Table 1.

Overview of Included AA PET Studies

Study	Tumor Grade (Number of Patients)	Tracer & Study type	AA PET Imaging Timing	Outcome Measurement	Assessment	Results and Conclusions
Assessing Response to RCT-TMZ
Piroth et al., 2011	GBM (22)	Static [18F]FET Prospective	T0: pretreatment (11–20 days after surgical resection) T1: 7–10 days after completing RCT-TMZ T2: 6–8 weeks later	OS DFS	TBRmean TBRmax Change in TBR Threshold: 1.6	[18F]FET-PET is a sensitive tool to predict early treatment response in GBM patients treated with RCT-TMZ. - Defined early responders as those who had at least 10% decrease in TBRmax 7-10 days post-treatment. - Identified 16 early responders and 6 nonresponders. Early PET responders had significantly longer DFS (10.3 vs. 5.8 months) and OS (“not reached” vs. 9.3 months) than the nonresponders.
Galldiks et al., 2012	GBM (25)	Static [18F]FET Prospective	T0: pretreatment (11–20 days after surgical resection) T1: 7–10 days after completing RCT-TMZ T2: 6–8 weeks later	OS PFS	TBRmean TBRmax Change in TBR Tvol Threshold: 1.6	Static [18F]FET-PET parameters, especially change in TBR, can detect treatment response to RCT-TMZ in GBM patients as early as one week post-treatment. - A decrease of 10% or more in TBRmax and TBRmean between T1 and T2 (early responders) correlated with a significantly longer median PFS and OS (also see study above). - Six to eight weeks later, the predictive value of TBR was less significant, but found an association between a decrease of Tvoland PFS. - Change in MRI tumor volume did not yield significant correlation to survival.
Piroth et al., 2013	GBM (25)	Static and Dynamic [18F]FET Prospective	T0: pretreatment (11–20 days after surgical resection) T1: 7–10 days after completing RCT-TMZ T2: 6–8 weeks later	OS PFS	TBRmean TBRmax Change in TBR Threshold: 1.6 TTP Slope of TAC SoD	Dynamic [18F]FET-PET does not add significant prognostic value in detecting treatment response to RCT-TMZ in GBM. - Confirmed the high predictive value of change in TBR pre- and post-treatment for patient outcome, as described in the above two studies. - Could not confirm the prognostic value of Tvol 1.6at 6–8 weeks post-treatment that was described in the above study. - Changes in TTP, SoD, and slope of TAC pre- and post-treatment did not correlate with outcome.
Santoni et al., 2014	GBM (22) HGG- AA (15) LGG (16)	Static [11C]MET Retrospective	T0: pretreatment (within 1 month from surgical resection) Follow-up: periodic imaging until progression	OS	SUVmax Mean uptake index Relative uptake index	Complementary [11C]MET-PET in addition to MRI/CT may be helpful in postoperative and successive tumor assessment in both HGG and LGG patients. -  The combination of [11C]MET-PET with MRI/CT distinguished treatment-related changes from residual disease with 93.97% sensitivity and 95.18% specificity in AA, and with 96.92% sensitivity and 100% specificity in GBM patients during their RCT-TMZ and adjuvant TMZ treatment. -  [11C]MET-PET allowed early detection of malignant progression from low grade to anaplastic astrocytoma with high sensitivity (91.56%) and specificity (95.18%). -  Mean uptake index on MET-PET was significantly correlated with histologic grading, with GBM demonstrating the highest mean uptake index.
Suchorska et al., 2015	GBM (79)	Static and Dynamic [18F]FET Prospective	T0: pretreatment T1: postoperatively (Cohort A only) T2: 4–6 weeks following treatment (n = 64) T3: after 3 cycles of adjuvant TMZ (n = 31)	OS PFS	SUV LBRmax BTV Threshold: 1.8 TAC pattern	Dynamic [18F]FET-PET TAC pattern and pretreatment BTVsignificantly predicted prognosis in GBM. - BTV defined by FET-PET before RCT-TMZ was the strongest predictor of PFS and OS, independent of MGMT methylation status. -  The following TAC patterns were associated with longer PFS (in descending order): 1. Increasing TAC 2. Change from increasing to decreasing TAC after treatment 3. Change from decreasing to increasing TAC after treatment 4. Decreasing TAC - Both BTV and LBRmaxdecreased after completion of RCT-TMZ, although no further decrease was seen after three cycles of adjuvant TMZ. - Did not find reduction in BTV or LBRmax to correlate with PFS or OS.
Lohmann et al., 2018	GBM (1)	Static and Dynamic [18F]FET Case Report	4 weeks after completion of RCT-TMZ	Progression on histology	TBR Threshold: 1.6 TAC pattern	Increased [18F]FET TBR and dynamic TAC pattern correlated well with tumor burden on histologic studies, suggesting [18F]FET-PET may accurately identify progressive tumor tissue. - Areas of histologically confirmed tumor showed TAC pattern that peaked early and then demonstrated a constant decrease in uptake,which is typical of malignant tissue. - Areas of histologically confirmed gliosis showeda constant rising TAC pattern that was consistent with normal brain.
Kawasaki et al., 2019	GBM (30)	Static [11C]MET Retrospective	T0: pretreatment(after surgical resection) Follow-up: every 3 months after completing RCT-TMZ	OS	L/N ratio Variation rate of L/N ratio Thresholds: 2.0 and 1.3	A decrease in [11C]MET L/N ratio at 3 months after RCT-TMZ was significantly related to the survival time for patients with GBM. - At 3 months post-treatment, a variation rate of –0.366 in the L/N ratio differentiated patients with > 23 months versus ≤ 23 months OS. - L/N ratio decreased for 9 months after RCT-TMZ, while MRI contrast enhancement volumes decreased for 3 months, and then increased for up to 9 months. This illustrated a discrepancy in longitudinal changes between [11C]MET-PET and contrast-enhanced MRI.
Assessing Response to Adjuvant TMZ
Galldiks et al., 2010	GBM (2)	Static [11C]MET Case Series	Variable, based on radiological changes and concern for recurrence	Treatment Response	Uptake ratio Threshold: 1.3	Utilized [11C]MET-PET to monitoradjuvantTMZ-treatment response and detected recurrence earlier than MRI or clinical symptoms. - Patient 1 underwent [11C]MET-PET imaging before beginning adjuvant TMZ (after second resection), during adjuvant TMZ, 6 months after adjuvant TMZ discontinuation, and during the 20th cycle of adjuvant TMZ. - Patient 2 underwent [11C]MET-PET imaging after resection and RCT-TMZ, during adjuvant TMZ, 7 months after TMZ dose reduction, and 3 months after TMZ dose escalation (in response to suspected recurrence on [11C]MET-PET).
Hirono et al., 2019	GBM (44)	Static [11C]MET Retrospective	After extended (12 or more cycles) adjuvant TMZ	Recurrence PFS	Tmax/Nave Threshold: 2.0	Tumor recurrence rate increased in a stepwise manner according to [11C]MET uptake as GBM patients with high uptake showed more frequent tumor progression than those with low uptake. Compared to MRI, [11C]MET-PET demonstrated improved ability to monitor and predict tumor progression. - A TBRmax threshold of 2.0 demonstrated 77.8% sensitivity and 80.8% specificity for predicting tumor progression within one year. - Subgroups with high uptake, even with continuation of TMZ, showed more frequent tumor progression than patients with low uptake. - Low MET uptake was associated with a 93% lower risk for recurrence within one year after PET.
Werner et al., 2019*	HGG (48)	Static and Dynamic [18F]FET Retrospective	Mean time between progression on MRI and [18F]FET-PET: 16 ±15 days Mean time from last treatment to suspected progression: 30±38 weeks	Progression Treatment Response OS	TBRmean TBRmax Threshold: 1.6 Slope of TAC TTP	Static and dynamic [18F]FET-PET parameters may be useful in differentiating progression from pseudoprogression after suspected progression on MRI. - Static parameters TBRmax or TBRmean < 1.95 were most accurate (83%) in diagnosing tumor progression alone(sensitivity, 100%; specificity, 79%). -  TBRmax or TBRmean < 1.95 also significantly differentiated OS in patients, with those below the 1.95 cutoff demonstrating greater OS. -  The most accurate model (93%) for diagnosing tumor progression involved the static parameters TBRmax or TBRmean < 1.95 and the dynamic parameter slope of TAC > 0.32 SUV/h (sensitivity, 78%; specificity 97%). -  The DWI parameter ADC demonstrated an accuracy of 69% (sensitivity, 60%; specificity,71%) but did increase the accuracy of the static parameter model to 89%(sensitivity, 67%; specificity, 94%).
Ceccon et al., 2021	HGG (41, 90% of which had GBM)	Static [18F]FET Prospective	T0: after completion of RCT-TMZ, within 7 days before initiating adjuvant TMZ T1: after two cycles of adjuvant TMZ	PFS OS MGMT promoter methylation	TBRmean TBRmax Change in TBR Tvol Threshold: 1.6	Changes in [18F]FET-PET parameters appear to be effective for identifying responders to adjuvant TMZ early during treatment in patients with newly diagnosed malignant glioma. - After two cycles of adjuvant TMZ, a reduction in [18F]FET Tvol and TBRmax predicted a significantly longer OS and PFS, independent of MGMT promoter methylation status and other prognostic factors such as age, whereas responders identified byRANO criteria using contrast-enhancedMRI did not correlate with clinical outcome. - At baseline before initiating adjuvant TMZ, absolute Tvol of ≤ 28.2 mL or a TBRmax ≤ 2.0 predicted a near doubled PFS; absolute baseline Tvol of ≤ 13.8 mL also predicted a significantly longer OS.
Assessing Response to TMZ Chemotherapy
Galldiks et al., 2006	HGG (14) LGG (1)	Static [11C]MET Prospective	T0: pretreatment T1: after 3rd cycle (n = 15) T2: after 6th cycle (n = 12)	OS Time to progression	TBRmax (uptake index) Change in TBRmax Threshold: 1.5	Changes in [11C]MET uptake correlated significantly to long-term outcome, suggesting that [11C]MET-PET is capable of monitoring metabolically active tumor when contrast enhancement is absent. - Patients with an uptake index that declined had significantly longer time to progression than patients with an uptake index that increased. - Contrast enhancement was not significantly correlated to [11C]MET uptake, supporting the ability of [11C]MET to detect tumor progression earlier than MRI.
Wyss et al., 2009	LGG (11)	Static [18F]FET Prospective	At 6-month intervals after 6 cycles of chemotherapy	PFS Time to maximal volume reduction	T:CBL ratio Threshold: 1.1	[18F]FET-PET may be useful for monitoring TMZ-treatment response in patients with LGG. - Time to maximal volume reduction was seen on [18F]FET-PET earlier (8.0 ± 4.4 months) than on MRI (15.0 ± 3.0 months). - Patients who demonstrated response on both [18F]FET-PET and MRI had the longest PFS.
Roelcke et al., 2016	LGG (33)	Static [18F]FET and [11C]MET Retrospective	T0: 1 month pretreatment T1: between 2–6 months thereafter	Response Seizure Control PFS OS	Mean T:CBL ratio Peak uptake ratio Tvol Threshold: 1.1	Seizure control was correlated with reduction of metabolically active tumor volumes on [18F]FET and [11C]MET-PET, following TMZ in LGG. - Seizure control was not correlated with changes in uptake ratios or T2-weighted MRI volume. - Decrease in active tumor volume by at least 80.5% significantly predicted PFS of 60 months or more.
Suchorska et al., 2018*	HGG-Grade III (17) LGG-Grade II (44)	Static and Dynamic [18F]FET Retrospective	T0: pretreatment T1: 6 months following initiation	Response Seizure Control PCS TTF	TBRmax TBRmean BTV Threshold: 1.8 TAC patterns	Patients with grade II and III glioma and no enhancement on MRI may benefit from [18F]FET-PET to monitor response to TMZ. - Patients who showed response to TMZ on [18F]FET-PET had significantly longer TTF and PCS than patients with stable or progressive disease. - Volume changes on MRI did not differ significantly between patients with responsive, stable, or progressive disease.
Diagnosing Pseudoprogression
Niyazi et al., 2012	GBM (79)	Static [18F]FET Retrospective	Four to six weeks following completion of RCT-TMZ and then every 3 months afterwards	OS PFS MGMT promoter methylation	SUVmax/BG Recurrence pattern Threshold: 1.8	Patients with an ex-field or marginal recurrence on [18F]FET had significantly longer PFS compared to patients with an in-fieldrecurrence. - Recurrence pattern categorized as follows:  1. In-Field = 80% recurrence in field of RT  2. Marginal = 20-80% recurrence in field  3. Ex-Field = < 20% recurrence outside the field - Patients with MGMT promoter methylation had significantly longer 1- and 2-year OS (93.1% and 78.1%) than patients without (64.9% and 7.3%). - Patients with MGMT promoter methylation had significantly longer median PFS (642 days) than patients without (231 days). - Patients with recurrence and MGMT promoter methylation were more likely to demonstrate an ex-field recurrence pattern (6/17, 35.3%) than patients with recurrence and no MGMT promoter methylation (2/18, 11.1%).
Galldiks et al., 2015	GBM (22)	Static and Dynamic [18F]FET Retrospective	Within 12 weeks of completing RCT-TMZ Median time between progression on MRI and [18F]FET-PET:7 days Median time between last treatment and suspected recurrence: 7 weeks	PsP Progression OS MGMT promoter methylation	TBRmax TBRmean Threshold: 1.6 TTP TAC	Patients with PsP had significantly lower TBRmax and TBRmean on [18F]FET-PETand longer TTPcompared to patients with early progression. - ROC analysis demonstrated that a TBRmax < 2.3 significantly differentiated PsP from early progression, with an accuracy of 96%. - Patients with PsP were significantly more likely to demonstrate positive MGMT promoter methylation status (6/11, 54.5%), compared to those with early progression (2/11, 18.2%). - Patients with early progression were most likely to demonstrate a TAC pattern of II or III, and no patients with PsP demonstrated a type III TAC pattern.
Kebir et al., 2016*	GBM (22)	Static and Dynamic [18F]FET Retrospective	More than 12 weeks after completion of RCT-TMZ	Late PsP Progression PFS OS MGMT promoter methylation	TBRmax TBRmean Threshold: 1.6 TTP TAC	Patients with late PsP had significantly lower TBRmax and TBRmean on [18F]FET-PET and longer TTP compared to patients with true progression, indicating [18F]FET-PET may be useful in diagnosing late PsP. - ROC analysis demonstrated that a TBRmax < 1.9 differentiated late PsP from true progression, with an accuracy of 85%. -  The majority of patients with late PsP (6/7, 86%) had MGMT methylation, which was in line with previous studies on methylation status in PsP. - No patients with late PsP demonstrated a TAC pattern of II or III.
Werner et al. 2021*	GBM (23)	Static and Dynamic [18F]FET Retrospective	Less than 26 days following discovery of suspicious MRI lesion during TMZ-lomustine treatment	PsP Progression MGMT promoter methylation (all patients had positive methylation)	TBRmax TBRmean Threshold: 1.6 TTP Slope of TAC	In 23 patients with newly diagnosed GBM (all with methylated MGMT promoter) treated with TMZ-lomustine RCT, combined static and dynamic [18F]FET-PET appeared to be an accurate diagnostic tool in identifying PsP that was inconclusive on contrast-enhanced MRI. - In 11 out of 23 patients, PsP was diagnosed within 5–25 weeks after completion of TMZ-lomustine RCT. The rest 12 patients had confirmed tumor progression. - TBRmean (1.9 ± 0.2 vs. 2.1 ± 0.2) and TBRmax (2.8 ± 0.6 vs. 3.2 ± 0.5) were significantly lower in PsP compared to true progression. Dynamic TTP was significantly higher in PsP than true progression (36.6 ± 8.3 vs. 24.8 ± 9.4 minutes). Slope of TAC did not reach statistical significance. -  The optimal TBRmean cutoff value for diagnosing PsP was 1.95 with an 87% accuracy. The optimal TTP cutoff was 35 minutes with a 74% accuracy. Furthermore, the combination of TBRmean and TTP yielded a specificity and positive predictive value of 100% in diagnosing PsP. - Conventional MRI following RANO criteria did not effectively diagnose PsP (accuracy, 58%).

*Indicates some patients in the study were also treated with lomustine and/or procarbazine.

Abbreviations: AA, Anaplastic Astrocytoma; ADC, apparent diffusion coefficients; AUC, area under the curve; BG, Background; BTV, biological tumor volume; [¹¹C]MET, [¹¹C]methyl-L-methionine; DFS, disease-free survival; DWI, Diffusion Weighted Imaging; [¹⁸F]FDG, 2-deoxy-2-[¹⁸F]fluoro-D-glucose; [¹⁸F]FET, O-(2-[¹⁸F]fluoroethyl)-L-tyrosine; HGG, high-grade glioma; LBR_max, lesion to brain ratio; LGG, low-grade glioma; L/N ratio, lesion to normal [brain] ratio; MGMT, O-6-methylguanine-DNA methyltransferase; NA, not applicable; OS, overall survival; PCS, Postchemotherapy survival; PFS, progression-free survival; PsP, Pseudoprogression; ROC, receiver operating characteristic; SoD, sum of difference; SUV, standardized uptake value; TAC, time-activity curve; TBR, tumor-to-background ratio; T:CBL ratio, active tumor uptake to mean cerebellum uptake ratio; TMZ, temozolomide; tOS, total OS; TTF, time-to-treatment failure; TTP, time to peak; T_vol, metabolically active tumor volume; T0, time of baseline imaging; T1, time of first post-treatment imaging; T2, time of second post-treatment imaging; T3, time of third post-treatment imaging.