Cost-effectiveness of [18F] fluoroethyl-L-tyrosine for temozolomide therapy assessment in patients with glioblastoma

Background and Purpose: Glioblastomas are the most aggressive of all gliomas. The prognosis of these gliomas, which are classified as grade IV tumors by the World Health Organization (WHO), is poor. Combination therapy, including surgery, radiotherapy, and chemotherapy has variable outcomes and is expensive. In light of rising healthcare costs, there are societal demands for the justification of medical expenses. Therefore, we calculated the cost-effectiveness of follow-up [F-18] fluoroethyl-L-tyrosine ([F-18] FET) positron emission tomography (PET) scans performed on patients with glioblastoma after surgery and before commencing temozolomide maintenance treatment. Materials and Methods: To determine the cost-effectiveness of follow-up [F-18] FET PET procedures, we examined published clinical data and calculated the associated costs in the context of Belgian healthcare. We subsequently performed one-way deterministic sensitivity analysis and Monte Carlo analysis on the calculated ratios. Results: The decision tree based on overall survival rates showed that the number of non-responders identified using PET was 57.14% higher than the number of non-responders identified using conventional MRI. Further, the decision tree based on progression-free survival rates revealed a comparable increase of 57.50% non-responders identified. The calculated cost of two required PET scans per patient during the follow-up treatment phase was 780.50 euros. Two cost-effectiveness ratios were determined for overall survival and progression-free survival rates. Both of these calculations yielded very similar results: incremental cost-effectiveness ratios of 1,365.86 and 1,357.38 euros, respectively, for each identified non-responder. The findings of the sensitivity analysis supported the calculated results, confirming that the obtained data were robust. Conclusion: Our comparative study of conventional MRI and [F-18] FET PET revealed that the latter is a valuable tool for predicting the treatment responses of patients with glioblastomas to follow-up temozolomide maintenance treatment while considering its cost-effectiveness. Thus, [F-18] FET PET scans enable clinical outcomes to be predicted accurately and at a low cost. Moreover, given the robustness of the data in the sensitivity analyses, the level of certainty of this outcome is acceptable

EphA2 as a Diagnostic Imaging Target in Glioblastoma: A Positron Emission Tomography/Magnetic Resonance Imaging Study

Noninvasive imaging is a critical technology for diagnosis, classification, and subsequent treatment planning for patients with glioblastoma. It has been shown that the EphA2 receptor tyrosine kinase (RTK) is overexpressed in a number of tumors, including glioblastoma. Expression levels of Eph RTKs have been linked to tumor progression, metastatic spread, and poor patient prognosis. As EphA2 is expressed at low levels in normal neural tissues, this protein represents an attractive imaging target for delineation of tumor infiltration, providing an improved platform for image-guided therapy. In this study, EphA2-4B3, a monoclonal antibody specific to human EphA2, was labeled with Cu-64 through conjugation to the chelator 1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA). The resulting complex was used as a positron emission tomography (PET) tracer for the acquisition of high-resolution longitudinal PET/magnetic resonance images. EphA2-4B3-NOTA-Cu-64 images were qualitatively and quantitatively compared to the current clinical standards of [F-18] FDOPA and gadolinium (Gd) contrast-enhanced MRI. We show that EphA2-4B3-NOTA-Cu-64 effectively delineates tumor boundaries in three different mouse models of glioblastoma. Tumor to brain contrast is significantly higher in EphA2-4B3-NOTA-Cu-64 images than in [F-18] FDOPA images and Gd contrast-enhanced MRI. Furthermore, we show that nonspecific uptake in the liver and spleen can be effectively blocked by a dose of nonspecific (isotype control) IgG

PET Studies of Cerebral Levodopa Metabolism: A Review of Clinical Findings and Modeling Approaches

[18F]Fluoro-3,4-dihydroxyphenyl-l-alanine (FDOPA) was one of the first successful tracers for molecular imaging by positron emission tomography (PET), and has proven immensely valuable for studies of Parkinson’s disease. Following intravenous FDOPA injection, the decarboxylated metabolite [18F] fluorodopamine is formed and trapped within terminals of the nigrostriatal dopamine neurons; reduction in the simple ratio between striatum and cerebellum is indicative of nigrostriatal degeneration. However, the kinetic analysis of dynamic FDOPA-PET recordings is formidably complex due to the entry into brain of the plasma metabolite O-methyl-FDOPA and due to the eventual washout of decarboxylated metabolites. Linear graphical analysis relative to a reference tissue input function is popular and convenient for routine clinical studies in which serial arterial blood samples are unavailable. This simplified approach has facilitated longitudinal studies in large patient cohorts. Linear graphical analysis relative to the metabolite-corrected arterial FDOPA input yields a more physiological index of FDOPA utilization, the net blood-brain clearance. Using a constrained compartmental model, FDOPA-PET recordings can be used to calculate the relative activity of the enzyme DOPA decarboxylase in living brain. We have extended this approach so as to obtain an index of steady-state trapping of [18F]fluorodopamine in synaptic vesicles. Although simple methods of image analysis are sufficient for the purposes of routine clinical studies, the more complex approaches have revealed hidden aspects of brain dopamine in personality, healthy aging, and in the pathophysiologies of Parkinson’s disease and schizophrenia

Voxel-based 18F-FET PET segmentation and automatic clustering of tumor voxels: A significant association with IDH1 mutation status and survival in patients with gliomas.

Aim was to develop a full automatic clustering approach of the time-activity curves (TAC) from dynamic 18F-FET PET and evaluate its association with IDH1 mutation status and survival in patients with gliomas. Thirty-seven patients (mean age: 45±13 y) with newly diagnosed gliomas and dynamic 18F-FET PET before any histopathologic investigation or treatment were retrospectively included. Each dynamic 18F-FET PET was realigned to the first image and spatially normalized in the Montreal Neurological Institute template. A tumor mask was semi-automatically generated from Z-score maps. Each brain tumor voxel was clustered in one of the 3 following centroids using dynamic time warping and k-means clustering (centroid #1: slowly increasing slope; centroid #2: rapidly increasing followed by slowly decreasing slope; and centroid #3: rapidly increasing followed by rapidly decreasing slope). The percentage of each dynamic 18F-FET TAC within tumors and other conventional 18F-FET PET parameters (maximum and mean tumor-to-brain ratios [TBRmax and TBRmean], time-to-peak [TTP] and slope) was compared between wild-type and IDH1 mutant tumors. Their prognostic value was assessed in terms of progression free-survival (PFS) and overall survival (OS) by Kaplan-Meier estimates. Twenty patients were IDH1 wild-type and 17 IDH1 mutant. Higher percentage of centroid #1 and centroid #3 within tumors were positively (P = 0.016) and negatively (P = 0.01) correlated with IDH1 mutated status. Also, TBRmax, TBRmean, TTP, and slope discriminated significantly between tumors with and without IDH1 mutation (P range 0.01 to 0.04). Progression occurred in 22 patients (59%) at a median of 13.1 months (7.6-37.6 months) and 13 patients (35%) died from tumor progression. Patients with a percentage of centroid #1 > 90% had a longer survival compared with those with a percentage of centroid #1 < 90% (P = 0.003 for PFS and P = 0.028 for OS). This remained significant after stratification on IDH1 mutation status (P = 0.029 for PFS and P = 0.034 for OS). Compared to other conventional 18F-FET PET parameters, TTP and slope were associated with PFS and OS (P range 0.009 to 0.04). Based on dynamic 18F-FET PET acquisition, we developed a full automatic clustering approach of TAC which appears to be a valuable noninvasive diagnostic and prognostic marker in patients with gliomas

Measuring dopaminergic function in the 6-OHDA-lesioned rat: a comparison of PET and microdialysis

BACKGROUND: [(18) F]fluorodopa (FDOPA) positron emission tomography (PET) allows assessment of levodopa (LDOPA) metabolism and is widely used to study Parkinson's disease. We examined how [(18) F]FDOPA PET-derived kinetic parameters relate the dopamine (DA) and DA metabolite content of extracellular fluid measured by microdialysis to aid in the interpretation of data from both techniques. METHODS: [(18) F]FDOPA PET imaging and microdialysis measurements were performed in unilaterally 6-hydroxydopamine-lesioned rats (n = 8) and normal control rats (n = 3). Microdialysis testing included baseline measurements and measurements following acute administration of LDOPA. PET imaging was also performed using [(11)C]dihydrotetrabenazine (DTBZ), which is a ligand for the vesicular monoamine transporter marker and allowed assessment of denervation severity. RESULTS: The different methods provided highly correlated data. Lesioned rats had reduced DA metabolite concentrations ipsilateral to the lesion (p < 0.05 compared to controls), with the concentration being correlated with FDOPA's effective distribution volume ratio (EDVR; r = 0.86, p < 0.01) and DTBZ's binding potential (BP(ND); r = 0.89, p < 0.01). The DA metabolite concentration in the contralateral striatum of severely (>80%) lesioned rats was lower (p < 0.05) than that of less severely lesioned rats (<80%) and was correlated with the ipsilateral PET measures (r = 0.89, p < 0.01 for BP(ND)) but not with the contralateral PET measures. EDVR and BP(ND) in the contralateral striatum were not different from controls and were not correlated with the denervation severity. CONCLUSIONS: The demonstrated strong correlations between the PET and microdialysis measures can aid in the interpretation of [(18) F]FDOPA-derived kinetic parameters and help compare results from different studies. The contralateral striatum was affected by the lesioning and so cannot always serve as an unaffected control

Imaging approaches to assess the therapeutic response of gastroenteropancreatic neuroendocrine tumors (GEP-NETs): current perspectives and future trends of an exciting field in development

Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are a family of neoplasms with a complex spectrum of clinical behavior. Although generally more indolent than carcinomas, once they progress beyond surgical resectability, they are essentially incurable. Systemic treatment options have substantially expanded in recent years for the management of advanced disease. Imaging plays a major role in new drug development, as it is the main tool used to objectively evaluate response to novel agents. However, current standard response criteria have proven suboptimal for the assessment of the antiproliferative effect of many targeted agents, particularly in the context of slow-growing tumors such as well-differentiated NETs. The aims of this article are to discuss the advantages and limitations of conventional radiological techniques and standard response assessment criteria and to review novel imaging modalities in development as well as alternative cancer- and therapy-specific criteria to assess drug efficacy in the field of GEP-NETs