A prospective clinical study of 18 F-FAZA PET-CT hypoxia imaging in head and neck squamous cell carcinoma before and during radiation therapy

  • Stéphanie Servagi-Vernat
  • Sarah Differding
  • Francois-Xavier Hanin
  • Daniel Labar
  • Anne Bol
  • John A. Lee
  • Vincent Grégoire
Original Article



Hypoxia in head and neck squamous cell carcinoma (HNSCC) is associated with poor prognosis and outcome. 18 F-Fluoroazomycin arabinoside (FAZA) is a positron emission tomography (PET) tracer developed to enable identification of hypoxic regions within tumor. The aim of this study was to evaluate the use of 18 F-FAZA-PET for assessment of hypoxia before and during radiation therapy.


Twelve patients with locally advanced HNSCC underwent 18 F-FAZA-PET scans before and at fraction 7 and 17 of concomitant chemo-radiotherapy. A hypoxic voxel was defined as a voxel expressing a standardized uptake value (SUV) equal or above the SUVmean of the posterior contralateral neck muscles plus three standard deviations. The fractional hypoxic volume fraction (FHV) and the spatial move of hypoxic volumes during treatment were analyzed.


A hypoxic volume could be identified in ten patients before treatment. FAZA-PET FHV varied from 0 to 54.3 % and from 0 to 41.4 % in the primary tumor and in the involved node, respectively. Six out of these ten patients completed all the FAZA-PET-computed tomography (CT) during the radiotherapy. In all patients, FHV and SUVmax values decreased. All patient presented a spatial move of hypoxic volume, but only three patients had newborn hypoxic voxels after 17 fractions.


This study indicated that 18 F-FAZA-PET could be used to identify and quantify tumor hypoxia before and during concomitant radio-chemotherapy in patients with locally advanced HNSCC. In addition to the information on prognostic value, the use of 18 F-FAZA-PET allowed the delineation of hypoxic volumes for dose escalation protocols. However, due to fluctuation of hypoxia during treatment, repeated scan will have to be performed (i.e. adaptive radiotherapy).


Positron emission tomography (PET) 18F FAZA Hypoxia imaging Head and neck squamous cell carcinoma Radiotherapy 


Conflict of interest

The authors declare that they have no conflict of interest.


  1. 1.
    Vaupel P, Kelleher DK, Hockel M. Oxygen status of malignant tumors: pathogenesis of hypoxia and significance for tumor therapy. Semin Oncol. 2001;28(2 Suppl 8):29–35.PubMedCrossRefGoogle Scholar
  2. 2.
    Koukourakis MI, Bentzen SM, Giatromanolaki A, Wilson GD, Daley FM, Saunders MI, et al. Endogenous markers of two separate hypoxia response pathways (hypoxia inducible factor 2 alpha and carbonic anhydrase 9) are associated with radiotherapy failure in head and neck cancer patients recruited in the CHART randomized trial. J Clin Oncol. 2006;24(5):727–35.PubMedCrossRefGoogle Scholar
  3. 3.
    Nordsmark M, Bentzen SM, Rudat V, Brizel D, Lartigau E, Stadler P, et al. Prognostic value of tumor oxygenation in 397 head and neck tumors after primary radiation therapy: an international multi-center study. Radiother Oncol. 2005;77(1):18–24.PubMedCrossRefGoogle Scholar
  4. 4.
    Fyles AW, Milosevic M, Wong R, Kavanagh MC, Pintilie M, Sun A, et al. Oxygenation predicts radiation response and survival in patients with cervix cancer. Radiother Oncol. 1998;48(2):149–56.PubMedCrossRefGoogle Scholar
  5. 5.
    Lee DJ, Pajak TF, Stetz J, Order SE, Weissberg JB, Fischer JJ. A phase I/II study of the hypoxic cell sensitizer misonidazole as an adjunct to high fractional dose radiotherapy in patients with unresectable squamous cell carcinoma of the head and neck: a RTOG randomized study (#79-04). Int J Radiat Oncol, Biol, Phys. 1989;16(2):465–70.CrossRefGoogle Scholar
  6. 6.
    Villar A, Martinez JC, de Serdio JL. Chemoradiation for advanced head and neck cancer: potential for improving results to match those of current treatment modalities for early-stage tumors–long-term results of hyperfractionated chemoradiation with carbogen breathing and anemia correction with erythropoietin. Int J Radiat Oncol, Biol, Phys. 2008;70(5):1382–8.CrossRefGoogle Scholar
  7. 7.
    Overgaard J, Horsman MR. Modification of Hypoxia-Induced Radioresistance in Tumors by the Use of Oxygen and Sensitizers. Semin Radiat Oncol. 1996;6(1):10–21.PubMedCrossRefGoogle Scholar
  8. 8.
    Mizoe JE, Hasegawa A, Jingu K, Takagi R, Bessyo H, Morikawa T, et al. Results of carbon ion radiotherapy for head and neck cancer. Radiother Oncol. 2012;103(1):32–7.PubMedCrossRefGoogle Scholar
  9. 9.
    Janssens GO, Rademakers SE, Terhaard CH, Doornaert PA, Bijl HP, van den Ende P, et al. Accelerated radiotherapy with carbogen and nicotinamide for laryngeal cancer: results of a phase III randomized trial. J Clin Oncol. 2012;30(15):1777–83.PubMedCrossRefGoogle Scholar
  10. 10.
    Toustrup K, Sorensen BS, Alsner J, Overgaard J. Hypoxia gene expression signatures as prognostic and predictive markers in head and neck radiotherapy. Semin Radiat Oncol. 2012;22(2):119–27.PubMedCrossRefGoogle Scholar
  11. 11.
    Mueller-Klieser W, Schlenger KH, Walenta S, Gross M, Karbach U, Hoeckel M, et al. Pathophysiological approaches to identifying tumor hypoxia in patients. Radiother Oncol. 1991;20 Suppl 1:21–8.PubMedCrossRefGoogle Scholar
  12. 12.
    Busk M, Horsman MR, Jakobsen S, Keiding S, van der Kogel AJ, Bussink J, et al. Imaging hypoxia in xenografted and murine tumors with 18F-fluoroazomycin arabinoside: a comparative study involving microPET, autoradiography, PO2-polarography, and fluorescence microscopy. Int J Radiat Oncol, Biol, Phys. 2008;70(4):1202–12.CrossRefGoogle Scholar
  13. 13.
    Rajendran JG, Hendrickson KR, Spence AM, Muzi M, Krohn KA, Mankoff DA. Hypoxia imaging-directed radiation treatment planning. Eur J Nucl Med Mol Imaging. 2006;33 Suppl 1:44–53.PubMedCrossRefGoogle Scholar
  14. 14.
    Vaupel P, Mayer A. Hypoxia in cancer: significance and impact on clinical outcome. Cancer Metastasis Rev. 2007;26(2):225–39.PubMedCrossRefGoogle Scholar
  15. 15.
    Lapi SE, Voller TF, Welch MJ. Positron Emission Tomography Imaging of Hypoxia. PET Clin. 2009;4(1):39–47.PubMedCentralPubMedCrossRefGoogle Scholar
  16. 16.
    Lehtio K, Oikonen V, Nyman S, Gronroos T, Roivainen A, Eskola O, et al. Quantifying tumour hypoxia with fluorine-18 fluoroerythronitroimidazole ([18 F]FETNIM) and PET using the tumour to plasma ratio. Eur J Nucl Med Mol Imaging. 2003;30(1):101–8.PubMedCrossRefGoogle Scholar
  17. 17.
    Mahy P, De Bast M, de Groot T, Cheguillaume A, Gillart J, Haustermans K, et al. Comparative pharmacokinetics, biodistribution, metabolism and hypoxia-dependent uptake of [18 F]-EF3 and [18 F]-MISO in rodent tumor models. Radiother Oncol. 2008;89(3):353–60.PubMedCrossRefGoogle Scholar
  18. 18.
    Mahy P, De Bast M, Gillart J, Labar D, Gregoire V. Detection of tumour hypoxia: comparison between EF5 adducts and [18F]EF3 uptake on an individual mouse tumour basis. Eur J Nucl Med Mol Imaging. 2006;33(5):553–6.PubMedCrossRefGoogle Scholar
  19. 19.
    Mahy P, De Bast M, Leveque PH, Gillart J, Labar D, Marchand J, et al. Preclinical validation of the hypoxia tracer 2-(2-nitroimidazol-1-yl)- N-(3,3,3-[(18)F]trifluoropropyl)acetamide, [(18)F]EF3. Eur J Nucl Med Mol Imaging. 2004;31(9):1263–72.PubMedCrossRefGoogle Scholar
  20. 20.
    Piert M, Machulla HJ, Picchio M, Reischl G, Ziegler S, Kumar P, et al. Hypoxia-specific tumor imaging with 18 F-fluoroazomycin arabinoside. J Nucl Med. 2005;46(1):106–13.PubMedGoogle Scholar
  21. 21.
    Komar G, Seppanen M, Eskola O, Lindholm P, Gronroos TJ, Forsback S, et al. 18 F-EF5: a new PET tracer for imaging hypoxia in head and neck cancer. J Nucl Med. 2008;49(12):1944–51.PubMedCrossRefGoogle Scholar
  22. 22.
    Chen L, Zhang Z, Kolb HC, Walsh JC, Zhang J, Guan Y. (1)(8)F-HX4 hypoxia imaging with PET/CT in head and neck cancer: a comparison with (1)(8)F-FMISO. Nucl Med Commun. 2012;33(10):1096–102.PubMedCrossRefGoogle Scholar
  23. 23.
    Wijsman R, Kaanders JH, Oyen WJ, Bussink J. Hypoxia and tumor metabolism in radiation oncology: targets visualized by positron emission tomography. Q J Nucl Med Mol Imaging. 2013;57(3):244–56.PubMedGoogle Scholar
  24. 24.
    Clausen MM, Hansen AE, Af Rosenschold PM, Kjaer A, Kristensen AT, McEvoy FJ, et al. Dose escalation to high-risk sub-volumes based on non-invasive imaging of hypoxia and glycolytic activity in canine solid tumors: a feasibility study. Radiat Oncol. 2013;8:262.PubMedCentralPubMedCrossRefGoogle Scholar
  25. 25.
    Geets X, Gregoire V, Lee JA. Implementation of hypoxia PET imaging in radiation therapy planning. Q J Nucl Med Mol Imaging. 2013;57(3):271–82.PubMedGoogle Scholar
  26. 26.
    Bentzen SM, Gregoire V. Molecular imaging-based dose painting: a novel paradigm for radiation therapy prescription. Semin Radiat Oncol. 2011;21(2):101–10.PubMedCentralPubMedCrossRefGoogle Scholar
  27. 27.
    Calais G, Alfonsi M, Bardet E, Sire C, Germain T, Bergerot P, et al. Randomized trial of radiation therapy versus concomitant chemotherapy and radiation therapy for advanced-stage oropharynx carcinoma. J Natl Cancer Inst. 1999;91(24):2081–6.PubMedCrossRefGoogle Scholar
  28. 28.
    Bonner JA, Harari PM, Giralt J, Azarnia N, Shin DM, Cohen RB, et al. Radiotherapy plus cetuximab for squamous-cell carcinoma of the head and neck. N Engl J Med. 2006;354(6):567–78.PubMedCrossRefGoogle Scholar
  29. 29.
    EudraLex TRGMPitEU. Good Manufacturing Practice Medicinal Products for Human and Veterinary Use. Volume 4; Annex 3 Manufacture of Radiopharmaceuticals.Google Scholar
  30. 30.
    Reischl G, Ehrlichmann W, Bieg C, Solbach C, Kumar P, Wiebe LI, et al. Preparation of the hypoxia imaging PET tracer [18 F]FAZA: reaction parameters and automation. Appl Radiat Isot. 2005;62(6):897–901.PubMedCrossRefGoogle Scholar
  31. 31.
    Souvatzoglou M, Grosu AL, Roper B, Krause BJ, Beck R, Reischl G, et al. Tumour hypoxia imaging with [18 F]FAZA PET in head and neck cancer patients: a pilot study. Eur J Nucl Med Mol Imaging. 2007;34(10):1566–75.PubMedCrossRefGoogle Scholar
  32. 32.
    Trinkaus ME, Blum R, Rischin D, Callahan J, Bressel M, Segard T, et al. Imaging of hypoxia with 18 F-FAZA PET in patients with locally advanced non-small cell lung cancer treated with definitive chemoradiotherapy. J Med Imaging Radiat Oncol. 2013;57(4):475–81.PubMedCrossRefGoogle Scholar
  33. 33.
    Busk M, Mortensen LS, Nordsmark M, Overgaard J, Jakobsen S, Hansen KV, et al. PET hypoxia imaging with FAZA: reproducibility at baseline and during fractionated radiotherapy in tumour-bearing mice. Eur J Nucl Med Mol Imaging. 2013;40(2):186–97.PubMedCrossRefGoogle Scholar
  34. 34.
    Mortensen LS, Johansen J, Kallehauge J, Primdahl H, Busk M, Lassen P, et al. FAZA PET/CT hypoxia imaging in patients with squamous cell carcinoma of the head and neck treated with radiotherapy: results from the DAHANCA 24 trial. Radiother Oncol. 2012;105(1):14–20.PubMedCrossRefGoogle Scholar
  35. 35.
    Grosu AL, Souvatzoglou M, Roper B, Dobritz M, Wiedenmann N, Jacob V, et al. Hypoxia imaging with FAZA-PET and theoretical considerations with regard to dose painting for individualization of radiotherapy in patients with head and neck cancer. Int J Radiat Oncol, Biol, Phys. 2007;69(2):541–51.CrossRefGoogle Scholar
  36. 36.
    Mahy P, De Bast M, Gallez B, Gueulette J, Koch CJ, Scalliet P, et al. In vivo colocalization of 2-nitroimidazole EF5 fluorescence intensity and electron paramagnetic resonance oximetry in mouse tumors. Radiother Oncol. 2003;67(1):53–61.PubMedCrossRefGoogle Scholar
  37. 37.
    Tran LB, Bol A, Labar D, Jordan B, Magat J, Mignion L, et al. Hypoxia imaging with the nitroimidazole 18 F-FAZA PET tracer: a comparison with OxyLite, EPR oximetry and 19F-MRI relaxometry. Radiother Oncol. 2012;105(1):29–35.PubMedCrossRefGoogle Scholar
  38. 38.
    Gagel B, Piroth M, Pinkawa M, Reinartz P, Zimny M, Kaiser HJ, et al. pO polarography, contrast enhanced color duplex sonography (CDS), [18 F] fluoromisonidazole and [18 F] fluorodeoxyglucose positron emission tomography: validated methods for the evaluation of therapy-relevant tumor oxygenation or only bricks in the puzzle of tumor hypoxia? BMC Cancer. 2007;7:113.PubMedCentralPubMedCrossRefGoogle Scholar
  39. 39.
    Gagel B, Reinartz P, Dimartino E, Zimny M, Pinkawa M, Maneschi P, et al. pO(2) Polarography versus positron emission tomography ([(18)F] fluoromisonidazole, [(18)F]-2-fluoro-2'-deoxyglucose). An appraisal of radiotherapeutically relevant hypoxia. Strahlenther Onkol. 2004;180(10):616–22.PubMedCrossRefGoogle Scholar
  40. 40.
    Bartlett RM, Beattie BJ, Naryanan M, Georgi JC, Chen Q, Carlin SD, et al. Image-guided PO2 probe measurements correlated with parametric images derived from 18 F-fluoromisonidazole small-animal PET data in rats. J Nucl Med. 2012;53(10):1608–15.PubMedCentralPubMedCrossRefGoogle Scholar
  41. 41.
    Zimny M, Gagel B, DiMartino E, Hamacher K, Coenen HH, Westhofen M, et al. FDG–a marker of tumour hypoxia? A comparison with [18 F]fluoromisonidazole and pO2-polarography in metastatic head and neck cancer. Eur J Nucl Med Mol Imaging. 2006;33(12):1426–31.PubMedCrossRefGoogle Scholar
  42. 42.
    Nordsmark M, Overgaard M, Overgaard J. Pretreatment oxygenation predicts radiation response in advanced squamous cell carcinoma of the head and neck. Radiother Oncol. 1996;41(1):31–9.PubMedCrossRefGoogle Scholar
  43. 43.
    Thorwarth D, Eschmann SM, Scheiderbauer J, Paulsen F, Alber M. Kinetic analysis of dynamic 18 F-fluoromisonidazole PET correlates with radiation treatment outcome in head-and-neck cancer. BMC Cancer. 2005;5:152.PubMedCentralPubMedCrossRefGoogle Scholar
  44. 44.
    Rischin D, Fisher R, Peters L, Corry J, Hicks R. Hypoxia in head and neck cancer: studies with hypoxic positron emission tomography imaging and hypoxic cytotoxins. Int J Radiat Oncol, Biol, Phys. 2007;69(2 Suppl):S61–3.CrossRefGoogle Scholar
  45. 45.
    Duprez F, De Neve W, De Gersem W, Coghe M, Madani I. Adaptive dose painting by numbers for head-and-neck cancer. Int J Radiat Oncol, Biol, Phys. 2011;80(4):1045–55.CrossRefGoogle Scholar
  46. 46.
    Madani I, Duprez F, Boterberg T, Van de Wiele C, Bonte K, Deron P, et al. Maximum tolerated dose in a phase I trial on adaptive dose painting by numbers for head and neck cancer. Radiother Oncol. 2011;101(3):351–5.PubMedCrossRefGoogle Scholar
  47. 47.
    Madani I, Duthoy W, Derie C, De Gersem W, Boterberg T, Saerens M, et al. Positron emission tomography-guided, focal-dose escalation using intensity-modulated radiotherapy for head and neck cancer. Int J Radiat Oncol, Biol, Phys. 2007;68(1):126–35.CrossRefGoogle Scholar
  48. 48.
    Malinen E, Sovik A, Hristov D, Bruland OS, Olsen DR. Adapting radiotherapy to hypoxic tumours. Phys Med Biol. 2006;51(19):4903–21.PubMedCrossRefGoogle Scholar
  49. 49.
    Sovik A, Malinen E, Skogmo HK, Bentzen SM, Bruland OS, Olsen DR. Radiotherapy adapted to spatial and temporal variability in tumor hypoxia. Int J Radiat Oncol, Biol, Phys. 2007;68(5):1496–504.CrossRefGoogle Scholar
  50. 50.
    Thorwarth D, Eschmann SM, Paulsen F, Alber M. Hypoxia dose painting by numbers: a planning study. Int J Radiat Oncol, Biol, Phys. 2007;68(1):291–300.CrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2014

Authors and Affiliations

  • Stéphanie Servagi-Vernat
    • 1
    • 3
  • Sarah Differding
    • 1
  • Francois-Xavier Hanin
    • 2
  • Daniel Labar
    • 1
  • Anne Bol
    • 1
  • John A. Lee
    • 1
  • Vincent Grégoire
    • 1
  1. 1.Department of Radiation Oncology and Center of Molecular Imaging, Radiotherapy and Oncology (MIRO)Institut de Recherche Clinique (IREC), Université catholique de Louvain, St-Luc University HospitalBrusselsBelgium
  2. 2.Department of Nuclear Medicine and Center of Molecular Imaging, Radiotherapy and Oncology (MIRO)Institut de Recherche Clinique (IREC), Université catholique de Louvain, St-Luc University HospitalBrusselsBelgium
  3. 3.Department of Radiation OncologyUniversity Hospital Jean MinjozBesanconFrance

Personalised recommendations