[18F]FLT is superior to [18F]FDG for predicting early response to antiproliferative treatment in high-grade lymphoma in a dose-dependent manner

  • Nicolas GrafEmail author
  • Ken Herrmann
  • Barbara Numberger
  • Daniela Zwisler
  • Michaela Aichler
  • Annette Feuchtinger
  • Tibor Schuster
  • Hans-Jürgen Wester
  • Reingard Senekowitsch-Schmidtke
  • Christian Peschel
  • Markus Schwaiger
  • Ulrich Keller
  • Tobias Dechow
  • Andreas K. Buck
Original Article



Positron emission tomography (PET) with the thymidine analogue [18F]fluorothymidine ([18F]FLT) has been shown to detect early response to chemotherapy in high-grade lymphoma. In this preclinical in vitro and in vivo study we compared [18F]FLT to the glucose analogue [18F]fluorodeoxyglucose ([18F]FDG) regarding dose-dependent visualization and prediction of early therapy response.


Immunodeficient mice bearing human diffuse large B-cell lymphoma (SUDHL-4) xenotransplants were treated intraperitoneally with increasing doses of the cytotoxic agent doxorubicin. Metabolic and antiproliferative effects were assessed 2 days after therapy by [18F]FLT and [18F]FDG PET. Explanted lymphomas were analysed histologically and by immunostaining against Ki67 and caspase 3. In vitro, lymphoma cells were incubated with increasing concentrations of doxorubicin and analysed using the tetrazolium assay, fluorescence-activated cell sorting, and [18F]FLT and [18F]FDG uptake 48 h later.


In vivo, tumour growth was inhibited by doses of doxorubicin ranging from 25 μg to 200 μg. The mean tumour-to-background ratio (TBR) of [18F]FLT on day +2 was significantly reduced in all dose groups compared to control and baseline values and preceded changes in tumour volume. Importantly, there was a significant inverse correlation between reduction in TBR and dose of chemotherapy (r = −0.54, p = 0.021). The mean TBR of [18F]FDG, however, increased after therapy and differed considerably between groups (r = −0.13, p = 0.668). Explanted tumours showed a dose-dependent decrease in the proliferation marker Ki67, but no change in the apoptotic marker caspase 3. In vitro, doxorubicin led to a dose-dependent reduction in cell viability and a decrease in S phase. Lymphoma cells showed a dose-dependent reduction in [18F]FLT uptake, in contrast to a variable and decelerated reduction in [18F]FDG uptake. Thus, the increase in [18F]FDG uptake in vivo presumably reflected nonspecific glucose metabolism of inflammatory cells, as confirmed by histology of explanted lymphomas.


Early responses to dose-dependent antiproliferative treatment in high-grade lymphoma are more accurately visualized with [18F]FLT PET than with [18F]FDG PET.


FLT PET FDG PET Lymphoma Dose-dependency Therapy monitoring 



We appreciate the excellent contributions made by our colleague Petra Watzlowik, PhD, and the great support of our the member of technical staff Sybille Reder, Elisabeth Aywanger and Brigitte Dzewas. Supported by the Deutsche Forschungsgemeinschaft (SFB824 to A. Buck and T. Dechow, SFB TRR54 to U. Keller).

Conflicts of interest



  1. 1.
    Cheson BD, Horning SJ, Coiffier B, Shipp MA, Fisher RI, et al. Report of an international workshop to standardize response criteria for non-Hodgkin’s lymphomas. NCI Sponsored International Working Group. J Clin Oncol. 1999;17:1244.PubMedGoogle Scholar
  2. 2.
    Surbone A, Longo DL, DeVita Jr VT, Ihde DC, Duffey PL, et al. Residual abdominal masses in aggressive non-Hodgkin’s lymphoma after combination chemotherapy: significance and management. J Clin Oncol. 1988;6:1832–7.PubMedGoogle Scholar
  3. 3.
    Juweid ME, Stroobants S, Hoekstra OS, Mottaghy FM, Dietlein M, et al. Use of positron emission tomography for response assessment of lymphoma: consensus of the Imaging Subcommittee of International Harmonization Project in Lymphoma. J Clin Oncol. 2007;25:571–8.PubMedCrossRefGoogle Scholar
  4. 4.
    Kazama T, Faria SC, Varavithya V, Phongkitkarun S, Ito H, et al. FDG-PET in the evaluation of treatment for lymphoma: clinical usefulness and pitfalls. Radiographics. 2005;25:191–207.PubMedCrossRefGoogle Scholar
  5. 5.
    van Waarde A, Cobben DC, Suurmeijer AJ, Maas B, Vaalburg W, et al. Selectivity of 18F-FLT and 18F-FDG for differentiating tumor from inflammation in a rodent model. J Nucl Med. 2004;45:695–700.PubMedGoogle Scholar
  6. 6.
    Shields AF, Mankoff DA, Link JM, Graham MM, Eary JF, et al. Carbon-11-thymidine and FDG to measure therapy response. J Nucl Med. 1998;39:1757–62.PubMedGoogle Scholar
  7. 7.
    Shields AF, Grierson JR, Dohmen BM, Machulla HJ, Stayanoff JC, et al. Imaging proliferation in vivo with [F-18]FLT and positron emission tomography. Nat Med. 1998;4:1334–6.PubMedCrossRefGoogle Scholar
  8. 8.
    Barthel H, Perumal M, Latigo J, He Q, Brady F, et al. The uptake of 3′-deoxy-3′-[18F]fluorothymidine into L5178Y tumours in vivo is dependent on thymidine kinase 1 protein levels. Eur J Nucl Med Mol Imaging. 2005;32:257–63.PubMedCrossRefGoogle Scholar
  9. 9.
    Eriksson S, Arnér E, Spasokoukotskaja T, Wang L, Karlsson A, et al. Properties and levels of deoxynucleoside kinases in normal and tumor cells; implications for chemotherapy. Adv Enzyme Regul. 1994;34:13–25.PubMedCrossRefGoogle Scholar
  10. 10.
    Seitz U, Wagner M, Neumaier B, Wawra E, Glatting G, et al. Evaluation of pyrimidine metabolising enzymes and in vitro uptake of 3′-[(18)F]fluoro-3′-deoxythymidine ([(18)F]FLT) in pancreatic cancer cell lines. Eur J Nucl Med Mol Imaging. 2002;29:1174–81.PubMedCrossRefGoogle Scholar
  11. 11.
    Rasey JS, Grierson JR, Wiens LW, Kolb PD, Schwartz JL. Validation of FLT uptake as a measure of thymidine kinase-1 activity in A549 carcinoma cells. J Nucl Med. 2002;43:1210–7.PubMedGoogle Scholar
  12. 12.
    Lu L, Samuelsson L, Bergstrom M, Sato K, Fasth KJ, et al. Rat studies comparing 11C-FMAU, 18F-FLT, and 76Br-BFU as proliferation markers. J Nucl Med. 2002;43:1688–98.PubMedGoogle Scholar
  13. 13.
    Chen W, Cloughesy T, Kamdar N, Satyamurthy N, Bergsneider M, et al. Imaging proliferation in brain tumors with 18F-FLT PET: comparison with 18F-FDG. J Nucl Med. 2005;46:945–52.PubMedGoogle Scholar
  14. 14.
    Cobben DC, Elsinga PH, Suurmeijer AJ, Vaalburg W, Maas B, et al. Detection and grading of soft tissue sarcomas of the extremities with (18)F-3′-fluoro-3′-deoxy-L-thymidine. Clin Cancer Res. 2004;10:1685–90.PubMedCrossRefGoogle Scholar
  15. 15.
    Smyczek-Gargya B, Fersis N, Dittmann H, Vogel U, Reischl G, et al. PET with [18F]fluorothymidine for imaging of primary breast cancer: a pilot study. Eur J Nucl Med Mol Imaging. 2004;31:720–4.PubMedCrossRefGoogle Scholar
  16. 16.
    Wagner M, Seitz U, Buck A, Neumaier B, Schultheiss S, et al. 3′-[18F]fluoro-3′-deoxythymidine ([18F]-FLT) as positron emission tomography tracer for imaging proliferation in a murine B-cell lymphoma model and in the human disease. Cancer Res. 2003;63:2681–7.PubMedGoogle Scholar
  17. 17.
    Buck AK, Bommer M, Stilgenbauer S, Juweid M, Glatting G, et al. Molecular imaging of proliferation in malignant lymphoma. Cancer Res. 2006;66:11055–61.PubMedCrossRefGoogle Scholar
  18. 18.
    Herrmann K, Wieder HA, Buck AK, Schöffel M, Krause BJ, et al. Early response assessment using 3′-deoxy-3′-[18F]fluorothymidine-positron emission tomography in high-grade non-Hodgkin’s lymphoma. Clin Cancer Res. 2007;13:3552–8.PubMedCrossRefGoogle Scholar
  19. 19.
    Graf N, Herrmann K, den Hollander J, Fend F, Schuster T, et al. Imaging proliferation to monitor early response of lymphoma to cytotoxic treatment. Mol Imaging Biol. 2008;10(6):349–55.PubMedCrossRefGoogle Scholar
  20. 20.
    Jerusalem G, Beguin Y, Fassotte MF, Najjar F, Paulus P, et al. Persistent tumor 18F-FDG uptake after a few cycles of polychemotherapy is predictive of treatment failure in non-Hodgkin’s lymphoma. Haematologica. 2000;85(6):613–8.PubMedGoogle Scholar
  21. 21.
    Spaepen K, Stroobants S, Dupont P, Vandenberghe P, Thomas J, et al. Early restaging positron emission tomography with (18)F-fluorodeoxyglucose predicts outcome in patients with aggressive non-Hodgkin’s lymphoma. Ann Oncol. 2002;13(9):1356–63.PubMedCrossRefGoogle Scholar
  22. 22.
    Moskowitz CH, Schöder H, Teruya-Feldstein J, Sima C, Iasonos A, et al. Risk-adapted dose-dense immunochemotherapy determined by interim FDG-PET in advanced-stage diffuse large B-cell lymphoma. J Clin Oncol. 2010;28(11):1896–903.PubMedCrossRefGoogle Scholar
  23. 23.
    Han HS, Escalón MP, Hsiao B, Serafini A, Lossos IS. High incidence of false-positive PET scans in patients with aggressive non-Hodgkin’s lymphoma treated with rituximab-containing regimens. Ann Oncol. 2009;20(2):309–18.PubMedCrossRefGoogle Scholar
  24. 24.
    Brepoels L, De Saint-Hubert M, Stroobants S, Verhoef G, Balzarini J, et al. Dose–response relationship in cyclophosphamide-treated B-cell lymphoma xenografts monitored with [18F]FDG PET. Eur J Nucl Med Mol Imaging. 2010;37(9):1688–95.PubMedCrossRefGoogle Scholar
  25. 25.
    Hamacher K, Coenen HH, Stöcklin G. Efficient stereospecific synthesis of no-carrier-added 2-[18F]-fluoro-2-deoxy-D-glucose using aminopolyether supported nucleophilic substitution. J Nucl Med. 1986;27(2):235–8.PubMedGoogle Scholar
  26. 26.
    Peyrade F, Jardin F, Thieblemont C, Thyss A, Emile JF, et al; Groupe d’Etude des Lymphomes de l’Adulte (GELA) investigators. Attenuated immunochemotherapy regimen (R-miniCHOP) in elderly patients older than 80 years with diffuse large B-cell lymphoma: a multicentre, single-arm, phase 2 trial. Lancet Oncol. 2011;12(5):460–8.PubMedCrossRefGoogle Scholar
  27. 27.
    Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144(5):646–74.PubMedCrossRefGoogle Scholar
  28. 28.
    Hurley LH. DNA and its associated processes as targets for cancer therapy. Nat Rev Cancer. 2002;2:188–200.PubMedCrossRefGoogle Scholar
  29. 29.
    Greiner DL, Hesselton RA, Shultz LD. SCID mouse models of human stem cell engraftment. Stem Cells. 1998;16(3):166–77.PubMedCrossRefGoogle Scholar
  30. 30.
    Spaepen K, Stroobants S, Dupont P, Bormans G, Balzarini J, et al. [(18)F]FDG-PET monitoring of tumour response to chemotherapy: does [(18)F]FDG uptake correlate with the viable tumour cell fraction? Eur J Nucl Med Mol Imaging. 2003;30(5):682–8.PubMedCrossRefGoogle Scholar
  31. 31.
    Kubota R, Yamada S, Kubota K, Ishiwata K, Tamahashi N, et al. Intratumoral distribution of fluorine-18-fluorodeoxyglucose in vivo: high accumulation in macrophages and granulation tissues studied by microautoradiography. J Nucl Med. 1992;33(11):1972–80.PubMedGoogle Scholar
  32. 32.
    Brepoels L, Stroobants S, Verhoef G, De Groot T, Mortelmans L, et al. (18)F-FDG and (18)F-FLT uptake early after cyclophosphamide and mTOR inhibition in an experimental lymphoma model. J Nucl Med. 2009;50(7):1102–9.PubMedCrossRefGoogle Scholar
  33. 33.
    Higashi K, Clavo AC, Wahl RL. In vitro assessment of 2-fluoro-2-deoxy-D-glucose, L-methionine and thymidine as agents to monitor the early response of a human adenocarcinoma cell line to radiotherapy. J Nucl Med. 1993;34(5):773–9.PubMedGoogle Scholar
  34. 34.
    Aloj L, Caracó C, Jagoda E, Eckelman WC, Neumann RD. Glut-1 and hexokinase expression: relationship with 2-fluoro-2-deoxy-D-glucose uptake in A431 and T47D cells in culture. Cancer Res. 1999;59(18):4709–14.PubMedGoogle Scholar
  35. 35.
    Haberkorn U, Morr I, Oberdorfer F, Bellemann ME, Blatter J, Altmann A, et al. Fluorodeoxyglucose uptake in vitro: aspects of method and effects of treatment with gemcitabine. J Nucl Med. 1994;35(11):1842–50.PubMedGoogle Scholar
  36. 36.
    Jensen MM, Jørgensen JT, Binderup T, Kjaer A. Tumor volume in subcutaneous mouse xenografts measured by microCT is more accurate and reproducible than determined by 18F-FDG-microPET or external caliper. BMC Med Imaging. 2008;8:16.PubMedCrossRefGoogle Scholar
  37. 37.
    Jensen MM, Erichsen KD, Björkling F, Madsen J, Jensen PB, et al. Early detection of response to experimental chemotherapeutic Top216 with [18F]FLT and [18F]FDG-PET in human ovary cancer xenografts in mice. PLoS One. 2010;5(9):e12965.PubMedCrossRefGoogle Scholar
  38. 38.
    Apisarnthanarax S, Alauddin MM, Mourtada F, Ariga H, Raju U, et al. Early detection of chemoradioresponse in esophageal carcinoma by 3′-deoxy-3′-3H-fluorothymidine using preclinical tumor models. Clin Cancer Res. 2006;12:4590–7.PubMedCrossRefGoogle Scholar
  39. 39.
    Herrmann K, Buck AK, Schuster T, Rudelius M, Wester HJ, et al. A pilot study to evaluate 3′-deoxy-3′-18F-fluorothymidine PET for initial and early response imaging in mantle cell lymphoma. J Nucl Med. 2011;52(12):1898–902.PubMedCrossRefGoogle Scholar
  40. 40.
    Herrmann K, Buck AK, Schuster T, Junger A, Wieder HA, et al. Predictive value of initial 18F-FLT uptake in patients with aggressive non-Hodgkin lymphoma receiving R-CHOP treatment. J Nucl Med. 2011;52(5):690–6.PubMedCrossRefGoogle Scholar
  41. 41.
    Troost EG, Vogel WV, Merkx MA, Slootweg PJ, Marres HA, et al. 18F-FLT-PET does not discriminate between reactive and metastatic lymph nodes in primary head and neck cancer patients. J Nucl Med. 2007;48:726–35.PubMedCrossRefGoogle Scholar
  42. 42.
    Wieder HA, Geinitz H, Rosenberg R, Lordick F, Becker K, et al. PET imaging with [(18)F]3′-deoxy-3′-fluorothymidine for prediction of response to neoadjuvant treatment in patients with rectal cancer. Eur J Nucl Med Mol Imaging. 2007;34:878–83.PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2012

Authors and Affiliations

  • Nicolas Graf
    • 1
    • 6
    Email author
  • Ken Herrmann
    • 2
  • Barbara Numberger
    • 2
  • Daniela Zwisler
    • 2
  • Michaela Aichler
    • 3
  • Annette Feuchtinger
    • 3
  • Tibor Schuster
    • 4
  • Hans-Jürgen Wester
    • 2
  • Reingard Senekowitsch-Schmidtke
    • 2
  • Christian Peschel
    • 1
  • Markus Schwaiger
    • 2
  • Ulrich Keller
    • 1
  • Tobias Dechow
    • 1
  • Andreas K. Buck
    • 2
    • 5
  1. 1.Department of Hematology/OncologyTechnische Universität MünchenMunichGermany
  2. 2.Department of Nuclear MedicineTechnische Universität MünchenMunichGermany
  3. 3.Institute of Pathology (Helmholtz Zentrum München)Technische Universität MünchenMunichGermany
  4. 4.Institute of Medical Statistics and EpidemiologyTechnische Universität MünchenMunichGermany
  5. 5.Department of Nuclear MedicineUniversitätsklinikum WürzburgWürzburgGermany
  6. 6.Department of Hematology and OncologySchön Klinik Starnberger SeeBergGermany

Personalised recommendations