fluoroethyl)-L-tyrosine PET Research Articles

NIMG-20. ASSESSMENT OF RESPONSE TO REGORAFENIB IN RECURRENT GLIOMA PATIENTS USING FET PET AND MRI INCLUDING ADC VALUES

Abstract INTRODUCTION Currently, data on O-(2-[18F]fluoroethyl)-L-tyrosine (FET) PET and MRI parameters for the evaluation of response to regorafenib in glioma patients remain scarce. METHODS Twenty patients (age range, 30-72 years) with recurrent CNS WHO grade 3 or 4 gliomas (glioblastoma, 85%) were treated according to the REGOMA trial. FET PET and MRI were performed at baseline and follow-up after the second cycle. Static FET PET parameters comprised tumor-to-brain ratios (TBR) and metabolic tumor volumes (MTV). Parameters derived from dynamic FET PET acquisition were time-to-peak and slope. MRI response assessment was based on RANO criteria. Additionally, various apparent diffusion coefficients (ADC) parameters were obtained from diffusion-weighted MRI. Thresholds derived from FET PET and ADC parameters were defined using ROC analyses to predict an overall survival (OS) of ≥6 months. The predictive values of FET PET parameters, ADC values, and RANO criteria were subsequently evaluated using univariate and multivariate survival estimates. RESULTS Patients received a median of three regorafenib cycles (range, 2-10 cycles). After treatment initiation, the median follow-up was 8.6 months (range, 3.2-27.3 months). After two cycles of regorafenib, a reduction of mean TBR values by ≥10% predicted significantly longer OS (9.9 vs. 5.3 months; P=0.023). Additionally, absolute mean TBR values ≤2.0 at follow-up were prognostic and associated with a significantly longer OS (10.6 vs. 4.5 months; P=0.007). In contrast, MTV, dynamic PET parameters, RANO criteria, and ADC values were not predictive for response or were prognostic (all P >0.05). Multivariate survival analyses revealed that relative mean TBR changes were most potent in predicting response to regorafenib (P=0.038; HR, 0.246) and absolute mean TBR values for prognostication (P< 0.001; HR, 0.005). CONCLUSION In contrast to MRI metrics, FET PET parameters are clinically valuable for identifying responders to regorafenib early after treatment initiation and helpful for prognostication.

NIMG-05. CHARACTERIZATION OF LONG-TERM METABOLIC CHANGES OF BRAIN METASTASES AFTER TREATMENT WITH STEREOTACTIC RADIOSURGERY USING SERIAL FET PET IMAGING

Abstract BACKGROUND In the present study, we characterized the long-term metabolic changes of brain metastases after treatment with stereotactic radiosurgery (SRS) by serial PET imaging using the radiolabeled amino acid O-(2-[18F]-fluoroethyl)-L-tyrosine (FET). We hypothesized that this approach is of considerable clinical value in differentiating between radiation-induced changes and local brain metastasis relapse. Patients and METHODS From 2010-2020, we retrospectively identified patients with brain metastases from solid extracranial primary tumors who (i) were treated with SRS with or without concurrent immunotherapy using checkpoint inhibitors, (ii) had equivocal MRI findings after SRS, and (iii) subsequently underwent two or more additional FET PET scans during follow-up for long-term evaluation. Mean tumor-to-brain ratios (TBR) were obtained. Diagnostic performances were calculated using receiver operating characteristic curve analyses. Diagnoses were confirmed by neuropathological evaluation (29%) or clinicoradiologically (71%). RESULTS We identified 14 patients with 42 FET PET scans (median number, 3; range, 2-4). Concurrent to SRS, 4 patients (29%) were treated with checkpoint inhibitors. Following SRS, equivocal MRI findings occurred after a median time of 7 months (range, 2-62 months). Subsequently, FET PET scans were acquired over a median 16 months (range, 7-99 months). Nine patients (64%) had radiation-induced changes, and five had local brain metastases relapse. TBRs calculated from the last available FET PET scan showed the highest accuracy (93%) in identifying radiation-induced changes (threshold, 1.95; P=0.011). In lesions consistent with local brain metastases relapse, TBR increased considerably over time (median increase, 17%; range, 11% - 32%). In contrast, in lesions considered as radiation-induced changes, TBR remained stable or even decreased (median change, -4%; range, -44% - 11%). The TBR evolution over time significantly differed between the two groups (P=0.011). CONCLUSIONS Serial FET PET imaging has a high diagnostic accuracy for characterizing long-term changes of brain metastases after treatment with stereotactic radiosurgery.

P15.15.B DIFFUSE ADULT-TYPE GLIOMA INFILTRATION DEFINED ON FET-PET

Abstract BACKGROUND O-(2-[18F]fluoroethyl)-L-tyrosine (FET)-PET is a valuable tool in glioma imaging used to the definition of biopsy site, monitoring of treatment response and differentiation of treatment-related changes from glioma progression The physiological uptake within reactive astrogliosis may limits FET-PET ability to precisely define glioma extent. For the implementation of FET-PET into clinical trials, a methodological PET standardization is urgently needed to enable more precise and reproducible FET PET quantification. The primary aim of our study was to define a glioma infiltration using threshold based method between astrogliosis and tumoral tissue in FET-PET. RESULTS Astrogliosis presented similar uptake to grade 2 glioma samples. Standard threshold method (1,6x uptake in contralateral brain) in PET aquisiton 40-60 minutes post injection is effective but the accuracy decrease outside contrast enhancement within FLAIR to 56% sensitivity and 41% specificity. Adding second aquisition increased sensitivity within FLAIR to 71%. Finally, using tumor-to-plexus ratio, it is possible to differentiate astrogliosis and grade 2, and achieve sensitivity of 73% and specificty of 84% within FLAIR or 90% sensitivity with 61% specificity. ROC curves are significantly different related to method used with best results specific to new strategy. CONCLUSION Determining glioma extent using standard threshold method in PET or FLAIR is limited. Improving is possible with dual aquisition and/or different tumor to background ratio. This may largely improve delineation of glioma for surgery or radiotherapy.

JS09.6.A ASSESSMENT OF RESPONSE TO REGORAFENIB IN RECURRENT GLIOMA PATIENTS USING FET PET AND MRI INCLUDING ADC VALUES

Abstract BACKGROUND The phase 2 REGOMA trial suggested that glioblastoma patients treated with the multikinase inhibitor regorafenib at first progression have significantly longer overall survival than patients treated with lomustine. Here, we evaluated the value of O-(2-[18F]fluoroethyl)-L-tyrosine (FET) PET and MRI for the evaluation of response to regorafenib in recurrent glioma patients. MATERIAL AND METHODS Twenty patients (age range, 30-72 years) with CNS WHO grade 3 or 4 gliomas (glioblastoma, 85%) at recurrence were treated according to the REGOMA trial with regorafenib at 160 mg/d for the first three weeks of each 4-week cycle, with individual dose adjustment according to toxicity. FET PET and MRI were performed at baseline and follow-up after the second cycle. Static FET PET parameters comprised tumor-to-brain ratios (TBR) and metabolic tumor volumes (MTV). Parameters derived from dynamic FET PET acquisition were time-to-peak and slope. MRI response assessment was based on RANO criteria. Additionally, mean and minimum apparent diffusion coefficients (ADC) were obtained from diffusion-weighted MRI. FET PET parameters and ADC thresholds were defined using ROC analyses to predict an overall survival of ≥ 6 months. The predictive values of FET PET parameters, ADC values, and RANO criteria were subsequently evaluated using univariate and multivariate survival estimates. RESULTS Patients received a median of three regorafenib cycles (range, 2-10 cycles). After treatment initiation, the median follow-up was 8.6 months (range, 3.2-27.3 months). The median number of previous treatment lines was two (range, 1-4 lines). At the time of data analysis, 17 patients (85%) had died. After two cycles of regorafenib, a regorafenib-induced reduction of mean TBR values by ≥ 10% predicted a longer overall survival (9.9 vs. 5.3 months; P=0.023). Interestingly, absolute mean TBR values ≤ 2.0 at follow-up were prognostic and associated with longer OS (10.6 vs. 4.5 months; P=0.007). In contrast, MTV, dynamic PET parameters, RANO criteria, and ADC values were not predictive for response or prognostic (all P>0.05). Multivariate survival analyses revealed that relative mean TBR changes were most potent in predicting response to regorafenib (P=0.038; HR, 0.246) and absolute mean TBR values for prognostication (P<0.001; HR, 0.005). CONCLUSION Data suggest that FET PET parameters are clinically valuable for identifying responders to regorafenib early after treatment initiation and helpful for prognostication. MRI parameters, including ADC values, do not appear to add valuable information in this context.

Delineation and agreement of FET PET biological volumes in glioblastoma: results of the nuclear medicine credentialing program from the prospective, multi-centre trial evaluating FET PET In Glioblastoma (FIG) study—TROG 18.06

PurposeThe O-(2-[18F]-fluoroethyl)-l-tyrosine (FET) PET in Glioblastoma (FIG) trial is an Australian prospective, multi-centre study evaluating FET PET for glioblastoma patient management. FET PET imaging timepoints are pre-chemoradiotherapy (FET1), 1-month post-chemoradiotherapy (FET2), and at suspected progression (FET3). Before participant recruitment, site nuclear medicine physicians (NMPs) underwent credentialing of FET PET delineation and image interpretation.MethodsSites were required to complete contouring and dynamic analysis by ≥ 2 NMPs on benchmarking cases (n = 6) assessing biological tumour volume (BTV) delineation (3 × FET1) and image interpretation (3 × FET3). Data was reviewed by experts and violations noted. BTV definition includes tumour-to-background ratio (TBR) threshold of 1.6 with crescent-shaped background contour in the contralateral normal brain. Recurrence/pseudoprogression interpretation (FET3) required assessment of maximum TBR (TBRmax), dynamic analysis (time activity curve [TAC] type, time to peak), and qualitative assessment. Intraclass correlation coefficient (ICC) assessed volume agreement, coefficient of variation (CoV) compared maximum/mean TBR (TBRmax/TBRmean) across cases, and pairwise analysis assessed spatial (Dice similarity coefficient [DSC]) and boundary agreement (Hausdorff distance [HD], mean absolute surface distance [MASD]).ResultsData was accrued from 21 NMPs (10 centres, n ≥ 2 each) and 20 underwent review. The initial pass rate was 93/119 (78.2%) and 27/30 requested resubmissions were completed. Violations were found in 25/72 (34.7%; 13/12 minor/major) of FET1 and 22/74 (29.7%; 14/8 minor/major) of FET3 reports. The primary reasons for resubmission were as follows: BTV over-contour (15/30, 50.0%), background placement (8/30, 26.7%), TAC classification (9/30, 30.0%), and image interpretation (7/30, 23.3%). CoV median and range for BTV, TBRmax, and TBRmean were 21.53% (12.00–30.10%), 5.89% (5.01–6.68%), and 5.01% (3.37–6.34%), respectively. BTV agreement was moderate to excellent (ICC = 0.82; 95% CI, 0.63–0.97) with good spatial (DSC = 0.84 ± 0.09) and boundary (HD = 15.78 ± 8.30 mm; MASD = 1.47 ± 1.36 mm) agreement.ConclusionThe FIG study credentialing program has increased expertise across study sites. TBRmax and TBRmean were robust, with considerable variability in BTV delineation and image interpretation observed.

NIMG-27. THE PROGNOSTIC VALUE OF FET PET IN PATIENTS WITH RECURRENT GLIOMA TREATED WITH BEVACIZUMAB

Abstract BACKGROUND After multiple recurrences in glioma patients, bevacizumab is frequently used as salvage therapy. In this group of patients, we evaluated the prognostic value of amino acid PET using O-(2-[18F]fluoroethyl)-L-tyrosine (FET) before initiation of bevacizumab. METHODS We retrospectively identified adult glioma patients at recurrence with (i) at least one or more previous recurrences, (ii) who were treated with bevacizumab, and (iii) who underwent FET PET imaging before bevacizumab initiation. Maximum and mean tumor-to-brain ratios (TBRmax, TBRmean), metabolic tumor volume (MTV), and dynamic parameters (i.e., time-to-peak, slope) were obtained from FET PET. Additionally, contrast-enhancing volumes on MRI were calculated. Threshold values of imaging parameters for evaluating the prognosis were established by ROC analyses using overall survival (OS) of ≥ 6 months as reference. The prognostic value of imaging parameters was subsequently evaluated using the log-rank test and multiple logistic regression analyses. RESULTS Twenty-eight patients (glioblastoma, 96%) with a median of 2 recurrences (range, 1-5) were eligible for data evaluation. The patients received a median number of 7 bevacizumab cycles (range, 1-27). The static FET PET parameter TBRmean was the best parameter (threshold, 2.1; AUC, 0.78; P=0.014) to identify patients with a significantly longer OS (8.2 vs. 4.9 months; P=0.044). In contrast, the MTV, contrast-enhancing volume, and dynamic FET PET parameters were not significant. TBRmean remained significant in multiple logistic regression analysis (P=0.031), indicating an independent predictor for OS. CONCLUSION Our data suggest that static FET PET allows identifying patients with longer OS before initiation of bevacizumab.

NIMG-83. MULTIMODAL PET/MRI RADIOMICS AND CLINICAL PARAMETERS FOR OVERALL SURVIVAL PREDICTION IN PATIENTS WITH IDH WILDTYPE GLIOBLASTOMA

Abstract BACKGROUND Currently, most radiomics studies on survival prediction in brain tumor patients are based on MRI only. The goal of our study was to evaluate multimodal radiomics derived from amino acid PET/MRI and clinical parameters for survival prediction in patients with newly diagnosed IDH wildtype glioblastoma. METHODS Sixty-three patients with newly diagnosed IDH wildtype glioblastoma were evaluated retrospectively. At initial diagnosis, all patients underwent structural MRI and O-(2-[18F]fluoroethyl)-L-tyrosine (FET) PET. Tumor volumes were automatically segmented using a deep learning-based tool followed by visual inspection. Predefined and deep radiomics features were extracted from both imaging modalities. Feature repeatability analyses and feature selection were performed to avoid overfitting. Cox regression models for overall survival were built from clinical parameters such as age or the extent of resection, radiomics features, and combinations thereof, and finally validated using 5-fold cross-validation. Further evaluation of the model in an external test dataset is ongoing. RESULTS The median overall survival was 12 months (range, 0-64 months). Higher age and larger FET PET tumor volumes were significantly correlated with shorter overall survival (age, r=-0.39, p< 0.001; volume, r=-0.31, p< 0.05). Models solely based on predefined FET PET or MRI radiomics features showed a similar mean concordance index (C-index) as the model based on clinical parameters (C-indices, 0.68±0.04; 0.64±0.03; and 0.69±0.08, respectively). Multimodal radiomics based on predefined and deep features yielded improved C-indices of 0.75±0.06 and 0.72±0.09, respectively. A model based on multimodal radiomics and clinical parameters achieved the best prognostic performance (C-index, 0.80±0.04). CONCLUSION Our results suggest an added clinical value of multimodal FET PET/MRI radiomics with clinical parameters for the non-invasive survival prediction in patients with IDH wildtype glioblastoma.

NIMG-84. PREDICTION OF RESPONSE TO LOMUSTINE-BASED CHEMOTHERAPY IN GLIOMA PATIENTS AT RECURRENCE USING MRI AND FET PET

Abstract BACKGROUND This study evaluates O-(2-[18F]fluoroethyl)-L-tyrosine (FET) PET and contrast-enhanced MRI for early response assessment in glioma patients at recurrence treated with lomustine-based chemotherapy. METHODS Thirty-six adult patients with WHO CNS Grade 3 or 4 gliomas (glioblastoma, 69%) at recurrence (median number of recurrences, 1; range, 1-3) were retrospectively identified. Besides MRI, serial FET PET scans were performed at baseline and early after chemotherapy initiation (median number of cycles, 2). Mean and maximum tumor-to-brain ratios (TBR), metabolic tumor volumes (MTV), the occurrence of new distant hotspots with a mean TBR > 1.6 at follow-up, and the dynamic parameter time-to-peak were derived from all FET PET scans. Threshold values of PET parameters were defined using receiver operating characteristic analyses to predict progression-free survival (PFS) of ≥ 6 months and overall survival (OS) of ≥ 12 months. MRI response assessment was based on RANO criteria. Using univariate and multivariate survival estimates, the predictive value of FET PET parameters and RANO criteria were subsequently evaluated. RESULTS After treatment initiation, the median follow-up time was 11 months (range, 3-71 months). Relative changes of the mean and maximum TBR, MTV, and RANO criteria predicted a significantly longer PFS (all P< 0.003) and OS (all P< 0.05). At follow-up, the occurrence of new distant hotspots (n≥ 1) predicted a worse outcome, with significantly shorter PFS (P=0.001) and OS (P< 0.001). Changes of the dynamic parameter time-to-peak did not predict a significantly longer PFS or OS (P > 0.05). Multivariate survival analyses revealed that new distant hotspots at follow-up had the highest significance level to predict non-response (P< 0.001; hazard ratio, 8.578), independent of RANO criteria, IDH mutation status, and O6-methylguanine-DNA-methyltransferase promoter methylation. CONCLUSIONS FET PET seems to be a powerful tool for identifying responders to lomustine-based chemotherapy early after treatment initiation.

Prediction of response to lomustine-based chemotherapy in glioma patients at recurrence using MRI and FET PET.

We evaluated O-(2-[18F]fluoroethyl)-l-tyrosine (FET) PET and MRI for early response assessment in recurrent glioma patients treated with lomustine-based chemotherapy. Thirty-six adult patients with WHO CNS grade 3 or 4 gliomas (glioblastoma, 69%) at recurrence (median number of recurrences, 1; range, 1-3) were retrospectively identified. Besides MRI, serial FET PET scans were performed at baseline and early after chemotherapy initiation (not later than two cycles). Tumor-to-brain ratios (TBR), metabolic tumor volumes (MTV), the occurrence of new distant hotspots with a mean TBR >1.6 at follow-up, and the dynamic parameter time-to-peak were derived from all FET PET scans. PET parameter thresholds were defined using ROC analyses to predict PFS of ≥6months and OS of ≥12months. MRI response assessment was based on RANO criteria. The predictive values of FET PET parameters and RANO criteria were subsequently evaluated using univariate and multivariate survival estimates. After treatment initiation, the median follow-up time was 11months (range, 3-71months). Relative changes of TBR, MTV, and RANO criteria predicted a significantly longer PFS (all P ≤ .002) and OS (all P ≤ .045). At follow-up, the occurrence of new distant hotspots (n ≥ 1)predicted a worse outcome, with significantly shorter PFS (P=.005) and OS (P < .001). Time-to-peak changes did not predict a significantly longer survival. Multivariate survival analyses revealed that new distant hotspots at follow-up FET PET were most potent in predicting non-response (P < .001; HR, 8.578). Data suggest that FET PET provides complementary information to RANO criteria for response evaluation of lomustine-based chemotherapy early after treatment initiation.

P15.05.A Prediction of response to lomustine-based chemotherapy in glioma patients at relapse using MRI and FET PET

Abstract Background This study evaluates O-(2-[18F]fluoroethyl)-L-tyrosine (FET) PET and contrast-enhanced MRI for early response assessment in glioma patients at relapse treated with lomustine-based chemotherapy. Material and Methods Thirty-seven adult patients with WHO CNS Grade 3 or 4 gliomas at relapse (glioblastoma, 70%; median number of relapses, 1) were retrospectively identified. Besides MRI, serial FET PET scans were performed at baseline and early after chemotherapy initiation (median number of cycles, 2). Mean and maximum tumor-to-brain ratios (TBR), metabolic tumor volumes (MTV), the occurrence of distant hotspots with a mean TBR &amp;gt; 1.6 at follow-up, and dynamic parameters (i.e., time-to-peak and slope) were derived from all FET PET scans. Threshold values of PET parameters were defined using receiver operating characteristic analyses to predict progression-free survival (PFS) of ≥6 months and overall survival (OS) of ≥12 months. MRI response assessment was based on RANO criteria. The predictive value of FET PET parameters and RANO criteria were subsequently evaluated using univariate and multivariate survival estimates. Results After treatment initiation, the median follow-up time was 11 months (range, 3-71 months). Maximum TBR and MTV (threshold, ≤0%) and RANO criteria predicted a significantly longer PFS (all P&amp;lt;0.001) and OS (all P&amp;lt;0.03). At follow-up FET PET imaging, the occurrence of new distant hotspots (n≥1) predicted a worse outcome, with significantly shorter PFS (P=0.001) and OS (P&amp;lt;0.001). Dynamic PET parameters did not predict a significantly longer PFS or OS (P&amp;gt;0.05). Multivariate survival analyses revealed that new distant hotspots at follow-up had the highest level of significance to predict non-response (P=0.002; hazard ratio, 5.722), independent of RANO criteria, IDH mutation status, and O6-methylguanine-DNA-methyltransferase promoter methylation. Conclusion FET PET seems to be a powerful tool for identifying responders to lomustine-based chemotherapy early after treatment initiation.

KS02.7.A Impact of FET PET on multidisciplinary neurooncological tumor board decisions in patients with brain tumors

Abstract Background Following neurooncological treatment of brain tumors, neurooncologists are often confronted with equivocal MRI findings (e.g., treatment-related changes such as pseudoprogression, non-measurable contrast-enhancing lesions, T2/FLAIR signal alterations, pseudoresponse). Especially in Europe, amino-acid PET is increasingly integrated into multidisciplinary neurooncological tumor boards (MNTB) to overcome these diagnostic uncertainties. We evaluated the correctness of MNTB decisions, in which amino acid PET findings were taken into account. Material and Methods In a single-university center study, we retrospectively evaluated 182 MNTB decisions of 154 patients with histomolecularly defined WHO grade 3 or 4 gliomas (n=123), including glioblastoma (n=80), anaplastic glioma (n=42), and gliosarcoma (n=1), or brain metastases (n=31) secondary to lung cancer, melanoma, breast cancer, or colorectal cancer presenting equivocal MRI findings following anticancer treatment. All patients underwent O-(2-[18F]-fluoroethyl)-L-tyrosine (FET) PET imaging as an adjunct for decision-making. Additionally, the patients’ clinical status, pretreatment, and conventional MRI findings were considered for decision-making. The presence of neoplastic tissue was considered if the mean FET uptake as assessed by tumor-to-brain ratios was &amp;gt; 2.0. MNTB decisions were validated using the neuropathological result in 42% (n=77) or clinicoradiologically in 58% (n=105). The diagnostic performance of MTNB decisions was evaluated using 2x2 contingency tables. Results The validation of all 182 MNTB recommendations, which integrated FET PET in the decision-making process, were correct in 95% (sensitivity, 97%; specificity, 75%; positive predictive value, 96%). Due to tumor progression, MNTB recommendations prompted a treatment change in 88% (n=160 of 182 decisions). When FET PET findings suggested progressive disease (n=157), MNTB decisions were correct in 96% (positive predictive value, 97%). In 22 MNTB decisions with the recommendation to continue the current treatment regimen, 82% were correctly identified as treatment-related changes. Conclusion FET PET seems to have a significant impact on MNTB decisions. A prospective evaluation of MNTB decisions with and without the integration of FET PET is warranted to define the added value of FET PET.

KS05.5.A Alterations in white matter fiber density associated with structural MRI and metabolic PET lesions following multimodal therapy in glioma patients

Abstract Background In glioma patients, multimodal therapy and recurrent tumor result in local brain tissue changes, characterized by pathologic findings in structural MRI and metabolic PET images. Little is known about these different lesion types’ impact on the local white matter fiber architecture and clinical outcome. Patients and Methods This study included data from 121 pretreated patients (median age, 52 years; ECOG, 01) with histomolecularly characterized glioma (WHO grade IV glioblastoma, n=81; WHO grade III anaplastic astrocytoma, n=28; WHO grade III anaplastic oligodendroglioma, n=12), who had a resection, radiotherapy, alkylating chemotherapy, or combinations thereof. After a median time of 14 months (range, 1-214 months), post-therapeutic structural and metabolic findings were evaluated using anatomical MRI and O-(2-[18F]fluoroethyl)-L-tyrosine (FET) PET acquired on a 3T hybrid PET/MR scanner. Local fiber density was estimated from tractography based on highangular resolution diffusion-weighted imaging. A cohort of 121 healthy subjects selected from the 1000BRAINS study and matched for age, gender and education served as a control group. Results The median volume of resection cavities, contrast-enhancing regions, regions with pathologically increased FET uptake, and T2/FLAIR hyperintense regions amounted to 20.9, 7.9, 30.3, and 53.4 mL, respectively. Compared to the control group, the average local fiber density in these regions was significantly reduced (p&amp;lt;0.001). Resection cavities showed the highest reduction, followed by contrast-enhancing lesions and metabolically active tumors on FET PET (relative fiber density reduction, -87%, -65%, -55%, respectively). The local fiber density was inversely related (p=0.005) to the FET uptake in recurrent tumors. T2/FLAIR hyperintense lesions, either assigned to peritumoral edema in recurrent glioma or radiation-induced gliosis, had a comparable impact on reducing fiber density (48% and 41%, respectively). The total fiber loss (average fiber loss multiplied by lesion volume) associated with contrast-enhancing lesions (p=0.006) and T2/FLAIR hyperintense lesions (p=0.013) had a significant impact on the general performance status of the patients (ECOG score). Conclusions Our results suggest that apart from resection cavities, reduction in local fiber density is greatest in contrast-enhancing recurrent tumors, but total fiber loss induced by edema or gliosis has an equal detrimental effect on the patients’ performance due to the larger volume affected. Funding Funded by the 1000BRAINS study (INM, Research Centre Juelich, Germany), Horizon 2020 (Grant No. 945539 (HBP SGA3; SC)), and Heinz Nixdorf Foundation.

Static FET PET radiomics for the differentiation of treatment-related changes from glioma progression

PurposeTo investigate the potential of radiomics applied to static clinical PET data using the tracer O-(2-[18F]fluoroethyl)-l-tyrosine (FET) to differentiate treatment-related changes (TRC) from tumor progression (TP) in patients with gliomas.Patients and MethodsOne hundred fifty-one (151) patients with histologically confirmed gliomas and post-therapeutic progressive MRI findings according to the response assessment in neuro-oncology criteria underwent a dynamic amino acid PET scan using the tracer O-(2-[18F]fluoroethyl)-l-tyrosine (FET). Thereof, 124 patients were investigated on a stand-alone PET scanner (data used for model development and validation), and 27 patients on a hybrid PET/MRI scanner (data used for model testing). Mean and maximum tumor to brain ratios (TBRmean, TBRmax) were calculated using the PET data from 20 to 40 min after tracer injection. Logistic regression models were evaluated for the FET PET parameters TBRmean, TBRmax, and for radiomics features of the tumor areas as well as combinations thereof to differentiate between TP and TRC. The best performing models in the validation dataset were finally applied to the test dataset. The diagnostic performance was assessed by receiver operating characteristic analysis.ResultsThirty-seven patients (25%) were diagnosed with TRC, and 114 (75%) with TP. The logistic regression model comprising the conventional FET PET parameters TBRmean and TBRmax resulted in an AUC of 0.78 in both the validation (sensitivity, 64%; specificity, 80%) and the test dataset (sensitivity, 64%; specificity, 80%). The model combining the conventional FET PET parameters and two radiomics features yielded the best diagnostic performance in the validation dataset (AUC, 0.92; sensitivity, 91%; specificity, 80%) and demonstrated its generalizability in the independent test dataset (AUC, 0.85; sensitivity, 81%; specificity, 70%).ConclusionThe developed radiomics classifier allows the differentiation between TRC and TP in pretreated gliomas based on routinely acquired static FET PET scans with a high diagnostic accuracy.

NIMG-20. DIFFERENTIATION OF TREATMENT-RELATED CHANGES FROM TUMOR PROGRESSION FOLLOWING BRACHYTHERAPY IN PATIENTS WITH WHO II AND III GLIOMAS USING FET PET

Abstract BACKGROUND Following brachytherapy, the differentiation of radiation-induced changes (e.g., radiation necrosis) from actual tumor progression using MRI is challenging. To overcome this diagnostic uncertainty, we evaluated the diagnostic value of O-(2-[18F]-fluoroethyl)-L-tyrosine (FET) PET in glioma patients treated with brachytherapy. MATERIAL AND METHODS From 2006-2019, we retrospectively identified WHO grade II or III glioma patients (i) treated with brachytherapy using Iodine-125 seeds, (ii) equivocal or progressive MRI findings inside the radiation field, and (iii) additional FET PET imaging for diagnostic evaluation. Static FET PET parameters such as maximum and mean tumor-to-brain ratios (TBR) and dynamic FET PET parameters (i.e., time-to-peak, slope) were obtained. Diagnostic performances were calculated using receiver operating characteristic curve analyses and Fisher’s exact test. Diagnoses were confirmed histologically or clinicoradiologically. RESULTS Following brachytherapy, suspect MRI findings occurred after a median time of 33 months (range, 5-111 months). In 10 of 21 patients (WHO grade II, n=5; WHO grade III, n=16), treatment-related changes were diagnosed. The best diagnostic performance for identification of treatment-related changes was obtained using maximum TBRs (threshold &amp;lt; 3.20;accuracy, 86%; sensitivity, 100%; specificity, 73%; P=0.007). Mean TBRs reached an accuracy of 76% (threshold &amp;lt; 2.05; sensitivity, 89%; specificity, 64%; P=0.010). Dynamic PET parameters did not reach statistically significant results. CONCLUSION Our data suggest that static FET PET parameters add valuable diagnostic information to diagnose radiation-induced changes in glioma patients treated with brachytherapy.

NIMG-27. REGORAFENIB RESPONSE ASSESSMENT USING FET PET IN PATIENTS WITH PROGRESSIVE GLIOMA

Abstract BACKGROUND The REGOMA phase 2 trial showed an encouraging overall survival benefit of the multikinase inhibitor regorafenib in glioblastoma patients at first progression. We used O-(2-[18F]fluoroethyl)-L-tyrosine (FET) PET for the early assessment of response to regorafenib in patients with progressive glioma in an advanced disease stage. METHODS Thirty patients with progressive glioma were treated according to the REGOMA trial and prospectively followed. FET PET and MRI were performed at baseline and after the second cycle of regorafenib. Static PET parameters such as maximum and mean tumor-to-brain ratios (TBRmax, TBRmean) and metabolic tumor volumes (MTV) were calculated. Threshold values of FET PET parameters to predict a response were established by ROC analyses using an overall survival of ≥ 6 months as reference. The predictive value of FET PET parameters and their changes concerning overall survival was subsequently evaluated using the Kaplan-Meier test. MRI changes were evaluated according to the RANO criteria. RESULTS Up to now, 18 of 30 patients (glioblastoma, 83%; age range, 24-71 years) were eligible for data evaluation. The median number of tumor relapses before regorafenib was 2 (range, 1-4). During regorafenib (median cycles, 4; range, 2-9 cycles), CTCAE grade 3 or 4 side effects occurred in 56% and 11%, respectively. The median overall survival was 6 months (range, 3-18 months). After two cycles of regorafenib, a TBRmean reduction of 13% predicted a significantly longer overall survival (12 vs. 6 months; P=0.034). In contrast, MRI changes evaluated according to RANO criteria (i.e., Stable Disease or Partial Response vs. Progressive Disease) were not predictive (11 vs. 8 months; P=0.644). CONCLUSION Data suggest that amino acid PET using the tracer FET may be clinically valuable for identifying responders to regorafenib early after treatment initiation.

NIMG-06. CHARACTERIZATION OF LONG-TERM METABOLIC CHANGES OF IRRADIATED BRAIN METASTASES USING SERIAL DYNAMIC FET PET IMAGING

Abstract BACKGROUND In the present study, we characterized the long-term metabolic changes of brain metastases irradiated with stereotactic radiosurgery (SRS) by sequential dynamic PET imaging using the radiolabeled amino acid O-(2-[18F]-fluoroethyl)-L-tyrosine (FET). We hypothesized that this approach is of considerable clinical value to diagnose delayed radiation-induced changes. PATIENTS AND METHODS From 2010-2021, we retrospectively identified patients with brain metastases from solid extracranial primary tumors who (i) were treated with SRS with or without concurrent immunotherapy using checkpoint inhibitors, (ii) had equivocal or progressive MRI findings after SRS, and (iii) subsequently underwent at least two additional dynamic FET PET scans during follow-up for long-term evaluation. Mean tumor-to-brain ratios (TBR) and the dynamic FET PET parameter time-to-peak were obtained. Diagnostic performances were calculated using receiver operating characteristic curve analyses. Diagnoses were confirmed histologically or clinicoradiologically. RESULTS We identified 36 patients with 98 FET PET scans (median number, 3; range, 2-6). Concurrent to SRS, 8 patients (22%) were treated with checkpoint inhibitors. Following SRS, suspicious MRI findings occurred after a median time of 11 months (range, 2-64 months). Subsequently, FET PET scans were acquired over a median period of 13 months (range, 5-60 months). The overall median follow-up time was 26 months (range, 8-101 months). Twenty-one patients (58%) had delayed radiation-induced changes. TBRs calculated from the last available FET PET scan showed the highest accuracy (92%) to identify delayed radiation-induced changes (threshold, 1.95; P&amp;lt; 0.001). CONCLUSIONS FET PET has a high diagnostic accuracy for characterizing the long-term changes of irradiated brain metastases.

Prognostic value of pre-irradiation FET PET in patients with not completely resectable IDH-wildtype glioma and minimal or absent contrast enhancement

In glioma patients, complete resection of the contrast-enhancing portion is associated with improved survival, which, however, cannot be achieved in a considerable number of patients. Here, we evaluated the prognostic value of O-(2-[18F]-fluoroethyl)-L-tyrosine (FET) PET in not completely resectable glioma patients with minimal or absent contrast enhancement before temozolomide chemoradiation. Dynamic FET PET scans were performed in 18 newly diagnosed patients with partially resected (n = 8) or biopsied (n = 10) IDH-wildtype astrocytic glioma before initiation of temozolomide chemoradiation. Static and dynamic FET PET parameters, as well as contrast-enhancing volumes on MRI, were calculated. Using receiver operating characteristic analyses, threshold values for which the product of paired values for sensitivity and specificity reached a maximum were obtained. Subsequently, the prognostic values of FET PET parameters and contrast-enhancing volumes on MRI were evaluated using univariate Kaplan–Meier and multivariate Cox regression (including the MTV, age, MGMT promoter methylation, and contrast-enhancing volume) survival analyses for progression-free and overall survival (PFS, OS). On MRI, eight patients had no contrast enhancement; the remaining patients had minimal contrast-enhancing volumes (range, 0.2–5.3 mL). Univariate analyses revealed that smaller pre-irradiation FET PET tumor volumes were significantly correlated with a more favorable PFS (7.9 vs. 4.2 months; threshold, 14.8 mL; P = 0.012) and OS (16.6 vs. 9.0 months; threshold, 23.8 mL; P = 0.002). In contrast, mean tumor-to-brain ratios and time-to-peak values were only associated with a longer PFS (P = 0.048 and P = 0.045, respectively). Furthermore, the pre-irradiation FET PET tumor volume remained significant in multivariate analyses (P = 0.043), indicating an independent predictor for OS. Our results suggest that pre-irradiation FET PET parameters have a prognostic impact in this subgroup of patients.

P14.41 Cost-effectiveness of FET PET for early treatment response assessment in glioma patients following adjuvant temozolomide chemotherapy

Abstract BACKGROUND In light of increasing healthcare costs, higher medical expenses should be justified socio-economically. Therefore, we calculated the effectiveness and cost-effectiveness of PET using the radiolabeled amino acid O-(2-[18F]-fluoroethyl)-L-tyrosine (FET) compared to conventional MRI for early identification of responders to adjuvant temozolomide chemotherapy. A recent study in IDH-wildtype glioma patients suggested that after two cycles, FET-PET parameter changes predicted a significantly longer survival while MRI changes were not significant. MATERIALS AND METHODS To determine the effectiveness and cost-effectiveness of serial FET-PET imaging, we analyzed published clinical data and calculated the associated costs in the context of the German healthcare system.Based on a decision-tree model, FET-PET and MRI’s effectiveness was calculated, i.e., the probability to correctly identify a responder as defined by an overall survival ≥15 months. To determine the cost-effectiveness, the incremental cost-effectiveness ratio (ICER) was calculated, i.e., the cost for each additionally identified responder by FET-PET who would have remained undetected by MRI. The robustness of the results was tested by deterministic and probabilistic (Monte Carlo simulation) sensitivity analyses. RESULTS Compared to MRI, FET-PET increases the rate of correctly identified responders to chemotherapy by 26%; thus, four patients need to be examined by FET-PET to identify one additional responder. Considering the respective cost for serial FET-PET and MRI, the ICER resulted in €4,396.83 for each additional correctly identified responder by FET-PET. The sensitivity analyses confirmed the robustness of the results. CONCLUSION In contrast to conventional MRI, the model suggests that FET PET is cost-effective in terms of ICER values. Concerning the high cost of temozolomide, the integration of FET-PET has the potential to avoid premature chemotherapy discontinuation at a reasonable cost.

OS03.3.A Characterization of long-term metabolic changes of irradiated brain metastases using serial dynamic FET PET imaging

Abstract BACKGROUND In the present study, we characterized the long-term metabolic changes of brain metastases irradiated with stereotactic radiosurgery (SRS) by sequential dynamic PET imaging using the radiolabeled amino acid O-(2-[18F]-fluoroethyl)-L-tyrosine (FET). We hypothesized that this approach is of considerable clinical value to diagnose delayed radiation-induced changes. MATERIAL AND METHODS From 2010–2021, we retrospectively identified patients with brain metastases from solid extracranial primary tumors who (i) were treated with SRS with or without concurrent immunotherapy using checkpoint inhibitors, (ii) had equivocal or progressive MRI findings after SRS, and (iii) subsequently underwent at least two additional dynamic FET PET scans during follow-up for long-term evaluation. Mean tumor-to-brain ratios (TBR) and the dynamic FET PET parameter time-to-peak were obtained. Diagnostic performances were calculated using receiver operating characteristic curve analyses. Diagnoses were confirmed histologically or clinicoradiologically. RESULTS We identified 36 patients with 98 FET PET scans (median number, 3; range, 2–6). Concurrent to SRS, 8 patients (22%) were treated with checkpoint inhibitors. Following SRS, suspicious MRI findings occurred after a median time of 11 months (range, 2–64 months). Subsequently, FET PET scans were acquired over a median period of 13 months (range, 5–60 months). The overall median follow-up time was 26 months (range, 8–101 months). Twenty-one patients (58%) had delayed radiation-induced changes. TBRs calculated from the last available FET PET scan showed the highest accuracy (92%) to identify delayed radiation-induced changes (threshold, 1.95; P&amp;lt;0.001). CONCLUSION FET PET has a high diagnostic accuracy for characterizing the long-term changes of irradiated brain metastases.

P14.79 Differentiation of treatment-related changes from tumor progression following brachytherapy in patients with WHO II and III gliomas using FET PET

Abstract BACKGROUND Following brachytherapy, the differentiation of radiation-induced changes (e.g., radiation necrosis) from actual tumor progression using MRI is challenging. To overcome this diagnostic uncertainty, we evaluated the diagnostic value of O-(2-[18F]-fluoroethyl)-L-tyrosine (FET) PET in glioma patients treated with brachytherapy. MATERIAL AND METHODS From 2006–2019, we retrospectively identified WHO grade II or III glioma patients (i) treated with brachytherapy using Iodine-125 seeds, (ii) equivocal or progressive MRI findings inside the radiation field, and (iii) additional FET PET imaging for diagnostic evaluation. Static FET PET parameters such as maximum and mean tumor-to-brain ratios (TBR) and dynamic FET PET parameters (i.e., time-to-peak, slope) were obtained. Diagnostic performances were calculated using receiver operating characteristic curve analyses and Fisher’s exact test. Diagnoses were confirmed histologically or clinicoradiologically. RESULTS Following brachytherapy, suspect MRI findings occurred after a median time of 33 months (range, 5–111 months). In 10 of 21 patients (WHO grade II, n=5; WHO grade III, n=16), treatment-related changes were diagnosed. The best diagnostic performance for identification of treatment-related changes was obtained using maximum TBRs (threshold &amp;lt;3.20; accuracy, 86%; sensitivity, 100%; specificity, 73%; P=0.007). Mean TBRs reached an accuracy of 76% (threshold &amp;lt;2.05; sensitivity, 89%; specificity, 64%; P=0.010). Dynamic PET parameters did not reach statistically significant results. CONCLUSION Our data suggest that static FET PET parameters add valuable diagnostic information to diagnose radiation-induced changes in glioma patients treated with brachytherapy.