FET PET reveals considerable spatial differences in tumour burden compared to conventional MRI in newly diagnosed glioblastoma

  • Philipp LohmannEmail author
  • Pantelis Stavrinou
  • Katharina Lipke
  • Elena K. Bauer
  • Garry Ceccon
  • Jan-Michael Werner
  • Bernd Neumaier
  • Gereon R. Fink
  • Nadim J. Shah
  • Karl-Josef Langen
  • Norbert Galldiks
Original Article



Areas of contrast enhancement (CE) on MRI are usually the target for resection or radiotherapy target volume definition in glioblastomas. However, the solid tumour mass may extend beyond areas of CE. Amino acid PET can detect parts of the tumour that show no CE. We systematically investigated tumour volumes delineated by amino acid PET and MRI in patients with newly diagnosed, untreated glioblastoma.


Preoperatively, 50 patients with neuropathologically confirmed glioblastoma underwent O-(2-[18F]-fluoroethyl)-l-tyrosine (FET) PET, and fluid-attenuated inversion recovery (FLAIR) and contrast-enhanced MRI. Areas of CE were manually segmented. FET PET tumour volumes were segmented using a tumour-to-brain ratio of ≥1.6. The percentage overlap volumes, and Dice and Jaccard spatial similarity coefficients (DSC, JSC) were calculated. FLAIR images were evaluated visually.


In 43 patients (86%), the FET tumour volume was significantly larger than the CE volume (21.5 ± 14.3 mL vs. 9.4 ± 11.3 mL; P < 0.001). Forty patients (80%) showed both increased uptake of FET and CE. In these 40 patients, the spatial similarity between FET uptake and CE was low (mean DSC 0.39 ± 0.21, mean JSC 0.26 ± 0.16). Ten patients (20%) showed no CE, and one of these patients showed no FET uptake. In five patients (10%), increased FET uptake was present outside areas of FLAIR hyperintensity.


Our results show that the metabolically active tumour volume delineated by FET PET is significantly larger than tumour volume delineated by CE. Furthermore, the results strongly suggest that the information derived from both imaging modalities should be integrated into the management of patients with newly diagnosed glioblastoma.


FET PET tumour volume Volumetry Amino acid PET MRI contrast enhancement FLAIR hyperintensity Target volume definition 



The authors thank Suzanne Schaden, Trude Plum, Natalie Judov, Silke Frensch, Kornelia Frey and Lutz Tellmann for assistance with the patient studies, and Johannes Ermert, Silke Grafmüller, Erika Wabbals and Sascha Rehbein for radiosynthesis of FET.


This study was funded by Wilhelm Sander-Stiftung, Munich, Germany (grant number 2016.069.1 to N.G.)

Compliance with ethical standards

Conflicts of interest


Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the principles of the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards. For this type of study formal consent is not required.

Informed consent

Informed consent was obtained from all individual participants included in the study.


  1. 1.
    Stupp R, Mason WP, van den Bent MJ, Weller M, Fisher B, Taphoorn MJ, et al. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med. 2005;352(10):987–96.CrossRefGoogle Scholar
  2. 2.
    Chinot OL, Wick W, Mason W, Henriksson R, Saran F, Nishikawa R, et al. Bevacizumab plus radiotherapy-temozolomide for newly diagnosed glioblastoma. N Engl J Med. 2014;370(8):709–22.CrossRefGoogle Scholar
  3. 3.
    Weller M, Butowski N, Tran DD, Recht LD, Lim M, Hirte H, et al. Rindopepimut with temozolomide for patients with newly diagnosed, EGFRvIII-expressing glioblastoma (ACT IV): a randomised, double-blind, international phase 3 trial. Lancet Oncol. 2017;18(10):1373–85.CrossRefGoogle Scholar
  4. 4.
    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.CrossRefGoogle Scholar
  5. 5.
    Albert FK, Forsting M, Sartor K, Adams HP, Kunze S. Early postoperative magnetic resonance imaging after resection of malignant glioma: objective evaluation of residual tumor and its influence on regrowth and prognosis. Neurosurgery. 1994;34(1):45–60.Google Scholar
  6. 6.
    Aghi MK, Nahed BV, Sloan AE, Ryken TC, Kalkanis SN, Olson JJ. The role of surgery in the management of patients with diffuse low grade glioma: a systematic review and evidence-based clinical practice guideline. J Neurooncol. 2015;125(3):503–30.CrossRefGoogle Scholar
  7. 7.
    Brown TJ, Brennan MC, Li M, Church EW, Brandmeir NJ, Rakszawski KL, et al. Association of the extent of resection with survival in glioblastoma: a systematic review and meta-analysis. JAMA Oncol. 2016;2(11):1460–9.CrossRefGoogle Scholar
  8. 8.
    Kreth FW, Thon N, Simon M, Westphal M, Schackert G, Nikkhah G, et al. Gross total but not incomplete resection of glioblastoma prolongs survival in the era of radiochemotherapy. Ann Oncol. 2013;24(12):3117–23.CrossRefGoogle Scholar
  9. 9.
    Lacroix M, Abi-Said D, Fourney DR, Gokaslan ZL, Shi W, DeMonte F, et al. A multivariate analysis of 416 patients with glioblastoma multiforme: prognosis, extent of resection, and survival. J Neurosurg. 2001;95(2):190–8.CrossRefGoogle Scholar
  10. 10.
    Niyazi M, Brada M, Chalmers AJ, Combs SE, Erridge SC, Fiorentino A, et al. ESTRO-ACROP guideline "target delineation of glioblastomas". Radiother Oncol. 2016;118(1):35–42.CrossRefGoogle Scholar
  11. 11.
    Halperin EC, Bentel G, Heinz ER, Burger PC. Radiation therapy treatment planning in supratentorial glioblastoma multiforme: an analysis based on post mortem topographic anatomy with CT correlations. Int J Radiat Oncol Biol Phys. 1989;17(6):1347–50.CrossRefGoogle Scholar
  12. 12.
    Lunsford LD, Martinez AJ, Latchaw RE. Magnetic resonance imaging does not define tumor boundaries. Acta Radiol Suppl. 1986;369:154–6.Google Scholar
  13. 13.
    Eidel O, Burth S, Neumann JO, Kieslich PJ, Sahm F, Jungk C, et al. Tumor infiltration in enhancing and non-enhancing parts of glioblastoma: a correlation with histopathology. PLoS One. 2017;12(1):e0169292.CrossRefGoogle Scholar
  14. 14.
    Tovi M, Hartman M, Lilja A, Ericsson A. MR imaging in cerebral gliomas. Acta Radiol. 1994;35(5):495–505.CrossRefGoogle Scholar
  15. 15.
    Ginsberg LE, Fuller GN, Hashmi M, Leeds NE, Schomer DF. The significance of lack of MR contrast enhancement of supratentorial brain tumors in adults: histopathological evaluation of a series. Surg Neurol. 1998;49(4):436–40.CrossRefGoogle Scholar
  16. 16.
    Rapp M, Heinzel A, Galldiks N, Stoffels G, Felsberg J, Ewelt C, et al. Diagnostic performance of 18F-FET PET in newly diagnosed cerebral lesions suggestive of glioma. J Nucl Med. 2013;54(2):229–35.CrossRefGoogle Scholar
  17. 17.
    Hutterer M, Nowosielski M, Putzer D, Jansen NL, Seiz M, Schocke M, et al. [18F]-fluoro-ethyl-l-tyrosine PET: a valuable diagnostic tool in neuro-oncology, but not all that glitters is glioma. Neuro Oncol. 2013;15(3):341–51.CrossRefGoogle Scholar
  18. 18.
    Weller M, van den Bent M, Tonn JC, Stupp R, Preusser M, Cohen-Jonathan-Moyal E, et al. European Association for Neuro-Oncology (EANO) guideline on the diagnosis and treatment of adult astrocytic and oligodendroglial gliomas. Lancet Oncol. 2017;18(6):e315–29.CrossRefGoogle Scholar
  19. 19.
    Pauleit D, Floeth F, Hamacher K, Riemenschneider MJ, Reifenberger G, Muller HW, et al. O-(2-[18F]fluoroethyl)-L-tyrosine PET combined with MRI improves the diagnostic assessment of cerebral gliomas. Brain. 2005;128(Pt 3):678–87.CrossRefGoogle Scholar
  20. 20.
    Galldiks N, Stoffels G, Filss C, Rapp M, Blau T, Tscherpel C, et al. The use of dynamic O-(2-18F-fluoroethyl)-l-tyrosine PET in the diagnosis of patients with progressive and recurrent glioma. Neuro Oncol. 2015;17(9):1293–300.Google Scholar
  21. 21.
    Jansen NL, Suchorska B, Wenter V, Schmid-Tannwald C, Todica A, Eigenbrod S, et al. Prognostic significance of dynamic 18F-FET PET in newly diagnosed astrocytic high-grade glioma. J Nucl Med. 2015;56(1):9–15.CrossRefGoogle Scholar
  22. 22.
    Albert NL, Weller M, Suchorska B, Galldiks N, Soffietti R, Kim MM, et al. Response Assessment in Neuro-Oncology working group and European Association for Neuro-Oncology recommendations for the clinical use of PET imaging in gliomas. Neuro Oncol. 2016;18(9):1199–208.CrossRefGoogle Scholar
  23. 23.
    Pirotte B, Goldman S, Massager N, David P, Wikler D, Vandesteene A, et al. Comparison of 18F-FDG and 11C-methionine for PET-guided stereotactic brain biopsy of gliomas. J Nucl Med. 2004;45(8):1293–8.Google Scholar
  24. 24.
    Galldiks N, Ullrich R, Schroeter M, Fink GR, Jacobs AH, Kracht LW. Volumetry of [(11)C]-methionine PET uptake and MRI contrast enhancement in patients with recurrent glioblastoma multiforme. Eur J Nucl Med Mol Imaging. 2010;37(1):84–92.CrossRefGoogle Scholar
  25. 25.
    Mosskin M, Ericson K, Hindmarsh T, Vonholst H, Collins VP, Bergstrom M, et al. Positron emission tomography compared with magnetic-resonance imaging and computed-tomography in supratentorial gliomas using multiple stereotactic biopsies as reference. Acta Radiol. 1989;30(3):225–32.CrossRefGoogle Scholar
  26. 26.
    Bergström M, Collins VP, Ehrin E, Ericson K, Eriksson L, Greitz T, et al. Discrepancies in brain tumor extent as shown by computed tomography and positron emission tomography using [68Ga]EDTA, [11C]glucose, and [11C]methionine. J Comput Assist Tomogr. 1983;7(6):1062–6.CrossRefGoogle Scholar
  27. 27.
    Hamacher K, Coenen HH. Efficient routine production of the 18F-labelled amino acid O-2-18F fluoroethyl-L-tyrosine. Appl Radiat Isot. 2002;57(6):853–6.CrossRefGoogle Scholar
  28. 28.
    Langen KJ, Bartenstein P, Boecker H, Brust P, Coenen HH, Drzezga A, et al. German guidelines for brain tumour imaging by PET and SPECT using labelled amino acids. Nuklearmedizin. 2011;50(4):167–73.CrossRefGoogle Scholar
  29. 29.
    Kops ER, Herzog H. Template based attenuation correction for PET in MR-PET scanners. IEEE Nuclear Science Symposium Conference Record. 2008. p. 3786–9.Google Scholar
  30. 30.
    Lohmann P, Herzog H, Rota Kops E, Stoffels G, Judov N, Filss C, et al. Dual-time-point O-(2-[(18)F]fluoroethyl)-L-tyrosine PET for grading of cerebral gliomas. Eur Radiol. 2015;25(10):3017–24.CrossRefGoogle Scholar
  31. 31.
    Besemer AE, Titz B, Grudzinski JJ, Weichert JP, Kuo JS, Robins HI, et al. Impact of PET and MRI threshold-based tumor volume segmentation on patient-specific targeted radionuclide therapy dosimetry using CLR1404. Phys Med Biol. 2017;62(15):6008–25.CrossRefGoogle Scholar
  32. 32.
    Dice LR. Measures of the amount of ecologic association between species. Ecology. 1945;26(3):297–302.CrossRefGoogle Scholar
  33. 33.
    Jaccard P. The distribution of the flora in the alpine zone. New Phytol. 1912;11(2):37–50.CrossRefGoogle Scholar
  34. 34.
    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.CrossRefGoogle Scholar
  35. 35.
    Grosu AL, Weber WA, Riedel E, Jeremic B, Nieder C, Franz M, et al. L-(methyl-11C) methionine positron emission tomography for target delineation in resected high-grade gliomas before radiotherapy. Int J Radiat Oncol Biol Phys. 2005;63(1):64–74.CrossRefGoogle Scholar
  36. 36.
    Mahasittiwat P, Mizoe JE, Hasegawa A, Ishikawa H, Yoshikawa K, Mizuno H, et al. l-[METHYL-(11)C] methionine positron emission tomography for target delineation in malignant gliomas: impact on results of carbon ion radiotherapy. Int J Radiat Oncol Biol Phys. 2008;70(2):515–22.CrossRefGoogle Scholar
  37. 37.
    Misch M, Guggemos A, Driever PH, Koch A, Grosse F, Steffen IG, et al. (18)F-FET-PET guided surgical biopsy and resection in children and adolescence with brain tumors. Childs Nerv Syst. 2015;31(2):261–7.CrossRefGoogle Scholar
  38. 38.
    Unterrainer M, Winkelmann I, Suchorska B, Giese A, Wenter V, Kreth FW, et al. Biological tumour volumes of gliomas in early and standard 20-40 min (18)F-FET PET images differ according to IDH mutation status. Eur J Nucl Med Mol Imaging. 2018;45(7):1242–9.CrossRefGoogle Scholar
  39. 39.
    Rieken S, Habermehl D, Giesel FL, Hoffmann C, Burger U, Rief H, et al. Analysis of FET-PET imaging for target volume definition in patients with gliomas treated with conformal radiotherapy. Radiother Oncol. 2013;109(3):487–92.CrossRefGoogle Scholar
  40. 40.
    Niyazi M, Geisler J, Siefert A, Schwarz SB, Ganswindt U, Garny S, et al. FET-PET for malignant glioma treatment planning. Radiother Oncol. 2011;99(1):44–8.CrossRefGoogle Scholar
  41. 41.
    Jaymanne DT, Kaushal S, Chan D, Schembri G, Brazier D, Bailey D, et al. Utilizing 18F-fluoroethyl-l-tyrosine positron emission tomography in high grade glioma for radiation treatment planning in patients with contraindications to MRI. J Med Imaging Radiat Oncol. 2018;62(1):122–7.CrossRefGoogle Scholar
  42. 42.
    Debus C, Waltenberger M, Floca R, Afshar-Oromieh A, Bougatf N, Adeberg S, et al. Impact of (18)F-FET PET on target volume definition and tumor progression of recurrent high grade glioma treated with carbon-ion radiotherapy. Sci Rep. 2018;8(1):7201.CrossRefGoogle Scholar
  43. 43.
    Henriksen OM, Larsen VA, Muhic A, Hansen AE, Larsson HB, Poulsen HS, et al. Simultaneous evaluation of brain tumour metabolism, structure and blood volume using [(18)F]-fluoroethyltyrosine (FET) PET/MRI: feasibility, agreement and initial experience. Eur J Nucl Med Mol Imaging. 2016;43(1):103–12.CrossRefGoogle Scholar
  44. 44.
    Unterrainer M, Fleischmann DF, Diekmann C, Vomacka L, Lindner S, Vettermann F, et al. Comparison of (18)F-GE-180 and dynamic (18)F-FET PET in high grade glioma: a double-tracer pilot study. Eur J Nucl Med Mol Imaging. 2018. Google Scholar
  45. 45.
    Sanai N, Polley MY, McDermott MW, Parsa AT, Berger MS. An extent of resection threshold for newly diagnosed glioblastomas. J Neurosurg. 2011;115(1):3–8.CrossRefGoogle Scholar
  46. 46.
    Schucht P, Knittel S, Slotboom J, Seidel K, Murek M, Jilch A, et al. 5-ALA complete resections go beyond MR contrast enhancement: shift corrected volumetric analysis of the extent of resection in surgery for glioblastoma. Acta Neurochir. 2014;156(2):305–12.CrossRefGoogle Scholar
  47. 47.
    Floeth FW, Sabel M, Ewelt C, Stummer W, Felsberg J, Reifenberger G, et al. Comparison of (18)F-FET PET and 5-ALA fluorescence in cerebral gliomas. Eur J Nucl Med Mol Imaging. 2011;38(4):731–41.CrossRefGoogle Scholar
  48. 48.
    Louis DN, Perry A, Reifenberger G, von Deimling A, Figarella-Branger D, Cavenee WK, et al. The 2016 World Health Organization classification of tumors of the central nervous system: a summary. Acta Neuropathol. 2016;131(6):1–18.CrossRefGoogle Scholar
  49. 49.
    Oehlke O, Mix M, Graf E, Schimek-Jasch T, Nestle U, Gotz I, et al. Amino-acid PET versus MRI guided re-irradiation in patients with recurrent glioblastoma multiforme (GLIAA) – protocol of a randomized phase II trial (NOA 10/ARO 2013-1). BMC Cancer. 2016;16(1):769.CrossRefGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  • Philipp Lohmann
    • 1
    Email author
  • Pantelis Stavrinou
    • 2
  • Katharina Lipke
    • 1
  • Elena K. Bauer
    • 3
  • Garry Ceccon
    • 3
  • Jan-Michael Werner
    • 3
  • Bernd Neumaier
    • 1
  • Gereon R. Fink
    • 1
    • 3
  • Nadim J. Shah
    • 1
    • 4
  • Karl-Josef Langen
    • 1
    • 5
  • Norbert Galldiks
    • 1
    • 3
    • 6
  1. 1.Institute of Neuroscience and Medicine (INM-3, -4, -5)Forschungszentrum JuelichJuelichGermany
  2. 2.Department of NeurosurgeryUniversity of CologneCologneGermany
  3. 3.Department of NeurologyUniversity of CologneCologneGermany
  4. 4.Department of NeurologyUniversity Hospital RWTH AachenAachenGermany
  5. 5.Department of Nuclear MedicineUniversity Hospital RWTH AachenAachenGermany
  6. 6.Center of Integrated Oncology (CIO)Universities of Cologne and BonnCologneGermany

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