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Evaluation of O-(2-[18F]-Fluoroethyl)-L-Tyrosine in the Diagnosis of Glioblastoma FREE

Alexandra Benouaich-Amiel, MD; Vincent Lubrano, MD; Mathieu Tafani, MD; Emmanuelle Uro-coste, MD, PhD; Pierre Gantet, PhD; Jean Christophe Sol, MD, PhD; Franck Roux, MD, PhD; Philippe Bousquet, MD; Anne Julian, MD; Jean Sabatier, MD, PhD; Michel Tremoulet, MD; Valerie Cances-Lauwers, MD; Marie Bernadette Delisle, MD, PhD; Michel Clanet, MD, PhD; Jean Philippe Esquerré, MD, PhD; Pierre Payoux, MD, PhD
[+] Author Affiliations

Author Affiliations: Pole NeuroSciences, Central Hospitalo Universitaire (CHU) Toulouse (Drs Benouaich-Amiel, Lubrano, Sol, Roux, Bousquet, Sabatier, Tremoulet, and Clanet); National Institute of Health and Medical Research (INSERM) U 825, Toulouse (Drs Lubrano, Roux, and Payoux); Research Team (EA) 3033, Université Paul Sabatier, Toulouse (Drs Tafani, Gantet, Julian, and Esquerré); and Pole Pharmacie (Dr Tafani), Pole Biologie (Drs Uro-coste and Delisle), Pole Imagerie (Drs Julian, Esquerré, and Payoux), Pole Santé-Société Réadaptation, CHU Toulouse (Dr Cances-Lauwers), France.


Arch Neurol. 2010;67(3):370-372. doi:10.1001/archneurol.2010.22.
Text Size: A A A
Published online

ABSTRACT

Objective  To assess the feasibility of synthesis of O-(2-[18F]-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.

Design  Prospective nonrandomized trial.

Patients  Twelve patients with suspicion of high-grade glioma.

Results  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.

Conclusion  The initial results are promising and indicate that FET PET is a valuable and applicable tool for the imaging of high-grade glioma.

Figures in this Article

Positron emission tomography (PET), a metabolic imaging modality widely used in systemic cancer, may be a valuable tool for obtaining additional data and for better treatment of patients with glioma.

L-[methyl-11C]-methionine (MET), usually considered the standard method of brain tumor molecular imaging in PET, cannot be used in clinical practice owing to the short half-life of carbon 11; thus, its applications are restricted to academic research centers.1,2

O-(2-[18F]-fluoroethyl)-L-tyrosine (FET) is a recently described amino acid analog radiolabeled with fluorine 18 (18F). It can be synthesized using an automated procedure and can be produced for clinical practice in a satellite concept similar to fludeoxyglucose, which is already widely used in general oncology.3,4

A few studies have already evaluated this new tracer, with promising results in glioma. Uptake and image contrast obtained with FET appear to be very similar to those obtained with MET.5,6 Use of FET has also demonstrated its potential in targeting biopsy sites, delineating extent of glioma, and diagnosing recurrence with a positive predictive value of 84%, as described by Mehrkens et al.7 Baseline FET uptake also seems predictive of outcome in low-grade glioma and may help evaluate therapeutic response.714 However, PET using FET is not yet considered routine and is not allowed in French centers in daily practice.

Thus, this prospective study aimed to assess the feasibility of FET synthesis in a conventional PET unit and the suitability of FET-PET in routine practice. We also aimed to consolidate the promising results concerning FET uptake in a homogeneous group of adult patients with newly diagnosed high-grade glioma. We sought to demonstrate clinically significant uptake similar to that described in the literature on high-grade glioma, ie, a tumor-to-brain ratio of 2.6 We consider such results to be indispensable prerequisites for further discussion of FET-PET indications in clinical neurooncology practice.

METHODS

PATIENTS

Between June 2005 and November 2006, 14 adult patients were screened in our unit. Clinical and magnetic resonance imaging data were discussed during a multidisciplinary session. Only patients with strong suspicion of high-grade glioma (grade III or IV) requiring histological analysis were selected. Details and objectives of the study were explained to the patients, and their written informed consent was obtained. The study protocol was approved by the ethics committee of our institution.

Positron emission tomography using FET was performed in 12 patients. In 2 patients, imaging could not be carried out in time owing to a technical problem.

Diagnosis of glioblastoma was histologically confirmed in 11 patients. One patient with brain metastasis of an epidermoid carcinoma was excluded from analysis in accordance with the provisions of the protocol.

Histological analysis was assessed within 10 days of the multidisciplinary session, either by biopsy or surgical resection, using the World Health Organization 2000 classification of tumors of the nervous system.

The amino acid tracer FET was produced according to the method described by Wester et al3 using a 2-step reaction. The fully automated FET synthesis was performed by the research unit of our university using the Synchrom synthesis module (Raytest GmbH, Straubenhardt, Germany). The total time required for synthesis was about 58 minutes, with radiochemical purity of more than 98% and a radiochemical yield of about 15%.

Positron emission tomography was performed within 10 days of the multidisciplinary session and no more than 10 days before histological confirmation. Images were acquired using an Exact HR+ camera (CTI/Siemens, Knoxville, Tennessee).

The frames were imported into a Mirage console (Segami Corporation, Columbia, Maryland) to draw the regions of interest (ROI). The procedure was robust and brief (<5 minutes). Uptake of FET was determined using the standard uptake value in each ROI according to accepted procedures.

The transaxial slice showing the highest activity was chosen, and an isocontour region was automatically drawn around the maximal intensity of uptake (Cmax) and around regions corresponding to 85% and 75% of Cmax (C85 and C75). As a reference, similarly sized ROI were drawn in analogous, normal-appearing regions of the contralateral hemisphere (Nmax, N85, and N75, respectively). Tumor to brain ratios were calculated and called, respectively, Rmax, R85, and R75.

An isocontour region corresponding to Cmax was also drawn in healthy gray matter, using the contralateral cortical band (Ngm) and used to calculate a brain to tumor ratio (Rgmax).

STATISTICAL ANALYSIS

All standard uptake value to normal brain ratios were tested for normality and are given as mean (standard deviation). To estimate whether standard uptake value ratios were higher than the theoretical value of 2 previously reported by Weber et al,6 we used a 1-tailed t test. Mean comparisons between standard uptake value ratios were done using balanced repeated-measures analyses of variance to take into account intraindividual variability.

The time to peak uptake was defined for each subject as the time to maximal uptake. We estimated the decreasing slope from peak uptake to the last frame using a mixed model analysis with random intercepts. Analysis was performed using Stata 9.0 software (Stata Corporation, College Station, Texas).

RESULTS

All patients showed significantly higher FET uptake in intracerebral lesions than in normal gray matter (Figure) or the contralateral hemisphere.

Place holder to copy figure label and caption
Figure.

Visual evaluation of O-(2-[18F]-fluoroethyl)-L-tyrosine uptake in a patient with glioblastoma (A) and magnetic resonance imaging of the same patient (B) are shown with coregistered images (C).

Graphic Jump Location

The tumor to brain ratio was significantly different from the theoretical value of 2 for all patients. The ratio for R75 was 3.16 (0.76) (P < .001); R85, 3.31 (0.71) (P < .001); Rmax, 3.33 (0.64) (P < .001); and Rgmax, 3.20 (0.92) (P = .002).

COMMENT

This study confirms that FET synthesis is feasible and that FET-PET can be carried out during a routine diagnostic procedure for patients with glioma. Synthesis of FET requires a radiopharmaceutical unit, but FET can also be purchased and is already commercialized in Europe. Unlike carbon 11–labeled methionine, the 109.7-minute half-life of this 18F-radiolabeled tracer allows its application under similar conditions to the widely used fludeoxyglucose, with centralized synthesis and distribution to the PET center without an on-site cyclotron. The radiation burden is low (mean effective dose, 3 mSv for each examination).8

In this homogeneous group of patients, we confirm the promising results previously reported in the literature with this radiolabeled tracer.5,6,14,15 Uptake of FET in malignant brain tumors is elevated, with an R75 of 3.16 (95% confidence interval, 2.70-3.61), and is significantly higher than the theoretical value of 2. These results suggest that FET-PET may be as clinically useful as MET-PET in the imaging of glioma.

Merkhens et al7 have demonstrated promising results, with a positive predictive value of 84%, for diagnosis of glioma progression. The population of patients evaluated in this study (31 patients with suspicion of glioma recurrence after various forms of treatment) is different from ours (newly diagnosed patients included before any treatment). However, their results strengthen the interest of FET-PET in the management of glioma.

The most appropriate method of calculating tumor to brain ratio must also be discussed. Various methods have been described in the literature; we have used several to measure FET uptake (several ROI were considered, and uptake ratio was defined using either gray matter or contralateral, same-sized, mirrored ROI as a reference). The results did not significantly differ with either method (P = .44).

In our study, the Cmax ROI represented a single pixel for all patients. The possibility that a quantification procedure based on a single pixel could be inaccurate must be considered, so R85 or R75 seemed to be the most relevant choice.

Our findings confirm that radiosynthesis of FET is effective and can be routinely used in a PET center. We demonstrate, in a homogeneous group of patients with newly diagnosed, histologically proven glioblastoma, that FET uptake is highly discriminant with respect to the normal brain. This study may be considered preliminary, and a multicenter trial aiming to pursue these possibilities is currently under way.

ARTICLE INFORMATION

Correspondence: Alexandra Benouaich-Amiel, MD, Pole NeuroSciences, CHU Toulouse Purpan, Place du Dr Baylac, 31059 Toulouse Cedex, France (benouaich-amiel.a@chu-toulouse.fr).

Financial Disclosure: None reported.

Funding/Support: This study was supported by local Toulouse University Hospital grant 2004.

Additional Contributions: We thank the teams at the Centre of Clinical Investigation of Toulouse Hospital and the Coordination Chemistry Laboratory of Toulouse for their contributions to the study. We are also grateful to the patients for their cooperation. We thank the positron emission tomography center technicians and nurses for their participation and motivation.

REFERENCES

Bénard  FRomsa  JHustinx  R Imaging gliomas with positron emission tomography and single-photon emission computed tomography. Semin Nucl Med 2003;33 (2) 148- 162
PubMed Link to Article
Chen  W Clinical applications of PET in brain tumors. J Nucl Med 2007;48 (9) 1468- 1481
PubMed Link to Article
Wester  HJHerz  MWeber  W  et al.  Synthesis and radiopharmacology of O-(2-[18F]fluoroethyl)-L-tyrosine for tumor imaging. J Nucl Med 1999;40 (1) 205- 212
PubMed
Hamacher  KCoenen  HH Efficient routine production of the 18F-labelled amino acid O-2-18F fluoroethyl-L-tyrosine. Appl Radiat Isot 2002;57 (6) 853- 856
PubMed Link to Article
Pauleit  DFloeth  FHamacher  K  et al.  O-(2-[18F]fluoroethyl)-L-tyrosine PET combined with MRI improves the diagnostic assessment of cerebral gliomas. Brain 2005;128 (pt 3) 678- 687
PubMed Link to Article
Weber  WAWester  HJGrosu  AL  et al.  O-(2-[18F]fluoroethyl)-L-tyrosine and L-[methyl-11C]methionine uptake in brain tumours: initial results of a comparative study. Eur J Nucl Med 2000;27 (5) 542- 549
PubMed Link to Article
Mehrkens  JHPopperl  GRachinger  W  et al.  The positive predictive value of O-(2-[18F]fluoroethyl)-L-tyrosine (FET) PET in the diagnosis of a glioma recurrence after multimodal treatment. J Neurooncol 2008;88 (1) 27- 35
PubMed Link to Article
Langen  K-JHamacher  KWeckesser  M  et al.  O-(2-[18F]fluoroethyl)-L-tyrosine: uptake mechanisms and clinical applications. Nucl Med Biol 2006;33 (3) 287- 294
PubMed Link to Article
Floeth  FWPauleit  DWittsack  HJ  et al.  Multimodal metabolic imaging of cerebral gliomas: positron emission tomography with [18F]fluoroethyl-L-tyrosine and magnetic resonance spectroscopy. J Neurosurg 2005;102 (2) 318- 327
PubMed Link to Article
Pöpperl  GGoldbrunner  RGildehaus  FJ  et al.  O-(2-[18F]fluoroethyl)-L-tyrosine PET for monitoring the effects of convection-enhanced delivery of paclitaxel in patients with recurrent glioblastoma. Eur J Nucl Med Mol Imaging 2005;32 (9) 1018- 1025
PubMed Link to Article
Pöpperl  GGötz  CRachinger  WGildehaus  FJTonn  JCTatsch  K Value of O-(2-[18F]fluoroethyl)- L-tyrosine PET for the diagnosis of recurrent glioma. Eur J Nucl Med Mol Imaging 2004;31 (11) 1464- 1470
PubMed Link to Article
Popperl  GGotz  CRachinger  W  et al.  Serial O-(2-[(18)F]fluoroethyl)-L-tyrosine PET for monitoring the effects of intracavitary radioimmunotherapy in patients with malignant glioma. Eur J Nucl Med Mol Imaging 2006;33 (7) 792- 800
PubMed Link to Article
Pöpperl  GKreth  FWHerms  J  et al.  Analysis of 18F-FET PET for grading of recurrent gliomas: is evaluation of uptake kinetics superior to standard methods? J Nucl Med 2006;47 (3) 393- 403
PubMed
Pöpperl  GKreth  FWMehrkens  JH  et al.  FET PET for the evaluation of untreated gliomas: correlation of FET uptake and uptake kinetics with tumour grading. Eur J Nucl Med Mol Imaging 2007;34 (12) 1933- 1942
PubMed Link to Article
Weckesser  MLangen  KJRickert  CH  et al.  O-(2-[18F]fluorethyl)-L-tyrosine PET in the clinical evaluation of primary brain tumours. Eur J Nucl Med Mol Imaging 2005;32 (4) 422- 429
PubMed Link to Article

Figures

Place holder to copy figure label and caption
Figure.

Visual evaluation of O-(2-[18F]-fluoroethyl)-L-tyrosine uptake in a patient with glioblastoma (A) and magnetic resonance imaging of the same patient (B) are shown with coregistered images (C).

Graphic Jump Location

Tables

References

Bénard  FRomsa  JHustinx  R Imaging gliomas with positron emission tomography and single-photon emission computed tomography. Semin Nucl Med 2003;33 (2) 148- 162
PubMed Link to Article
Chen  W Clinical applications of PET in brain tumors. J Nucl Med 2007;48 (9) 1468- 1481
PubMed Link to Article
Wester  HJHerz  MWeber  W  et al.  Synthesis and radiopharmacology of O-(2-[18F]fluoroethyl)-L-tyrosine for tumor imaging. J Nucl Med 1999;40 (1) 205- 212
PubMed
Hamacher  KCoenen  HH Efficient routine production of the 18F-labelled amino acid O-2-18F fluoroethyl-L-tyrosine. Appl Radiat Isot 2002;57 (6) 853- 856
PubMed Link to Article
Pauleit  DFloeth  FHamacher  K  et al.  O-(2-[18F]fluoroethyl)-L-tyrosine PET combined with MRI improves the diagnostic assessment of cerebral gliomas. Brain 2005;128 (pt 3) 678- 687
PubMed Link to Article
Weber  WAWester  HJGrosu  AL  et al.  O-(2-[18F]fluoroethyl)-L-tyrosine and L-[methyl-11C]methionine uptake in brain tumours: initial results of a comparative study. Eur J Nucl Med 2000;27 (5) 542- 549
PubMed Link to Article
Mehrkens  JHPopperl  GRachinger  W  et al.  The positive predictive value of O-(2-[18F]fluoroethyl)-L-tyrosine (FET) PET in the diagnosis of a glioma recurrence after multimodal treatment. J Neurooncol 2008;88 (1) 27- 35
PubMed Link to Article
Langen  K-JHamacher  KWeckesser  M  et al.  O-(2-[18F]fluoroethyl)-L-tyrosine: uptake mechanisms and clinical applications. Nucl Med Biol 2006;33 (3) 287- 294
PubMed Link to Article
Floeth  FWPauleit  DWittsack  HJ  et al.  Multimodal metabolic imaging of cerebral gliomas: positron emission tomography with [18F]fluoroethyl-L-tyrosine and magnetic resonance spectroscopy. J Neurosurg 2005;102 (2) 318- 327
PubMed Link to Article
Pöpperl  GGoldbrunner  RGildehaus  FJ  et al.  O-(2-[18F]fluoroethyl)-L-tyrosine PET for monitoring the effects of convection-enhanced delivery of paclitaxel in patients with recurrent glioblastoma. Eur J Nucl Med Mol Imaging 2005;32 (9) 1018- 1025
PubMed Link to Article
Pöpperl  GGötz  CRachinger  WGildehaus  FJTonn  JCTatsch  K Value of O-(2-[18F]fluoroethyl)- L-tyrosine PET for the diagnosis of recurrent glioma. Eur J Nucl Med Mol Imaging 2004;31 (11) 1464- 1470
PubMed Link to Article
Popperl  GGotz  CRachinger  W  et al.  Serial O-(2-[(18)F]fluoroethyl)-L-tyrosine PET for monitoring the effects of intracavitary radioimmunotherapy in patients with malignant glioma. Eur J Nucl Med Mol Imaging 2006;33 (7) 792- 800
PubMed Link to Article
Pöpperl  GKreth  FWHerms  J  et al.  Analysis of 18F-FET PET for grading of recurrent gliomas: is evaluation of uptake kinetics superior to standard methods? J Nucl Med 2006;47 (3) 393- 403
PubMed
Pöpperl  GKreth  FWMehrkens  JH  et al.  FET PET for the evaluation of untreated gliomas: correlation of FET uptake and uptake kinetics with tumour grading. Eur J Nucl Med Mol Imaging 2007;34 (12) 1933- 1942
PubMed Link to Article
Weckesser  MLangen  KJRickert  CH  et al.  O-(2-[18F]fluorethyl)-L-tyrosine PET in the clinical evaluation of primary brain tumours. Eur J Nucl Med Mol Imaging 2005;32 (4) 422- 429
PubMed Link to Article

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