Skip to main content


Log in

Diagnosis of pseudoprogression in patients with glioblastoma using O-(2-[18F]fluoroethyl)-l-tyrosine PET

  • Original Article
  • Published:
European Journal of Nuclear Medicine and Molecular Imaging Aims and scope Submit manuscript



The follow-up of glioblastoma patients after radiochemotherapy with conventional MRI can be difficult since reactive alterations to the blood–brain barrier with contrast enhancement may mimic tumour progression (i.e. pseudoprogression, PsP). The aim of this study was to assess the clinical value of O-(2-18F-fluoroethyl)-l-tyrosine (18F-FET) PET in the differentiation of PsP and early tumour progression (EP) after radiochemotherapy of glioblastoma.


A group of 22 glioblastoma patients with new contrast-enhancing lesions or lesions showing increased enhancement (>25 %) on standard MRI within the first 12 weeks after completion of radiochemotherapy with concomitant temozolomide (median 7 weeks) were additionally examined using amino acid PET with 18F-FET. Maximum and mean tumour-to-brain ratios (TBRmax, TBRmean) were determined. 18F-FET uptake kinetic parameters (i.e. patterns of time–activity curves, TAC) were also evaluated. Classification as PsP or EP was based on the clinical course (no treatment change at least for 6 months), follow-up MR imaging and/or histopathological findings. Imaging results were also related to overall survival (OS).


PsP was confirmed in 11 of the 22 patients. In patients with PsP, 18F-FET uptake was significantly lower than in patients with EP (TBRmax 1.9 ± 0.4 vs. 2.8 ± 0.5, TBRmean 1.8 ± 0.2 vs. 2.3 ± 0.3; both P < 0.001) and presence of MGMT promoter methylation was significantly more frequent (P = 0.05). Furthermore, a TAC type II or III was more frequently present in patients with EP (P = 0.04). Receiver operating characteristic analysis showed that the optimal 18F-FET TBRmax cut-off value for identifying PsP was 2.3 (sensitivity 100 %, specificity 91 %, accuracy 96 %, AUC 0.94 ± 0.06; P < 0.001). Univariate survival analysis showed that a TBRmax <2.3 predicted a significantly longer OS (median OS 23 vs. 12 months; P = 0.046).


18F-FET PET may facilitate the diagnosis of PsP following radiochemotherapy of glioblastoma.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others


  1. Wen PY, Macdonald DR, Reardon DA, Cloughesy TF, Sorensen AG, Galanis E, et al. Updated response assessment criteria for high-grade gliomas: response assessment in neuro-oncology working group. J Clin Oncol. 2010;28:1963–72.

    Article  PubMed  Google Scholar 

  2. Brandsma D, van den Bent MJ. Pseudoprogression and pseudoresponse in the treatment of gliomas. Curr Opin Neurol. 2009;22:633–8.

    Article  PubMed  Google Scholar 

  3. Brandsma D, Stalpers L, Taal W, Sminia P, van den Bent MJ. Clinical features, mechanisms, and management of pseudoprogression in malignant gliomas. Lancet Oncol. 2008;9:453–61.

    Article  PubMed  Google Scholar 

  4. Brandes AA, Franceschi E, Tosoni A, Blatt V, Pession A, Tallini G, et al. MGMT promoter methylation status can predict the incidence and outcome of pseudoprogression after concomitant radiochemotherapy in newly diagnosed glioblastoma patients. J Clin Oncol. 2008;26:2192–7.

    Article  PubMed  Google Scholar 

  5. Hegi ME, Diserens AC, Gorlia T, Hamou MF, de Tribolet N, Weller M, et al. MGMT gene silencing and benefit from temozolomide in glioblastoma. N Engl J Med. 2005;352:997–1003.

    Article  CAS  PubMed  Google Scholar 

  6. Stuplich M, Hadizadeh DR, Kuchelmeister K, Scorzin J, Filss C, Langen KJ, et al. Late and prolonged pseudoprogression in glioblastoma after treatment with lomustine and temozolomide. J Clin Oncol. 2012;30:e180–3.

    Article  CAS  PubMed  Google Scholar 

  7. Young RJ, Gupta A, Shah AD, Graber JJ, Zhang Z, Shi W, et al. Potential utility of conventional MRI signs in diagnosing pseudoprogression in glioblastoma. Neurology. 2011;76:1918–24.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  8. Yang I, Aghi MK. New advances that enable identification of glioblastoma recurrence. Nat Rev Clin Oncol. 2009;6:648–57.

    Article  PubMed  Google Scholar 

  9. Yang I, Huh NG, Smith ZA, Han SJ, Parsa AT. Distinguishing glioma recurrence from treatment effect after radiochemotherapy and immunotherapy. Neurosurg Clin N Am. 2010;21:181–6.

    Article  CAS  PubMed  Google Scholar 

  10. Galldiks N, Langen K, Holy R, Pinkawa M, Stoffels G, Nolte K, et al. Assessment of treatment response in patients with glioblastoma using [18F]fluoroethyl-L-tyrosine PET in comparison to MRI. J Nucl Med. 2012;53:1048–57.

    Article  CAS  PubMed  Google Scholar 

  11. Rachinger W, Goetz C, Pöpperl G, Gildehaus FJ, Kreth FW, Holtmannspotter M, et al. Positron emission tomography with O-(2-[18F]fluoroethyl)-l-tyrosine versus magnetic resonance imaging in the diagnosis of recurrent gliomas. Neurosurgery. 2005;57:505–11.

    Article  PubMed  Google Scholar 

  12. Herholz K, Langen KJ, Schiepers C, Mountz JM. Brain tumors. Semin Nucl Med. 2012;42:356–70.

    Article  PubMed Central  PubMed  Google Scholar 

  13. Langen KJ, Hamacher K, Weckesser M, Floeth F, Stoffels G, Bauer D, et al. O-(2-[18F]fluoroethyl)-L-tyrosine: uptake mechanisms and clinical applications. Nucl Med Biol. 2006;33:287–94.

    Article  CAS  PubMed  Google Scholar 

  14. Moulin-Romsée G, D’Hondt E, de Groot T, Goffin J, Sciot R, Mortelmans L, et al. Non-invasive grading of brain tumours using dynamic amino acid PET imaging: does it work for 11C-methionine? Eur J Nucl Med Mol Imaging. 2007;34:2082–7.

    Article  PubMed  Google Scholar 

  15. 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;352:987–96.

    Article  CAS  PubMed  Google Scholar 

  16. 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;114:97–109.

    Article  PubMed Central  PubMed  Google Scholar 

  17. Felsberg J, Rapp M, Loeser S, Fimmers R, Stummer W, Goeppert M, et al. Prognostic significance of molecular markers and extent of resection in primary glioblastoma patients. Clin Cancer Res. 2009;15:6683–93.

    Article  CAS  PubMed  Google Scholar 

  18. Hamacher K, Coenen HH. Efficient routine production of the 18F-labelled amino acid O-2-18F fluoroethyl-L-tyrosine. Appl Radiat Isot. 2002;57:853–6.

    Article  CAS  PubMed  Google Scholar 

  19. Wester HJ, Herz M, Weber W, Heiss P, Senekowitsch-Schmidtke R, Schwaiger M, et al. Synthesis and radiopharmacology of O-(2-[18F]fluoroethyl)-L-tyrosine for tumor imaging. J Nucl Med. 1999;40:205–12.

    CAS  PubMed  Google Scholar 

  20. 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;50:167–73.

    Article  PubMed  Google Scholar 

  21. 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;54:229–35.

    Article  CAS  PubMed  Google Scholar 

  22. Calcagni ML, Galli G, Giordano A, Taralli S, Anile C, Niesen A, et al. Dynamic O-(2-[18F]fluoroethyl)-L-tyrosine (F-18 FET) PET for glioma grading: assessment of individual probability of malignancy. Clin Nucl Med. 2011;36:841–7.

    Article  PubMed  Google Scholar 

  23. Galldiks N, Stoffels G, Ruge MI, Rapp M, Sabel M, Reifenberger G, et al. Role of O-(2-18F-fluoroethyl)-L-tyrosine PET as a diagnostic tool for detection of malignant progression in patients with low-grade glioma. J Nucl Med. 2013;54:2046–54.

    Article  CAS  PubMed  Google Scholar 

  24. 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 the diagnostic assessment of cerebral gliomas. Brain. 2005;128:678–87.

    Article  PubMed  Google Scholar 

  25. Hutterer M, Nowosielski M, Putzer D, Waitz D, Tinkhauser G, Kostron H, et al. O-(2-18F-fluoroethyl)-L-tyrosine PET predicts failure of antiangiogenic treatment in patients with recurrent high-grade glioma. J Nucl Med. 2011;52:856–64.

    Article  CAS  PubMed  Google Scholar 

  26. Galldiks N, Rapp M, Stoffels G, Fink GR, Shah NJ, Coenen HH, et al. Response assessment of bevacizumab in patients with recurrent malignant glioma using [18F]fluoroethyl-L-tyrosine PET in comparison to MRI. Eur J Nucl Med Mol Imaging. 2013;40:22–33.

    Article  CAS  PubMed  Google Scholar 

  27. Jansen NL, Suchorska B, Wenter V, Eigenbrod S, Schmid-Tannwald C, Zwergal A, et al. Dynamic 18F-FET PET in newly diagnosed astrocytic low-grade glioma identifies high-risk patients. J Nucl Med. 2014;55:198–203.

    Article  CAS  PubMed  Google Scholar 

  28. Dunet V, Rossier C, Buck A, Stupp R, Prior JO. Performance of 18F-fluoro-ethyl-tyrosine (18F-FET) PET for the differential diagnosis of primary brain tumor: a systematic review and metaanalysis. J Nucl Med. 2012;53:207–14.

    Article  CAS  PubMed  Google Scholar 

  29. Galldiks N, Stoffels G, Filss CP, Piroth MD, Sabel M, Ruge MI, et al. Role of O-(2-18F-fluoroethyl)-L-tyrosine PET for differentiation of local recurrent brain metastasis from radiation necrosis. J Nucl Med. 2012;53:1367–74.

    Article  CAS  PubMed  Google Scholar 

  30. Cha J, Kim ST, Kim HJ, Kim BJ, Kim YK, Lee JY, et al. Differentiation of tumor progression from pseudoprogression in patients with posttreatment glioblastoma using multiparametric histogram analysis. AJNR Am J Neuroradiol. 2014;35(7):1309–17.

    Article  CAS  PubMed  Google Scholar 

  31. Kong DS, Kim ST, Kim EH, Lim DH, Kim WS, Suh YL, et al. Diagnostic dilemma of pseudoprogression in the treatment of newly diagnosed glioblastomas: the role of assessing relative cerebral blood flow volume and oxygen-6-methylguanine-DNA methyltransferase promoter methylation status. AJNR Am J Neuroradiol. 2011;32:382–7.

    Article  PubMed  Google Scholar 

  32. Mangla R, Singh G, Ziegelitz D, Milano MT, Korones DN, Zhong J, et al. Changes in relative cerebral blood volume 1 month after radiation-temozolomide therapy can help predict overall survival in patients with glioblastoma. Radiology. 2010;256:575–84.

    Article  PubMed  Google Scholar 

  33. Asao C, Korogi Y, Kitajima M, Hirai T, Baba Y, Makino K, et al. Diffusion-weighted imaging of radiation-induced brain injury for differentiation from tumor recurrence. AJNR Am J Neuroradiol. 2005;26:1455–60.

    PubMed  Google Scholar 

  34. Hygino da Cruz Jr LC, Rodriguez I, Domingues RC, Gasparetto EL, Sorensen AG. Pseudoprogression and pseudoresponse: imaging challenges in the assessment of posttreatment glioma. AJNR Am J Neuroradiol. 2011;32:1978–85.

    Article  PubMed  Google Scholar 

  35. Baek HJ, Kim HS, Kim N, Choi YJ, Kim YJ. Percent change of perfusion skewness and kurtosis: a potential imaging biomarker for early treatment response in patients with newly diagnosed glioblastomas. Radiology. 2012;264:834–43.

    Article  PubMed  Google Scholar 

  36. Kim HS, Kim JH, Kim SH, Cho KG, Kim SY. Posttreatment high-grade glioma: usefulness of peak height position with semiquantitative MR perfusion histogram analysis in an entire contrast-enhanced lesion for predicting volume fraction of recurrence. Radiology. 2010;256:906–15.

    Article  PubMed  Google Scholar 

  37. Yoshii Y. Pathological review of late cerebral radionecrosis. Brain Tumor Pathol. 2008;25:51–8.

    Article  PubMed  Google Scholar 

Download references

Conflicts of interest


Author information

Authors and Affiliations


Corresponding author

Correspondence to Norbert Galldiks.

Additional information

Norbert Galldiks and Veronika Dunkl contributed equally to this work.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Galldiks, N., Dunkl, V., Stoffels, G. et al. Diagnosis of pseudoprogression in patients with glioblastoma using O-(2-[18F]fluoroethyl)-l-tyrosine PET. Eur J Nucl Med Mol Imaging 42, 685–695 (2015).

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: