Clinical impact of amino acid PET in gliomas.

With an incidence of 20.5 per 100,000 people each year, tumors of the central nervous system are a heterogeneous group, with meningiomas (35.5%) and gliomas (30%) being the most common (1). Although 97% of meningiomas are benign, 54% of gliomas are highly malignant glioblastomas of World Health Organization (WHO) grade IV. Survival rates are 35.7% at 1 y and 4%–7% at 5 y for glioblastoma, 60%–80% at 1 y and 26%–46% at 5 y for astrocytomas and oligodendrogliomas of WHO grade III, and 94% at 1 y and 67% at 5 y for astrocytomas and oligodendrogliomas of WHO grade II (2). Additionally, the central nervous system may be invaded by metastases from other malignancies. Brain tumors create structural lesions whose diagnosis is primarily dependent on imaging with CT and MR. However, it is possible to improve clinical management by using PET to provide physiologic and biochemical information on tumor metabolism, proliferation rate, and invasiveness, as well as to determine the relationship of the tumor to important functional tissue and to monitor the effects of treatment (3). Imaging of brain tumors with 18F-FDG was the first oncologic application of PET. As in other malignancies, glucose consumption is increased in brain tumors, especially in malignant gliomas, but differentiating tumors from normal tissue or nontumorous lesions is often difficult because of the high metabolism in normal cortex. 18FFDG uptake in low-grade tumors is usually similar to that in normal white matter, and uptake in high-grade tumors can be less than or similar to that in normal gray matter. The sensitivity of detection of lesions is further decreased by the high variance of 18F-FDG uptake and its heterogeneity within a single tumor. Labeled amino acids and their analogs are particularly attractive for imaging brain tumors because of the high uptake in tumor tissue and low uptake in normal brain. This increased amino acid uptake, especially in gliomas, is not a direct measure of protein synthesis or dependent on blood–brain barrier breakdown but rather is related to increased transport mediated by type L amino acid carriers: facilitated transport is upregulated because of the increased transporter expression in tumor vasculature (4). Additionally, the countertransport system A is overexpressed in neoplastic cells and seems to correlate positively with the rate of tumor cell growth (5). Therefore, elevated transport of amino acids not only is a result of increased protein synthesis but also reflects the increased demand by different types of metabolism in the tumor cell. The most frequently used radiolabeled amino acid is methyl-11CL-methionine (MET) (6,7). Especially in low-grade gliomas, amino acid uptake is related to prognosis and survival. With regard to tumor extent and infiltration into surrounding tissue, assessment of amino acid uptake is superior to measurement of glucose consumption (8) and toconventional contrast-enhancedMRimaging (9)orMRspectroscopy (10). 11C-MET PET detects solid parts of tumors as well as the infiltration zone with high sensitivity and specificity (11). Because 11Clabeled tracers can be used only in centers with an onsite cyclotron, amino acids were recently labeled with 18F-fluorine to facilitate wider use. Clinically relevant findings have been obtainedmainly with two of them: O-(2-18F-fluoroethyl)-L-tyrosine (FET) and 6-18F-fluoro-L-dopa (FDOPA). 18F-FETand 18F-FDOPA are transported into the brain and tumor but are not further metabolized. Thus, they—in contrast to 11CMET—reflect transport only. Tumor uptake of 18F-FET and 18FFDOPA is similar to that of 11C-MET (6,7,12,13). 18F-FET PET is well suited for differential diagnosis of primary brain tumors (14) and for differentiationbetween low-andhigh-gradegliomas. 18F-FETPETalso indicatesmalignant progression of low-gradegliomas during the course of the disease (15). Uptake of 18F-FET is not dependent on changes in the blood–brain barrier but on cell density (16). Dynamic 18F-FET PET may even help to identify high-risk patients (17) and to predict survival (18). In a large study, 18F-FDOPA demonstrated excellent visualization of highand low-grade tumors and was more sensitive and specific than 18F-FDG (19). Especially in newly diagnosed tumors, uptake has been shown to be related to proliferation, whereas this correlation has not been observed in recurrent gliomas (20). In astrocytomas, 18F-FDOPA PET has detected areas with more actively proliferating cell populations (as proven by biopsy) and permitted targeted radiation (21). 18F-fluoro-L-thymidine (FLT) PET in some instances has been superior to amino acid PET for imaging proliferation in different gliomas and may add significant information about invasiveness, but 18F-FDOPAPEThas been found to be superior to 18F-FDG and 18F-FLT in the evaluation of low-grade gliomas (22). Because of the high cortical background activity, 18F-FDG is limited in the detection of residual tumor after therapy. The effects of radiation and chemotherapy can be shown only after a few weeks of treatment, and recurrent tumor or malignant transformation is marked by newly occurring hypermetabolism. Hypermetabolism after radiotherapy, however, can also be mimicked by infiltration of macrophages. With these limitations, 18F-FDG PET is not the preferred method to assess therapeutic effects. For this application, amino acid and nucleoid tracers are better suited. Several studies have suggested that patient outcomes are better when 11C-MET or 18F-FET PET is coregistered to MR imaging than when MR imaging is used alone (23). 11C-MET PET coregistered to MR imaging has high sensitivity and specificity (;75%) for differentiation between recurrent tumor as a sign of treatment failure and necrosis as a sign of success (24,25). Malignant progression in nontreated and treated patients has been detected with high sensitivity and specificity by 11C-MET PET. The volume of metabolically active tumor in recurrent glioblastoma multiforme is underestimated by gadolinium-enhanced MR imaging. In one study, the additional information supplied by 11C-MET PET changed management in half the cases (26). Responses after chemotherapy can be detected by amino acid PET early in the course of disease (27), suggesting that deactivation of Received May 28, 2014; revision accepted Jun. 23, 2014. For correspondence or reprints contact: Wolf-Dieter Heiss, Max Planck Institute for Neurological Research, Gleueler Strasse 50, Cologne 50931, Germany. E-mail: [email protected] COPYRIGHT © 2014 by the Society of Nuclear Medicine and Molecular Imaging, Inc. DOI: 10.2967/jnumed.114.142661