Clinical Investigation
An Interindividual Comparison of O-(2- [18F]Fluoroethyl)-L-Tyrosine (FET)– and L-[Methyl-11C]Methionine (MET)–PET in Patients With Brain Gliomas and Metastases

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Purpose

L-[methyl-11C]methionine (MET)–positron emission tomography (PET) has a high sensitivity and specificity for imaging of gliomas and metastatic brain tumors. The short half-life of 11C (20 minutes) limits the use of MET-PET to institutions with onsite cyclotron. O-(2- [18F]fluoroethyl)-L-tyrosine (FET) is labeled with 18F (half-life, 120 minutes) and could be used much more broadly. This study compares the uptake of FET and MET in gliomas and metastases, as well as treatment-induced changes. Furthermore, it evaluates the gross tumor volume (GTV) of gliomas defined on PET and magnetic resonance imaging (MRI).

Methods and Materials

We examined 42 patients with pretreated gliomas (29 patients) or brain metastases (13 patients) prospectively by FET- and MET-PET on the same day. Uptake of FET and MET was quantified by standardized uptake values. Imaging contrast was assessed by calculating lesion–to–gray matter ratios. Tumor extension was quantified by contouring GTV in 17 patients with brain gliomas. Gross tumor volume on PET was compared with GTV on MRI. Sensitivity and specificity of MET- and FET-PET for differentiation of viable tumor from benign changes were evaluated by comparing the PET result with histology or clinical follow-up.

Results

There was a strong linear correlation between standardized uptake values calculated for both tracers in cortex and lesions: r = 0.78 (p = 0.001) and r = 0.84 (p < 0.001), respectively. Image contrast was similar for MET- and FET-PET (lesion–to–gray matter ratios of 2.36 ± 1.01 and 2.33 ± 0.77, respectively). Mean GTV in 17 glioma patients was not significantly different on MET- and FET-PET. Both MET- and FET-PET delineated tumor tissue outside of MRI changes. Both tracers provided differentiated tumor tissue and treatment-related changes with a sensitivity of 91% at a specificity of 100%.

Conclusions

O-(2- [18F]fluoroethyl)-L-tyrosine–PET and MET-PET provide comparable diagnostic information on gliomas and brain metastases. Like MET-PET, FET-PET can be used for differentiation of residual or recurrent tumor from treatment-related changes/pseudoprogression, as well as for delineation of gliomas.

Introduction

In brain tumors treatment planning and evaluation of local response to therapy are usually based on magnetic resonance imaging (MRI) and computed tomography (CT). These investigations show the anatomy of the brain with high accuracy. However, the correlation between real tumor extension and the radiologic imaging of the malignant tissue on CT or MRI is quite different for gliomas and brain metastases. In brain gliomas stereotactic biopsy specimens showed that malignant tissue could be located far beyond the margins of the tumor visualized on MRI or CT 1, 2, 3, 4. In contrast, in brain metastases the correlation between real tumor extension and the imaging of the lesions on MRI or CT is very high 5, 6, 7. In both gliomas and metastases treatment-related changes (TRCs) (after radiochemotherapy, also called “pseudoprogression”) such as blood–brain barrier (BBB) disturbance or edema can generally not be differentiated from viable tumor tissue 8, 9.

Several studies suggest that because of its high sensitivity and specificity for tumor tissue, L-[methyl-11C]methionine (MET)–positron emission tomography (PET) is a useful tool for the visualization of brain tumors 10, 11, 12, 13, 14, 15. MET is transported across the BBB by the L-type amino acid transport system and intensely accumulated by tumor cells. Disruption of the BBB is therefore not necessary for MET accumulation in the tumor tissue. In a intracellular manner, MET can enter multiple metabolic pathways. However, studies have indicated that at the time of PET imaging, tumor uptake of MET mainly reflects AA transport (16). When we compare CT, MRI, and MET-PET with stereotactic biopsy in brain gliomas, MET-PET has shown a significantly higher accuracy in defining the extent of tumor than CT and MRI 10, 11, 12, 13, 14, 15. Therefore MET-PET can improve tumor delineation for surgery 17, 18 or radiation therapy planning 19, 20, 21 and could have an impact on the evaluation of treatment outcome. Nevertheless, the application of MET-PET has been limited to a small number of research centers, because the short physical half-life of 11C (20 minutes) necessitates an onsite cyclotron for MET-PET examinations.

O-(2- [18F]fluoroethyl)-L-tyrosine (FET) is an analog of tyrosine that is not metabolized and not incorporated into proteins. The uptake by tumor cells is mediated by the L-type AA transport system 22, 23. The sensitivity and specificity for tumor tissue, evaluated by use of stereotactic biopsy specimens, are higher for FET-PET than for MRI and CT 24, 25, 26. In contrast to MET the physical half-life for 18F (110 minutes) allows FET-PET studies to be performed in centers without an onsite cyclotron. Similar transport characteristics for FET and MET were shown in studies using F98 rat glioma cells (27). In a previous clinical study we observed a close correlation between the intensity of MET and FET uptake in tumoral and non-tumoral cerebral lesions (28). However, this trial included only 16 patients and did not assess differences in tumor extension between the two imaging modalities.

The aim of this study was to perform an intraindividual comparison of FET-PET and MET-PET in patients with brain gliomas or metastases. Tracer uptake in normal and tumor tissue, sensitivity and specificity for differentiation of tumor tissue vs. TRCs, and macroscopic tumor extension were compared for FET-PET and MET-PET.

Section snippets

Patients

Forty-two consecutive patients were included in the study within 24 months. All patients had previously been treated for gliomas or brain metastases (Table 1) and now presented with MRI findings suggesting the presence of residual or recurrent tumor tissue. Of the patients, 29 had a high-grade (n = 25) or low-grade (n = 4) glioma and 13 had had brain metastases. The patient population includes 16 patients who were reported on previously (28).

In all patients the two FET- and MET-PET studies were

Uptake of MET and FET in normal gray matter and lesions

Time–activity curves showed a similar time course of MET and FET uptake by normal gray matter and lesions. L-[methyl-11C]methionine uptake reached a plateau within 10 minutes. O-(2- [18F]fluoroethyl)-L-tyrosine uptake was somewhat slower and plateaued within 20 minutes. Thus, for further analysis, MET-PET images were summed between 10 and 30 minutes part injection, and FET-PET images were summed between 20 and 40 minutes p.i.

For the whole group, the mean SUV on FET-PET was 2.3 ± 0.9 (range,

Discussion

We found a high correlation between the uptake of MET and FET in normal cortex and tumor tissue (brain gliomas and metastases). In gliomas both PET investigations give additional information in comparison to MRI concerning the location of the residual/progressive tumor. Both FET- and MET-PET showed a high sensitivity and specificity for tumor tissue of 91% and 100%, respectively, making it possible to differentiate brain gliomas and metastases from TRCs. These findings support the use of FET as

Conclusion

This is the first larger trial evaluating the use of FET-PET in comparison to MET-PET in determining tumor extension for treatment planning and monitoring in gliomas and brain metastases in the same group of patients investigated with both tracers within the same day. The study included patients with brain lesions (gliomas and metastases) after therapy: surgery, radiation therapy, and chemotherapy. The study showed that FET-PET and MET-PET provide comparable diagnostic information: (1) Uptake

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