Molecular Imaging and Biology

, 11:343 | Cite as

NCI-Sponsored Trial for the Evaluation of Safety and Preliminary Efficacy of 3′-Deoxy-3′-[18F]fluorothymidine (FLT) as a Marker of Proliferation in Patients with Recurrent Gliomas: Preliminary Efficacy Studies

  • Alexander M. Spence
  • Mark Muzi
  • Jeanne M. Link
  • Finbarr O’Sullivan
  • Janet F. Eary
  • John M. Hoffman
  • Lalitha K. Shankar
  • Kenneth A. Krohn
Research Article



3′-Deoxy-3′-[18F]fluorothymidine ([18F]FLT) is being developed for imaging cellular proliferation. The goals were to explore the capacity of FLT-positron emission tomography (PET) to distinguish between recurrence and radionecrosis in gliomas and compare the results to those obtained with 2-fluoro-2-deoxy-d-glucose (FDG).


Fifteen patients with tumor recurrence and four with radionecrosis, determined by clinical course and magnetic resonance imaging results, were studied by dynamic [18F]FLT-PET with arterial blood sampling. A two-tissue compartment four-rate constant model was used to determine metabolic flux (K FLT), blood to tissue transport (K 1), and phosphorylation (k 3). FDG-PET scans were obtained 75–90 min postinjection.


K FLT and k 3, but not K 1 or k 3/k 2 + k 3, reached significance for separating the recurrence from radionecrosis groups. Standardized uptake value and visual analyses of FLT or FDG images did not reach significance.


K FLT (flux) appears to distinguish recurrence from radionecrosis better than other parameters, FLT and FDG semiquantitative approaches, or visual analysis of images of either tracer.

Key Words

3′-[18F]fluoro-3′-deoxythymidine FLT Fluorothymidine Positron emission tomography (PET) Glioma Radionecrosis Proliferation imaging 



Pam Pham, Michele F. Wanner, Jeffrey Scharnhorst, and Neha Patel are gratefully acknowledged for their indispensable help. Supported by National Cancer Institute Contract N01-CM-37008 and NIH grants CA42045 and S10 RR17229.


  1. 1.
    Grierson JR, Schwartz JL, Muzi M, Jordan R, Krohn KA (2004) Metabolism of 3′-deoxy-3′-[F-18]fluorothymidine in proliferating A549 cells: validations for positron emission tomography. Nucl Med Biol 31:829–837PubMedCrossRefGoogle Scholar
  2. 2.
    Brandes AA, Tosoni A, Spagnolli F et al (2008) Disease progression or pseudoprogression after concomitant radiochemotherapy treatment: pitfalls in neurooncology. Neuro Oncol 10:361–367PubMedCrossRefGoogle Scholar
  3. 3.
    Chamberlain MC, Glantz MJ, Chalmers L, Van Horn A, Sloan AE (2007) Early necrosis following concurrent Temodar and radiotherapy in patients with glioblastoma. J Neurooncol 82:81–83PubMedCrossRefGoogle Scholar
  4. 4.
    Spence AM, Muzi M, Link JM, Hoffman JM, Eary JF, Krohn KA (2008) NCI-sponsored trial for the evaluation of safety and preliminary efficacy of FLT as a marker of proliferation in patients with recurrent gliomas: safety studies. Mol Imaging Biol 10:271–280PubMedCrossRefGoogle Scholar
  5. 5.
    Muzi M, Spence AM, O'Sullivan F et al (2006) Kinetic analysis of 3′-deoxy-3′-18F-fluorothymidine in patients with gliomas. J Nucl Med 47:1612–1621PubMedGoogle Scholar
  6. 6.
    Hein PA, Eskey CJ, Dunn JF, Hug EB (2004) Diffusion-weighted imaging in the follow-up of treated high-grade gliomas: tumor recurrence versus radiation injury. AJNR Am J Neuroradiol 25:201–209PubMedGoogle Scholar
  7. 7.
    Kahn D, Follett KA, Bushnell DL et al (1994) Diagnosis of recurrent brain tumor: value of 201Tl SPECT vs 18F-fluorodeoxyglucose PET. AJR Am J Roentgenol 163:1459–1465PubMedGoogle Scholar
  8. 8.
    Kim EE, Chung SK, Haynie TP et al (1992) Differentiation of residual or recurrent tumors from post-treatment changes with F-18 FDG PET. Radiographics 12:269–279PubMedGoogle Scholar
  9. 9.
    Lichy MP, Bachert P, Hamprecht F et al (2006) Application of (1)H MR spectroscopic imaging in radiation oncology: choline as a marker for determining the relative probability of tumor progression after radiation of glial brain tumors. RoFo 178:627–633PubMedGoogle Scholar
  10. 10.
    Valk PE, Budinger TF, Levin VA, Silver P, Gutin PH, Doyle WK (1988) PET of malignant cerebral tumors after interstitial brachytherapy. J Neurosurg 69:830–838PubMedCrossRefGoogle Scholar
  11. 11.
    Weybright P, Sundgren PC, Maly P et al (2005) Differentiation between brain tumor recurrence and radiation injury using MR spectroscopy. AJR Am J Roentgenol 185:1471–1476PubMedCrossRefGoogle Scholar
  12. 12.
    Xiangsong Z, Weian C (2007) Differentiation of recurrent astrocytoma from radiation necrosis: a pilot study with (13)N-NH (3) PET. J Neurooncol 82:305–311PubMedCrossRefGoogle Scholar
  13. 13.
    Zeng QS, Li CF, Liu H, Zhen JH, Feng DC (2007) Distinction between recurrent glioma and radiation injury using magnetic resonance spectroscopy in combination with diffusion-weighted imaging. Int J Radiat Oncol Biol Phys 68:151–158PubMedGoogle Scholar
  14. 14.
    Reischl G, Blocher A, Wei R et al (2006) Simplified, automated synthesis of 3′[18F]fluoro-3′-deoxy-thymidine ([18F]FLT) and simple method for metabolite analysis in plasma. Radiochim Acta 94:447–451CrossRefGoogle Scholar
  15. 15.
    Hamacher K, Coenen HH, Stocklin G (1986) Efficient stereospecific synthesis of no-carrier-added 2-[18F]-fluoro-2-deoxy-d-glucose using aminopolyether supported nucleophilic substitution. J Nucl Med 27:235–238PubMedGoogle Scholar
  16. 16.
    Minoshima S, Berger K, Lee K, Mintun M (1992) An automated method for rotational correction and centering of three-dimensional functional brain images. J Nucl Med 33:1579–1585PubMedGoogle Scholar
  17. 17.
    Graham MM, Lewellen BL (1993) High-speed automated discrete blood sampling for positron emission tomography. J Nucl Med 34:1357–1360PubMedGoogle Scholar
  18. 18.
    Lundgren B, Bottiger D, Ljungdahl-Stahle E et al (1991) Antiviral effects of 3′-fluorothymidine and 3′-azidothymidine in cynomolgus monkeys infected with simian immunodeficiency virus. J Acquir Immune Defic Syndr 4:489–498PubMedGoogle Scholar
  19. 19.
    Muzi M, Mankoff DA, Grierson JR, Wells JM, Vesselle H, Krohn KA (2005) Kinetic modeling of 3′-deoxy-3′-fluorothymidine in somatic tumors: mathematical studies. J Nucl Med 46:371–380PubMedGoogle Scholar
  20. 20.
    Lewellen TK, Kohlmyer SG, Miyaoka RS, Kaplan MS, Stearns CW, Schubert SF (1996) Investigation of the performance of the General Electric ADVANCE positron emission tomograph in 3D mode. IEEE Trans Nucl Sci 43:2199–2206CrossRefGoogle Scholar
  21. 21.
    Kinahan PE, Townsend DW, Beyer T, Sashin D (1998) Attenuation correction for a combined 3D PET/CT scanner. Med Phys 25:2046–2053PubMedCrossRefGoogle Scholar
  22. 22.
    Mankoff DA, Shields AF, Graham MM, Link JM, Krohn KA (1996) A graphical analysis method to estimate blood-to-tissue transfer constants for tracers with labeled metabolites. J Nucl Med 37:2049–2057PubMedGoogle Scholar
  23. 23.
    Patlak CS, Blasberg RG (1985) Graphical evaluation of blood-to-brain transfer constants from multiple-time uptake data. Generalizations. J Cereb Blood Flow Metab 5:584–590PubMedGoogle Scholar
  24. 24.
    Chishty M, Begley DJ, Abbott NJ, Reichel A (2003) Functional characterisation of nucleoside transport in rat brain endothelial cells. Neuroreport 14:1087–1090PubMedCrossRefGoogle Scholar
  25. 25.
    Wells JM, Mankoff DA, Muzi M et al (2002) Kinetic analysis of 2-[11C]thymidine PET imaging studies of malignant brain tumors: compartmental model investigation and mathematical analysis. Mol Imaging 1:151–159PubMedCrossRefGoogle Scholar
  26. 26.
    O'Sullivan F (1994) Metabolic images from dynamic positron emission tomography studies. Stat Methods Med Res 3:87–101PubMedCrossRefGoogle Scholar
  27. 27.
    O'Sullivan F (1993) Imaging radiotracer model parameters in PET: a mixture analysis approach. IEEE Trans Med Imaging 12:399–412PubMedCrossRefGoogle Scholar
  28. 28.
    Spence AM, Muzi M, Graham MM et al (1998) Glucose metabolism in human malignant gliomas measured quantitatively with PET, 1-[C-11]glucose and FDG: analysis of the FDG lumped constant. J Nucl Med 39:440–448PubMedGoogle Scholar
  29. 29.
    Chen W, Cloughesy T, Kamdar N et al (2005) Imaging proliferation in brain tumors with 18F-FLT PET: comparison with 18F-FDG. J Nucl Med 46:945–952PubMedGoogle Scholar
  30. 30.
    Choi SJ, Kim JS, Kim JH et al (2005) [18F]3′-deoxy-3′-fluorothymidine PET for the diagnosis and grading of brain tumors. Eur J Nucl Med Mol Imaging 32:653–659PubMedCrossRefGoogle Scholar
  31. 31.
    Jacobs AH, Thomas A, Kracht LW et al (2005) 18F-fluoro-l-thymidine and 11C-methylmethionine as markers of increased transport and proliferation in brain tumors. J Nucl Med 46:1948–1958PubMedGoogle Scholar
  32. 32.
    Saga T, Kawashima H, Araki N et al (2006) Evaluation of primary brain tumors with FLT-PET: usefulness and limitations. Clin Nucl Med 31:774–780PubMedCrossRefGoogle Scholar
  33. 33.
    Yamamoto Y, Wong TZ, Turkington TG, Hawk TC, Reardon DA, Coleman RE (2006) 3′-Deoxy-3′-[F-18]fluorothymidine positron emission tomography in patients with recurrent glioblastoma multiforme: comparison with Gd-DTPA enhanced magnetic resonance imaging. Mol Imaging Biol 8:340–347PubMedCrossRefGoogle Scholar
  34. 34.
    Schiepers C, Chen W, Dahlbom M, Cloughesy T, Hoh CK, Huang SC (2007) (18)F-fluorothymidine kinetics of malignant brain tumors. Eur J Nucl Med Mol Imaging 34:1003–1011PubMedCrossRefGoogle Scholar
  35. 35.
    Asensio C, Perez-Castejon MJ, Maldonado A et al (1998) The role of PET-FDG in questionable diagnosis of relapse in the presence of radionecrosis of brain tumors. Rev Neurol 27:447–452PubMedGoogle Scholar
  36. 36.
    Chao ST, Suh JH, Raja S, Lee SY, Barnett G (2001) The sensitivity and specificity of FDG PET in distinguishing recurrent brain tumor from radionecrosis in patients treated with stereotactic radiosurgery. Int J Cancer 96:191–197PubMedCrossRefGoogle Scholar
  37. 37.
    Di Chiro G, Oldfield E, Wright DC et al (1988) Cerebral necrosis after radiotherapy and/or intraarterial chemotherapy for brain tumors: PET and neuropathologic studies. AJR Am J Roentgenol 150:189–197PubMedGoogle Scholar
  38. 38.
    Gomez-Rio M, Rodriguez-Fernandez A, Ramos-Font C, Lopez-Ramirez E, Llamas-Elvira JM (2008) Diagnostic accuracy of 201Thallium-SPECT and 18F-FDG-PET in the clinical assessment of glioma recurrence. Eur J Nucl Med Mol Imaging 35:966–975PubMedCrossRefGoogle Scholar
  39. 39.
    Henze M, Mohammed A, Schlemmer HP et al (2004) PET and SPECT for detection of tumor progression in irradiated low-grade astrocytoma: a receiver-operating-characteristic analysis. J Nucl Med 45:579–586PubMedGoogle Scholar
  40. 40.
    Langleben DD, Segall GM (2000) PET in differentiation of recurrent brain tumor from radiation injury. J Nucl Med 41:1861–1867PubMedGoogle Scholar
  41. 41.
    Ricci PE, Karis JP, Heiserman JE, Fram EK, Bice AN, Drayer BP (1998) Differentiating recurrent tumor from radiation necrosis: time for re-evaluation of positron emission tomography? AJNR Am J Neuroradiol 19:407–413PubMedGoogle Scholar
  42. 42.
    Van Laere K, Ceyssens S, Van Calenbergh F et al (2005) 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 32:39–51PubMedCrossRefGoogle Scholar
  43. 43.
    Wang SX, Boethius J, Ericson K (2006) FDG-PET on irradiated brain tumor: ten years' summary. Acta Radiol 47:85–90PubMedCrossRefGoogle Scholar
  44. 44.
    Spence AM, Muzi M, Mankoff DA et al (2004) 18F-FDG PET of gliomas at delayed intervals: improved distinction between tumor and normal gray matter. J Nucl Med 45:1653–1659PubMedGoogle Scholar
  45. 45.
    Singhal T, Narayanan TK, Jain V, Mukherjee J, Mantil J (2008) (11)C-L-methionine positron emission tomography in the clinical management of cerebral gliomas. Mol Imaging Biol 10:1–18PubMedCrossRefGoogle Scholar
  46. 46.
    Terakawa Y, Tsuyuguchi N, Iwai Y et al (2008) Diagnostic accuracy of 11C-methionine PET for differentiation of recurrent brain tumors from radiation necrosis after radiotherapy. J Nucl Med 49:694–699PubMedCrossRefGoogle Scholar
  47. 47.
    Chen W, Silverman DH, Delaloye S et al (2006) 18F-FDOPA PET imaging of brain tumors: comparison study with 18F-FDG PET and evaluation of diagnostic accuracy. J Nucl Med 47:904–911PubMedGoogle Scholar
  48. 48.
    Dadparvar S, Hussain R, Koffler SP, Gillan MM, Bartolic EI, Miyamoto C (2000) The role of Tc-99m HMPAO functional brain imaging in detection of cerebral radionecrosis. Cancer J 6:381–387PubMedGoogle Scholar
  49. 49.
    Gomez-Rio M, Martinez Del Valle Torres D, Rodriguez-Fernandez A et al (2004) (201)Tl-SPECT in low-grade gliomas: diagnostic accuracy in differential diagnosis between tumour recurrence and radionecrosis. Eur J Nucl Med Mol Imaging 31:1237–1243PubMedCrossRefGoogle Scholar
  50. 50.
    Lichy MP, Henze M, Plathow C, Bachert P, Kauczor HU, Schlemmer HP (2004) Metabolic imaging to follow stereotactic radiation of gliomas—the role of 1H MR spectroscopy in comparison to FDG-PET and IMT-SPECT. RoFo 176:1114–1121PubMedGoogle Scholar
  51. 51.
    Prigent-Le Jeune F, Dubois F, Perez S, Blond S, Steinling M (2004) Technetium-99m sestamibi brain SPECT in the follow-up of glioma for evaluation of response to chemotherapy: first results. Eur J Nucl Med Mol Imaging 31:714–719PubMedCrossRefGoogle Scholar
  52. 52.
    Soler C, Beauchesne P, Maatougui K et al (1998) Technetium-99m sestamibi brain single-photon emission tomography for detection of recurrent gliomas after radiation therapy. Eur J Nucl Med 25:1649–1657PubMedCrossRefGoogle Scholar
  53. 53.
    Ando K, Ishikura R, Nagami Y et al (2004) Usefulness of Cho/Cr ratio in proton MR spectroscopy for differentiating residual/recurrent glioma from non-neoplastic lesions. Nippon Igaku Hoshasen Gakkai Zasshi 64:121–126PubMedGoogle Scholar
  54. 54.
    Hollingworth W, Medina LS, Lenkinski RE et al (2006) A systematic literature review of magnetic resonance spectroscopy for the characterization of brain tumors. AJNR Am J Neuroradiol 27:1404–1411PubMedGoogle Scholar
  55. 55.
    Plotkin M, Eisenacher J, Bruhn H et al (2004) 123I-IMT SPECT and 1H MR-spectroscopy at 3.0 T in the differential diagnosis of recurrent or residual gliomas: a comparative study. J Neurooncol 70:49–58PubMedCrossRefGoogle Scholar
  56. 56.
    Rabinov JD, Lee PL, Barker FG et al (2002) In vivo 3-T MR spectroscopy in the distinction of recurrent glioma versus radiation effects: initial experience. Radiology 225:871–879PubMedCrossRefGoogle Scholar
  57. 57.
    Zeng QS, Li CF, Zhang K, Liu H, Kang XS, Zhen JH (2007) Multivoxel 3D proton MR spectroscopy in the distinction of recurrent glioma from radiation injury. J Neurooncol 84:63–69PubMedCrossRefGoogle Scholar

Copyright information

© Academy of Molecular Imaging 2009

Authors and Affiliations

  • Alexander M. Spence
    • 1
  • Mark Muzi
    • 2
  • Jeanne M. Link
    • 2
  • Finbarr O’Sullivan
    • 3
  • Janet F. Eary
    • 2
  • John M. Hoffman
    • 4
  • Lalitha K. Shankar
    • 5
  • Kenneth A. Krohn
    • 2
  1. 1.Department of NeurologyUniversity of WashingtonSeattleUSA
  2. 2.Department of RadiologyUniversity of WashingtonSeattleUSA
  3. 3.Department of StatisticsUniversity College CorkCorkIreland
  4. 4.Departments of Radiology and NeurologyUniversity of UtahSalt Lake CityUSA
  5. 5.Cancer Imaging Program, Division of Cancer Treatment and DiagnosisNational Cancer InstituteBethesdaUSA

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