fluoroethyl)-L-tyrosine PET Research Articles

Repeatability of Quantitative 18F-FET PET in Glioblastoma

Purpose: O-(2-[18F]fluoroethyl)-L-tyrosine (FET), a PET radiotracer of amino acid uptake, has shown potential for diagnosis and treatment planning in patients with glioblastoma (GBM). To improve quantitative assessment of FET PET imaging, we evaluated the repeatability of uptake of this tracer in patients with GBM. Methods: Test-retest FET PET imaging was performed on 8 patients with histologically confirmed GBM, who previously underwent surgical resection of the tumour. Data were acquired according to the protocol of a prospective clinical trial validating FET PET as a clinical tool in GBM. SUVmean, SUVmax and SUV98% metrics were extracted for both test and retest images and used to calculate 95% Bland-Altman limits of agreement (LoA) on lesion-level, as well as on volumes of varying sizes. Impact of healthy brain normalization on repeatability of lesion SUV metrics was evaluated. Results: Tumour LoA were [0.72, 1.46] for SUVmean and SUVtotal, [0.79,1.23] for SUVmax, and [0.80,1.18] for SUV98%. Healthy brain LoA were [0.80,1.25] for SUVmean, [0.80,1.25] for SUVmax, and [0.81,1.23] for SUV98%. Voxel-level SUV LoA were [0.76, 1.32] for tumour volumes and [0.80, 1.25] for healthy brain. When sampled over maximum volume, SUV LoA were [0.90,1.12] for tumour and [0.92,1.08] for healthy brain. Normalization of uptake using healthy brain volumes was found to improve repeatability, but not after normalization volume size of about 15 cm3. Conclusions Advances in Knowledge and Implications for Patient Care: Repeatability of FET PET is comparable to existing tracers such as FDG and FLT. Healthy brain uptake is slightly more repeatable than uptake of tumour volumes. Repeatability was found to increase with sampled volume. SUV normalization between scans using healthy brain uptake should be performed using volumes at least 15 cm3 in size to ensure best imaging repeatability.

Evaluation of FET PET Radiomics Feature Repeatability in Glioma Patients.

Simple SummaryInitial studies suggested the additional diagnostic value of amino acid positron emission tomography (PET) radiomics using the tracer O-(2-[18F]fluoroethyl)-L-tyrosine (FET) in brain tumor patient management. However, to ensure the reliable performance of the generated FET PET radiomics models for clinical diagnostics, repeatability of radiomics features is essential. Hence, we assessed the impact of brain tumor volumes and key molecular alterations such as an isocitrate dehydrogenase (IDH) mutation on the repeatability of FET PET radiomics features in 50 newly diagnosed glioma patients. In a test–retest approach based on routinely acquired FET PET scans, we identified 297 repeatable features. The IDH genotype did not affect feature repeatability. Moreover, these robust features were able to differentiate patients with IDH-wildtype glioma from those with an IDH mutation. Our results suggest that robust radiomics features can be obtained from routinely acquired FET PET scans, which are valuable for further standardization of radiomics analyses in neurooncology.Amino acid PET using the tracer O-(2-[18F]fluoroethyl)-L-tyrosine (FET) has attracted considerable interest in neurooncology. Furthermore, initial studies suggested the additional diagnostic value of FET PET radiomics in brain tumor patient management. However, the conclusiveness of radiomics models strongly depends on feature generalizability. We here evaluated the repeatability of feature-based FET PET radiomics. A test–retest analysis based on equivalent but statistically independent subsamples of FET PET images was performed in 50 newly diagnosed and histomolecularly characterized glioma patients. A total of 1,302 radiomics features were calculated from semi-automatically segmented tumor volumes-of-interest (VOIs). Furthermore, to investigate the influence of the spatial resolution of PET on repeatability, spherical VOIs of different sizes were positioned in the tumor and healthy brain tissue. Feature repeatability was assessed by calculating the intraclass correlation coefficient (ICC). To further investigate the influence of the isocitrate dehydrogenase (IDH) genotype on feature repeatability, a hierarchical cluster analysis was performed. For tumor VOIs, 73% of first-order features and 71% of features extracted from the gray level co-occurrence matrix showed high repeatability (ICC 95% confidence interval, 0.91–1.00). In the largest spherical tumor VOIs, 67% of features showed high repeatability, significantly decreasing towards smaller VOIs. The IDH genotype did not affect feature repeatability. Based on 297 repeatable features, two clusters were identified separating patients with IDH-wildtype glioma from those with an IDH mutation. Our results suggest that robust features can be obtained from routinely acquired FET PET scans, which are valuable for further standardization of radiomics analyses in neurooncology.

NIMG-43. IMAGING FINDINGS FOLLOWING REGORAFENIB IN PATIENTS WITH MALIGNANT GLIOMA: FET PET ADDS VALUABLE INFORMATION TO ANATOMICAL MRI

Abstract BACKGROUND Recent phase 2 data showed that the small molecule regorafenib with antiangiogenic properties has promising effectivity in glioblastoma patients at first progression. Following antiangiogenic therapy with bevacizumab, amino acid PET provides valuable additional diagnostic information regarding bevacizumab-related effects on MRI (e.g., pseudoresponse). In contrast, only a little is known about regorafenib. Thus, we evaluated prospectively the value of O-(2-[18F]fluoroethyl)-L-tyrosine (FET) PET for the assessment of regorafenib-related treatment effects. METHODS Twenty-two patients with progressive malignant glioma (median number of relapses, 2; range, 1-4) were included. Up to now, 10 of 22 patients were eligible for data evaluation and underwent regorafenib therapy (median number of cycles, 2; range, 1-5 cycles). FET PET and MRI were performed at baseline and after the second cycle. After the second cycle, MRI was performed every 8 weeks. In case of a suspicious MRI after the second cycle, a FET PET scan was added. MRI changes were evaluated according to the RANO criteria. Maximum tumor-to-brain ratios (TBRmax) were calculated. Pseudoresponse was considered if (i) the follow-up MRI showed an improvement (i.e., at least “partial response” according to RANO criteria) despite subsequent clinical progression, and (ii) an increase of TBRmax>25% occurred. Pseudoresponse was confirmed if (i) the subsequent MRI follow-up showed progression, and/or (ii) the clinical status worsened, or the patient died. RESULTS In 4 of 10 patients, FET PET provided clinically relevant additional information. In two patients, pseudoresponse could be confirmed. Furthermore, in one patient with stable disease according to MRI, increasing TBRmax (+138%) enabled earlier diagnosis of tumor progression (time benefit, 5 weeks). In another patient without signs of MRI response after 2 cycles, decreasing TBRmax (-23%) indicated metabolic response and was associated with a significant clinical improvement. CONCLUSIONS FET PET seems to add valuable diagnostic information for regorafenib therapy monitoring.

NIMG-38. NON-INVASIVE PREDICTION OF MGMT PROMOTER METHYLATION USING COMBINED FET PET/MRI RADIOMICS

Abstract BACKGROUND Recently, the Response Assessment in Neuro-Oncology (RANO) Working Group emphasized the additional diagnostic value of amino acid PET in addition to MRI. However, the number of studies using amino acid PET/MRI radiomics is still low. We investigated the potential of combined O-(2-[18F]fluoroethyl)-L-tyrosine (FET) PET/MRI radiomics for the non-invasive prediction of the O6-methylguanine-DNA methyl-transferase (MGMT) promoter methylation status in glioma patients. METHODS Seventy-one patients with newly diagnosed glioma (predominantly WHO grade III and IV glioma, 82%) underwent a hybrid FET PET/MRI scan. Forty-six patients (65%) had a methylated MGMT promoter. The tumor and tumor subregions were manually segmented on conventional MRI. In total, 199 standardized features were obtained from FET PET, contrast-enhanced T1-weighted, T2-weighted, and fluid attenuated inversion recovery (FLAIR) MRI. After feature extraction and data normalization, patients were randomly assigned to a training and a test dataset for final model evaluation in a ratio of 70/30, with a balanced distribution of the MGMT promoter methylation status. Feature selection was performed by recursive feature elimination using random forest regressors. For the final model generation, the number of features was limited to seven to avoid data overfitting. Different algorithms for model generation were compared, and the model performance in the training data was assessed by 5-fold cross-validation. Finally, the best performing models were applied to the test dataset to evaluate the robustness of the models. RESULTS In the test dataset, the best radiomics signatures obtained from MRI or FET PET alone achieved diagnostic accuracies for the prediction of the MGMT promoter methylation of 64% and 70%, respectively. In contrast, the highest diagnostic accuracy of 83% was obtained by combining FET PET and MRI features. CONCLUSION Combined FET PET/MRI radiomics allows the non-invasive prediction of the MGMT promoter methylation status in patients with gliomas, providing more diagnostic information than either modality alone.

NIMG-26. DIAGNOSIS OF PSEUDOPROGRESSION FOLLOWING RADIOTHERAPY PLUS LOMUSTINE-TEMOZOLOMIDE CHEMOTHERAPY IN NEWLY DIAGNOSED GLIOBLASTOMA PATIENTS USING FET PET

Abstract BACKGROUND The CeTeG/NOA-09 trial demonstrated a significant survival benefit of radiotherapy plus lomustine-temozolomide chemotherapy in glioblastoma patients with methylated O6-methylguanine-DNA-methyltransferase (MGMT) promoter compared to standard temozolomide chemoradiation (1). However, data on pseudoprogression following treatment according to the CeTeG/NOA-09 trial is lacking. Due to the limited specificity of conventional MRI we evaluated the value of O-(2-[18F]fluoroethyl)-L-tyrosine (FET) PET for the differentiation of pseudoprogression from actual tumor progression. METHODS Twenty-one patients with newly diagnosed IDH-wildtype glioblastoma and methylated MGMT promoter with conventional MRI findings suspicious for tumor progression according to RANO criteria (2) after radiotherapy completion were investigated using FET PET. The maximum and mean tumor-to-brain ratios (TBRmax, TBRmean) were calculated. Pseudoprogression was diagnosed neuropathologically or clinicoradiologically (i.e, if (i) a stable clinical course, (ii) stable or improved MRI findings, and (iii) no treatment change occurred within the next six months). Diagnostic performance of FET PET parameters was evaluated using receiver-operating-characteristic (ROC) analyses and Fisher’s exact test. Imaging results were also related to progression-free survival (PFS). RESULTS Pseudoprogression was identified in 9 of 21 patients (43%). In the majority of patients (n=8; 89%), pseudoprogression was diagnosed clinicoradiologically. The median time between radiotherapy completion and pseudoprogression was nine weeks (range, 5-25 weeks). ROC analysis yielded an optimal cutoff value of 1.95 for TBRmean to differentiate between pseudoprogression and tumor progression (sensitivity, 89%; specificity, 75%; accuracy, 81%; area under the curve, 0.72±0.13; P = 0.008). CONCLUSIONS In a considerable number of patients, pseudoprogression may occur following radiotherapy plus off-study lomustine-temozolomide chemotherapy according to the CeTeG/NOA-09 trial. FET PET appears of value for the differentiation of pseudoprogression from tumor progression in this group of patients. Literature: 1. Herrlinger et al., 2019 Lancet; 2. Wen et al., 2010 J Clin Oncol

32. TREATMENT MONITORING OF IMMUNOTHERAPY AND TARGETED THERAPY USING AMINO ACID PET IN PATIENTS WITH BRAIN METASTASES

PURPOSERecently, the RANO group has analyzed the additional diagnostic value of amino acid PET in patients with primary and secondary brain tumors and recommended the use of this imaging technique in addition to conventional MRI. Here, we investigated the value of PET using the radiolabled amino acid O-(2-[18F]fluoroethyl)-L-tyrosine (FET) for treatment monitoring of immune checkpoint inhibition (ICI) or targeted therapy (TT) alone or in combination with radiotherapy in patients with brain metastases (BM) since contrast-enhanced MRI often remains inconclusive.METHODSWe retrospectively identified 40 patients with 107 BM secondary to melanoma (n=29 with 75 BM) or non-small cell lung cancer (n=11 with 32 BM) treated with ICI or TT who had FET PET (n=60 scans) for treatment monitoring from 2015–2019. The majority of patients (n=37; 92.5%) had radiotherapy during the course of disease. In 27 patients, FET PET was used for the differentiation of treatment-related changes from BM relapse following ICI or TT. In 13 patients, FET PET was performed for response assessment to ICI or TT using baseline and follow-up scans (median time between scans, 4.2 months). In all lesions, static and dynamic FET PET parameters were obtained (i.e., mean tumour-to-brain ratios (TBR), time-to-peak values). Diagnostic accuracies of PET parameters were evaluated by receiver-operating-characteristic analyses using the clinical follow-up or neuropathological findings as reference.RESULTSA TBR threshold of 1.95 differentiated BM relapse from treatment-related changes with an accuracy of 85% (P=0.003). Metabolic Responders to ICI or TT on FET PET had a significantly longer stable follow-up (threshold of TBR reduction relative to baseline, ≥10%; accuracy, 82%; P=0.004). Furthermore, at follow-up, time-to-peak values in metabolic responders increased significantly (P=0.019).CONCLUSIONSFET PET may add valuable information for treatment monitoring in BM patients treated with ICI or TT.

Prediction of survival in patients with IDH-wildtype astrocytic gliomas using dynamic O-(2-[18F]-fluoroethyl)-l-tyrosine PET

PurposeIntegrated histomolecular diagnostics of gliomas according to the World Health Organization (WHO) classification of 2016 has refined diagnostic accuracy and prediction of prognosis. This study aimed at exploring the prognostic value of dynamic O-(2-[18F]-fluoroethyl)-l-tyrosine (FET) PET in newly diagnosed, histomolecularly classified astrocytic gliomas of WHO grades III or IV.MethodsBefore initiation of treatment, dynamic FET PET imaging was performed in patients with newly diagnosed glioblastoma (GBM) and anaplastic astrocytoma (AA). Static FET PET parameters such as maximum and mean tumour/brain ratios (TBRmax/mean), the metabolic tumour volume (MTV) as well as the dynamic FET PET parameters time-to-peak (TTP) and slope, were obtained. The predictive ability of FET PET parameters was evaluated concerning the progression-free and overall survival (PFS, OS). Using ROC analyses, threshold values for FET PET parameters were obtained. Subsequently, univariate Kaplan-Meier and multivariate Cox regression survival analyses were performed to assess the predictive power of these parameters for survival.ResultsSixty patients (45 GBM and 15 AA patients) of two university centres were retrospectively identified. Patients with isocitrate dehydrogenase (IDH)-mutant or O6-methylguanine-DNA-methyltransferase (MGMT) promoter-methylated tumours had a significantly longer PFS and OS (both P < 0.001). Furthermore, ROC analysis of IDH-wildtype glioma patients (n = 45) revealed that a TTP > 25 min (AUC, 0.90; sensitivity, 90%; specificity, 87%; P < 0.001) was highly prognostic for longer PFS (13 vs. 7 months; P = 0.005) and OS (29 vs. 12 months; P < 0.001). In contrast, at a lower level of significance, TBRmax, TBRmean, and MTV were only prognostic for longer OS (P = 0.004, P = 0.038, and P = 0.048, respectively). Besides complete resection and a methylated MGMT promoter, TTP remained significant in multivariate survival analysis (all P ≤ 0.02), indicating an independent predictor for OS.ConclusionsOur data suggest that dynamic FET PET allows the identification of patients with longer OS among patients with newly diagnosed IDH-wildtype GBM and AA.

NIMG-46. 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 frequently confronted with equivocal MRI findings (e.g., treatment-related changes, nonmeasurable (speckled) contrast-enhancing lesions, increase of T2/FLAIR signal alterations, pseudoresponse). Especially in Europe, amino acid PET is increasingly being integrated into multidisciplinary neurooncological tumor boards (MNTB) to overcome these diagnostic uncertainties as well as to improve patient management. We here evaluated the correctness of MNTB decisions, in which amino acid PET findings were taken into account. METHODS In a single university center, we retrospectively evaluated 114 MNTB decisions concerning 99 patients with malignant glioma (n=81) (glioblastoma, n=54; anaplastic glioma, n=26; gliosarcoma, n=1) or brain metastases (n=18) secondary to NSCLC, melanoma, breast cancer, or colorectral cancer, presenting with equivocal MRI findings following neurooncological treatment. All patients underwent amino acid PET imaging using O-(2-[18F]-fluoroethyl)-L-tyrosine (FET) as an adjunct for decision-making. Additionally, the patients’ clinical status, pretreatment, and multimodal MRI findings were considered for decision-making. Presence of neoplastic tissue in PET was considered if the mean FET uptake as assessed by tumor-to-brain ratios was &gt;2. The decisions’ diagnostic performance was evaluated by 2x2 contingency tables using the neuropathological results or clinicoradiological follow-up. RESULTS In the majority of MNTB decisions (n=102; 89%), FET PET results were integrated into the decision-making with considerable impact on the clinical management. In particular, 85% of MNTB decisions (n=87) prompted a treatment change (i.e., resection, radiotherapy, chemotherapy, or combinations thereof, as well as palliative therapy), or, in the case of suspected treatment-related changes, the continuation of the initial treatment regimen (15%; n=15). The MNTB decisions were validated using neuropathological data in 38% (n=39) or clinicoradiological information in 62% (n=63) and yielded a diagnostic accuracy of 88% (sensitivity, 89%; specificity, 75%; P=0.008). CONCLUSIONS Our results suggest that the integration of FET PET derived information significantly aids MNTB decisions.

NIMG-05. THE T2-FLAIR MISMATCH SIGN IN IDH-MUTANT ASTROCYTOMAS - IS THERE AN ASSOCIATION WITH FET PET UPTAKE?

Abstract BACKGROUND The purpose of this study was (i) to assess the reproducibility of the previously described T2-FLAIR mismatch sign as a highly specific MR imaging marker in non-enhancing IDH-mutant, 1p/19q non-codeleted lower-grade gliomas (LGG) of the WHO grades II or III, and (ii) its association with the uptake of the radiolabeled amino acid O-(2-[18F]-fluoroethyl)-L-tyrosine (FET) in PET to further metabolically characterize that sign, which is currently poorly understood. METHODS Consecutive MRI and dynamic FET PET scans (n=134) from newly diagnosed and neuropathologically confirmed IDH-mutant LGG (n=65) and IDH-wildtype gliomas as control group (n=69) were evaluated by two independent raters to assess presence/absence of the T2-FLAIR mismatch sign as well as FET uptake. Interrater agreement was assessed using Cohen’s kappa (κ), as well as diagnostic performance (i.e., positive/negative predictive value; PPV, NPV) of the T2-FLAIR mismatch sign to identify IDH-mutant astrocytomas. RESULTS In the LGG group, 13 patients (20%) had a T2-FLAIR mismatch sign, which could be identified with a substantial interrater agreement (κ=0.75). In contrast, that sign was absent in IDH-wildtype gliomas. All 13 cases that were positive for the T2/FLAIR mismatch sign were IDH-mutant, 1p/19q non-codeleted tumors (PPV=100%, NPV=57%). Interestingly, compared to IDH-mutant gliomas without the T2-FLAIR mismatch sign, the sign was significantly (P=0.027; 10 of 13 patients) associated with a negative FET PET scan (i.e., 5 tumors with indifferent FET uptake comparable to the background activity, or FET uptake below background activity (photopenic defect) in 5 tumors). CONCLUSIONS With a robust interrater agreement, our findings are in line with previously reported findings regarding the T2-FLAIR mismatch sign. Additionally, the T2-FLAIR mismatch sign seems to be significantly related with a lack of increased FET uptake in PET, which may help to further characterize patients with that sign. Notwithstanding, the clinical relevance of this imaging constellation warrants further investigation.

O-(2-[18F]-Fluoroethyl)-L-Tyrosine (FET) in Neurooncology: A Review of Experimental Results.

In recent years, PET using radiolabelled amino acids has gained considerable interest as an additional tool besides MRI to improve the diagnosis of cerebral gliomas and brain metastases. A very successful tracer in this field is O-(2-[18F]fluoroethyl)-L-tyrosine (FET) which in recent years has replaced short-lived tracers such as [11C]-methyl-L-methionine in many neuro-oncological centers in Western Europe. FET can be produced with high efficiency and distributed in a satellite concept like 2- [18F]fluoro-2-deoxy-D-glucose. Many clinical studies have demonstrated that FET PET provides important diagnostic information regarding the delineation of cerebral gliomas for therapy planning, an improved differentiation of tumor recurrence from treatment-related changes and sensitive treatment monitoring. In parallel, a considerable number of experimental studies have investigated the uptake mechanisms of FET on the cellular level and the behavior of the tracer in various benign lesions in order to clarify the specificity of FET uptake for tumor tissue. Further studies have explored the effects of treatment related tissue alterations on tracer uptake such as surgery, radiation and drug therapy. Finally, the role of blood-brain barrier integrity for FET uptake which presents an important aspect for PET tracers targeting neoplastic lesions in the brain has been investigated in several studies. Based on a literature research regarding experimental FET studies and corresponding clinical applications this article summarizes the knowledge on the uptake behavior of FET, which has been collected in more than 30 experimental studies during the last two decades and discusses the role of these results in the clinical context.

P14.32 Spatial discrepancies between FET PET and conventional MRI in patients with newly diagnosed glioblastoma

Abstract BACKGROUND In patients with glioblastoma, the tissue showing contrast enhancement (CE) in MRI is usually the target for resection or radiotherapy. However, the solid tumor mass typically extends beyond the area of CE. Amino acid PET can detect tumor parts that show no CE. We systematically investigated tumor volumes delineated by amino acid PET and MRI in newly diagnosed, untreated glioblastoma patients. MATERIAL AND METHODS Preoperatively, 50 patients with subsequently neuropathologically confirmed glioblastoma underwent O-(2-[18F]-fluoroethyl)-L-tyrosine (FET) PET, fluid-attenuated inversion recovery (FLAIR), and CE MRI. Areas of CE were manually delineated. FET PET tumor volumes were segmented using a tumor-to-brain ratio ≥ 1.6. The percentage of overlapping volumes (OV), as well as Dice and Jaccard spatial similarity coefficients (DSC; JSC), were calculated. FLAIR images were evaluated visually. RESULTS In 86% of patients (n = 43), the FET PET tumor volume was significantly larger than the volume of CE (21.5 ± 14.3 mL vs. 9.4 ± 11.3 mL; P &lt; 0.001). Forty patients (80%) showed both an increased uptake of FET and CE. In these 40 patients, the spatial similarity between FET and CE was low (mean DSC, 0.39 ± 0.21; mean JSC, 0.26 ± 0.16). Ten patients (20%) showed no CE, and one of these patients showed no FET uptake. In 10% of patients (n = 5), increased FET uptake was present outside of areas of FLAIR hyperintensity. CONCLUSION Our results show that the metabolically active tumor volume delineated by FET PET is significantly larger than tumor volume delineated by CE. The data strongly suggest that the information derived from FET PET should be integrated into the management of newly diagnosed glioblastoma patients. FUNDING This work was supported by the Wilhelm-Sander Stiftung, Germany

OS9.6 Diagnosis of pseudoprogression using FET PET radiomics

Abstract BACKGROUND Radiomics derived from different imaging modalities is gaining increasing interest in the field of neuro-oncology. Besides MRI, amino acid PET radiomics may also improve the to date challenging, clinically relevant diagnostic problem of differentiating pseudoprogression (PsP) from tumor progression (TP). To this end, we here explored the potential of O-(2-[18F]fluoroethyl)-L-tyrosine (FET) PET radiomics to discriminate between PsP and TP. MATERIAL AND METHODS Thirty-five newly diagnosed IDH-wildtype glioblastoma patients with MRI findings suspicious for TP within 12 weeks after completion of chemoradiation with temozolomide underwent an additional dynamic FET PET scan. FET PET tumor volumes were segmented using a tumor-to-brain ratio (TBR) ≥ 1.6. The static PET parameters TBRmax and TBRmean, as well as the dynamic parameter time-to-peak (TTP), were calculated. For radiomics analysis, the number of datasets for model generation was increased using data augmentation techniques. Subsequently, 70 datasets were available for model generation. Prior to further processing, patients were randomly assigned to a discovery and a validation dataset in a ratio of 70/30, with balanced distribution of PsP and TP diagnoses. Forty-two radiomics features (4 shape-based, 6 first- and 32 second-order features) were obtained using the software LifeX (lifexsoft.org). Afterwards, a z-score transformation was performed for data normalization. For feature selection, recursive feature elimination using random forest regressors was performed. For the final model generation, the number of parameters was limited to three to avoid data overfitting. Different algorithms for model calculation were compared, and the diagnostic accuracy was assessed using leave-one-out cross-validation. Finally, the resulting models were applied to the validation dataset to evaluate model robustness. RESULTS Eighteen patients were diagnosed with TP, and 17 patients had PsP. Diagnoses were based on a neuropathological confirmation or clinicoradiological follow-up (26% and 74%, respectively). The diagnostic accuracy of the best single FET PET parameter was 75% (TBRmax). Combining TBRmax and TTP increased the diagnostic accuracy to 83%. Other combinations of static and dynamic FET PET parameters, however, did not further increase the accuracy. The highest diagnostic accuracy of 92% was achieved by a three-parameter model combining the FET PET parameter TTP with two radiomics features. The model demonstrated its robustness in the validation dataset with a diagnostic accuracy of 86%. CONCLUSION The results suggest that FET PET radiomics improves the diagnostic accuracy for discerning PsP and TP considerably. Given the clinical significance of differentiating PSP and TP, prospective multicenter studies are warranted. FUNDING Wilhelm-Sander Stiftung and the DAAD GERSS Program, Germany

P14.29 Prediction of overall survival in patients with malignant glioma using dynamic O-(2-[18F]-fluoroethyl)-L-tyrosine PET

Abstract BACKGROUND Characterization of gliomas according to the revised World Health Organization (WHO) classification of 2016 has gained major importance regarding prognostication. The present study aimed at exploring the prognostic value of dynamic O-(2-[18F]-fluoroethyl)-L-tyrosine (FET) PET in newly diagnosed and molecularly defined astrocytic high-grade glioma (HGG) of the WHO grades III or IV. MATERIAL AND METHODS Before initiation of treatment, dynamic FET PET imaging was performed in patients with newly diagnosed glioblastoma (GBM) and anaplastic astrocytoma (AA). Static FET PET parameters such as maximum and mean tumor/brain ratios (TBRmax/mean), as well as the dynamic FET PET parameters time-to-peak (TTP) and slope, were obtained. The predictive ability of FET PET parameters was evaluated with regard to the overall survival (OS). Using ROC analyses, threshold values for FET PET parameters were obtained. Subsequently, univariate Kaplan-Meier and multivariate Cox regression survival analyses were performed to assess their predictive power for OS. RESULTS Sixty patients (45 GBM, 15 AA) of two university centers were retrospectively identified. Patients with a methylated MGMT promoter as well as with an IDH mutation had a significantly longer OS (both P&lt;0.001). Furthermore, ROC analysis revealed in IDH-wildtype HGG (n=45) that a TTP&gt;25 minutes (AUC, 0.90; sensitivity, 90%; specificity, 87%; P&lt;0.001) was highly prognostic for a longer OS (29 vs. 12 months; P&lt;0.001). Besides a complete resection and a methylated MGMT promoter, TTP remained significant in the multivariate survival analysis (P=0.002, P=0.016, and P=0.003, respectively), indicating an independent predictor for OS. In contrast, both TBRmax and TBRmean were not prognostic (AUC, 0.37 and 0.32, respectively). CONCLUSION Data suggest that within the subgroup of patients with newly diagnosed and untreated IDH-wildtype GBM and AA, dynamic FET PET additionally allows the identification of patients with an improved OS.

P14.17 Differentiation of treatment-related changes from tumor progression: A direct comparison between dynamic FET PET and ADC values obtained from DWI MRI

Abstract BACKGROUND Following brain cancer treatment, the capacity of anatomical MRI to differentiate neoplastic tissue from treatment-related changes (e.g., pseudoprogression) is limited. This study compared apparent diffusion coefficients (ADC) obtained by diffusion-weighted MRI (DWI) with static and dynamic parameters of O-(2-[18F]fluoroethyl)-L-tyrosine (FET) PET for the differentiation of treatment-related changes from tumor progression. MATERIAL AND METHODS Forty-eight pretreated high-grade glioma patients with anatomical MRI findings suspicious for progression (median time elapsed since last treatment, 16 weeks) were investigated using DWI and dynamic FET PET. Maximum and mean tumor-to-brain ratios (TBRmax, TBRmean) as well as dynamic parameters (time-to-peak and slope values) of FET uptake were calculated. For mean ADC calculation, regions-of-interest analyses were performed on ADC maps calculated from DWI co-registered with the contrast-enhanced MR image. Diagnoses were confirmed neuropathologically (21%) or clinicoradiologically. Diagnostic performance was evaluated using receiver-operating-characteristic analyses or Fisher’s exact test for a combinational approach. RESULTS Ten of 48 patients had treatment-related changes (21%). The diagnostic performance of FET PET was significantly higher (threshold for both TBRmax and TBRmean, 1.95; accuracy, 83%; AUC, 0.89±0.05; P&lt;0.001) than that of ADC values (threshold ADC, 1.09x10-3 mm2/s; accuracy, 69%; AUC, 0.73±0.09; P=0.13). The addition of static FET PET parameters to ADC values increased the latter’s accuracy to 89%. The highest accuracy was achieved by combining static and dynamic FET PET parameters (93%). CONCLUSION Data suggest that static and dynamic FET PET provide valuable information concerning the differentiation of early treatment-related changes from tumor progression and outperform ADC measurement for this highly relevant clinical question.

P14.18 Prognostic value of serial dynamic O-(2-[18F]-fluoroethyl)-L-tyrosine PET in patients with non-resectable malignant glioma undergoing chemoradiation

Abstract BACKGROUND A complete resection of high-grade gliomas (HGG) is associated with improved survival, which, however, cannot be achieved in a considerable number of patients. We here evaluated the prognostic value of serial O-(2-[18F]-fluoroethyl)-L-tyrosine (FET) PET in patients with newly diagnosed, non-resectable astrocytic HGG undergoing chemoradiation with temozolomide. MATERIAL AND METHODS Serial dynamic FET PET scans were performed in 18 newly diagnosed patients with molecularly defined, non-resectable HGG at baseline and after chemoradiation (8±3 weeks). Both static (tumor/brain ratios, FET tumor volumes) and dynamic FET PET parameters (time-to-peak, slope), as well as MRI changes according to RANO criteria at first follow-up after chemoradiation (8±3 weeks), were obtained. The predictive ability of FET PET parameters and RANO criteria was evaluated with regard to the progression-free survival (PFS). Using ROC analyses, threshold values for FET PET parameters were obtained. Subsequently, univariate and multivariate survival analyses were performed to assess their predictive power for PFS. RESULTS ROC analysis revealed that the mean tumor/brain ratio (AUC, 0.84), FET tumor volume (AUC, 0.89), and slope (AUC, 0.72) at baseline were predictive for a prolonged PFS (9.3 vs. 5.7 months, P=0.05; 10.3 vs. 5.9 months; P=0.03; 13.5 vs. 6.2 months, P=0.02, respectively). Furthermore, FET tumor volume and slope remained significant in the multivariate survival analysis (both P&lt;0.05). In contrast, relative changes of static or dynamic FET PET parameters at follow-up and MRI changes according to RANO criteria were not significant in this albeit small series of patients. CONCLUSION Results suggest that before initiation of chemoradiation FET PET parameters at baseline can be used to predict PFS in patients with non-resectable HGG.

MLTI-17. DIFFERENTIATION OF RADIATION INJURY FROM RECURRENT BRAIN METASTASIS USING COMBINED FET PET/MRI RADIOMICS

BACKGROUND: The aim of this study was to investigate the potential of combined radiomics textural feature analysis of contrast-enhanced MRI (CE MRI) and static O-(2-[18F]fluoroethyl)-L-tyrosine(FET) PET for the differentiation of recurrent brain metastasis from radiation injury. PATIENTS AND METHODS: Fifty-two patients with newly diagnosed or progressive contrast-enhancing brain lesions on MRI after radiotherapy (predominantly radiosurgery, 84% of patients) of brain metastases were additionally investigated using FET PET. Based on histology (n=19) or clinicoradiological follow-up (n=33), local recurrent brain metastases were diagnosed in 21 patients (40%) and radiation injury in 31 patients (60%). Forty-two features (shape-based, first and second order features) were calculated on both unfiltered and filtered CE MRI and summed FET PET images (20–40 min p.i). After feature selection, logistic regression models using a maximum of five features to avoid overfitting were calculated for each imaging modality separately and for the combined FET PET/MRI features. The resulting models were validated using cross-validation. Diagnostic accuracies were calculated for each imaging modality separately as well as for the combined model. RESULTS: For differentiation between radiation injury and brain metastasis recurrence, textural features extracted from CE MRI had a diagnostic accuracy of 81%. FET PET textural features revealed a slightly higher diagnostic accuracy of 83%. However, the highest diagnostic accuracy was obtained when combining CE MRI and FET PET features (accuracy, 89%). CONCLUSION: Our findings suggest that combined FET PET/MRI radiomics using textural feature analysis offers a great potential to contribute significantly to the management of patients with brain metastases. SUPPORT: This work was supported by the Wilhelm-Sander Stiftung, Germany

Treatment monitoring of immunotherapy and targeted therapy using FET PET in patients with melanoma and lung cancer brain metastases: Initial experiences.

e13525 Background: Due to the lack of specificity of contrast-enhanced (CE) MRI, the differentiation of progression from pseudoprogression (PsP) following immunotherapy using checkpoint inhibitors (IT) or targeted therapy (TT) may be challenging, especially when IT or TT is applied in combination with radiotherapy (RT). Similarly, for response assessment of RT plus IT or targeted therapy (TT), the use of CE MRI alone may also be difficult. For problem solving, the integration of advanced imaging methods may add valuable information. Here, we evaluated the value of amino acid PET using O-(2-[18F]fluoroethyl)-L-tyrosine (FET) in comparison to CE MRI for these important clinical situations in patients with brain metastases (BM) secondary to malignant melanoma (MM) and non-small cell lung cancer (NSCLC). Methods: From 2015-2018, we retrospectively identified 31 patients with 74 BM secondary to MM (n = 20 with 42 BM) and NSCLC (n = 11 with 32 BM) who underwent 52 FET PET scans during the course of disease. All patients had RT prior to IT or TT initiation (61%) or RT concurrent to IT or TT (39%). In 13 patients, FET PET was performed for treatment response assessment of IT or TT using baseline and follow-up scans (median time between scans, 4.2 months). In the remaining 18 patients, FET PET was used for the differentiation of progression from PsP related to RT plus IT or TT. In all BM, metabolic activity on FET PET was evaluated by calculation of tumor/brain ratios. FET PET imaging findings were compared to CE MRI and correlated to the clinical follow-up or neuropathological findings after neuroimaging. Results: In 4 of 13 patients (31%), FET PET provided additional information for treatment response evaluation beyond the information provided by CE MRI alone. Furthermore, responding patients on FET PET had a median stable clinical follow-up of 10 months. In 10 of 18 patients (56%) with CE MRI findings suggesting progression, FET PET detected PsP. In 9 of these 10 patients, PsP was confirmed by a median stable clinical follow-up of 11 months. Conclusions: FET PET may add valuable information for treatment monitoring in individual BM patients undergoing RT in combination with IT or TT.

Photopenic defects on O-(2-[18F]-fluoroethyl)-L-tyrosine PET: clinical relevance in glioma patients.

O-(2-[18F]-fluoroethyl)-L-tyrosine (FET) PET has a sensitivity of more than 90% to detect gliomas. In the remaining small fraction of gliomas without increased tracer uptake, some tumors even show photopenic defects whose clinical significance is unclear. Glioma patients with a negative FET PET scan prior to neuropathological confirmation were identified retrospectively. Gliomas were rated visually as (i) having indifferent FET uptake or (ii) photopenic, if FET uptake was below background activity. FET uptake in the area of signal hyperintensity on the T2/fluid attenuated inversion recovery-weighted MRI was evaluated by mean standardized uptake value (SUV) and mean tumor-to-brain ratio (TBR). The progression-free survival (PFS) of photopenic gliomas was compared with that of gliomas with indifferent FET uptake. Of 100 FET-negative gliomas, 40 cases with photopenic defects were identified. Fifteen of these 40 cases (38%) had World Health Organization (WHO) grades III and IV gliomas. FET uptake in photopenic gliomas was significantly decreased compared with both the healthy-appearing brain tissue (SUV, 0.89 ± 0.26 vs 1.08 ± 0.23; P < 0.001) and gliomas with indifferent FET uptake (TBR, 0.82 ± 0.09 vs 0.96 ± 0.13; P < 0.001). Irrespective of the applied treatment, isocitrate dehydrogenase (IDH)-mutated WHO grade II diffuse astrocytoma patients with indifferent FET uptake (n = 25) had a significantly longer PFS than patients with IDH-mutated diffuse astrocytomas (WHO grade II) with photopenic defects (n = 11) (51 vs 24 mo; P = 0.027). The multivariate survival analysis indicated that photopenic defects predict an unfavorable PFS (P = 0.009). Photopenic gliomas in negative FET PET scans should be managed more actively, as they seem to have a higher risk of harboring a higher-grade glioma and an unfavorable outcome.

Predicting IDH genotype in gliomas using FET PET radiomics

Mutations in the isocitrate dehydrogenase (IDH mut) gene have gained paramount importance for the prognosis of glioma patients. To date, reliable techniques for a preoperative evaluation of IDH genotype remain scarce. Therefore, we investigated the potential of O-(2-[18F]fluoroethyl)-L-tyrosine (FET) PET radiomics using textural features combined with static and dynamic parameters of FET uptake for noninvasive prediction of IDH genotype. Prior to surgery, 84 patients with newly diagnosed and untreated gliomas underwent FET PET using a standard scanner (15 of 56 patients with IDH mut) or a dedicated high-resolution hybrid PET/MR scanner (11 of 28 patients with IDH mut). Static, dynamic and textural parameters of FET uptake in the tumor area were evaluated. Diagnostic accuracy of the parameters was evaluated using the neuropathological result as reference. Additionally, FET PET and textural parameters were combined to further increase the diagnostic accuracy. The resulting models were validated using cross-validation. Independent of scanner type, the combination of standard PET parameters with textural features increased significantly diagnostic accuracy. The highest diagnostic accuracy of 93% for prediction of IDH genotype was achieved with the hybrid PET/MR scanner. Our findings suggest that the combination of conventional FET PET parameters with textural features provides important diagnostic information for the non-invasive prediction of the IDH genotype.

The diagnostic accuracy of detecting malignant transformation of low-grade glioma using O-(2-[18F]fluoroethyl)-l-tyrosine positron emission tomography: a retrospective study.

The diagnostic accuracy of O-(2-[18F]fluoroethyl)-l-tyrosine (FET) PET scanning in detecting the malignant transformation of low-grade gliomas (LGGs) is controversial. In this study, the authors retrospectively assessed the diagnostic potential of FET PET in patients with MRI-suspected malignant progression of LGGs that had previously been treated and the relationship between FET uptake and MRI and molecular biomarkers. Forty-two patients who had previously undergone surgical or multimodal treatment for a histologically verified LGG were referred for FET PET assessment because of clinical signs and/or MRI findings suggestive of tumor progression. Maximal and mean tumor-to-brain ratios (TBRmax and TBRmean, respectively) on FET PET as well as kinetic FET PET parameters (time to peak [TTP] and time-activity curve [TAC]) were determined. Final diagnoses were confirmed histologically. The diagnostic accuracy of FET parameters, separately and combined, for the detection of malignant progression was evaluated using receiver operating characteristic (ROC) curve analysis. Possible predictors that might influence the diagnostic accuracy of FET PET were assessed using multiple linear regression analysis. Spearman’s rank correlation r method was applied to determine the correlation between TBRmax and TAC, and molecular biomarkers from tumor tissues. A total of 47 FET PET scans were obtained and showed no significant association between FET parameters and contrast enhancement on MRI. ROC curve analyses overall were unable to demonstrate any significant differentiation between nontransformed LGGs and LGGs that had transformed to high-grade gliomas when evaluating FET parameters separately or combined. After excluding the oligodendroglial subgroup, a significant difference was observed between nontransformed and transformed LGGs when combining FET parameters (i.e., TBRmax > 1.6, TAC describing a plateau or decreasing pattern, and TTP < 25 minutes), with the best result yielded by a combined analysis of TBRmax > 1.6 and TAC with a plateau or decreasing pattern (sensitivity 75% and specificity 83%, p = 0.003). The difference was even greater when patients who had previously undergone oncological treatment were also excluded (sensitivity 93% and specificity 100%, p = 0.001). Multiple linear regression analysis revealed that the presence of an oligodendroglial component (p = 0.029), previous oncological treatment (p = 0.039), and the combined FET parameters (p = 0.027) were significant confounding factors in the detection of malignant progression. TBRmax was positively correlated with increasing cell density (p = 0.040) and inversely correlated with IDH1 mutation (p = 0.006). A single FET PET scan obtained at the time of radiological and/or clinical progression seems to be of limited value in distinguishing transformed from nontransformed LGGs, especially if knowledge of the primary tumor histopathology is not known. Therefore, FET PET imaging alone is not adequate to replace histological confirmation, but it may provide valuable information on the location and delineation of active tumor tissue, as well as an assessment of tumor biology in a subgroup of LGGs.