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Preprint
Review

FET- PET RANO for Radiotherapy Assessment of Gliomas

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Submitted:

02 February 2024

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05 February 2024

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Abstract
Conventional MRI sequences are standard methods to monitor patients with brain tumors but have significant limitations especially after irradiation. Currently, the role of FET-PET in radiotherapy of glioblastoma is emerging, starting from target definition, response assessment and in distinguishing progression from post-irradiation changes. Recently a PET RANO criteria have been published providing optimal strategy for treatment evaluation with amino-acid PET. Earlier, a PET/RANO group reported contribution of PET imaging to radiotherapy planning and monitoring in glioma patients. Also, increasing evidence have showed advantages of amino-acid PET vs. RANO MRI for prediction of overall survival. In this narrative review we aimed to summarize published data on FET-PET based treatment response assessment to radiotherapy and focused on details in protocols.
Keywords: 
Subject: Medicine and Pharmacology  -   Oncology and Oncogenics

1. Introduction

Glioblastoma is the most common malignant brain tumor among adults. Standard treatment includes maximal safe resection followed by radiotherapy plus concomitant and adjuvant temozolomide. Despite advances in molecular diagnostic and new WHO classification, glioblastoma is connected with tremendously poor prognosis – median overall survival is 14,6 months and median PFS is 10-12 months [1,2,3,4].
The diagnose of recurrent glioblastoma is usually based on MRI. However, conventional MRI sequences may not distinguish post-treatment changes (such as radionecrosis and pseudoprogression) from actual tumor progression and result in inappropriate therapeutical decisions. In recent years PET has been used to assess response to treatment [5,6,7]. The most commonly used PET tracer in oncology is 18F-fluorodeoxyglucose ([18F]FGD). However, high physiological glucose uptake in brain decreases its diagnostic value [8,9]. Gliomas have overexpression of L-amino acid transporters compared to normal brain cells [10]. Amino acid tracers used in neurooncology are: 11 C-methionine ([11C] MET), 18 F-dihydroxyphenylalanine ([18 F]F-DOPA) and 18 F-fluoroethyl-L-tyrosine ([18 F]FET). They have unique ability to cross blood-brain barrier (BBB) and visualize tumor extent beyond areas with contrast enhancement on MRI [11]. PET has higher sensitivity and specificity for neoplastic tissue than MRI, is superior in metabolic response to treatment and has higher accuracy in differentiation of progression from radiation-induced changes [12,13,14]. It has been demonstrated that PET is also useful in brain metastases and meningiomas [15]. Other PET tracers that may be useful in response assessment in neurooncology are: FACBC (anti-1-amino-3-18F-fluorocyclobutane-1-carboxylic acid or Fluciclovine), FMISO ([18]F fluoromisonidazole) and TSPO (translocator protein) but their role is still under investigation [16,17,18]. PET RANO 1.0 and RANO 2.0 provide criteria for response assessment in gliomas [19,20]. PET/RANO working group prepared a summary of the available evidence with recommendations for the use of PET imaging for radiotherapy of glioma patients [21]. The aim of this review is to summarize the evidence of FET-PET response assessment to radiation therapy in glioblastoma and to prepare practical recommendations for clinical routine.

2. PET-based response assessment criteria for diffuse gliomas

Published in 2024 report of the RANO group has proposed standardized criteria for evaluation of amino acid PET.
Baseline PET in newly diagnosed patients should be obtained 14 days before postoperative treatment but as late as possible after surgery. In patients without postoperative treatment baseline PET should be performed 4-6 weeks after surgery. Without surgical resection (e.g biopsy only) preoperative PET can be used as baseline but should not be obtained more than 14 days before therapeutic intervention.
In recurrent glioma, PET should be performed as close as possible before any therapeutic intervention (not exceeding 14 days). A postoperative PET should be acquired within 14 days before postoperative treatment.
In follow-up of CNS WHO G4 diffuse gliomas PET should be performed at intervals of 2-3 months, parallel to MRI. For assessment of early metabolic response, additional PET 2-3 weeks after treatment initiation can be considered. If needed, additional PET with MRI can be performed (e.g., worse clinical condition). If PET findings are unclear, PET imaging should be repeated in closer intervals, e.g., after 1-2 treatment cycles.
Background activity on amino acid PET should be assessed in the contralateral healthy-appearing cerebral CNS tissue (including grey and white matter within a crescend-shaped volume in the frontoparietal region). PET-positive disease has been defined as volumes with standardized uptake volume (SUV) of 1.6 x mean background activity or higher. Visual check and manual correction are recommended to avoid encompassing structures with physiological high uptake. The maximal SUV and mean SUV in the PET-positive volume are a ratio to the mean SUV of healthy background and serve as measures for uptake intensity (maximal and mean target-background ratio, TBRmax, TBRmean). TBRmax and TBRmean can not be obtained if no PET-positive volume can be found.
Measurable disease has been defined as PET-positive disease with volume exceeding 0.5ml. In non-measurable disease visible lesions have intensity below a TBRmax of 1.6 or volumes below 0.5ml. No measurable disease is the absence of any increased signal abnormality in PET. Patients without measurable disease can not show a partial (PR) or complete response (CR) to subsequent treatment – they can only have stable (SD) or progressive disease (PD).
The assessment of response in PET should be based on the comparison with the baseline PET or nadir.
PD has been defined as an increase of 30% or more in TBRmax or of 10% and more in TBRmean, or of 40% or more in PET volume. Any new measurable lesion is considered as PD. In case of multiple lesions, progression of a least one target is considered as PET-based PD.
PR has been defined as a decrease of 30% or more in TBRmax or of 10% and more in TBRmean or of 40% or more in PET volume without PET-based progressive disease. In case of multiple lesions in PR each target lesion must fulfill PR response criteria or there can be CR for one but one target or if no PD or SD criteria are fulfilled.
CR has been defined as complete disappearance of all previously PET-positive disease and the absence of new lesions. A change of lesion status from measurable disease to non-measurable or no measurable disease is considered as PR or CR, respectively.
SD does not fulfill criteria of PD, PR or CR [19].

3. FET-PET after treatment

A study by Galldiks showed that change of FET-PET parameters is associated with OS and PFS after treatment of glioblastoma. Twenty-five patients had FET-PET and MRI imaging at three different timepoints: after surgery, 7-10 days after radiochemotherapy with temozolomide (R-CHTH) and 6-8 weeks later. FET-PET done early after R-CHTH showed that decrease of TBRmax and TBRmean of 10% and more was a prognostic factor for PFS (TBRmax 9.3 vs. 4.7 months; p= 0.002; TBRmean 10.3 vs. 5.1 months p <0.001) and OS (TBRmax 15.4 vs. 8.5 months; p = 0.001; TBRmean 16.1 vs. 9.3 months, p<0.001). FET-PET done 6-8 weeks later had less significant predictive value of TBR but there was an association of between decreased TVOL1.6 and PFS (9.3 vs. 5.1 months; p = 0.002). MRI changes of tumor volume were not associated with survival [22].
Another prospective study by Suchorska showed that smaller biological tumor volume (BTV) before radiation with temozolomide is a prognostic factor for PFS and OS. The cutpoint of BTV was 9.5 cm3 (sensitivity 64%, specificity 70%). Median OS (PFS) for BTV below 9.5 cm3 was 17.5 (8.8) months, and 10.7 (3.9) months, for BTV above 9.5 (p <0.002 and p <0.08). The outcomes were independent of MGMT promoter methylation status and type of surgical intervention (resection vs biopsy). Patients with initially increased TACs (time-activity curves) had longer OS (29.7 vs 12.5 months; p <0.02, HR 2.1) and longer PFS (11.9 vs 5.8 months; p < 0.05, HR 1.8) [23].
A prospective study by Piroth revealed that static FET-PET parameters (20-40min postinjection) are related to survival in glioma patients after R-CHTH. A decrease in the TBRmax between FET-PET before treatment and 7-10 after R-CHTH (cutoff 10%) had a significantly longer median PFS (9.3 vs 4.7 months; p =0.002) and OS (18.0 vs 8.5 months; p <0.01) than an increase of TBRmax. The results for TBRmean (cutoff 25%) were similar: median PFS (10.3 vs 5.1 months) and OS (22.8 vs 9.3 months) (p < 0.001 for both). However, changes in TTP and the slope of the TAC (10–50 minutes postinjection) after R-CHTH showed no relationship with survival [24].
Another prospective study by Ceccon demonstrated that after R-CHTH and 2 cycles of adjuvant temozolomide a reduction of TBRmax and MTV (metabolic tumor volume) were associated with longer OS (24 vs. 12 months; p =0.032, and 29 vs. 12 months; p = 0.005) and PFS (both 11 vs. 8 months; p = 0.031 and 0.007, respectively). The results were independent of MGMT promoter methylation status, extent of resection and baseline MTV and TBRmax values. There were no significant correlations between MRI results and OS and PFS [25].
Patients after chemoradiation with concomitant and adjuvant temozolomide at first progression treated with bevacizumab + lomustine had reductions of FET-PET parameters. TBRmax reduction of 27% and more was related to improved OS of more than 9 months (sensitivity 92%, specificity 63%; p = 0.036). TBRmean reduction of more than 17% at follow-up PET had the same sensitivity and specificity for differentiating responders from non-responders (p =0.020). Absolute MTV
below 5 ml at follow-up was related to significantly longer OS (12 vs. 6 months, sensitivity 85%; specificity, 88%; p < 0.001). Response assessment based on MRI was not predicted for OS [26].
Response assessment was also compared with RANO criteria I in one prospective study. At the time of response assessment, there was discordance between PET and RANO criteria in 81% of cases. Progressive disease was defined in 72% (8/11) of cases according to RANO criteria but PET showed a partial response in 62% (5/8) of these cases. Responses according to RANO criteria and PET (measured as PD vs. SD or PR) were also examined with respect to survival. Neither factor was significant. However, PD defined by RANO 6 months after treatment was close to significance in terms of association with OS (HR = 3.6, 95% CI, 0.98–13.5; P = 0.05). Relative changes in PET volume and PET volume at time of response assessment were associated with OS [27].
Abovementioned studies have been summarized in Table 1.

4. Differentiation of radionecrosis from progression

Differentiating radionecrosis from progression is one of most crucial aspects after irradiation as it may occure in even 30% of patients [28].Reirradiation is being offered widely to progressive gliomas and exact diagnosis is crucial for optimal candidate selection before intervention.
A systematic review summarized the role of PET imaging with different radiopharmaceuticals ([F]FDG, [18F]FET, [11C]MET, [11C]CHO, [68Ga]Ga-PSMA) in differential diagnosis of radionecrosis and glioblastoma recurrence. The authors analyzed three studies with FET-PET. The cohorts were heterogenous and included patients also with lower grade gliomas. Two studies identified comparable TBRmax cutoffs - 2.07 and 2.09. Amino acid radiotracers had higher specificity (78–95% for [18F]FET and 78–93% for [11C]MET versus 70–88% for [18F]FDG) and sensitivity that FDG-PET (82–91% for [18F]FET and 78–93% for [11C]MET versus 70–84% for [18F]FDG). Overall specificity and sensitivity was high and improved by the use of dedicated amino-acid tracers [29,30,31,32].
A retrospective study evaluated accuracy of 168 FET-PET scans in 146 patients with suspected glioblastoma recurrence in MRI 6 months after radiotherapy PET parameters were higher in patients with recurrent glioblastoma compared with patients with posttreatment changes – defined as necrotizing tissue (TBRmax, 3.2 vs 1.6; TBRmean, 2.0 vs 1.6; and BTV, 14.8 cm3 vs 0.01 cm3; p < 0.0001). Optimal thresholds for differentiation between posttreatment changes and recurrent glioblastoma for TBRmax and TBRmean were 2.0 and 1.8, respectively and 0.55 cm3 for BTV, with the best performance of TBRmax (sensitivity 99%, specificity 94%, accuracy 99%; p < 0.0001). Increasing TBRmax (HR 1.328, 95% CI: 1.116–1.582; p = 0.001) and increasing log BTV (HR 1.303, 95% CI: 1.179–1.439; p < 0.0001) were connected with shorter OS. The results from PET scans were verified by histopathology or by clinical/radiological follow-up. 166 PET scans were correctly classified [33].
Another retrospective study evaluated static and dynamic parameters of FET-PET and apparent diffusion coefficients (ADC) obtained by diffusion-weighted MRI in 48 high grade glioma patients with suspected findings in MRI. Treatment-related changes (defined as prominent necrosis) were present in 10 of 48 patients (21%). The diagnostic performance of FET PET was significantly higher (threshold for both TBRmax and TBRmean, 1.95; accuracy, 83%; p < 0.001) than that of ADC values (threshold ADC, 1.09 × 10−3 mm2/s; accuracy, 69%; p = 0.13). TTP cut-off value of 32.5 min was optimal for the differentiation of treatment-related changes from tumor progression (accuracy, 72%; sensitivity, 80%; specificity, 69%; p< 0.01). For slope the optimal cut-off value was 0.32 SUV/h had a slightly higher diagnostic accuracy of 74% (sensitivity, 70%; specificity, 75%; p= 0.02). Static FET PET parameters with ADC values increased accuracy to 89%. The highest accuracy was achieved by combining static and dynamic FET PET parameters (93%). TBR <1.95 at suspected progression was connected with longer OS (p = 0.01) [34].
FET-PET has been showed to be accurate in distinguishing between glioma recurrence and treatment induced changes with a sensitivity of 86.2% (95% CI: 68.3–96.1%) and a specificity of 81.3% (95% CI: 54.4–96.1%), but the cohort included also patients with astrocytoma and oligodendroglioma. The optimal cutoff values for recurrence were TBRmax ≥ 2.1, SUVmax ≥ 3.5, and TTP ≤ 29 min. However, in this analysis no FET-PET parameters were found to impact survival [35].

5. Differentiation of pseudoprogression from progression

A retrospective study evaluated the role of FET-PET in distinguishing from pseudoprogression and tumor progression in 22 patients with glioblastoma within 12 weeks after standard treatment with suspected MRI findings. Pseudoprogression was confirmed in 11 patients. In patients with pseudoprogression, 18F-FET uptake was significantly lower than in patients with progression (TBRmax 1.9±0.4 vs. 2.8±0.5, TBRmean 1.8±0.2 vs. 2.3±0.3; both p<0.001). TAC type II (18F-FET uptake peaking at a mid-point; >20–40 min) or III (18F-FET uptake peaking early (≤20 min) followed by a constant descent) was more frequently present in patients with progression (p=0.04). The optimal 18F-FET TBRmax cut-off value for identifying pseudoprogression was 2.3 (sensitivity 100 %, specificity 91 %, accuracy 96 %, p<0.001). TBRmax <2.3 was connected with longer OS (median OS 23 vs 12 months, p=0.046) [36].
Another retrospective study evaluated FET-PET in similar cohort (26 patients) but 3 months after treatment. Late pseudoprogression occurred in 7 patients, remaining patients showed true tumor progression. TBRmax and TBRmean were significantly higher in patients with true progression than in patients with late pseudoprogression (TBRmax 2.4±0.1 vs. 1.5± 0.2, P =0.003; TBRmean 2.1±0.1 vs. 1.5±0.2, p =0.012) whereas TTP was significantly shorter (mean TTP 25±2 vs. 40 ±2 min, p< 0.001). The optimal cutoff to differentiate between true progression and late pseudoprogression for TBRmax and TBRmean was 1.9 (TBRmax - sensitivity 84%, specificity 86%, accuracy 85%, p =0.015; TBRmean -sensitivity 74%, specificity 86%, accuracy 77%, p= 0.023). TAC type II or III was more frequently observed in patients with true tumor progression than in patients with late pseudoprogression (sensitivity of 84%, specificity of 100%, and an accuracy of 89%; p< 0.001). The author suggest to diagnose late progression when TBRmax is higher than 2.4 and late pseudoprogression when TBRmax is below 1.0, Values between 1.0 and 2.4 should be interpreted with caution. [37]. In both abovementioned studies there was a higher rate of MGMT metylation in patients wth pseundoprogression than in the patients with true progression. That may suggest that pseudoprogression is a response to radiosensitizing effects of temozolomide.

6. Prognostic value of FET-PET in glioma re-irradiation

A retrospective study evaluated FET-PET in 72 patients with recurrent malignant glioma before and after reirradiation +/- bevacizumab. Re-RT was performed at least 6 months after the first course of RT. Total dose of re-RT was 36Gy in conventional fractions of 2Gy. Patients treated with bevacizumab received a dose of 10mg/kg at day 1. and 15. of re-RT, some patients received maintenance therapy. TTPmin had prognostic value prior to Re-RT with concomitant bevacizumab - shorter TTPmin was connected with shorter PRS (post-recurrence survival) after re-RT (6 months for TTPmin <12,5min, 7 months for TTPmin 12.5–25 min and 11 months for TTPmin >25 min (p=0.027)). Early TBRmax and the other conventional PET parameters were not significantly related to PRS [38].
Another study retrospectively evaluated FET-PET in 56 patients with recurrent malignant glioma and re-RT. The most common dose-fractionation scheme of re-RT was 36Gy in fractions of 2Gy. There was a significant decrease of median SUVmax/BG after second course of RTH (3.3 vs 2.6, p <0.001) and BTV (13.7 cc vs 7.3 cc, p = 0.006) but without significant influence on PFS. The change of SUVmean/BG did not reach significance (2.2 vs 2.3, p = 0.13). Patients with decreasing pretherapeutic FET kinetics had worse survival than patients with other kinetics (p = 0.01) [39].
A phase I clinical trial evaluated prognostic value of FET-PET in reirradiation of 31 patients with recurrent high grade glioma. FET-PET data were obtained at baseline, during 2nd week of treatment and 4 weeks after RT. The prescribed dose to the PTV were: 35 Gy in 10 fractions (group 1), 35 Gy in 10 fractions plus a 7 Gy simultaneous integrated boost to PET-positive volumes - 42 Gy to PET-GTV (group 2), 29.5 Gy in 5 fractions (group 3) and 35 Gy in 10 fractions to tumor volumes above 100cm3 (group 4). All treatment was delivered with 5 fractions/week. Baseline BTV and baseline MRI volume were prognostic for OS (HR = 1.3 p < 0.01 and HR = 1.3 p < 0.01, respectively). Changes in BTV and Tmax/B were not connected with survival. There were no significant differences in Tmax/B and BTV changes between treatment groups [40].
A systematic review summarized prognostic value of amino acid PET (FET/DOPA/MET) versus MRI RANO in prediction of OS in patients with recurrent high grade glioma and bevacizumab therapy. OS was significantly (p < 0.001) lower in the PET + (median = 6.1; n = 39) than in the PET−(median=12.3; n=33) group. OS was marginally (p = 0.052) lower in the MRI + (median = 6.8; n = 18) than in the MRI − (median = 10.5; n = 54) group. The PET+ findings predicted OS at 9 months with a sensitivity and specificity of 76% (95% CI 60–87) and 71% (95% CI 53–83), respectively. Corresponding values for MRI were 32% (95% CI 19–48) and 82% (95% CI 66–92) [41].
Abovementioned studies have been summarized in Table 2.

7. Future directions and controversies

PET RANO-stable disease corresponds to a stable uptake after treatment. However, it may still represent a metabolically active tumor. Future studies should examine whether additional therapies to a metabolically stable glioblastoma can improve outcomes. Most papers relate to standard acquisition but new data suggests that early acquisition shows the most aggressive parts of gliomas [42,43].High uptake in early phase is more common in IDH-wildtype gliomas and time to peak may have a positive prognostic impact [44]. Early uptake assessment that localizes tumor extent outside BTV in standard acquisition may provide new insights. Its decrease should be analyzed and correlated with prognosis in future studies. Re-irradiation based on FET PET still requires further studies as based on current evidence FET-PET distinguishes radiation necrosis and may improve target definition adding infiltration areas outside contrast enhancement.

8. Conclusions

Increasing evidence has proved the efficacy of FET-PET in guiding multidisciplinary decisions after irradiation. Most papers have showed that TBRmean and TBRmax above 2.0 should be considered as progression or active disease. However, a fraction of tumors after irradiation may present lower uptakes, in those cases additional factors should be analyzed. PET-RANO is a systematic attempt to standardize our opinions based on amino-acid PET results after irradiation in order to increase patient safety and re-treatment efficacy. However, PET-RANO stable disease with biological active tumor needs to be carefully evaluated and optimal strategy for this subgroup remains unclear.

Author Contributions

Maciej Harat made a contribution to the concept and design of the article. Izabela Zarębska was responsible for collecting and interpreting the data as well as drafting the manuscript. Both authors analyzed the evidence and revised critically the content. The final version of the manuscript was accepted by both authors.

Funding

This research received no external funding.

Institutional Review Board Statement

Not applicable.

Conflicts of Interest

The authors declare that they have no competing interests.

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Table 1. Overview of studies analyzing FET-PET in treatment response.
Table 1. Overview of studies analyzing FET-PET in treatment response.
StudySStudy N of pts Newly diagnosed or recurrence Time of PET after irradiation Evaluated parameters Dynamic vs static acquisition Prognostic of OS or PFS
Galldiks et al.
[22]		 25 Newly diagnosed 7-10 days and 6-8 weeks after RTH TBRmean, TBRmax, Tvol Static A decrease of TBRmax and TBRmean in early PET - predictors for longer PFS and OS;
6-8 weeks later Tvol decrease related to longer PFS
Suchorska et al. [23] 79 Newly diagnosed 4 -6 weeks after RTH and after 3 cycles of TMZ BTV, TAC Static and dynamic Longer OS and PFS in patients with smaller pretreatment BTV.
Initially increased TAC associated with longer PFS.
Piroth et al. [24] 25 Newly diagnosed 7-10 days and 6-8 weeks after RTH TBRmax, TBRmean, TTP, TAC Static and dynamic Decrease of TBRmean and TBRmax after RTH – longer PFS and OS. No significant correlation of dynamic parameters and survival.
Ceccon et al. [25] 41 Newly diagnosed 7 days before adjuvant TMZ and after 2 cycle of adjuvant TMZ TBRmax, TBRmean, MTV Static Reductions of MTV and TBRmax predicted longer OS and PFS.
Galldiks et al. [26] 21 Recurrence 9-11 days before bevacizumab/lomustine inintiation and after 8-10 weeks TBRmean, TBRmax, MTV Static TBRmax, TBRmean and MTV reduction correlated with longer OS.
Harat et al. [27] 11 Newly diagnosed 3-8 months after RTH MTV Static, dynamic No correlation
RTH – radiotherapy, TMZ- temozolomide, TBR – tumor to background ratio, Tvol – tumor volume, BTV – biological tumor volume, TAC – time activity curve, TTP – time to peak, MTV- metabolic tumor volume, OS – overall survival, PFS – progression free survival.
Table 2. Overview of studies analyzing FET-PET in distinguishing between radionecrosis, pseudoresponse and recurrence as well as prognostic value in reirradiation.
Table 2. Overview of studies analyzing FET-PET in distinguishing between radionecrosis, pseudoresponse and recurrence as well as prognostic value in reirradiation.
Study N of pts Newly diagnosed or recurrence Time of PET after irradiation Evaluated parameters Dynamic vs static acquisition Prognostic of OS or PFS
Bashir et al. [33] 146 Recurrence 6 months TBRmax, TBRmean, BTV Static Increasing BTV associated with shorter OS
PET parameters higher in recurrence than in posttreatment changes
Werner et al. [34] 48 Recurrence 16 weeks TBRmax, TBRmean, TTP Static and dynamic TBRs <1.95 at suspected progression predicted longer survival
Celli et al. [35] 45 Recurrence 12 weeks TBRmax, MTV, TTM, TTP, TAC Static and dynamic No impact of FET-PET parameters on OS/PFS.
Galdiks et al. [36] 22 Recurrence 12 weeks TBRmax, TBRmean, TTP, TAC Static and dynamic TBRmax <2.3 correlated with longer OS
Kebir et al. [37] 26 Recurrence 3 months TBRmax, TBRmean, TTP, TAC Static and dynamic Not assessed
Fleischmann et al. [38] 72 Recurrence 6 months TBRmax, BTV, TAC, TTP Static and dynamic Longer TTP before reirradiation connected with longer post-recurrence survival
Niyazi et al. [39] 56 Recurrence 6 months SUVmax/BG, SUVmean/BG, TAC Static and dynamic Increasing TAC prior to re-irradiation correlated with longer survival
Moller et al. [40] 31 Recurrence 6 months BTV, Tmax/B Static Baseline BTV prognostic for OS
TBR – tumor to background ratio, B/BG- background, BTV – biological tumor volume, TAC – time activity curve, TTP – time to peak, TTM – total tumor metabolism, MTV- metabolic tumor volume, OS – overall survival, PFS – progression free survival.
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