18F-fluorothymidine kinetics of malignant brain tumors

  • Christiaan Schiepers
  • Wei Chen
  • Magnus Dahlbom
  • Timothy Cloughesy
  • Carl K. Hoh
  • Sung-Cheng Huang
Original article

Abstract

Purpose

18F-labeled deoxy-fluorothymidine (FLT), a marker of cellular proliferation, has been used in PET tumor imaging. Here, the FLT kinetics of malignant brain tumors were investigated.

Methods

Seven patients with high-grade tumors and two patients with metastases had 12 studies. After 1.5 MBq/kg 18F-FLT had been administered intravenously, dynamic PET studies were acquired for 75 min. Images were reconstructed with iterative algorithms, and corrections applied for attenuation and scatter. Parametric images were generated with factor analysis, and vascular input and tumor output functions were derived. Compartmental models were used to estimate the rate constants.

Results

The standard three-compartment model appeared appropriate to describe 18F-FLT uptake. Corrections for blood volume, metabolites, and partial volume were necessary. Kinetic parameters were correlated with tumor pathology and clinical follow-up data. Two groups could be distinguished: lesions that were tumor predominant (TumP) and lesions that were treatment change predominant (TrcP). Both groups had a widely varying k1 (transport across the damaged BBB, range 0.02–0.2). Group TrcP had a relatively low k3 (phosphorylation rate, range 0.017–0.027), whereas k3 varied sevenfold in group TumP (range 0.015–0.11); the k3 differences were significant (p < 0.01). The fraction of transported FLT that is phosphorylated [k3/(k2+k3)] was able to separate the two groups (p < 0.001).

Conclusion

A three-compartment model with blood volume, metabolite, and partial volume corrections could adequately describe 18F-FLT kinetics in malignant brain tumors. Patients could be distinguished as having: (1) tumor-predominant or (2) treatment change-predominant lesions, with significantly different phosphorylation rates.

Keywords

18F-FLT Positron emission tomography Brain tumor Kinetic modeling Factor analysis 

References

  1. 1.
    Shields AF, Grierson JR, Dohmen BM, Machulla HJ, Stayanoff JC, Lawhorn-Crews JM, et al. Imaging proliferation in vivo with [F-18]FLT and positron emission tomography. Nat Med 1998;4(11):1334–6.PubMedCrossRefGoogle Scholar
  2. 2.
    Shields AF. PET imaging with 18F-FLT and thymidine analogs: promise and pitfalls. J Nucl Med 2003;44(9):1432–4.PubMedGoogle Scholar
  3. 3.
    Toyohara J, Waki A, Takamatsu S, Yonekura Y, Magata Y, Fujibayashi Y. Basis of FLT as a cell proliferation marker: comparative uptake studies with [3H]thymidine and [3H]arabinothymidine, and cell-analysis in 22 asynchronously growing tumor cell lines. Nucl Med Biol 2002;29(3):281–7.PubMedCrossRefGoogle Scholar
  4. 4.
    Seitz U, Wagner M, Neumaier B, Wawra E, Glatting G, Leder G, et al. Evaluation of pyrimidine metabolising enzymes and in vitro uptake of 3′-[18F]fluoro-3′-deoxythymidine ([18F]FLT) in pancreatic cancer cell lines. Eur J Nucl Med Mol Imaging 2002;29(9):1174–81.PubMedCrossRefGoogle Scholar
  5. 5.
    Chen W, Cloughesy T, Kamdar N, Satyamurthy N, Bergsneider M, Liau L, et al. Imaging proliferation in brain tumors with 18F-FLT PET: comparison with 18F-FDG. J Nucl Med 2005;46(6):945–52.PubMedGoogle Scholar
  6. 6.
    Cobben DC, Elsinga PH, Hoekstra HJ, Suurmeijer AJ, Vaalburg W, Maas B, et al. Is 18F-3′-fluoro-3′-deoxy-L-thymidine useful for the staging and restaging of non-small cell lung cancer? J Nucl Med 2004;45(10):1677–82.PubMedGoogle Scholar
  7. 7.
    Francis DL, Visvikis D, Costa DC, Croasdale I, Arulampalam TH, Luthra SK, et al. Assessment of recurrent colorectal cancer following 5-fluorouracil chemotherapy using both 18FDG and 18FLT PET. Eur J Nucl Med Mol Imaging 2004;31(6):928.PubMedCrossRefGoogle Scholar
  8. 8.
    Cobben DC, van der Laan BF, Maas B, Vaalburg W, Suurmeijer AJ, Hoekstra HJ, et al. 18F-FLT PET for visualization of laryngeal cancer: comparison with 18F-FDG PET. J Nucl Med 2004;45(2):226–31.PubMedGoogle Scholar
  9. 9.
    Visvikis D, Francis D, Mulligan R, Costa DC, Croasdale I, Luthra SK, et al. Comparison of methodologies for the in vivo assessment of 18FLT utilisation in colorectal cancer. Eur J Nucl Med Mol Imaging 2004;31(2):169–78.PubMedCrossRefGoogle Scholar
  10. 10.
    Muzi M, Vesselle H, Grierson JR, Mankoff DA, Schmidt RA, Peterson L, et al. Kinetic analysis of 3′-deoxy-3′-fluorothymidine PET studies: validation studies in patients with lung cancer. J Nucl Med 2005;46(2):274–82.PubMedGoogle Scholar
  11. 11.
    Muzi M, Mankoff DA, Grierson JR, Wells JM, Vesselle H, Krohn KA. Kinetic modeling of 3′-deoxy-3′-fluorothymidine in somatic tumors: mathematical studies. J Nucl Med 2005;46(2):371–80.PubMedGoogle Scholar
  12. 12.
    Yun M, Oh SJ, Ha HJ, Ryu JS, Moon DH. High radiochemical yield synthesis of 3′-deoxy-3′-[18F]fluorothymidine using (5′-O-dimethoxytrityl-2′-deoxy-3′-O-nosyl-beta-D-threo pentofuranosyl)thymine and its 3-N-BOC-protected analogue as a labeling precursor. Nucl Med Biol 2003;30(2):151–7.PubMedCrossRefGoogle Scholar
  13. 13.
    Nuyts J, Baete K, Beque D, Dupont P. Comparison between MAP and postprocessed ML for image reconstruction in emission tomography when anatomical knowledge is available. IEEE Trans Med Imaging 2005;24(5):667–75.PubMedCrossRefGoogle Scholar
  14. 14.
    Nuyts J, Michel C, Dupont P. Maximum-likelihood expectation-maximization reconstruction of sinograms with arbitrary noise distribution using NEC-transformations. IEEE Trans Med Imaging 2001;20(5):365–75.PubMedCrossRefGoogle Scholar
  15. 15.
    Schiepers C, Hoh CK, Dahlbom M, Wu HM, Phelps ME. Factor analysis for delineation of organ structures, creation of in- and output functions, and standardization of multicenter kinetic modeling. Proc SPIE 1999;3661:1343–50.CrossRefGoogle Scholar
  16. 16.
    Phelps ME, Huang SC, Hoffman EJ, Selin C, Sokoloff L, Kuhl DE. Tomographic measurement of local cerebral glucose metabolic rate in humans with (F-18)2-fluoro-2-deoxy-D-glucose: validation of method. Ann Neurol 1979;6(5):371–88.PubMedCrossRefGoogle Scholar
  17. 17.
    Huang SC, Phelps ME, Hoffman EJ, Sideris K, Selin CJ, Kuhl DE. Noninvasive determination of local cerebral metabolic rate of glucose in man. Am J Physiol 1980;238(1):E69–82.PubMedGoogle Scholar
  18. 18.
    Schiepers C, Wu HM, Nuyts J, Dahlbom M, Hoh CK, Huang SC, et al. F-18 fluoride PET: Is non-invasive quantitation feasible with factor analysis? J Nucl Med 1997;38(5 Suppl):93P.Google Scholar
  19. 19.
    Schiepers C, Hoh CK, Dahlbom M, Wu HM, Phelps ME. Reproducibility of input functions obtained with factor analysis in breast cancer. J Nucl Med 1998;39(5 Suppl):165P.Google Scholar
  20. 20.
    Schiepers C, Hoh CK, Seltzer MA, Phelps ME, Dahlbom M. Factor analysis for quantification of 11C-acetate PET in primary prostate cancer. J Nucl Med 2000;41(5 Suppl):100P.Google Scholar
  21. 21.
    Schiepers C, Hoh CK, Nuyts J, Wu HM, Phelps ME, Dahlbom M. Factor analysis in prostate cancer: delineation of organ structures and automatic generation of in- and output functions. IEEE Trans Nucl Sci 2002;49(5):2338–43.CrossRefGoogle Scholar
  22. 22.
    Wu HM, Hoh CK, Choi Y, Schelbert HR, Hawkins RA, Phelps ME, et al. Factor analysis for extraction of blood time-activity curves in dynamic FDG-PET studies. J Nucl Med 1995;36(9):1714–22.PubMedGoogle Scholar
  23. 23.
    Schiepers C, Czernin J, Hoh CK, Nuyts J, Phelps ME, Dahlbom M. Factor analysis for automatic determination of myocardial flow in 13N-ammonia PET studies. J Nucl Med 2002;43(5 Suppl):52P.Google Scholar
  24. 24.
    Schiepers C, Nuyts J, Wu HM, Verma RC. PET with 18F-fluoride: effects of iterative versus filtered backprojection reconstruction on kinetic modeling. IEEE Trans Nucl Sci 1997;44:1591–9.CrossRefGoogle Scholar
  25. 25.
    Schiepers C, Nuyts J, Wu HM, Dahlbom M, Huang SC, Phelps ME. Influence of iterative reconstruction on parameter estimation with three-compartment kinetic modeling. J Nucl Med 1997;38(5 Suppl):102P.Google Scholar
  26. 26.
    Wells JM, Mankoff DA, Eary JF, Spence AM, Muzi M, O’Sullivan F, et al. Kinetic analysis of 2-[11C]thymidine PET imaging studies of malignant brain tumors: preliminary patient results. Mol Imaging 2002;1(3):145–50.PubMedCrossRefGoogle Scholar
  27. 27.
    Muzi M, Spence AM, O’Sullivan F, Mankoff DA, Wells JM, Grierson JR, et al. Kinetic analysis of 3′-deoxy-3′-18F-fluorothymidine in patients with gliomas. J Nucl Med 2006;47(10):1612–21.PubMedGoogle Scholar

Copyright information

© Springer-Verlag 2007

Authors and Affiliations

  • Christiaan Schiepers
    • 1
  • Wei Chen
    • 1
  • Magnus Dahlbom
    • 1
  • Timothy Cloughesy
    • 2
  • Carl K. Hoh
    • 3
  • Sung-Cheng Huang
    • 1
  1. 1.Department of Molecular and Medical Pharmacology, David Geffen School of MedicineUniversity of CaliforniaLos AngelesUSA
  2. 2.Department of Neurology, David Geffen School of MedicineUniversity of CaliforniaLos AngelesUSA
  3. 3.Department of Radiology, School of MedicineUniversity of CaliforniaSan DiegoUSA

Personalised recommendations