• No results found

Prognosis/patient selection

As shown earlier, 18F-FAZA-PET can be used to identify tumor regions with hypoxia.

Theoretically, such knowledge can be used to make a better estimation of prognosis, but also to select patients for some kind of hypoxia-targeted treatment.

For example, accelerated radiotherapy combined with the hyperoxic gas carbogen and nicotinamide (ARCON) is recently investigated in phase 3 trials50-53. For head and neck cancer, ARCON showed no benefit compared with accelerated radiation, except for regional control in T2-T4 laryngeal cancer51, but a significant gain in regional control rate was observed among the patients receiving ARCON with equal levels of toxicity53. In this study, no hypoxic imaging has been performed before the treatment, because at the time of patient selection no hypoxic image tool was available. For the future, 18F-FAZA-PET may be able to select patients with hypoxic tumors, which might indeed benefit from ARCON and consequently the true value of ARCON defined.

Tirapazamine is a drug with selective cytotoxicity for hypoxic cells. Recently, in a phase 3 trial54, 861 patients with locally advanced head and neck cancer were randomly assigned to receive chemoradiation or chemoradiation with tirapazamine. No benefit was found in terms of overall survival, failure-free survival, time to locoregional failure, or quality of life. Although in this study no advantage was found, in a substudy18 tirapazamine was found to be effective in patients with hypoxic tumors as assessed by 18F-FMISO-PET. Again, this finding suggests that introducing hypoxia imaging would better help selecting patients for additional treatment.

Radiotherapy dose escalation

In the past, several attempts have been made to overcome tumor hypoxia, such as the use of hyperbaric oxygen, radiosensitizers, vasodilators or hypoxic cytotoxins such as tirapazamine combined with (chemo)radiation. Unfortunately, generally speaking, these combined approaches have come to the expense of increased acute and late radiation-induced side-effects55.

Another approach, which may overcome hypoxic tumor resistance, is increasing the radiation dose. However, increasing the radiation dose may also increase radiation-induced side effects, especially in the head and neck area where critical structures, such as the spinal cord, carotid arteries and parotid glands,

are in close proximity to the tumor. Ideally, only hypoxic tumor cells or hypoxic cell islets should receive such a higher dose. Currently, with modern radiotherapy techniques like intensity-modulated radiotherapy, it has become possible to intensify radiation dose in specific subvolumes within the gross tumor volume56. It has been hypothesized that 18F-FAZA-PET/CT can be used to guide radiotherapy in order to substantially increase the dose to hypoxic tumor subvolumes16. This might improve local control and subsequently survival of patients with locally advanced head and neck squamous cell carcinoma. To the best of our knowledge, few clinical data are available so far to prove this hypothesis. In addition, little is known about the way hypoxic areas behave during the radiotherapy course:

hypoxic areas may disappear and subsequently appear at different locations. To achieve the most optimal hypoxic tumor subvolume dose escalation, several strategies are developed (e.g., gradual dose escalation using intensity-modulated radiation therapy with a simultaneous integrated boost, intensity modulated arc therapy, stereotactic boost, or protons). Additional information is required with regard to these possible changes.


Based on this review, we conclude that 18F-FAZA-PET is feasible to detect tumor hypoxia and to have superior biokinetics compared to 18F-FMISO. 18F-FAZA is a promising PET radiopharmaceutical for visualization of tumor hypoxia, although clinical studies must still confirm the exact role of 18F-FAZA-PET scanning in head and neck oncology. Also, the superior hypoxia PET radiopharmaceutical is not known yet. Therefore, a clinical study directly comparing different hypoxia radiopharmaceuticals (e.g., 18F-FMISO, 18F-FAZA, 18F-HX4) in the same patients would be desirable.



1. Vaupel P, Mayer A, Hockel M. Tumor hypoxia and malignant progression. Methods Enzymol.


2. Harris AL. Hypoxia—a key regulatory factor in tumour growth. Nat Rev Cancer. 2002;2:38-47.

3. Le QT, Denko NC, Giaccia AJ. Hypoxic gene expression and metastasis. Cancer Metastasis Rev.


4. Vanselow B, Eble MJ, Rudat V, et al. Oxygenation of advanced head and neck cancer: Prognostic marker for the response to primary radiochemotherapy. Otolaryngol Head Neck Surg. 2000;122:856-862.

5. Prosnitz RG, Yao B, Farrell CL, et al. Pretreatment anemia is correlated with the reduced effectiveness of radiation and concurrent chemotherapy in advanced head and neck cancer. Int J Radiat Oncol Biol Phys. 2005;61:1087-1095.

6. Isa AY, Ward TH, West CM, Slevin NJ, Homer JJ. Hypoxia in head and neck cancer. Br J Radiol.


7. Vaupel P, Mayer A. Hypoxia in cancer: Significance and impact on clinical outcome. Cancer Metastasis Rev. 2007;26(2):225-239.

8. Adam MF, Gabalski EC, Bloch DA, et al. Tissue oxygen distribution in head and neck cancer patients.

Head Neck. 1999;21:146-153.

9. Chitneni SK, Palmer GM, Zalutsky MR, et al. Molecular imaging of hypoxia. J Nucl Med. 2011;52:165-168.

10. Nordsmark M, Overgaard M, Overgaard J. Pretreatment oxygenation predicts radiation response in advanced squamous cell carcinoma of the head and neck. Radiother Oncol. 1996;41:31-39.

11. Brizel DM, Sibley GS, Prosnitz LR, et al. Tumor hypoxia adversely affects the prognosis of carcinoma of the head and neck. Int J Radiat Oncol Biol Phys. 1997;38:285-289.

12. Becker A, Hansgen G, Bloching M, et al. Oxygenation of squamous cell carcinoma of the head and neck:

Comparison of primary tumors, neck node metastases, and normal tissue. Int J Radiat Oncol Biol Phys.


13. Le QT, Kovacs MS, Dorie MJ, et al. Comparison of the comet assay and the oxygen microelectrode for measuring tumor oxygenation in head-and-neck cancer patients. Int J Radiat Oncol Biol Phys.


14. Troost EG, Laverman P, Kaanders JH, et al. Imaging hypoxia after oxygenation-modification: Comparing [18F]FMISO autoradiography with pimonidazole immunohistochemistry in human xenograft tumors.

Radiother Oncol. 2006;80:157-164.

15. Gagel B, Piroth M, Pinkawa M, et al. pO polarography, contrast enhanced color duplex sonography (CDS), [18F] fluoromisonidazole and [18F] 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.

16. Grosu AL, Souvatzoglou M, Roper B, 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;69:541-551.

17. Rajendran JG, Schwartz DL, O’Sullivan J, et al. Tumor hypoxia imaging with [F-18] fluoromisonidazole positron emission tomography in head and neck cancer. Clin Cancer Res. 2006;12:5435-5441.

18. Rischin D, Hicks RJ, Fisher R, et al. Prognostic significance of [18F]-misonidazole positron emission tomography-detected tumor hypoxia in patients with advanced head and neck cancer randomly assigned to chemoradiation with or without tirapazamine: A substudy of trans-tasman radiation oncology group study 98.02. J Clin Oncol. 2006;24:2098-2104.

19. Eschmann SM, Paulsen F, Reimold M, et al. Prognostic impact of hypoxia imaging with 18F-misonidazole PET in non-small cell lung cancer and head and neck cancer before radiotherapy. J Nucl Med.


20. Thorwarth D, Eschmann SM, Holzner F, et al. Combined uptake of [18F]FDG and [18F]FMISO correlates with radiation therapy outcome in head-and-neck cancer patients. Radiother Oncol. 2006;80:151-156.

21. Eschmann SM, Paulsen F, Bedeshem C, et al. Hypoxia-imaging with (18)F-misonidazole and PET:

Changes of kinetics during radiotherapy of head-and-neck cancer. Radiother Oncol. 2007;83:406-410.

22. Zips D, Zophel K, Abolmaali N, et al. Exploratory prospective trial of hypoxia-specific PET imaging during radiochemotherapy in patients with locally advanced head-and-neck cancer. Radiother Oncol.


23. Garcia C, Flamen P. Role of positron emission tomography in the management of head and neck cancer in the molecular therapy era. Curr Opin Oncol. 2008;20:275-279.

24. Dubois LJ, Lieuwes NG, Janssen MH, et al. Preclinical evaluation and validation of [18F]HX4, a promising hypoxia marker for PET imaging. Proc Natl Acad Sci U S A. 2011;108:14620-14625.

25. Chen L, Zhang Z, Kolb HC, et al. (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;33:1096-1102.

26. Komar G, Seppanen M, Eskola O, et al. 18F-EF5: A new PET tracer for imaging hypoxia in head and neck cancer. J Nucl Med. 2008;49:1944-1951.

27. Lehtio K, Oikonen V, Nyman S, et al. Quantifying tumour hypoxia with fluorine-18 fluoroerythronitroimidazole ([18F]FETNIM) and PET using the tumour to plasma ratio. Eur J Nucl Med Mol Imaging. 2003;30:101-108.

28. Lehtio K, Eskola O, Viljanen T, et al. Imaging perfusion and hypoxia with PET to predict radiotherapy response in head-and-neck cancer. Int J Radiat Oncol Biol Phys. 2004;59:971-982.

29. Chao KS, Bosch WR, Mutic S, et al. A novel approach to overcome hypoxic tumor resistance: Cu-ATSM-guided intensity-modulated radiation therapy. Int J Radiat Oncol Biol Phys. 2001;49:1171-1182.

30. Reischl G, Ehrlichmann W, Bieg C, et al. Preparation of the hypoxia imaging PET tracer [18F]FAZA:

Reaction parameters and automation. Appl Radiat Isot. 2005;62:897-901.

31. Kumar P, Stypinski D, Xie H, et al. Fluoroazomycin arabinoside (FAZA): Synthesis, 2H and 3H-labelling and preliminary biological evaluation of a novel 2-nitroimidazole marker of tissue hypoxia. J Label Compounds Radiopharm. 1999;42:3-16.

32. Busk M, Horsman MR, Jakobsen S, et al. Cellular uptake of PET tracers of glucose metabolism and hypoxia and their linkage. Eur J Nucl Med Mol Imaging. 2008;35:2294-2303.

33. Sorger D, Patt M, Kumar P, et al. [18F]fluoroazomycinarabinofuranoside (18FAZA) and [18F]

fluoromisonidazole (18FMISO): A comparative study of their selective uptake in hypoxic cells and PET imaging in experimental rat tumors. Nucl Med Biol. 2003;30:317-326.

34. Piert M, Machulla HJ, Picchio M, et al. Hypoxia-specific tumor imaging with 18F-fluoroazomycin arabinoside. J Nucl Med. 2005;46:106-113.

35. Beck R, Roper B, Carlsen JM, et al. Pretreatment 18F-FAZA PET predicts success of hypoxia-directed radiochemotherapy using tirapazamine. J Nucl Med. 2007;48:973-980.

36. Busk M, Horsman MR, Jakobsen S, 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;70:1202-1212.

37. Busk M, Horsman MR, Jakobsen S, et al. Can hypoxia-PET map hypoxic cell density heterogeneity accurately in an animal tumor model at a clinically obtainable image contrast? Radiother Oncol.


38. Janssen HL, Haustermans KM, Balm AJ, et al. Hypoxia in head and neck cancer: How much, how important? Head Neck. 2005;27:622-638.

39. Busk M, Munk OL, Jakobsen S, et al.Assessing hypoxia in animal tumor models based on pharmocokinetic analysis of dynamic FAZA PET. Acta Oncol. 2010;49:922-933.

40. Maier FC, Kneilling M, Reischl G, et al. Significant impact of different oxygen breathing conditions on noninvasive in vivo tumor-hypoxia imaging using [(1)(8)F]-fluoro-azomycinarabino-furanoside ([(1)(8)F]

FAZA). Radiat Oncol. 2011;6:165,717X-6-165.

41. Mortensen LS, Busk M, Nordsmark M, et al. Accessing radiation response using hypoxia PET imaging and oxygen sensitive electrodes: A preclinical study. Radiother Oncol. 2011;99:418-423.

42. Busk M, Mortensen LS, Nordsmark M, et al. PET hypoxia imaging with FAZA: Reproducibility at baseline and during fractionated radiotherapy in tumour-bearing mice. Eur J Nucl Med Mol Imaging.



43. Souvatzoglou M, Grosu AL, Roper B, et al. Tumour hypoxia imaging with [18F]FAZA PET in head and neck cancer patients: A pilot study. Eur J Nucl Med Mol Imaging. 2007;34:1566-1575.

44. Postema EJ, McEwan AJ, Riauka TA, et al. Initial results of hypoxia imaging using 1-alpha-D: -(5-deoxy-5-[18F]-fluoroarabinofuranosyl)-2-nitroimidazole (18F-FAZA). Eur J Nucl Med Mol Imaging. 2009;36:1565-1573.

45. Schuetz M, Schmid MP, Potter R, et al. Evaluating repetitive 18F-fluoroazomycin-arabinoside (18FAZA) PET in the setting of MRI guided adaptive radiotherapy in cervical cancer. Acta Oncol. 2010;49:941-947.

46. Shi K, Souvatzoglou M, Astner ST, et al. Quantitative assessment of hypoxia kinetic models by a cross-study of dynamic 18F-FAZA and 15O-H2O in patients with head and neck tumors. J Nucl Med.


47. Garcia-Parra R, Wood D, Shah RB, et al. Investigation on tumor hypoxia in resectable primary prostate cancer as demonstrated by 18F-FAZA PET/CT utilizing multimodality fusion techniques. Eur J Nucl Med Mol Imaging. 2011;38:1816-1823.

48. Mortensen LS, Johansen J, Kallehauge J, 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;105:14-20.

49. Bollineni VR, Kerner GS, Pruim J, et al. PET imaging of tumor hypoxia using 18F-fluorazomycin arabinoside in stage III-IV non-small cell lung cancer patients. J Nucl Med. 2013;54:1175-1180.

50. Mendenhall WM, Morris CG, Amdur RJ, et al. Radiotherapy alone or combined with carbogen breathing for squamous cell carcinoma of the head and neck: A prospective, randomized trial. Cancer.


51. Hoskin PJ, Rojas AM, Bentzen SM, et al. Radiotherapy with concurrent carbogen and nicotinamide in bladder carcinoma. J Clin Oncol. 2010;28:4912-4918.

52. Kaanders J, Terhaard C, Doornaert P, et al. Outcome after ARCON for clinical stage T2-4 laryngeal cancer: Early results of a phase III randomized trial. Radiother Oncol. 2010;96(suppl 1):S158.

53. Janssens GO, Rademakers SE, Terhaard CH, et al. Accelerated radiotherapy with carbogen and nicotinamide for laryngeal cancer: Results of a phase III randomized trial. J Clin Oncol. 2012;30:1777-1783.

54. Rischin D, Peters LJ, O’Sullivan B, et al. Tirapazamine, cisplatin, and radiation versus cisplatin and radiation for advanced squamous cell carcinoma of the head and neck (TROG 02.02, HeadSTART): A phase III trial of the trans-tasman radiation oncology group. J Clin Oncol. 2010;28:2989-2995.

55. Hoogsteen IJ, Marres HA, van der Kogel AJ, et al. The hypoxic tumour microenvironment, patient selection and hypoxia-modifying treatments. Clin Oncol (R Coll Radiol). 2007;19:385-396.

56. Thorwarth D, Eschmann SM, Paulsen F, et al. Hypoxia dose painting by numbers: A planning study. Int J Radiat Oncol Biol Phys. 2007;68:291-300.

Chapter 3

Assessment of hypoxic