁸F-FET PET demonstrated good diagnostic performance. ¹⁸F-FET PET outcome and metrics were significantly predictive only for PFS.

Keywords: 18F-FET PET; metabolic tumor volume; total tumor metabolism; treated gliomas; treatment-related changes.

Figure 1

A 35-year-old patient with left frontal glioblastoma (IDH wild-type; MGMT methylated) treated with partial resection in August 2017, chemoradiation (completed in November 2017), and four cycles of adjuvant temozolomide (last cycle in March 2018). In August 2018, left frontal cavity re-irradiation was performed for glioblastoma relapse. Follow-up MRI scans in November 2018 demonstrated an increasing pseudonodular area of contrast-enhancement along the left frontal surgical cavity without functional indices abnormalities, deemed dubious for GR. ¹⁸F-FET PET performed in December 2018 demonstrated faint tracer uptake at late static imaging (TBRmax: 1.6) and TAC pattern 3 with TTP at 35 min. ¹⁸F-FET PET was considered suggestive of TICs. MRI demonstrated disease progression in August 2019 (PFS: 8 months; OS not reached), and bevacizumab was commenced. At last MRI follow-up (January 2021) MRI demonstrated stable disease.

Figure 2

A 60-year-old patient with bioptic diagnosis of astrocytoma WHO grade 3 with lesions in the left frontal lobe and corpus callosum (IDH wild-type; MGMT methylated) treated with chemoradiation (completed in March 2018) and re-irradiation in July 2018. Follow-up MRI scans in October 2018 documented an increasing T2/FLAIR signal and irregular contrast-enhancement at the medial aspect of the left frontal lobe and corpus callosum; no diffusion restriction was seen, and perfusion weighted imaging demonstrated slight increase in Ktrans e Ve values without abnormal Vp. MRI appearances were deemed dubious for GR, favouring the hypothesis of TICs. ¹⁸F-FET PET performed in November 2018 demonstrated focal tracer uptake at late static imaging (TBRmax: 3.4), a TAC pattern with a TTP at 20 min and subsequent plateau (TAC pattern 2). ¹⁸F-FET PET was considered suggestive of GR. MRI performed in January 2019 documented GR, and chemotherapy was started. This patient died in July 2019 (PFS: 1 month; OS: 8 months).