o-(2-fluoroethyl)tyrosine and Glioblastoma

O-(2-18 F-fluoroethyl)-L-tyrosine-(FET)-PET may be helpful to improve the definition of radiation target volumes in glioblastomas compared with MRI. We analyzed the relapse patterns in FET-PET after a FET- and MRI-based integrated-boost intensity-modulated radiotherapy (IMRT) of glioblastomas to perform an optimized target volume definition.. A relapse pattern analysis was performed in 13 glioblastoma patients treated with radiochemotherapy within a prospective phase-II-study between 2008 and 2009. Radiotherapy was performed as an integrated-boost intensity-modulated radiotherapy (IB-IMRT). The prescribed dose was 72 Gy for the boost target volume, based on baseline FET-PET (FET-1) and 60 Gy for the MRI-based (MRI-1) standard target volume. The single doses were 2.4 and 2.0 Gy, respectively. Location and volume of recurrent tumors in FET-2 and MRI-2 were analyzed related to initial tumor, detected in baseline FET-1. Variable target volumes were created theoretically based on FET-1 to optimally cover recurrent tumor.. The tumor volume overlap in FET and MRI was poor both at baseline (median 12 %; range 0-32) and at time of recurrence (13 %; 0-100). Recurrent tumor volume in FET-2 was localized to 39 % (12-91) in the initial tumor volume (FET-1). Over the time a shrinking (mean 12 (5-26) ml) and shifting (mean 6 (1-10 mm) of the resection cavity was seen. A simulated target volume based on active tumor in FET-1 with an additional safety margin of 7 mm around the FET-1 volume covered recurrent FET tumor volume (FET-2) significantly better than a corresponding target volume based on contrast enhancement in MRI-1 with a same safety margin of 7 mm (100 % (54-100) versus 85 % (0-100); p < 0.01). A simulated planning target volume (PTV), based on FET-1 and additional 7 mm margin plus 5 mm margin for setup-uncertainties was significantly smaller than the conventional, MR-based PTV applied in this study (median 160 (112-297) ml versus 231 (117-386) ml, p < 0.001).. In this small study recurrent tumor volume in FET-PET (FET-2) overlapped only to one third with the boost target volume, based on FET-1. The shrinking and shifting of the resection cavity may have an influence considering the limited overlap of initial and relapse tumor volume. A simulated target volume, based on FET-1 with 7 mm margin covered 100 % of relapse volume in median and led to a significantly reduced PTV, compared to MRI-based PTVs. This approach may achieve similar therapeutic efficacy but lower side effects offering a broader window to intensify concomitant systemic treatment focusing distant failures.

Topics: Adult; Aged; Chemoradiotherapy; Female; Follow-Up Studies; Glioblastoma; Humans; Magnetic Resonance Imaging; Male; Middle Aged; Positron-Emission Tomography; Prognosis; Prospective Studies; Radiopharmaceuticals; Radiotherapy Dosage; Radiotherapy Planning, Computer-Assisted; Radiotherapy, Image-Guided; Radiotherapy, Intensity-Modulated; Retrospective Studies; Tumor Burden; Tyrosine

Dose escalations above 60 Gy based on MRI have not led to prognostic benefits in glioblastoma patients yet. With positron emission tomography (PET) using [(18)F]fluorethyl-L-tyrosine (FET), tumor coverage can be optimized with the option of regional dose escalation in the area of viable tumor tissue.. In a prospective phase II study (January 2008 to December 2009), 22 patients (median age 55 years) received radiochemotherapy after surgery. The radiotherapy was performed as an MRI and FET-PET-based integrated-boost intensity-modulated radiotherapy (IMRT). The prescribed dose was 72 and 60 Gy (single dose 2.4 and 2.0 Gy, respectively) for the FET-PET- and MR-based PTV-FET((72 Gy)) and PTV-MR((60 Gy)). FET-PET and MRI were performed routinely for follow-up. Quality of life and cognitive aspects were recorded by the EORTC-QLQ-C30/QLQ Brain20 and Mini-Mental Status Examination (MMSE), while the therapy-related toxicity was recorded using the CTC3.0 and RTOG scores.. Median overall survival (OS) and disease-free survival (DFS) were 14.8 and 7.8 months, respectively. All local relapses were detected at least partly within the 95% dose volume of PTV-MR((60 Gy)). No relevant radiotherapy-related side effects were observed (excepted alopecia). In 2 patients, a pseudoprogression was observed in the MRI. Tumor progression could be excluded by FET-PET and was confirmed in further MRI and FET-PET imaging. No significant changes were observed in MMSE scores and in the EORTC QLQ-C30/QLQ-Brain20 questionnaires.. Our dose escalation concept with a total dose of 72 Gy, based on FET-PET, did not lead to a survival benefit. Acute and late toxicity were not increased, compared with historical controls and published dose-escalation studies.

Topics: Adult; Aged; Brain; Chemoradiotherapy, Adjuvant; Combined Modality Therapy; Disease-Free Survival; Dose Fractionation, Radiation; Female; Follow-Up Studies; Glioblastoma; Humans; Magnetic Resonance Imaging; Male; Mental Status Schedule; Middle Aged; Positron-Emission Tomography; Prospective Studies; Quality of Life; Radiation Injuries; Radiotherapy Planning, Computer-Assisted; Radiotherapy, Intensity-Modulated; Supratentorial Neoplasms; Tyrosine

To assess the feasibility of synthesis of O-(2-[(18)F]-fluoroethyl)-l-tyrosine (FET), a new positron emission tomographic (PET) tracer described in several studies but not yet considered standard in management of glioma, in routine practice and to determine FET uptake in a homogeneous group of patients with suspected high-grade glioma.. Prospective nonrandomized trial.. Twelve patients with suspicion of high-grade glioma.. The mean (SD) FET uptake ratio was 3.15 (0.72) for the 12 patients and 3.16 (0.75) for the 11 patients with glioblastoma.. The initial results are promising and indicate that FET PET is a valuable and applicable tool for the imaging of high-grade glioma.

Topics: Brain; Brain Neoplasms; Glioblastoma; Humans; Image Interpretation, Computer-Assisted; Image Processing, Computer-Assisted; Positron-Emission Tomography; Prospective Studies; Tyrosine

Biological brain tumor imaging using O-(2-[18F]fluoroethyl)-L-tyrosine (FET)-PET combined with inverse treatment planning for locally restricted dose escalation in patients with glioblastoma multiforme seems to be a promising approach.The aim of this study was to compare inverse with forward treatment planning for an integrated boost dose application in patients suffering from a glioblastoma multiforme, while biological target volumes are based on FET-PET and MRI data sets.. In 16 glioblastoma patients an intensity-modulated radiotherapy technique comprising an integrated boost (IB-IMRT) and a 3-dimensional conventional radiotherapy (3D-CRT) technique were generated for dosimetric comparison. FET-PET, MRI and treatment planning CT (P-CT) were co-registrated. The integrated boost volume (PTV1) was auto-contoured using a cut-off tumor-to-brain ratio (TBR) of > or = 1.6 from FET-PET. PTV2 delineation was MRI-based. The total dose was prescribed to 72 and 60 Gy for PTV1 and PTV2, using daily fractions of 2.4 and 2 Gy.. After auto-contouring of PTV1 a marked target shape complexity had an impact on the dosimetric outcome. Patients with 3-4 PTV1 subvolumes vs. a single volume revealed a significant decrease in mean dose (67.7 vs. 70.6 Gy). From convex to complex shaped PTV1 mean doses decreased from 71.3 Gy to 67.7 Gy. The homogeneity and conformity for PTV1 and PTV2 was significantly improved with IB-IMRT. With the use of IB-IMRT the minimum dose within PTV1 (61.1 vs. 57.4 Gy) and PTV2 (51.4 vs. 40.9 Gy) increased significantly, and the mean EUD for PTV2 was improved (59.9 vs. 55.3 Gy, p < 0.01). The EUD for PTV1 was only slightly improved (68.3 vs. 67.3 Gy). The EUD for the brain was equal with both planning techniques.. In the presented planning study the integrated boost concept based on inversely planned IB-IMRT is feasible. The FET-PET-based automatically contoured PTV1 can lead to very complex geometric configurations, limiting the achievable mean dose in the boost volume. With IB-IMRT a better homogeneity and conformity, compared to 3D-CRT, could be achieved.

Topics: Adult; Aged; Brain Neoplasms; Female; Glioblastoma; Humans; Magnetic Resonance Imaging; Male; Middle Aged; Positron-Emission Tomography; Radiopharmaceuticals; Radiotherapy Planning, Computer-Assisted; Radiotherapy, Conformal; Radiotherapy, Intensity-Modulated; Tyrosine

Thermotherapy using magnetic nanoparticles (nano cancer therapy) is a new concept of local tumour therapy, which is based on controlled heating of intra-tumoural injected magnetic nanoparticles. The aim of this study was to evaluate the usefulness of PET with a recently introduced amino acid tracer O-(2-[18F]fluoroethyl)-]L-tyrosine (FET) for targeting the nanoparticles implantation.. Eleven patients with glioblastoma recurrences underwent MR and FET-PET imaging for planning of the nano cancer therapy. Thereafter, the gross tumour volumes (GTV) were defined, taking into consideration the results of both imaging tools.. The MRI-based mean GTV was 24.3 cm3 (range 2.5-59.7) and the PET-based mean GTV 31.9 cm3 (range 5.2-77.9). On the average the MRI identified an additional 8.9 +/- 4.7 cm3 and the FET-PET scan-an additional 16.5 +/- 15.2 cm3 outside of the common GTV (15.4 +/- 11.0 cm3). The mean final GTV accounted to 33.8 cm3 (range, 5.2-77.9). The additional information of FET-PET led to an increase in GTV by 22-286% in eight patients and to a decrease of 23% and 26%, respectively, in two patients. In one patient, the final GTV was defined on the basis of MRI data only.. FET-PET adds important information on the actual tumour volume in recurrent glioblastomas and is highly valuable for defining the target volume for the nano cancer therapy.

Topics: Adult; Aged; Brain Neoplasms; Female; Glioblastoma; Humans; Hyperthermia, Induced; Magnetic Resonance Imaging; Magnetics; Male; Middle Aged; Nanostructures; Neoplasm Recurrence, Local; Positron-Emission Tomography; Radiotherapy Planning, Computer-Assisted; Tyrosine

Convection-enhanced delivery (CED) of paclitaxel is a new locoregional approach for patients with recurrent glioblastoma. The aim of this study was to evaluate O-(2-[(18)F]fluoroethyl)-L-tyrosine (FET) positron emission tomography (PET) in monitoring the effects of this type of direct drug delivery.. Eight patients with recurrent glioblastoma underwent CED of paclitaxel, which was infused over stereotactically placed catheters into the tumour. FET PET and MRI were performed before and 4 weeks after therapy and then at 3-month intervals to document follow-up. For quantitative evaluation, SUV(max)(tumour)/SUV(mean)(background) ratios were calculated.. At baseline all tumours showed gadolinium enhancement and high FET uptake (SUV(max)/BG 3.2+/-0.8). Four weeks after CED, a statistically significant decrease in FET uptake was seen (SUV(max)/BG-17%; p<0.01). During follow-up, no recurrence was observed within the CED area. Two out of eight patients with extended tumours died 4 and 5 months after treatment, most probably from local complications. Temporarily stable disease with stable FET uptake was observed in six of eight patients; this was followed by progression and increasing FET uptake ratios (+46%) distant from the CED area in five of the six patients 3-13 months after CED. One patient still presents stable FET uptake 10 months after CED. MRI showed unchanged/increasing contrast enhancement and oedema without ability to reliably assess disease progression.. FET PET is a valuable tool in monitoring the effects of CED of paclitaxel. In long-term follow-up, stable or decreasing FET uptake, even in contrast-enhancing lesions, is suggestive of reactive changes, whereas increasing ratios appear always to be indicative of recurrence. Therefore, FET PET is more reliable than MRI in differentiating stable disease from tumour regrowth.

Topics: Antineoplastic Agents; Brain Neoplasms; Convection; Drug Delivery Systems; Female; Glioblastoma; Humans; Infusions, Intralesional; Male; Middle Aged; Neoplasm Recurrence, Local; Paclitaxel; Positron-Emission Tomography; Prognosis; Radiopharmaceuticals; Reproducibility of Results; Sensitivity and Specificity; Treatment Outcome; Tyrosine

The CeTeG/NOA-09 phase III trial demonstrated a significant survival benefit of lomustine-temozolomide chemoradiation in patients with newly diagnosed glioblastoma with methylated O. We retrospectively identified patients (i) who were treated off-study according to the CeTeG/NOA-09 protocol, (ii) had equivocal MRI findings after radiotherapy, and (iii) underwent additional FET-PET imaging for diagnostic evaluation (number of scans, 1-3). Maximum and mean tumor-to-brain ratios (TBR. We identified 23 patients with 32 FET-PET scans. Within 5-25 weeks after radiotherapy (median time, 9 weeks), pseudoprogression occurred in 11 patients (48%). The parameter TBR. The data suggest that FET-PET parameters are of significant clinical value to diagnose pseudoprogression related to lomustine-temozolomide chemoradiation.

Topics: Adult; Aged; Antineoplastic Agents, Alkylating; Antineoplastic Combined Chemotherapy Protocols; Brain Neoplasms; Chemoradiotherapy; Disease Progression; Female; Glioblastoma; Humans; Lomustine; Male; Middle Aged; Positron-Emission Tomography; Retrospective Studies; Temozolomide; Tyrosine

Topics: Adult; Aged; Brain Neoplasms; Diagnosis, Differential; Female; Glioblastoma; Humans; Male; Middle Aged; Neoplasm Recurrence, Local; Positron-Emission Tomography; Retrospective Studies; Tyrosine; Young Adult

GTV definition for re-irradiation treatment planning in recurrent glioblastoma (rGBM) is usually based on contrast-enhanced MRI (GdT1w-MRI) and, for an increased specificity, on amino acid PET. Diffusion-weighted (DWI) MRI and ADC maps can reveal regions of high cellularity as surrogate for active tumor. The objective of this study was to compare the localization and quality of diffusion restriction foci (GTV-ADClow) with FET-PET (GTV-PET) and GdT1w-MRI (GTV-GdT1w-MRI).. We prospectively evaluated 41 patients, who received a fractionated stereotactic re-irradiation for rGBM. GTV-PET was generated automatically (tumor-to-background ratio 1.7-1.8) and manually customized. GTV-ADClow was manually defined based on DWI data (3D diffusion gradients, b = 0, 1000 s/mm. Unexpectedly, GTV-ADClow overlapped only partially with FET-PET and GdT1w-MRI in rGBM. Moreover, GTV-ADClow correlated poorly with later rGBM-recurrences. Seeing as a restricted diffusion is known to correlate with hypercellularity, this imaging discrepancy could only be further explained in histopathological studies.

Topics: Adult; Aged; Brain Neoplasms; Diffusion Magnetic Resonance Imaging; Female; Glioblastoma; Humans; Magnetic Resonance Imaging; Male; Middle Aged; Multimodal Imaging; Positron-Emission Tomography; Prospective Studies; Radiosurgery; Re-Irradiation; Tumor Burden; Tyrosine

Glioblastoma inevitably recurs despite aggressive therapy. Therefore, it would be helpful to predict the location of tumor recurrence from postoperative imaging to customize further treatment. O-(2-. Thirty-two consecutive patients with perioperative and follow-up imaging data available were included. On postoperative FET-PET, the tumor/normal brain (TTB) ratio around the resection cavity borders was measured. Increased TTB ratios were recorded and anatomically correlated with the site of later tumor recurrence. On postoperative magnetic resonance imaging (MRI), residual contrast-enhancing tumor correlated with the site of later tumor recurrence.. Location of progression was predictable using MRI alone in 42% of patients by residual tumor on postoperative MRI. FET-PET was predictive in 25 patients by a clear hot spot at the site of later tumor recurrence. In 3 patients, it was partially predictive and in 4 was not predictive of the tumor recurrence location. One patient without any tracer uptake was recurrence free at the last follow-up examination. In contrast to the postoperative MRI results, tumor recurrence was found in 79% at a site of elevated TTB ratio on postoperative FET-PET. Therefore, the predictability of the tumor recurrence location using postoperative FET-PET was greater than that with MRI, and all cases predictable using MRI could have been predicted using FET-PET.. Postoperative FET-PET can be helpful for planning subsequent therapy, such as repeat resection or radiotherapy, because tumor recurrence can be predicted with relatively greater sensitivity than with MRI alone.

Topics: Adult; Aged; Aged, 80 and over; Brain Neoplasms; Electroencephalography; Evoked Potentials, Somatosensory; Female; Follow-Up Studies; Glioblastoma; Humans; Magnetic Resonance Imaging; Male; Middle Aged; Neoplasm Recurrence, Local; Positron-Emission Tomography; Predictive Value of Tests; Retrospective Studies; Tomography Scanners, X-Ray Computed; Tyrosine

We sought to assess the influence of the clinical introduction of new radiotherapy technologies on glioblastoma patients' outcomes.. Newly diagnosed glioblastoma patients treated with 60 Gy and temozolomide (2005-2014) were analyzed. The patients' GTV and CTV were defined based on MR (n = 521) or FET-PET/MR (n = 190), and were treated using conformal radiotherapy (CRT, n = 159) or image-guided volumetric modulated arc therapy with hippocampal sparing (IG-VMAT, n = 362). Progression-free survival (PFS) was assessed using the McDonald criteria. Associations between clinical data, dosimetry data, treatment technology, for PFS and overall survival (OS) were explored.. The PFS (7 months) and OS (15 months) were unaffected by CRT, IG-VMAT and FET-PET technology. Mean brain dose was correlated with tumor volume, and was lower for IG-VMAT vs. CRT (p < 0.001). Larger mean brain dose was associated with inferior PFS (univariate/multivariate Cox models, p < 0.001) and OS (univariate, p < 0.001). Multivariate Cox models revealed association of larger mean brainstem dose (p < 0.001), BTV (p = 0.045), steroid use at baseline (p = 0.003), age (p = 0.019) and MGMT status (p = 0.022) with lower OS.. Introduction of hippocampal-sparing IG-VMAT technology appeared to be safe, and may have reduced toxicity and cognitive impairment. Larger mean brain dose was strongly associated with inferior PFS and OS.

Topics: Adult; Brain Neoplasms; Glioblastoma; Humans; Middle Aged; Positron-Emission Tomography; Proportional Hazards Models; Radiotherapy, Intensity-Modulated; Treatment Outcome; Tumor Burden; Tyrosine

PET/CT using O-(2-[F]fluoroethyl)-L-tyrosine (F-FET) has proven valuable in differentiating tumor recurrence and progression from therapy-induced changes. This study aimed to investigate the diagnostic performance of several analytic approaches in the setting of suspected late pseudoprogression (PsP) in glioblastoma multiforme (GBM).. Retrospective analysis of tumor recurrence was performed in 36 patients with histopathologically confirmed GBM and suspicion of recurrence/disease progression more than 12 weeks from cessation of irradiation based on MRI and Response Assessment in Neuro-Oncology working group criteria. For differentiation of late PsP from true tumor recurrence, images were analyzed semiquantitatively employing tumor-to-brain ratios using 5 different approaches for tumor and normal brain reference region definition, respectively. Histopathology and/or clinical and imaging follow-up served as reference. Respective areas under the receiver operating characteristic curve were compared.. F-FET PET was able to reliably differentiate PsP from true tumor progression with areas under the receiver operating characteristic curve ranging from 0.80 to 0.88 (all P < 0.01). Irrespective of the approach chosen, the classification differences between the applied methods were not significant (all P > 0.05), albeit approaches focusing on voxels with the highest uptake tended to perform superior.. Irrespective of the analytical approach, F-FET PET is a robust tool for detection of late PsP with only minor differences between different analytical approaches. However, methodological standardization and harmonization are needed to ensure comparability between different centers.

Topics: Adult; Aged; Brain Neoplasms; Disease Progression; Female; Glioblastoma; Humans; Male; Middle Aged; Positron Emission Tomography Computed Tomography; Retrospective Studies; ROC Curve; Tyrosine; Young Adult

Amino acid positron emission tomography (PET) using O-(2-[. A 61-year-old patient with glioblastoma initially underwent partial tumor resection and died 11 weeks after completion of chemoradiation with concurrent temozolomide. Three days before the patient died, a follow-up FET PET and MRI scan indicated tumor progression. Autopsy was performed 48 hours after death. After formalin fixation, a 7-cm bihemispherical segment of the brain containing the entire tumor mass was cut into 3500 consecutive 20μm coronal sections. Representative sections were stained with hematoxylin and eosin stain, cresyl violet, and glial fibrillary acidic protein immunohistochemistry. An experienced neuropathologist identified areas of dense and diffuse neoplastic infiltration, astrogliosis, and necrosis. In vivo FET PET, MRI datasets, and postmortem histology were co-registered and compared by 3 experienced physicians.. Increased uptake of FET in the area of equivocal contrast enhancement on MRI correlated very well with dense infiltration by vital tumor cells and showed tracer kinetics typical for malignant gliomas. An area of predominantly reactive astrogliosis showed only moderate uptake of FET and tracer kinetics usually observed in benign lesions.. This case report impressively documents the correct imaging of a progressive glioblastoma by FET PET.

Topics: Brain; Brain Neoplasms; Combined Modality Therapy; Fatal Outcome; Glioblastoma; Humans; Magnetic Resonance Imaging; Middle Aged; Neuroimaging; Positron-Emission Tomography; Radiopharmaceuticals; Tyrosine

Glioblastoma patients show a great variability in progression free survival (PFS) and overall survival (OS). To gain additional pretherapeutic information, we explored the potential of O-(2-. We retrospectively analyzed 146 consecutively treated, newly diagnosed glioblastoma patients. All patients were treated with temozolomide and radiation therapy (RT). CT/MR and FET PET scans were obtained postoperatively for RT planning. We used Cox proportional hazards models with OS and PFS as endpoints, to test the prognostic value of FET PET biological tumor volume (BTV).. Median follow-up time was 14 months, and median OS and PFS were 16.5 and 6.5 months, respectively. In the multivariate analysis, increasing BTV (HR = 1.17, P < 0.001), poor performance status (HR = 2.35, P < 0.001), O(6)-methylguanine-DNA methyltransferase protein status (HR = 1.61, P = 0.024) and higher age (HR = 1.32, P = 0.013) were independent prognostic factors of poor OS. For poor PFS, only increasing BTV (HR = 1.18; P = 0.002) was prognostic. A prognostic index for OS was created based on the identified prognostic factors.. Large BTV on FET PET is an independent prognostic factor of poor OS and PFS in glioblastoma patients. With the introduction of FET PET, we obtain a prognostic index that can help in glioblastoma treatment planning.

Topics: Adult; Aged; Brain Neoplasms; Female; Glioblastoma; Humans; Magnetic Resonance Imaging; Male; Middle Aged; Positron-Emission Tomography; Predictive Value of Tests; Radiopharmaceuticals; Radiotherapy Planning, Computer-Assisted; Tomography, X-Ray Computed; Tyrosine

To evaluate the patterns of failure following clinical introduction of amino-acid O-(2-[. The first 66 consecutive patients with confirmed histology, scanned using FET-PET/CT and MRI were selected for evaluation. Chemo-radiotherapy was delivered to a volume based on both MRI and FET-PET (PET. Fifty patients were evaluable, with median follow-up of 45months. Central, in-field, marginal and distant recurrences were observed for 82%, 10%, 2%, and 6% of the patients, respectively. We found a volumetric overlap of 26%, 31% and 39% of the RV with the contrast-enhancing MR volume, PET. The combined MRPET

Topics: Adult; Aged; Aged, 80 and over; Brain Neoplasms; Disease Progression; Female; Glioblastoma; Humans; Magnetic Resonance Imaging; Male; Middle Aged; Neoplasm Recurrence, Local; Positron Emission Tomography Computed Tomography; Positron-Emission Tomography; Radiology, Interventional; Radiopharmaceuticals; Radiotherapy, Image-Guided; Retrospective Studies; Treatment Failure; Tyrosine

Pseudoprogression (PsP) is characterized by therapy-associated but not tumor growth-associated increases of contrast-enhancing glioblastoma lesions on MRI. Although typically occurring during the first 3 months after radiochemotherapy, PsP may occur later in the course of the disease and may then be particularly difficult to distinguish from true tumor progression. We explored PET using O-(2-[(18)F]fluoroethyl)-L-tyrosine ((18)F-FET-PET) to approach the diagnostic dilemma.. Twenty-six patients with glioblastoma that presented with increasing contrast-enhancing lesions later than 3 months after completion of radiochemotherapy underwent (18)F-FET-PET. Maximum and mean tumor/brain ratios (TBRmax and TBRmean) of (18)F-FET uptake as well as time-to-peak (TTP) and patterns of the time-activity curves were determined. The final diagnosis of true progression versus late PsP was based on follow-up MRI using RANO criteria.. Late PsP occurred in 7 patients with a median time from radiochemotherapy completion of 24 weeks while the remaining patients showed true tumor progression. TBRmax and TBRmean were significantly higher in patients with true progression than in patients with late PsP (TBRmax 2.4 ± 0.1 vs. 1.5 ± 0.2, P = 0.003; TBRmean 2.1 ± 0.1 vs. 1.5 ± 0.2, P = 0.012) whereas TTP was significantly shorter (mean TTP 25 ± 2 vs. 40 ± 2 min, P < 0.001). ROC analysis yielded an optimal cutoff value of 1.9 for TBRmax to differentiate between true progression and late PsP (sensitivity 84%, specificity 86%, accuracy 85%, P = 0.015).. O-(2-[(18)F]fluoroethyl)-L-tyrosine PET provides valuable information in assessing the elusive phenomenon of late PsP. Clin Cancer Res; 22(9); 2190-6. ©2015 AACR.

Topics: Adult; Aged; Brain Neoplasms; Chemoradiotherapy; Disease Progression; Female; Glioblastoma; Humans; Magnetic Resonance Imaging; Male; Middle Aged; Positron-Emission Tomography; Radiopharmaceuticals; Retrospective Studies; Sensitivity and Specificity; Tyrosine; Young Adult

O-(2-fluoroethyl)-L-tyrosine (FET) labeled with fluorine-18 is an important and specific tracer for diagnostics of glioblastoma via positron emission tomography (PET). However, the mechanism of its quite specific accumulation in tumor tissue has not been understood so far. In this work we demonstrate that [(3)H]L-tyrosine is primarily transported by the system L transporter LAT1 in human LN229 glioblastoma cells. FET reduced tyrosine transport, suggesting that it shares the same uptake pathway. More importantly, accumulation of FET was significantly reduced after siRNA-mediated downregulation of LAT1. Xenopus laevis oocytes expressing human LAT1 together with the glycoprotein 4F2hc (necessary to pull LAT-1 to the plasma membrane) exhibited a similar accumulation of FET as observed in glioblastoma cells. In contrast, no accumulation was observed in control oocytes, not overexpressing an exogenous transporter. Because LAT1 works exclusively as an exchanger of amino acids, substrates at one side of the membrane stimulate exchange against substrates at the other side. Extracellular FET stimulated the efflux of intracellular [(3)H]L-leucine, demonstrating that FET is indeed an influx substrate for LAT1. However, FET injected into oocytes was not able to stimulate uptake of extracellular [(3)H]L-leucine, indicating that FET is not a good efflux substrate. Our data, therefore, suggest that FET is trapped within cells due to the asymmetry of its intra- and extracellular recognition by LAT1. If also found for other transporters in tumor cells, asymmetric substrate recognition may be further exploited for tumor-specific accumulation of PET-tracers and/or other tumor-related drugs.

Topics: Animals; Cell Line, Tumor; Contrast Media; Fusion Regulatory Protein 1, Heavy Chain; Glioblastoma; Humans; Large Neutral Amino Acid-Transporter 1; Neoplasm Proteins; Positron-Emission Tomography; Radiography; Tyrosine; Xenopus laevis

The follow-up of glioblastoma patients after radiochemotherapy with conventional MRI can be difficult since reactive alterations to the blood-brain barrier with contrast enhancement may mimic tumour progression (i.e. pseudoprogression, PsP). The aim of this study was to assess the clinical value of O-(2-(18)F-fluoroethyl)-L-tyrosine ((18)F-FET) PET in the differentiation of PsP and early tumour progression (EP) after radiochemotherapy of glioblastoma.. A group of 22 glioblastoma patients with new contrast-enhancing lesions or lesions showing increased enhancement (>25 %) on standard MRI within the first 12 weeks after completion of radiochemotherapy with concomitant temozolomide (median 7 weeks) were additionally examined using amino acid PET with (18)F-FET. Maximum and mean tumour-to-brain ratios (TBRmax, TBRmean) were determined. (18)F-FET uptake kinetic parameters (i.e. patterns of time-activity curves, TAC) were also evaluated. Classification as PsP or EP was based on the clinical course (no treatment change at least for 6 months), follow-up MR imaging and/or histopathological findings. Imaging results were also related to overall survival (OS).. PsP was confirmed in 11 of the 22 patients. In patients with PsP, (18)F-FET uptake was significantly lower than in patients with EP (TBRmax 1.9 ± 0.4 vs. 2.8 ± 0.5, TBRmean 1.8 ± 0.2 vs. 2.3 ± 0.3; both P < 0.001) and presence of MGMT promoter methylation was significantly more frequent (P = 0.05). Furthermore, a TAC type II or III was more frequently present in patients with EP (P = 0.04). Receiver operating characteristic analysis showed that the optimal (18)F-FET TBRmax cut-off value for identifying PsP was 2.3 (sensitivity 100 %, specificity 91 %, accuracy 96 %, AUC 0.94 ± 0.06; P < 0.001). Univariate survival analysis showed that a TBRmax <2.3 predicted a significantly longer OS (median OS 23 vs. 12 months; P = 0.046).. (18)F-FET PET may facilitate the diagnosis of PsP following radiochemotherapy of glioblastoma.

Topics: Adult; Aged; Brain Neoplasms; Disease Progression; False Positive Reactions; Female; Glioblastoma; Humans; Male; Middle Aged; Positron-Emission Tomography; Radiopharmaceuticals; Tyrosine

Monitoring of radiochemotherapy (RCX) in patients with glioblastoma is difficult because unspecific alterations in magnetic resonance imaging with contrast enhancement can mimic tumor progression. Changes in tumor to brain ratios (TBRs) in positron emission tomography (PET) using O-(2-¹⁸fluoroethyl)-l-tyrosine (¹⁸F-FET) after RCX with temozolomide of patients with glioblastoma have been shown to be valuable parameters to predict survival. The kinetic behavior of ¹⁸F-FET in the tumors is another promising parameter to analyze tumor metabolism. In this study, we investigated the predictive value of dynamic ¹⁸F-FET PET during RCX of glioblastoma. Time-activity curves (TACs) of ¹⁸F-FET uptake of 25 patients with glioblastoma were evaluated after surgery (FET-1), early (7-10 days) after completion of RCX (FET-2), and 6 to 8 weeks later (FET-3). Changes in the time to peak (TTP) and the slope of the TAC (10-50 minutes postinjection) were analyzed and related to survival. Changes in kinetic parameters of ¹⁸F-FET uptake after RCX showed no relationship with survival time. In contrast, the high predictive value of changes of TBR to predict survival was confirmed. We conclude that dynamic ¹⁸F-FET PET does not provide additional prognostic information during RCX. Static ¹⁸F-FET PET imaging (20-40 minutes postinjection) appears to be sufficient for this purpose and reduces costs.

Topics: Adult; Aged; Area Under Curve; Brain Neoplasms; Female; Fluorine Radioisotopes; Glioblastoma; Humans; Kaplan-Meier Estimate; Male; Middle Aged; Positron-Emission Tomography; Prospective Studies; Radiopharmaceuticals; Tyrosine

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.. 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).. 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.. 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.

Topics: Adult; Aged; Antineoplastic Agents, Alkylating; Brain Neoplasms; Combined Modality Therapy; Contrast Media; Cranial Irradiation; Dacarbazine; Dose Fractionation, Radiation; Female; Fluorine Radioisotopes; Gadolinium DTPA; Glioblastoma; Humans; Image Interpretation, Computer-Assisted; Magnetic Resonance Imaging; Male; Middle Aged; Neoplasm, Residual; Positron-Emission Tomography; Prognosis; Proportional Hazards Models; Prospective Studies; Survival Rate; Temozolomide; Treatment Outcome; Tumor Burden; Tyrosine

To investigate the potential of (18)F-fluoroethyltyrosine-positron emission tomography-((18)F-FET-PET-)based dose painting by numbers with protons.. Due to its high specificity to brain tumor cells, FET has a high potential to serve as a target for dose painting by numbers. Biological image-based dose painting might lead to an inhomogeneous dose prescription. For precise treatment planning of such a prescribed dose, an intensity-modulated radiotherapy (IMRT) algorithm including a Monte Carlo dose-calculation algorithm for spot-scanning protons was used. A linear tracer uptake to dose model was used to derive a dose prescription from the (18)F-FET-PET. As a first investigation, a modified modulation transfer function (MTF) of protons was evaluated and compared to the MTF of photons. In a clinically adapted planning study, the feasibility of (18)F-FET-PET-based dose painting with protons was demonstrated using three patients with glioblastome multiforme. The resulting dose distributions were evaluated by means of dose-difference and dose-volume histograms and compared to IMRT data.. The MTF for protons was constantly above that for photons. The standard deviations of the dose differences between the prescribed and the optimized dose were smaller in case of protons compared to photons. Furthermore, the escalation study showed that the doses within the subvolumes identified by biological imaging techniques could be escalated remarkably while the dose within the organs at risk was kept at a constant level.. The presented investigation fortifies the feasibility of (18)F-FET-PET-based dose painting with protons.

Topics: Algorithms; Brain Neoplasms; Fluorine Radioisotopes; Glioblastoma; Humans; Linear Energy Transfer; Monte Carlo Method; Photons; Positron-Emission Tomography; Radiotherapy Planning, Computer-Assisted; Radiotherapy, Intensity-Modulated; Tyrosine

To demonstrate the feasibility of a biologically adapted dose-escalation approach to brain tumors.. Due to the specific accumulation of fluoroethyltyrosine (FET) in brain tumors, (18)F-FET-PET imaging is used to derive a voxel-by-voxel dose distribution. Although the kinetics of (18)F-FET are not completely understood, the authors regard regions with high tracer uptake as vital and aggressive tumor and use a linear dose-escalation function between SUV (standard uptake value) 3 and SUV 5. The resulting dose distribution is then planned using the inverse Monte Carlo treatment- planning system IKO. In a theoretical study, the dose range is clinically adapted from 1.8 Gy to 2.68 Gy per fraction (with a total of 30 fractions). In a second study, the maximum dose of the model is increased step by step from 2.5 Gy to 3.4 Gy to investigate whether a significant dose escalation to tracer-accumulating subvolumes is possible without affecting the shell-shaped organ at risk (OAR). For all dose-escalation levels the dose difference Delta D of each voxel inside the target volume is calculated and the mean dose difference Delta D and their standard deviation sigma Delta D are determined. The dose to the OAR is evaluated by the dose values D OAR 50% and D OAR 5%, which are the dose values not exceeded by 50% and 5% of the volume, respectively.. The inhomogeneous dose prescription is achieved with high accuracy (Delta D < 0.03 +/- 0.3 Gy/fraction). The maximum dose can be increased remarkably, without increasing the dose to the OAR (standard deviation of D OAR 50% < 0.02 Gy/fraction and of D OAR 5% < 0.05 Gy/fraction).. Assuming that regions with high tracer uptake can be interpreted as target for radiotherapy, (18)F-FET-PET-based "dose painting by numbers" applied to brain tumors is a feasible approach. The dose, and therefore potentially the chance of tumor control, can be enhanced. The proposed model can easily be transferred to other tracers and tumor entities.

Topics: Aged; Brain Neoplasms; Feasibility Studies; Female; Fluorine Radioisotopes; Glioblastoma; Humans; Image Processing, Computer-Assisted; Male; Middle Aged; Monte Carlo Method; Positron-Emission Tomography; Radiotherapy Dosage; Radiotherapy Planning, Computer-Assisted; Tomography, X-Ray Computed; Tyrosine

To develop a 18F-labeled amino acid, O-(2-[18F]fluoroethyl) - L-tyrosine(18F-FET), as a positron emission tomography (PET) tracer for imaging cerebral tumors.. 18F-FET was synthesized. Preclinical studies including sterility, endotoxin, and toxicity tests were performed. Two brain tumor cases were studied using 18F-FET and compared with 18F-FDG.. Radiochemical purity of 18F-FET was over 95% which remained stable for 6 hours. The 18F-FET injection was sterile and its endotoxin content accorded with the standards of Chinese Pharmacopoeia. The uptake of 18F-FET in the normal brain tissues was significantly lower than that of the tumor, and the images of the brain tumor were clearer than those of 18F-FDG.. 18F-FET can accumulate in the tumor tissues to give high quality images. It suggests that 18F-FET may be a safe and effective tracer for brain tumor imaging.

Topics: Adult; Animals; Brain Neoplasms; Female; Fluorine Radioisotopes; Fluorodeoxyglucose F18; Glioblastoma; Humans; Male; Mice; Middle Aged; Sarcoma 180; Tomography, Emission-Computed; Tyrosine