Diagnostic Accuracy of MR Spectroscopic Imaging and 18F-FET PET for Identifying Glioma: A Biopsy-Controlled Hybrid PET/MRI Study.

Contrast-enhanced MRI is the method of choice for brain tumor diagnostics, despite its low specificity for tumor tissue. This study compared the contribution of MR spectroscopic imaging (MRSI) and amino acid PET to improve the detection of tumor tissue. Methods: In 30 untreated patients with suspected glioma, O-(2-[18F]fluoroethyl)-l-tyrosine (18F-FET) PET; 3-T MRSI with a short echo time; and fluid-attenuated inversion recovery, T2-weighted, and contrast-enhanced T1-weighted MRI were performed for stereotactic biopsy planning. Serial samples were taken along the needle trajectory, and their masks were projected to the preoperative imaging data. Each sample was individually evaluated neuropathologically. 18F-FET uptake and the MRSI signals choline (Cho), N-acetyl-aspartate (NAA), creatine, myoinositol, and derived ratios were evaluated for each sample and classified using logistic regression. The diagnostic accuracy was evaluated by receiver operating characteristic analysis. Results: On the basis of the neuropathologic evaluation of tissue from 88 stereotactic biopsies, supplemented with 18F-FET PET and MRSI metrics from 20 areas on the healthy-appearing contralateral hemisphere to balance the glioma/nonglioma groups, 18F-FET PET identified glioma with the highest accuracy (area under the receiver operating characteristic curve, 0.89; 95% CI, 0.81-0.93; threshold, 1.4 × background uptake). Among the MR spectroscopic metabolites, Cho/NAA normalized to normal brain tissue showed the highest diagnostic accuracy (area under the receiver operating characteristic curve, 0.81; 95% CI, 0.71-0.88; threshold, 2.2). The combination of 18F-FET PET and normalized Cho/NAA did not improve the diagnostic performance. Conclusion: MRI-based delineation of gliomas should preferably be supplemented by 18F-FET PET.

Automated Brain Tumor Detection and Segmentation for Treatment Response Assessment Using Amino Acid PET.

Evaluation of metabolic tumor volume (MTV) changes using amino acid PET has become an important tool for response assessment in brain tumor patients. MTV is usually determined by manual or semiautomatic delineation, which is laborious and may be prone to intra- and interobserver variability. The goal of our study was to develop a method for automated MTV segmentation and to evaluate its performance for response assessment in patients with gliomas. Methods: In total, 699 amino acid PET scans using the tracer O-(2-[18F]fluoroethyl)-l-tyrosine (18F-FET) from 555 brain tumor patients at initial diagnosis or during follow-up were retrospectively evaluated (mainly glioma patients, 76%). 18F-FET PET MTVs were segmented semiautomatically by experienced readers. An artificial neural network (no new U-Net) was configured on 476 scans from 399 patients, and the network performance was evaluated on a test dataset including 223 scans from 156 patients. Surface and volumetric Dice similarity coefficients (DSCs) were used to evaluate segmentation quality. Finally, the network was applied to a recently published 18F-FET PET study on response assessment in glioblastoma patients treated with adjuvant temozolomide chemotherapy for a fully automated response assessment in comparison to an experienced physician. Results: In the test dataset, 92% of lesions with increased uptake (n = 189) and 85% of lesions with iso- or hypometabolic uptake (n = 33) were correctly identified (F1 score, 92%). Single lesions with a contiguous uptake had the highest DSC, followed by lesions with heterogeneous, noncontiguous uptake and multifocal lesions (surface DSC: 0.96, 0.93, and 0.81 respectively; volume DSC: 0.83, 0.77, and 0.67, respectively). Change in MTV, as detected by the automated segmentation, was a significant determinant of disease-free and overall survival, in agreement with the physician's assessment. Conclusion: Our deep learning-based 18F-FET PET segmentation allows reliable, robust, and fully automated evaluation of MTV in brain tumor patients and demonstrates clinical value for automated response assessment.

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

BACKGROUND: 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. 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 (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 ≥6 months and OS of ≥12 months. 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. RESULTS: After treatment initiation, the median follow-up time was 11 months (range, 3-71 months). 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). CONCLUSIONS: Data suggest that FET PET provides complementary information to RANO criteria for response evaluation of lomustine-based chemotherapy early after treatment initiation.

Cost Effectiveness of 18F-FET PET for Early Treatment Response Assessment in Glioma Patients After Adjuvant Temozolomide Chemotherapy.

In light of increasing health-care costs, higher medical expenses should be justified socioeconomically. Therefore, we calculated the effectiveness and cost effectiveness of PET using the radiolabeled amino acid O-(2-18F-fluoroethyl)-l-tyrosine (18F-FET) compared with conventional MRI for early identification of responders to adjuvant temozolomide chemotherapy. A recently published study in isocitrate dehydrogenase wild-type glioma patients suggested that 18F-FET PET parameter changes predicted a significantly longer survival already after 2 cycles whereas MRI changes were not significant. Methods: To determine the effectiveness and cost effectiveness of serial 18F-FET PET imaging, we analyzed published clinical data and calculated the associated costs from the perspective of the German Statutory Health Insurance system. Based on a decision-tree model, the effectiveness of 18F-FET PET and MRI was calculated-that is, the probability to correctly identify a responder as defined by an overall survival of at least 15 mo. To determine the cost effectiveness, the incremental cost effectiveness ratio (ICER) was calculated-that is, the cost for each additionally identified responder by 18F-FET PET who would have remained undetected by MRI. The robustness of the results was tested by deterministic and probabilistic Monte Carlo sensitivity analyses. Results: Compared with MRI, 18F-FET PET increased the rate of correctly identified responders to chemotherapy by 26%; thus, 4 patients needed to be examined by 18F-FET PET to identify 1 additional responder. Considering the respective costs for serial 18F-FET PET and MRI, the ICER resulted in €4,396.83 for each additional correctly identified responder by 18F-FET PET. Sensitivity analyses confirmed the robustness of the results. Conclusion: In contrast to conventional MRI, the model suggests that 18F-FET PET is cost-effective in terms of ICER values. Considering the high cost of temozolomide, the integration of 18F-FET PET has the potential to avoid premature chemotherapy discontinuation at reasonable cost.

18F-FET-PET-guided gross total resection improves overall survival in patients with WHO grade III/IV glioma: moving towards a multimodal imaging-guided resection.

PURPOSE: PET using radiolabeled amino acid [18F]-fluoro-ethyl-L-tyrosine (FET-PET) is a well-established imaging modality for glioma diagnostics. The biological tumor volume (BTV) as depicted by FET-PET often differs in volume and location from tumor volume of contrast enhancement (CE) in MRI. Our aim was to investigate whether a gross total resection of BTVs defined as < 1 cm3 of residual BTV (PET GTR) correlates with better oncological outcome. METHODS: We retrospectively analyzed imaging and survival data from patients with primary and recurrent WHO grade III or IV gliomas who underwent FET-PET before surgical resection. Tumor overlap between FET-PET and CE was evaluated. Completeness of FET-PET resection (PET GTR) was calculated after superimposition and semi-automated segmentation of pre-operative FET-PET and postoperative MRI imaging. Survival analysis was performed using the Kaplan-Meier method and the log-rank test. RESULTS: From 30 included patients, PET GTR was achieved in 20 patients. Patients with PET GTR showed improved median OS with 19.3 compared to 13.7 months for patients with residual FET uptake (p = 0.007; HR 0.3; 95% CI 0.12-0.76). This finding remained as independent prognostic factor after performing multivariate analysis (HR 0.19, 95% CI 0.06-0.62, p = 0.006). Other survival influencing factors such as age, IDH-mutation, MGMT promotor status, and adjuvant treatment modalities were equally distributed between both groups. CONCLUSION: Our results suggest that PET GTR improves the OS in patients with WHO grade III or IV gliomas. A multimodal imaging approach including FET-PET for surgical planning in newly diagnosed and recurrent tumors may improve the oncological outcome in glioma patients.

Joint EANM/EANO/RANO practice guidelines/SNMMI procedure standards for imaging of gliomas using PET with radiolabelled amino acids and [18F]FDG: version 1.0.

These joint practice guidelines, or procedure standards, were developed collaboratively by the European Association of Nuclear Medicine (EANM), the Society of Nuclear Medicine and Molecular Imaging (SNMMI), the European Association of Neurooncology (EANO), and the working group for Response Assessment in Neurooncology with PET (PET-RANO). Brain PET imaging is being increasingly used to supplement MRI in the clinical management of glioma. The aim of these standards/guidelines is to assist nuclear medicine practitioners in recommending, performing, interpreting and reporting the results of brain PET imaging in patients with glioma to achieve a high-quality imaging standard for PET using FDG and the radiolabelled amino acids MET, FET and FDOPA. This will help promote the appropriate use of PET imaging and contribute to evidence-based medicine that may improve the diagnostic impact of this technique in neurooncological practice. The present document replaces a former version of the guidelines published in 2006 (Vander Borght et al. Eur J Nucl Med Mol Imaging. 33:1374-80, 2006), and supplements a recent evidence-based recommendation by the PET-RANO working group and EANO on the clinical use of PET imaging in patients with glioma (Albert et al. Neuro Oncol. 18:1199-208, 2016). The information provided should be taken in the context of local conditions and regulations.

Early treatment response evaluation using FET PET compared to MRI in glioblastoma patients at first progression treated with bevacizumab plus lomustine.

BACKGROUND: The goal of this prospective study was to compare the value of both conventional MRI and O-(2-18F-fluoroethyl)-L-tyrosine (FET) PET for response evaluation in glioblastoma patients treated with bevacizumab plus lomustine (BEV/LOM) at first progression. METHODS: After chemoradiation with concomitant and adjuvant temozolomide, 21 IDH wild-type glioblastoma patients at first progression (age range, 33-75 years; MGMT promoter unmethylated, 81%) were treated with BEV/LOM. Contrast-enhanced MRI and FET-PET scans were performed at baseline and after 8-10 weeks. We obtained FET metabolic tumor volumes (MTV) and tumor/brain ratios. Threshold values of FET-PET parameters for treatment response were established by ROC analyses using the post-progression overall survival (OS) ≤/>9 months as the reference. MRI response assessment was based on RANO criteria. The predictive ability of FET-PET thresholds and MRI changes on early response assessment was evaluated subsequently concerning OS using uni- and multivariate survival estimates. RESULTS: Early treatment response as assessed by RANO criteria was not predictive for an OS>9 months (P = 0.203), whereas relative reductions of all FET-PET parameters significantly predicted an OS>9 months (P < 0.05). The absolute MTV at follow-up enabled the most significant OS prediction (sensitivity, 85%; specificity, 88%; P = 0.001). Patients with an absolute MTV below 5 ml at follow-up survived significantly longer (12 vs. 6 months, P < 0.001), whereas early responders defined by RANO criteria lived only insignificantly longer (9 vs. 6 months; P = 0.072). The absolute MTV at follow-up remained significant in the multivariate survival analysis (P = 0.006). CONCLUSIONS: FET-PET appears to be useful for identifying responders to BEV/LOM early after treatment initiation.

The Treatment of Gliomas in Adulthood.

BACKGROUND: Gliomas are the most common intrinsic tumors of the brain, with an incidence of 6 per 100 000 persons per year. Recent years have seen marked changes in the diagnosis and treatment of gliomas, with molecular parameters now being an integral part of the diagnostic evaluation. METHODS: This review is based on pertinent articles retrieved by a selective search in PubMed, with special attention to the new WHO glioma classification. RESULTS: The classification of gliomas on the basis of additional molecular parameters enables more accurate prognostication and serves as a basis for therapeutic decision-making and treatment according to precisely specified algorithms. PET scanning with 18F-fluoroethyl tyrosine and 11C-methionine for the measurement of metabolic activity in gliomas has further refined the diagnostic evaluation. The median overall survival of patients with glioblastoma who have undergone resection of all tumor tissue with a disrupted blood-brain barrier (i.e., all contrast-enhancing tumor tissue) has been prolonged to up to 20 months. The 5-year survival of patients with WHO grade II gliomas is now as high as 97% after near-total resection. The surgical resection of all contrast-enhancing tumor tissue and subsequent radiotherapy and chemotherapy remain the key elements of treatment. New surgical strategies and new methods of planning radiotherapy have made these techniques safer and more effective. The percutaneous application of tumor-treating fields is a new therapeutic option that has gained a degree of acceptance. Accompanying measures such as psycho-oncology and palliative care are very important for patients and should be considered mandatory. CONCLUSION: The consistent application of the existing multimodal treatment options for glioma has led in recent years to improved survival. Areas of important current and future scientific activity include immunotherapy and targeted and combined chemotherapy, as well as altered neurocognition, modern approaches to palliative care, and complementary therapies.

Influence of Bevacizumab on Blood-Brain Barrier Permeability and O-(2-18F-Fluoroethyl)-l-Tyrosine Uptake in Rat Gliomas.

Restoration of the blood-brain barrier (BBB) after antiangiogenic therapy of gliomas with bevacizumab may result in a decrease in contrast enhancement on MRI despite tumor progression. This so-called pseudoresponse is difficult to differentiate from a true tumor response with conventional MRI. Initial patient studies have indicated that PET using O-(2-18F-fluoroethyl)-l-tyrosine (18F-FET) may be helpful for solving this diagnostic problem. This study was performed to investigate the effects of bevacizumab on BBB permeability and 18F-FET uptake in a human xenograft model. Methods: Human U87 glioblastoma cells were implanted into the striatum of immunodeficient RNU rats. 18F-FET PET scans and ex vivo autoradiography were performed in animals receiving a single high dose of bevacizumab (45 mg/kg 2 d before PET; n = 9) or in animals receiving 2 lower doses (10 mg/kg 9 and 2 d before PET; n = 10) to evaluate short-term and long-term effects on the BBB, respectively, and in control animals without bevacizumab treatment (n = 8). Time-activity curves, slope, and tumor-to-brain ratios of 18F-FET uptake (18-61 min after injection) were evaluated using a volume-of-interest analysis. After PET scanning, Evans blue dye (EBD) was injected into animals, and cryosections of the brains were evaluated by autoradiography, by histology, and for EBD fluorescence to assess BBB permeability. Results: Compared with the control, short-term bevacizumab therapy resulted in a trend toward BBB restoration (P = 0.055) and long-term therapy resulted in a significant decrease (P = 0.004) in BBB permeability, as assessed by EBD fluorescence. In contrast, no significant differences in tumor-to-brain ratios or slope of 18F-FET uptake were observed in PET and autoradiography (P > 0.05). Conclusion:8F-FET uptake in glioblastomas seems to be largely independent of BBB permeability and reflects the viability of tumor tissue during antiangiogenic therapy more reliably than contrast-enhanced MRI.

Low-dose rate stereotactic iodine-125 brachytherapy for the treatment of inoperable primary and recurrent glioblastoma: single-center experience with 201 cases.

Treatment options for inoperable glioblastoma are limited. Low-dose-rate stereotactic iodine-125 brachytherapy (SBT) has been reported as an effective and low-risk treatment option for circumscribed low-grade gliomas and brain metastases. The present study evaluates this treatment approach for patients with inoperable glioblastoma. Between 1990 and 2012, 201 patients with histologically proven glioblastoma were treated with SBT (iodine-125 seeds; median cumulative surface dose, 60 Gy; median dose-rate, 6 cGy/h; median gross-tumor-volume, 17 ml) either as primary treatment (n = 103) or at recurrence (n = 98). In addition to SBT, 90.3 % of patients in the primary treatment group received external boost radiotherapy (median dose, 25.2 Gy). Adjuvant chemotherapy was added for 30.8 % of patients following SBT and consisted of temozolomide for the majority of cases (88.7 %). Procedure-related complications, clinical outcome, progression-free and overall survival (PFS, OS) were evaluated. Median follow-up was 9.8 months. The procedure-related mortality was zero. During follow-up, transient and permanent procedure-related morbidity was observed in 7.5 and 2.0 %, respectively. Calculated from the time of SBT, median OS and PFS rates were 10.5 and 6.2 months, with no significant differences among primary and recurrent tumors (11.1 vs.10.4 months for OS and 6.2 vs. 5.9 months for PFS). For OS, multivariate analysis revealed Karnofsky performance score, age, and adjuvant chemotherapy as independent prognostic factors (all p < 0.01). Low-dose-rate SBT is a relatively safe and potentially effective local treatment option for patients with circumscribed inoperable glioblastoma initially or at recurrence. It deserves prospective validation since it may improve the outcome for a subset of patients with inoperable GBM.

Detection of remote neuronal reactions in the Thalamus and Hippocampus induced by rat glioma using the PET tracer cis-4-[¹8F]fluoro-D-proline.

After cerebral ischemia or trauma, secondary neurodegeneration may occur in brain regions remote from the lesion. Little is known about the capacity of cerebral gliomas to induce secondary neurodegeneration. A previous study showed that cis-4-[(18)F]fluoro-D-proline (D-cis-[(18)F]FPro) detects secondary reactions of thalamic nuclei after cortical infarction with high sensitivity. Here we investigated the potential of D-cis-[(18)F]FPro to detect neuronal reactions in remote brain areas in the F98 rat glioma model using ex vivo autoradiography. Although the tumor tissue of F98 gliomas showed no significant D-cis-[(18)F]FPro uptake, we observed prominent tracer uptake in 7 of 10 animals in the nuclei of the ipsilateral thalamus, which varied with the specific connectivity with the cortical areas affected by the tumor. In addition, strong D-cis-[(18)F]FPro accumulation was noted in the hippocampal area CA1 in two animals with ipsilateral F98 gliomas involving hippocampal subarea CA3 rostral to that area. Furthermore, focal D-cis-[(18)F]FPro uptake was present in the necrotic center of the tumors. Cis-4-[(18)F]fluoro-D-proline uptake was accompanied by microglial activation in the thalamus, in the hippocampus, and in the necrotic center of the tumors. The data suggest that brain tumors induce secondary neuronal reactions in remote brain areas, which may be detected by positron emission tomography (PET) using D-cis-[(18)F]FPro.

11C-Methionine positron emission tomographic imaging of biologic activity of a recurrent glioblastoma treated with stereotaxy-guided laser-induced interstitial thermotherapy.

In patients with recurrent glioblastoma multiforme (GBM), local minimally invasive treatment modalities have gained increasing interest recently because they are associated with fewer side effects than open surgery. For example, local tumor coagulation by laser-induced interstitial thermotherapy (LITT) is such a minimally invasive technique. We monitored the metabolic effects of stereotaxy-guided LITT in a patient with a recurrent GBM using amino acid positron emission tomography (PET). Serial 11C-methyl-L-methionine positron emission tomography (MET-PET) and contrast-enhanced computed tomography (CT) were performed using a hybrid PET/CT system in a patient with recurrent GBM before and after LITT. To monitor the biologic activity of the effects of stereotaxy-guided LITT, a threshold-based volume of interest analysis of the metabolically active tumor volume (MET uptake index of ≥ 1.3) was performed. A continuous decline in metabolically active tumor volume after LITT could be observed. MET-PET seems to be useful for monitoring the short-term therapeutic effects of LITT, especially when patients have been pretreated with a multistep therapeutic regimen. MET-PET seems to be an appropriate tool to monitor and guide experimental LITT regimens and should be studied in a larger patient group to confirm its clinical value.

Prognostic impact of postoperative, pre-irradiation (18)F-fluoroethyl-l-tyrosine uptake in glioblastoma patients treated with radiochemotherapy.

BACKGROUND AND PURPOSE: Resection is considered as essential for the efficacy of modern adjuvant treatment of glioblastoma multiforme (GBM). Previous studies have indicated that amino acid PET is more specific than contrast enhancement on MRI for detecting residual tumor tissue after surgery. In a prospective study we investigated the prognostic impact of postoperative tumor volume and tumor/brain ratios (TBR) in PET using O-(2-[(18)F]fluoroethyl)-l-tyrosine (FET) in comparison with MRI. MATERIALS AND METHODS: Forty-four patients with GBM were investigated by FET PET and MRI after surgery. Tumor volume in FET PET with a tumor/brain ratio (TBR)>1.6 and a TBR>2, mean and maximum TBR and gadolinium contrast-enhancement on MRI (Gd-volume) were determined. Thereafter patients received a fractionated radiotherapy with concomitant temozolomide (RCX). The median follow-up was 15.4 (3-35) months. The prognostic value of postoperative residual tumor volume in FET PET, TBR(mean,) TBR(max) and Gd-volume was evaluated using Kaplan-Maier estimates for disease-free survival (DFS) and overall survival (OS). RESULTS: Postoperative tumor volume in FET PET had a significant independent influence on OS and DFS (OS 20.0 vs. 6.9 months; DFS 9.6 vs. 5.1 months, p<0.001; cut-off 25 ml). Similar results were observed when a TBR ≥ 2 (cut-off 10 ml) was used to define the tumor volume in (18)F-FET PET. The TBR(mean) and TBR(max) of FET uptake had a significant influence on DFS (p<0.05). Gd-volume in MRI had significant effect on OS and DFS in the univariate analysis. No independent significant influence in OS or DFS could be observed for Gd-volume in MRI. CONCLUSIONS: Our data indicate that the tumor volume in FET PET after surgery of GBM has a strong prognostic impact for these patients. FET PET appears to be helpful to determine the residual tumor volume after surgery of GBM and may serve as a valuable tool for optimal planning of radiation treatment.