Diagnostic Performance and Safety of Positron Emission Tomography Using 18F-Fluciclovine in Patients with Clinically Suspected High- or Low-grade Gliomas: A Multicenter Phase IIb Trial

Document Type: Original Article


1 Department of Neurosurgery, Nagoya University, Graduate School of Medicine

2 Division of Neurological Surgery, Chiba Cancer Center

3 Department of Neurosurgery, Osaka City University Graduate School of Medicine

4 Department of Neuro-Oncology/Neurosurgery, Saitama International Medical Center, Saitama Medical University

5 Department of Neurosurgery, Kyoto University Graduate School of Medicine

6 Department of Neurosurgery, Kobe University Graduate School of Medicine

7 Department of Neurological Surgery, Faculty of Medicine, Kagawa University

8 Department of Neurosurgery, Tokyo Medical and Dental University

9 Department of Neurosurgery and Neuro-Oncology, National Cancer Center Hospital

10 Department of Neurosurgery, Osaka University Graduate School of Medicine

11 Department of Neurosurgery, Juntendo Tokyo Koto Geriatric Medical Center

12 Integrative Brain Imaging Center, National Center of Neurology and Psychiatry

13 Division of Nuclear Medicine, Department of Radiology, National Center for Global Health and Medicine

14 Department of Radiology, Tokyo Metropolitan Geriatric Hospital and Institute of Gerontology

15 Department of Pathology, Hidaka Hospital

16 Clinical Development Department, Nihon Medi-Physics Co., Ltd.


Objective(s): The study objective was to assess the diagnostic performance of positron emission tomography (PET) for gliomas using the novel tracer 18F-fluciclovine (anti-[18F]FACBC) and to evaluate the safety of this tracer in patients with clinically suspected gliomas.
Methods: Anti-[18F]FACBC was administered to 40 patients with clinically suspected high- or low-grade gliomas, followed by PET imaging. T1-weighted, contrast-enhanced T1-weighted, and fluid-attenuated inversion recovery (or T2-weighted) magnetic resonance imaging (MRI) scans were obtained to plan for the tissue collection. Tissues were collected from either “areas visualized using anti-[18F]FACBC PET imaging but not using contrast-enhanced T1-weighted imaging” or “areas visualized using both anti-[18F]FACBC-PET imaging and contrast-enhanced T1-weighted imaging” and were histopathologically examined to assess the diagnostic accuracy of anti-[18F]FACBC-PET for gliomas.
Results: The positive predictive value of anti-[18F]FACBC-PET imaging for glioma in areas visualized using anti-[18F]FACBC-PET imaging, but not visualized using contrast-enhanced T1- weighted images, was 100.0% (26/26), and the value in areas visualized using both contrastenhanced T1-weighted imaging and anti- [18F]FACBC-PET imaging was 87.5% (7/8). Twelve adverse events occurred in 7 (17.5%) of the 40 patients who received anti-[18F]FACBC. Five events in five patients were considered to be adverse drug reactions; however, none of the events were serious, and all except one resolved spontaneously without treatment.
Conclusion: This Phase IIb trial showed that anti-[18F]FACBC-PET imaging was effective for the detection of gliomas in areas not visualized using contrast-enhanced T1-weighted MRI and the tracer was well tolerated.


Main Subjects

1. Shibui S. Report of brain tumor registry of Japan (1984-2000). Neurol Med Chir (Tokyo). 2009;49(Suppl):PS1-96.
2. Committee of Brain Tumor Registry of Japan. Report of brain tumor registry of Japan (2001-2004). Neurol Med Chir (Tokyo). 2014;54(Suppl):1-102.
3. Nabors LB, Ammirati M, Bierman PJ, Brem H, Butowski N, Chamberlain MC, et al. Central nervous system cancers. J Natl Compr Canc Netw. 2013;11(9):1114-51.
4. Sanai N, Berger MS. Glioma extent of resection and its impact on patient outcome. Neurosurgery. 2008;62(4):753-64.
5. Youland RS, Brown PD, Giannini C, Parney IF, Uhm JH, Laack NN. Adult low-grade glioma: 19-year experience at a single institution. Am J Clin Oncol. 2013;36(6):612-9.
6. Tanaka Y, Nariai T, Momose T, Aoyagi M, Maehara T, Tomori T, et al. Glioma surgery using a multimodal navigation system with integrated metabolic images. J Neurosurg. 2009;110(1):163-72.
7. Stummer W, Pichlmeier U, Meinel T, Wiestler OD, Zanella F, Reulen HJ, et al. Fluorescence-guided surgery with 5-aminolevulinic acid for resection of malignant glioma: a randomised controlled multicentre phase III trial. Lancet Oncol. 2006;7(5):392-401.
8. Miwa K, Shinoda J, Yano H, Okumura A, Iwama T, Nakashima T, et al. Discrepancy between lesion distributions on methionine PET and MR images in patients with glioblastoma multiforme: insight from a
PET and MR fusion image study. J Neurol Neurosurg Psychiatry. 2004;75(10):1457-62.
9. Pauleit D, Floeth F, Hamacher K, Riemenschneider MJ, Reifenberger G, Müller HW, et al. O-(2-[18F]fluoroethyl)-L-tyrosine PET combined with MRI improves thediagnostic assessment of cerebral gliomas. Brain.2005;128(Pt 3):678-87.
10. Floeth FW, Pauleit D, Sabel M, Stoffels G, Reifenberger G, Riemenschneider MJ, et al. Prognostic value of O-(2-18F-fluoroethyl)-L-tyrosine PET and MRI in low-grade glioma. J Nucl Med. 2007; 48(4): 519-27.
11. Nariai T, Tanaka Y, Wakimoto H, Aoyagi M, Tamaki M, Ishiwata K, et al. Usefulness of L-[methyl-11C]methionine-positron emission tomography as a biological monitoring tool in the treatment of glioma.
J Neurosurg. 2005;103(3):498-507.
12. Van Laere K, Ceyssens S, Van Calenbergh F, de Groot T, Menten J, Flamen P, et al. Direct comparison of 18F-FDG and 11C-methionine PET in suspected recurrence of glioma: sensitivity, inter-observer variability and prognostic value. Eur J Nucl Med Mol Imaging. 2005; 32(1):39-51.
13. The PET Nuclear Medicine Committee of the Japanese Society of Nuclear Medicine. The ninth report of a questionnaire survey on the number of PET examinations. Isotope N. 2012;697(5):26-30.
14. Ono M, Oka S, Okudaira H, Schuster DM, Goodman MM, Kawai K, et al. Comparative evaluation of transport mechanisms of trans-1-amino-3-[18F] fluorocyclobutanecarboxylic acid and L-[methyl-¹¹C]
methionine in human glioma cell lines. Brain Res.2013;1535:24-37.
15. Oka S, Okudaira H, Ono M, Schuster DM, Goodman MM, Kawai K, et al. Differences in transport mechanisms of trans-1-amino-3-[18F] fluorocyclobutanecarboxylic acid in inflammation, prostate cancer, and gliomacells: comparison with L-[methyl-11C] methionine and 2-deoxy-2-[18F] fluoro-D-glucose. Mol Imaging Biol. 2014;16(3):322-9.
16. Shoup TM, Olson J, Hoffman JM, Votaw J, Eshima D, Eshima L, et al. Synthesis and evaluation of [18F]1-amino-3-fluorocyclobutane-1-carboxylic acid to image brain tumors. J Nucl Med.1999;40(2):331-8.
17. Akhurst T, Beattie B, Gogiberidze G, Montiel J, Cai S,Lassman A, et al. [18F] FACBC imaging of recurrent gliomas: A comparison with [11C] methionine and MRI. J Nucl Med. 2006;47(Suppl 1):79P.
18. Oka S, Hattori R, Kurosaki F, Toyama M, Williams LA, Yu W, et al. A preliminary study of anti-1-amino-3-18Ffluorocyclobutyl-1-carboxylic acid for the detection of prostate cancer. J Nucl Med. 2007; 48(1): 46-55.
19. Sasajima T, Ono T, Shimada N, Doi Y, Oka S, Kanagawa M,et al. Trans-1-amino-3-18F-fluorocyclobutanecarboxylic acid (anti-18F- FACBC) is a feasible alternative to11C-methyl-L-methionine and magnetic resonance imaging for monitoring treatment response in gliomas. Nucl Med Biol. 2013;40(6):808-15.
20. Kondo A, Ishii H, Aoki S, Suzuki M, Nagasawa H, Kubota K, et al. Phase IIa clinical study of [18F]fluciclovine: efficacy and safety of a new PET tracer for brain tumors. Ann Nucl Med. 2016;30(9):608-18.
21. McConathy J, Voll RJ, Yu W, Crowe RJ, Goodman MM. Improved synthesis of anti-[18F]FACBC: improved preparation of labeling precursor and automated radiosynthesis. Appl Radiat Isot. 2003; 58(6):657-66.
22. Kimura Y, Nishida H, Ikari Y, Matsumoto K, Oda K, Nishio T, et al. Qualification of PET cameras and imaging sites for 11C-methionine PET on brain tumor in Japan. J Nucl Med. 2014;55(Suppl 1):2060.
23. Louis DN, Ohgaki H, Wiestler OD, Cavenee WK, Burger PC, Jouvet A, et al. The 2007 WHO classification of tumours of the central nervous system. Acta Neuropathol. 2007;114(2):97-109.
24. Tanaka G, Nakazato Y. Conditional entropy as an indicator of pleomorphism in astrocytic tumors. Neuropathology. 2004; 24(3): 183-93.
25. Tanaka G, Nakazato Y. Automatic quantification of the MIB-1 immunoreactivity in brain tumors. Int Congr Ser. 2004;1259:15-9.
26. Pirotte BJ, Levivier M, Goldman S, Massager N, Wikler D, Dewitte O, et al. Positron emission tomography-guided volumetric resection of supratentorial high-grade gliomas: a survival analysis in 66 consecutive patients. Neurosurgery. 2009;64(3):471-81.
27. Galldiks N, Langen KJ, Pope WB. From the clinician’s point of view - What is the status quo of positron emission tomography in patients with brain tumors? Neuro Oncol. 2015;17(11):1434-44.
28. Chen W, Silverman DH, Delaloye S, Czernin J, Kamdar N, Pope W, et al. 18F-FDOPA PET imaging of brain tumors: comparison study with 18F-FDG PET and evaluation of diagnostic accuracy. J Nucl Med. 2006;47(6):904-11.
29. Bell C, Dowson N, Puttick S, Gal Y, Thomas P, Fay M, et al. Increasing feasibility and utility of 18F-FDOPA PET for the management of glioma. Nucl Med Biol.2015;42(10):788-95.
30. Nihashi T, Dahabreh IJ, Terasawa T. Diagnostic accuracy of PET for recurrent glioma diagnosis: a meta-analysis. AJNR Am J Neuroradiol. 2013;34(5):944-50.
31. Asano Y, Inoue Y, Ikeda Y, Kikuchi K, Hara T, Taguchi C, et al. Phase I clinical study of NMK36: a new PET tracer with the synthetic amino acid analogue anti-[18F]FACBC. Ann Nucl Med. 2011; 25(6): 414-8.
32. Inoue Y, Asano Y, Satoh T, Tabata K, Kikuchi K, Woodhams R, et al. Phase IIa clinical trial of trans-1-amino-3-18F-fluoro-cyclobutane carboxylic acid in metastatic prostate cancer. Asia Oceania J Nucl Med
Biol. 2014;2(2):87-94.
33. Sörensen J, Owenius R, Lax M, Johansson S. Regional distribution and kinetics of [18F]fluciclovine (anti-[18F]FACBC), a tracer of amino acid transport, in subjects with primary prostate cancer. Eur J Nucl Med Mol Imaging. 2013;40(3):394-402.
34. Turkbey B, Mena E, Shih J, Pinto PA, Merino MJ, Lindenberg ML, et al. Localized prostate cancer detection with 18F FACBC PET/CT: comparison with MR imaging and histopathologic analysis. Radiology.
35. Schuster DM, Nieh PT, Jani AB, Amzat R, Bowman FD, Halkar RK, et al. Anti-3-[18F]FACBC positron emission tomography-computerized tomography and 111In-capromab pendetide single photon emission computerized tomography-computerized tomography for recurrent prostate carcinoma: results of a prospective clinical trial. J Urol. 2014; 191(5):1446–53.