Journal of Nuclear Medicine, published on August 7, 2012 as doi:10.2967/jnumed.112.103325 Role of O-(2-18F-Fluoroethyl)-L-Tyrosine PET for Differentiation of Local Recurrent Brain Metastasis from Radiation Necrosis Norbert Galldiks1,2, Gabriele Stoffels1,3, Christian P. Filss1,3, Marc D. Piroth3,4, Michael Sabel5, Maximilian I. Ruge6, Hans Herzog1,3, Nadim J. Shah1,3, Gereon R. Fink1,2, Heinz H. Coenen1,3, and Karl-Josef Langen1,3 1Institute of Neuroscience and Medicine (INM-3,-4,-5), Forschungszentrum Julich,¨ Julich,¨ Germany; 2Department of Neurology, University of Cologne, Cologne, Germany; 3JARA-Brain Section, Julich¨ Aachen Research Alliance (JARA), Julich,¨ Germany; 4Department of Radiation Oncology, RWTH Aachen University Hospital, Aachen, Germany; 5Department of Neurosurgery, University Hospital Dusseldorf,¨ Dusseldorf,¨ Germany; and 6Department for Stereotaxy and Functional Neurosurgery, University of Cologne, Cologne, Germany local recurrent metastasis was obtained when both a TBRmean The aim of this study was to investigate the potential of greater than 1.9 and curve pattern II or III were present (AUC, 6 P , O-(2-18F-fluoroethyl)-L-tyrosine (18F-FET) PET for differentiating 0.959 0.03; sensitivity, 95%; specificity, 91%; 0.001). local recurrent brain metastasis from radiation necrosis after Conclusion: Our findings suggest that the combined evaluation 18 radiation therapy because the use of contrast-enhanced MRI of the TBRmean of F-FET uptake and the pattern of the time– for this issue is often difficult. Methods: Thirty-one patients activity curve can differentiate local brain metastasis recurrence (mean age 6 SD, 53 6 11 y) with single or multiple contrast- from radionecrosis with high accuracy. 18F-FET PET may thus enhancing brain lesions (n 5 40) on MRI after radiation therapy contribute significantly to the management of patients with of brain metastases were investigated with dynamic 18F-FET brain metastases. PET. Maximum and mean tumor-to-brain ratios (TBRmax and Key Words: radiation necrosis; stereotactic radiosurgery; recurrent 18 18 18 TBRmean, respectively; 20–40 min after injection) of F-FET up- brain metastasis; amino acid PET; F-fluoroethyl-L-tyrosine ( F- take were determined. Time–activity curves were generated, FET) and the time to peak (TTP) was calculated. Furthermore, J Nucl Med 2012; 53:1–8 time–activity curves of each lesion were assigned to one of DOI: 10.2967/jnumed.112.103325 the following curve patterns: (I) constantly increasing 18F-FET uptake, (II) 18F-FET uptake peaking early (TTP # 20 min) fol- lowed by a plateau, and (III) 18F-FET uptake peaking early (TTP # 20 min) followed by a constant descent. The diagnostic 18 accuracy of the TBRmax and TBRmean of F-FET uptake and the he improvement in the treatment of solid tumors has curve patterns for the correct identification of recurrent brain T metastasis were evaluated by receiver-operating-characteristic led to an increasing number of patients who experience analyses or Fisher exact test for 2 · 2 contingency tables using brain metastases during the course of the disease. Stereo- subsequent histologic analysis (11 lesions in 11 patients) or tactic radiosurgery (SRS) and whole-brain radiation therapy clinical course and MRI findings (29 lesions in 20 patients) as (WBRT) are commonly used to treat brain metastases, and Results: reference. Both TBRmax and TBRmean were signifi- a growing percentage of patients live long enough to expe- n 5 cantly higher in patients with recurrent metastasis ( 19) than rience a local relapse of these metastases. Thus, the number in patients with radiation necrosis (n 5 21) (TBR , 3.2 6 0.9 max of patients experiencing local recurrence of previously ir- vs. 2.3 6 0.5, P , 0.001; TBRmean, 2.1 6 0.4 vs. 1.8 6 0.2, P , 0.001). The diagnostic accuracy of 18F-FET PET for the correct radiated brain metastases can be expected to increase. identification of recurrent brain metastases reached 78% using Contrast-enhanced MRI is the method of choice for the TBRmax (area under the ROC curve [AUC], 0.822 6 0.07; sen- evaluation of metastatic brain tumors. However, in many sitivity, 79%; specificity, 76%; cutoff, 2.55; P 5 0.001), 83% patients, the differentiation of local recurrent brain metas- 6 using TBRmean (AUC, 0.851 0.07; sensitivity, 74%; specificity, tasis from radiation necrosis after radiotherapy (e.g., SRS P , 90%; cutoff, 1.95; 0.001), and 92% for curve patterns II or WBRT) using contrast-enhanced MRI is difficult (1). and III versus curve pattern I (sensitivity, 84%; specificity, This problem necessitates novel diagnostic methods for 100%; P , 0.0001). The highest accuracy (93%) to diagnose the follow-up and management of patients with recurrent Received Jan. 19, 2012; revision accepted Apr. 2, 2012. brain metastases. For correspondence or reprints contact: Norbert Galldiks, Institute of In addition to MRI, PET using 18F-FDG (2) has been Neuroscience and Medicine, Forschungszentrum Ju¨ lich, 52425 Ju¨ lich, Germany. considered for the evaluation of metastatic brain tumors, E-mail: [email protected] but the high physiologic glucose consumption of the brain Published online nnnn. COPYRIGHT ª 2012 by the Society of Nuclear Medicine and Molecular and the variable glucose uptake of metastatic brain lesions Imaging, Inc. limit its use. For example, in a study of 48 patients with 18F-FET PET AND BRAIN METASTASES • Galldiks et al. 1 jnm103325-pm n 8/2/12 Copyright 2012 by Society of Nuclear Medicine. lung cancer and brain metastasis, 33% of the brain lesions suggestive MRI findings such as newly contrast-enhancing lesions showed hypometabolism on 18F-FDG PET, although all or progression of contrast enhancement at the site of the initial primary lung lesions were hypermetabolic (3). Another metastasis, in order to differentiate local recurrent brain metastasis 18 study demonstrated that after SRS using a g-knife, 18F- from radiation necrosis using F-FET PET. All patients had been FDG PET is not sensitive enough to differentiate viable previously treated with SRS (range of radiation dose, 8–25 Gy) and partly with WBRT (range of radiation dose, 20–30 Gy). The brain metastases from radiation necrosis (4). A recent study, median interval between radiotherapy and PET was 11.5 mo. All however, indicated that dual-phase imaging may improve patients gave written informed consent to the PET investigation. 18 the diagnostic accuracy of F-FDG PET for the differen- Histopathologic results for definite diagnosis were available tiation of recurrent brain metastasis from radiation necrosis for 11 patients (11 lesions). For the remaining patients, diagnosis (5). A limitation of that approach is the long time interval of recurrent brain metastasis or radiation necrosis was based on between PET scans (2–5.7 h). Therefore, alternative imag- the clinical course and results of MRI in the further follow-ups. ing methods are still of great interest. Recurrent disease was anticipated if a new contrast-enhancing Amino acid tracers are particularly useful for PET in lesion appeared at exactly the same site as the treated metastasis neurooncology because of a high amino acid uptake in after initial complete response, if the treated metastasis grew tumor tissue together with low uptake in normal brain during follow-up according to the Macdonald criteria (22)(in- . tissue, resulting in an enhanced tumor–to–normal tissue crease of 25% in the pretreated volume on contrast-enhanced T1-weighted MR images), or if new neurologic deficits or an contrast. Previously, it has been shown that PET using 11 11 exacerbation of existing neurologic symptoms occurred. Radia- L-[methyl- C]methionine ( C-MET) may be effective in tion necrosis or unspecific posttherapeutic changes in the tissue differentiating recurrent metastatic brain tumor from radi- were assumed when the lesions showed spontaneous shrinkage ation-induced changes with a sensitivity of 78% and a spec- or remained stable in size on contrast-enhanced MRI after a ificity of 100%, respectively (6). In a subsequent study (7) long-term follow-up (median time, 12 mo) and neurologic de- with a larger number of patients (n 5 51), these findings ficits remained unchanged or no new neurologic symptoms could be confirmed, at least in part, with similar sensitivity occurred. (79%) but with lower specificity (75%). The use of 11C- 18 MET, however, remains restricted to centers with an on-site PET with F-FET and Data Analysis cyclotron because of the short half-life of the 11C isotope The amino acid 18F-FET was produced via nucleophilic 18F- (20 min). In contrast, amino acids labeled with 18F (half- fluorination with a specific radioactivity of greater than 200 GBq/ mmol as described previously (11). The radiochemical yield of life, 110 min) such as O-(2-18F-fluoroethyl)-L-tyrosine (18F- tracer was about 60%–65% at a radiochemical purity greater than FET) allow a more widespread use and can be distributed 98%. The tracer was administered as isotonic neutral solution. via the satellite concept as has been shown with the widely According to the German guidelines for brain tumor imaging 18 used F-FDG (8–11). Several studies have demonstrated using labeled amino acid analogs, all patients fasted for at least the clinical utility of 18F-FET PET, especially in the diag- 12 h before PET (23). Dynamic PET studies were acquired up to nostics and therapy assessment of cerebral gliomas (12– 50 min after intravenous injection of approximately 200 MBq of 14). The tracer exhibits high in vivo stability, low uptake 18F-FET on an ECAT EXACT HR1 scanner (Siemens Medical in inflammatory tissue, and suitable uptake kinetics for Systems, Inc.) in 3-dimensional mode (32 rings; axial field of clinical imaging (15–17). Contrast-enhancing nontumoral view, 15.5 cm). The emission recording consisted of 16 time tissue on MRI, for example, due to radionecrosis, is usually frames (1–5, 1 min; 6–10, 3 min; and 11–16, 5 min) covering negative on 18F-FET PET (14).