[18F]GE180 PET scans of 88 recurrent glioma patients were evaluated. Median age was 49 years (range 23.6–71.9). Fifty-six (63.6%) patients were male, 32 female (36.4%). Forty-two (47.7%) tumors were diagnosed as IDH-wild-type glioblastoma, 46 (52.3%) as IDH-mutant glioma. Among all 28 IDH-mutant astrocytoma, 10 were classified as WHO 2021 grade 4, 17 as WHO grade 3, and one as WHO grade 2, respectively. Eighteen tumors were classified as oligodendroglioma, IDH-mutant, and 1p/19q-codeleted; 11 WHO grade 3; and 7 WHO grade 2.

Median follow-up time was 15.6 months (95% confidence interval (CI): 13.3–18.0 months). In 59 (67.0%) cases, tumor recurrence was verified histologically; in all other cases, clinical deterioration confirmed tumor recurrence. All cases of low-grade tumors with new contrast enhancement or new [18F]FET enhancement were histologically verified to prove or rule out malignant transformation. For recurrence treatment, radiotherapy was performed in 60 cases (68.2%), 26 of them (29.5% of all patients) in combination with chemotherapy. Chemotherapy alone was administered in 22 cases (25.0%), 15 (17.0%) patients underwent craniotomy and tumor resection, 3 (3.4%) received other/experimental treatment, and 3 received best supportive care due to clinical deterioration or refusing therapy. TSPO binding affinity status was available for 78 patients; of these, 7 (9.0%) were low-affinity binders, 27 (34.6%) were medium-affinity binders, and 44 (56.4%) were high-affinity binders.

SUVmax values were correlated with 2021 CNS WHO grade (Table 1). No significant difference was found between recurrent IDH-mutant and IDH-wild-type tumors (Table 1).

Among all 42 patients with IDH-wild-type glioblastoma, 3 patients with a sub-median SUVmax and 2 patients with a supra-median SUVmax underwent craniotomy and tumor resection as part of their recurrence treatment (p = 0.89). Among patients with IDH-mutant tumors, 7 with a sub-median SUVmax and 3 with a supra-median SUVmax underwent craniotomy and tumor resection (p = 0.36). Systemic post-recurrence therapies did not differ between patients with a sub- or supra-median SUVmax (p = 0.22 for IDH-wild type, p = 0.30 for IDH-mutant tumors (Chi-square test, Table 2).

Overall, uptake intensity on [18F]GE180 PET at recurrence was highly associated with patients’ outcome: patients with low SUVmax (≤ 1.68; median split) survived more than three times longer than those with high SUVmax (median PRS 41.6 vs. 12.6 months; p < 0.01) (Table 3). Also, the TTF was significantly longer in cases with low SUVmax compared to high SUVmax (14.9 vs. 6.2 months; p < 0.01) (Table 3). Other significant factors in the univariate analysis were IDH mutation status and CNS WHO 2021 grade for TTF (both p < 0.01) and PRS (p < 0.01 and p < 0.01). In the multivariate analysis including CNS WHO 2021 grade, IDH status, and age, SUVmax remained an independent significant factor for PRS (p = 0.03) and TTF (p = 0.03), whereas CNS WHO 2021 grade (p = 0.02) was the only other independent factor for TTF. Accordingly, the association between uptake intensity on [18F]GE180 PET and outcome was likewise found in the subgroups of molecularly defined tumors: for patients with recurrent IDH-wild-type glioblastoma, median PRS after recurrence was 8.2 months for patients with an SUVmax higher than the median of 1.89, and not reached for patients with a sub-median SUVmax (p < 0.01). Median TTF after recurrence was 6.1 months for all IDH-wild-type glioblastoma (6.8 for sub-median vs. 5.4 months for supra-median SUVmax, p = 0.14).

Among patients with IDH-mutant tumors, median PRS was 36.9 months, and median TTF was 18.4 months (Table 3). PRS was significantly longer in patients with low SUVmax (≤ 1.60; median split; 41.6 vs. 25.3 months, p = 0.03, see Fig. 1). This difference was also found for median TTF (32.2 vs 8.7 months, p < 0.01), also in the subgroups of all astrocytoma, IDH-mutant (22.6 vs 6.2 months, p = 0.01 for TTF, 36.9 vs 13.5, p = 0.01 for PRS), and even within the very homogeneous subgroup of CNS WHO 2021 grade 3 astrocytoma, IDH-mutant (32.2 vs 2.7 months, p = 0.03 for TTF, 36.9 vs 13.1, p = 0.02 for PRS) (Table 3 and Fig. 2). Exemplary cases of IDH-mutant tumors with supra- or sub-median SUVmax are shown in Figs. 3 and 4. The small subgroup of oligodendroglioma, IDH-mutant and 1p/19q codeleted, did not have enough events for a separate statistical evaluation (Table 3).

Time to treatment failure and post recurrence survival in IDH-wild-type and IDH-mutant glioma patients according to maximum [18F]GE180 uptake. SUVmax maximum standardized uptake value, IDH isocitrate dehydrogenase

Survival of IDH-mutant astrocytoma. SUVmax maximum standardized uptake value, IDH isocitrate dehydrogenase

Exemplary case of a 39.5-year-old patient with recurrent astrocytoma, IDH-mutant, CNS WHO 2021 grade 3 (SUVmax 2.85). The patient progressed soon after re-radiochemotherapy and died 6 months after recurrence

Exemplary case of a 31.0-year-old patient with histologically verified recurrent astrocytoma, IDH-mutant, CNS WHO 2021 grade 3 (SUVmax 0.79, Ki67 at recurrence 20%). The patient remained stable 15 months after recurrence and re-radiochemotherapy

Among patients with IDH-wild-type glioblastoma and a high [18F]GE180 SUVmax, slightly more tumors (11/21) were MGMT-methylated than in the subgroup of patients with a sub-median SUVmax (8/20, Table 4). MGMT-methylated tumors tended to be treated with chemotherapy, either alone or combined with radiotherapy, more often than unmethylated tumors (63.2% vs 45.5%, p = 0.26). In the 35 IDH-wild-type glioblastoma for whom additional [18F]FET PET was available, [18F]FET TBRmax was higher in the subgroup with supra-median [18F]GE180 uptake (3.44 vs 3.10, p = 0.05), while [18F]FET PET-based volume did not differ significantly (Table 4). Inversely, no significant difference in TTF (sub-median 6.8 vs supra-median 7.2 months) or PRS (sub-median 10.4 vs supra-median 11.8 months, both p = 0.95) could be seen between patients with a TBRmax higher or lower than the median of 3.18 (Supplementary Fig. 1).

In IDH-mutant glioma, tumors with a sub- or supra-median [18F]GE180-uptake showed a significantly different median [18F]FET volume (5.14 vs 33.08, p < 0.01), TBRmax (2.51 vs 4.15, p < 0.01) as well as contrast-enhancing volume on MRI (0.06 vs 10.10cm3, p < 0.01) (Table 4). Similar results were found in the subgroup of patients with grade 3 astrocytoma, IDH-mutant (Table 4). Patients with IDH-mutant glioma and an [18F]FET TBRmax higher than the median of 3.53 had a shorter median TTF (10.5 vs 29.3 months, p = 0.03), but not significantly different PRS compared to patients with a sub-median [18F]FET TBRmax (27.9 vs 41.6 months, p = 0.21) (Supplementary Fig. 1).

Among IDH-wild-type glioblastoma patients, 28 (66.7%) were scanned at the time of their first, 11 (26.2%) at their second, and 3 (7.1%) at their third recurrence. Among IDH-mutant glioma patients, 18 (39.1%) had their first, 14 (30.4%) their second, and 14 (30.4%) a third or later recurrence at the time of the scan. In the IDH-wild-type group, there was an intercorrelation between the number of recurrences and [18F]GE180 SUVmax with highest SUVmax values at latest recurrence. However, the recurrence stages did not result in different median PRS or TTF in this group (Supplementary table 1). In IDH-mutant tumor patients, contrariwise, a longer median TTF and PRS was found after their first or second recurrence, yet no significant correlation between recurrence stage and SUVmax was found here (Supplementary table 1).

Among all patients, there was a low to moderate correlation between [18F]GE180 SUVmax and both [18F]FET tumor volume (r = 0.490, p < 0.01), volume in contrast-enhanced MRI (r = 0.47, p < 0.01), and T2 MRI volume (r = 0.30, p < 0.01).

Among all patients, CNS WHO 2021 grade correlated with [18F]GE180 TBRmax (Supplementary table 2). Recurrence treatments did not differ between patients with a supra- or submedian TBRmax (Supplementary table 3). No significant difference in survival between supra- or sub-median TBRmax was observed among all patients or IDH-wild-type patients (Supplementary table 4). Among IDH-mutant and astrocytoma, IDH-mutant, patients, TTF was longer in cases with sub-median TBRmax, whereas PRS did not differ significantly (Supplementary table 4). PRS was longer for patients with a sub-median TBRmax in the subgroup of IDH-mutant CNS WHO 2021 grade 2 and 3 gliomas, while TTF did not differ significantly. Similarly to median-split subgroups using SUVmax, patients with a supra-median TBRmax had a higher CNS WHO 2021 grade, and larger FET TBRmax, and contrast-enhancing volume (Supplementary table 5).