Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Imaging hypoxia to improve radiotherapy outcome

Nature Reviews Clinical Oncology volume 9, pages 674–687 (2012)Cite this article

Subjects

Abstract

Reduced oxygen levels (hypoxia) is one of the most important factors influencing clinical outcome after radiotherapy. This is primarily because hypoxic cells are resistant to radiation treatment; hence, the greater the number of clonogenic cancer stem cells that exist under hypoxia, the lower the local tumour control. Reduced local control will influence overall survival, as may the hypoxic conditions by increasing malignant progression; however, to fight hypoxia, we should first be able to see it. We need noninvasive approaches that can accurately and reliably image hypoxia in tumours, especially using techniques that are routinely available in the clinic, such as PET, MRI and CT. All these imaging methods are already under clinical evaluation in this context. Such data should allow us to identify those patients on an individual basis who have hypoxic tumours and, thus, at the very least should receive some form of hypoxic modifier in conjunction with radiotherapy. Alternatively, the radiation dose could be either increased to the whole tumour or, if the imaging is accurate enough, only to the hypoxic subvolumes. The aim of this Review is to critically assess the potential use of imaging to help improve clinical outcome to radiotherapy.

Key Points

  • Low oxygenation (hypoxia) is a characteristic feature of solid tumours that significantly reduces the efficacy of radiotherapy, resulting in lower tumour control and overall survival

  • Accurately identifying tumour hypoxia will improve our ability to predict outcome and select appropriate techniques to overcome the effects of hypoxia

  • Future attempts to identify hypoxia should use noninvasive imaging based on techniques that are routinely available in the clinic, such as PET, MRI and CT

  • A meta-analysis of clinical studies using imaging methods for monitoring hypoxia demonstrated that patients with more hypoxic tumours had a significantly poorer response to radiotherapy

  • Clinical studies need to demonstrate that hypoxia-imaging techniques can predict radiotherapy outcome and that resistance resulting from hypoxia can be reversed using hypoxic modifiers or overcome by increasing radiation dose

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Illustration of tumour cells growing as a cord around blood vessels from which they obtain oxygen and nutrients.
Figure 2: Illustration of a PET image of a FAZA scan used for dose painting.
Figure 3: The reduction process of nitroimidazoles designated by R-NO2.
Figure 4: Illustration of the resolution problem in PET imaging of hypoxia.
Figure 5: Meta-analysis showing a forest plot of the relationship between hypoxia imaging and the outcome to radiation therapy.

Similar content being viewed by others

References

  1. Horsman, M. R., Lindegaard, J. C., Grau, C., Nordsmark, M. & Overgaard, J. in Clinical Radiation Oncology, 3rd edn (ed. Gunderson, L. L. & Tepper, J. E.) 53–64 (Saunders, Philadelphia, 2012).

    Book  Google Scholar 

  2. Baumann, M., Krause, M. & Hill, R. Exploring the role of cancer stem cells in radioresistance. Nat. Rev. Cancer 8, 545–554 (2008).

    Article  CAS  PubMed  Google Scholar 

  3. Gray, L. H., Conger, A. D., Ebert, M., Hornsey, S. & Scott, O. C. A. The concentration of oxygen dissolved in tissues at the time of irradiation as a factor in radiotherapy. Br. J. Radiol. 26, 638–648 (1953).

    Article  CAS  PubMed  Google Scholar 

  4. Thomlinson, R. H. & Gray, L. H. The histological structure of some human lung cancers and the possible implications for radiotherapy. Br. J. Cancer 9, 539–549 (1955).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Vaupel, P., Kallinowski, F. & Okunieff, P. Blood flow, oxygen and nutrient supply, and metabolic micro-environment of human tumors: a review. Cancer Res. 49, 6449–6465 (1989).

    CAS  PubMed  Google Scholar 

  6. Overgaard, J. Hypoxic modification of radiotherapy in squamous cell carcinoma of the head and neck – a systematic review and meta-analysis. Radiother. Oncol. 100, 22–32 (2011).

    Article  PubMed  Google Scholar 

  7. Harris, A. L. Hypoxia–a key regulatory factor in tumour growth. Nat. Rev. Cancer 2, 38–47 (2002).

    Article  CAS  PubMed  Google Scholar 

  8. Dewhirst, M. W., Cao, Y. & Moeller, B. Cycling hypoxia and free radicals regulate angiogenesis and radiotherapy response. Nat. Rev. Cancer 8, 425–437 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Brem, S., Brem, H., Folkman, J., Finkelstein, D. & Patz, A. Prolonged tumor dormancy by prevention of neovascularization in the vitreous. Cancer Res. 36, 2807–2812 (1976).

    CAS  PubMed  Google Scholar 

  10. Brown, J. M. Evidence for acutely hypoxic cells in mouse tumours, and a possible mechanism of reoxygenation. Br. J. Radiol. 52, 650–656 (1979).

    Article  CAS  PubMed  Google Scholar 

  11. Chaplin, D. J., Olive, P. L. & Durand, R. E. Intermittent blood flow in a murine tumor: radiobiological effects. Cancer Res. 47, 597–601 (1987).

    CAS  PubMed  Google Scholar 

  12. Powell, M. E., Hill, S. A., Saunders, M. I., Hoskin, P. J. & Chaplin, D. J. Human tumor blood flow is enhanced by nicotinamide and carbogen breathing. Cancer Res. 57, 5261–5264 (1997).

    CAS  PubMed  Google Scholar 

  13. Begg, A. C. et al. Hypoxia and perfusion measurements in human tumours—initial experience with pimonidazole and IUdR. Acta Oncol. 40, 924–928 (2001).

    Article  CAS  PubMed  Google Scholar 

  14. Höckel, M. & Vaupel, P. Tumor hypoxia: definitions and current clinical, biologic, and molecular aspects. J. Natl Cancer Inst. 93, 266–276 (2001).

    Article  PubMed  Google Scholar 

  15. Bayer, C., Shi, K., Astner, S. T., Maftei, C. A. & Vaupel, P. Acute versus chronic hypoxia: why a simplified classification is simply not enough. Int. J. Radiat. Oncol. Biol. Phys. 80, 965–968 (2011).

    Article  PubMed  Google Scholar 

  16. Helmlinger, G., Yuan, F., Dellian, M. & Jain, R. K. Interstitial pH and pO2 gradients in solid tumors in vivo: high-resolution measurements reveal a lack of correlation. Nat. Med. 3, 177–182 (1997).

    Article  CAS  PubMed  Google Scholar 

  17. Wouters, B. G. & Brown, J. M. Cells at intermediate oxygen levels can be more important than the “hypoxic fraction” in determining tumor response to fractionated radiotherapy. Radiat. Res. 147, 541–550 (1997).

    Article  CAS  PubMed  Google Scholar 

  18. Menegakis, A. et al. Residual DNA double strand breaks in perfused but not in unperfused areas determine different radiosensitivity of tumours. Radiother. Oncol. 100, 137–144 (2011).

    Article  CAS  PubMed  Google Scholar 

  19. Hoff, C. M. Importance of hemoglobin concentration and its modification for the outcome of head and neck cancer patients treated with radiotherapy. Acta Oncol. 51, 419–432 (2012).

    Article  CAS  PubMed  Google Scholar 

  20. Chaplin, D. J. & Trotter, M. J. in Tumor Blood Supply and Metabolic Microenvironment: Characterization and Implications for Therapy (eds Vaupel, P. & Jain, R. K.) 65–85 (Gustav Fischer Verlag, Stuttgart, 1991).

    Google Scholar 

  21. Kimura, H. et al. Fluctuations in red cell flux in tumor microvessels can lead to transient hypoxia and reoxygenation in tumor parenchyma. Cancer Res. 56, 5522–5528 (1996).

    CAS  PubMed  Google Scholar 

  22. Horsman, M. R., Wouters, B. G., Joiner, M. C. & Overgaard, J. in Basic Clinical Radiobiology, 4th edn (eds van der Kogel, A. J. & Joiner, M. C.) 207–216 (Hodder Arnold, London, 2009).

    Book  Google Scholar 

  23. Howard-Flanders, P. & Moore, D. The time interval after pulsed irradiation within which injury to bacteria can be modified by dissolved oxygen. 1. A search for an effect of oxygen 0.02 seconds after pulsed irradiation. Radiat. Res. 9, 422–437 (1958).

    Article  CAS  PubMed  Google Scholar 

  24. Denekamp, J. & Dasu, A. Inducible repair and the two forms of tumour hypoxia–time for a paradigm shift. Acta Oncol. 38, 903–918 (1999).

    Article  CAS  PubMed  Google Scholar 

  25. Overgaard, J. Hypoxic radiosensitization: adored and ignored. J. Clin. Oncol. 25, 4066–4074 (2007).

    Article  PubMed  Google Scholar 

  26. Lunt, S. J., Chaudary, N. & Hill, R. P. The tumor microenvironment and metastatic disease. Clin. Exp. Metastasis. 26, 19–34 (2009).

    Article  PubMed  Google Scholar 

  27. Horsman, M. R. & Overgaard, J. Hyperthermia: a potent enhancer of radiotherapy. Clin. Oncol. 19, 418–426 (2007).

    Article  CAS  Google Scholar 

  28. Rischin, D. 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. 24, 2098–2104 (2006).

    Article  PubMed  Google Scholar 

  29. Overgaard, J., Eriksen, J. G., Nordsmark, M., Alsner, J. & Horsman, M. R. Plasma osteopontin, hypoxia, and response to the hypoxia sensitiser nimorazole in radiotherapy of head and neck cancer: results from the DAHANCA 5 randomised double-blind placebo-controlled trial. Lancet Oncol. 6, 757–764 (2005).

    Article  CAS  PubMed  Google Scholar 

  30. Janssens, G. O. et al. Accelerated radiotherapy with carbogen and nicotinamide for laryngeal cancer: results of a phase III randomized trial. J. Clin. Oncol. 30, 1777–1783 (2012).

    Article  CAS  PubMed  Google Scholar 

  31. Toustrup, K. et al. Development of a hypoxia gene expression classifier with predictive impact for hypoxic modification of radiotherapy in head and neck cancer. Cancer Res. 71, 5923–5931 (2011).

    Article  CAS  PubMed  Google Scholar 

  32. Søvik, Å, Malinen, E. & Olsen, D. R. Strategies for biologic image-guided dose escalation: a review. Int. J. Radiat. Oncol. Biol. Phys. 73, 650–658 (2009).

    Article  PubMed  Google Scholar 

  33. Bentzen, S. M. & Gregoire, V. Molecular imaging-based dose painting: a novel paradigm for radiation therapy prescription. Semin. Radiat. Oncol. 21, 101–110 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  34. Ling, C. C. et al. Towards multidimensional radiotherapy (MD-CRT): biological imaging and biological conformality. Int. J. Radiat. Oncol. Biol. Phys. 47, 551–560 (2000).

    Article  CAS  PubMed  Google Scholar 

  35. Galvin, J. M. & De Neve, W. Intensity modulating and other radiation therapy devices for dose painting. J. Clin. Oncol. 25, 924–930 (2007).

    Article  PubMed  Google Scholar 

  36. Bentzen, S. M. Theragnostic imaging for radiation oncology: dose-painting by numbers. Lancet Oncol. 6, 112–117 (2005).

    Article  PubMed  Google Scholar 

  37. Busk, M. et al. Can hypoxia-PET map hypoxic cell density heterogeneity accurately in an animal tumor model at a clinically obtainable image contrast? Radiother. Oncol. 92, 429–436 (2009).

    Article  CAS  PubMed  Google Scholar 

  38. Popple, R. A., Ove, R. & Shen, S. Tumor control probability for selective boosting of hypoxic sub-volumes, including the effect of reoxygenation. Int. J. Radiat. Oncol. Biol. Phys. 54, 921–927 (2002).

    Article  PubMed  Google Scholar 

  39. Hendrickson, K. et al. Hypoxia imaging with [18F] FMISO-PET in head and neck cancer: potential for guiding intensity modulated radiation therapy in overcoming hypoxia-induced treatment resistance. Radiother. Oncol. 101, 369–375 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  40. Søvik, A., Malinen, E., Bruland, Ø. S., Bentzen, S. M. & Olsen, D. R. Optimization of tumour control probability in hypoxic tumours by radiation dose redistribution: a modelling study. Phys. Med. Biol. 52, 499–513 (2007).

    Article  PubMed  Google Scholar 

  41. Thorwarth, D., Eschmann, S. M., Paulsen, F. & Alber, M. Hypoxia dose painting by numbers: a planning study. Int. J. Radiat. Oncol. Biol. Phys. 68, 291–300 (2007).

    Article  PubMed  Google Scholar 

  42. Adams, G. E. & Cooke, M. S. Electron.-affinic sensitization. I. A structural basis for chemical radiosensitizers in bacteria. Int. J. Radiat. Biol. Relat. Stud. Phys. Chem. Med. 15, 457–471 (1969).

    Article  CAS  PubMed  Google Scholar 

  43. Varghese, A. J. & Whitmore, G. F. Binding to cellular macromolecules as a possible mechanism for the cytotoxicity of misonidazole. Cancer Res. 40, 2165–2169 (1980).

    CAS  PubMed  Google Scholar 

  44. Koh, W. J. et al. Imaging of hypoxia in human tumors with [F-18] fluoromisonidazole. Int. J. Radiat. Oncol. Biol. Phys. 22, 199–212 (1992).

    Article  CAS  PubMed  Google Scholar 

  45. Rasey, J. S. et al. Quantifying regional hypoxia in human tumors with positron emission tomography of [18F]fluoromisonidazole: a pretherapy study of 37 patients. Int. J. Radiat. Oncol. Biol. Phys. 36, 417–428 (1996).

    Article  CAS  PubMed  Google Scholar 

  46. Busk, M., Horsman, M. R. & Overgaard, J. Resolution in PET hypoxia imaging: voxel size matters. Acta Oncol. 47, 1201–1210 (2008).

    Article  PubMed  Google Scholar 

  47. Schuetz, M. et al. Evaluating repetitive 18F-fluoroazomycin-arabinoside (18FAZA) PET in the setting of MRI guided adaptive radiotherapy in cervical cancer. Acta Oncol. 49, 941–947 (2010).

    Article  CAS  PubMed  Google Scholar 

  48. van Loon, J. et al. PET imaging of hypoxia using [18F] HX4: a phase I trial. Eur. J. Nucl. Med. Mol. Imaging 37, 1663–1668 (2010).

    Article  CAS  PubMed  Google Scholar 

  49. Ljungkvist, A. S. E., Bussink, J., Kaanders, J. H. A. M. & van der Kogel, A. J. Dynamics of tumor hypoxia measured with bioreductive hypoxic cell markers. Radiat. Res. 167, 127–145 (2007).

    Article  CAS  PubMed  Google Scholar 

  50. Reischl, G. et al. Imaging of tumor hypoxia with [124I]IAZA in comparison with [18F]FMISO and [18F]FAZA--first small animal PET results. J. Pharm. Pharm. Sci. 10, 203–211 (2007).

    CAS  PubMed  Google Scholar 

  51. Thorwarth, D., Eschmann, S. M., Scheiderbauer, J., Paulsen, F. & Alber, M. Kinetic analysis of dynamic 18F-fluoromisonidazole PET correlates with radiation treatment outcome in head-and-neck cancer. BMC Cancer 5, 152 (2005).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  52. Lehtiö, K. et al. Imaging perfusion and hypoxia with PET to predict radiotherapy response in head-and-neck cancer. Int. J. Radiat. Oncol. Biol. Phys. 59, 971–982 (2004).

    Article  PubMed  Google Scholar 

  53. Rajendran, J. G. et al. Tumor hypoxia imaging with [F-18] fluoromisonidazole positron emission tomography in head and neck cancer. Clin. Cancer Res. 12, 5435–5441 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Thorwarth, D., Eschmann, S. M., Holzner, F., Paulsen, F. & Alber, M. Combined uptake of [18F]FDG and [18F]FMISO correlates with radiation therapy outcome in head-and-neck cancer patients. Radiother. Oncol. 80, 151–156 (2006).

    Article  CAS  PubMed  Google Scholar 

  55. Eschmann, S. M. et al. Hypoxia-imaging with (18)F-misonidazole and PET: changes of kinetics during radiotherapy of head-and-neck cancer. Radiother. Oncol. 83, 406–410 (2007).

    Article  CAS  PubMed  Google Scholar 

  56. Khamly, K. et al. Hypoxia in soft-tissue sarcomas on [18F]-fluoroazomycin arabinoside positron emission tomography (FAZA-PET) powerfully predicts response to radiotherapy and early relapse [abstract 35029]. Presented at the 14th Connective Tissue Oncology Society Annual Meeting, November 13–15 (London, 2008).

  57. Spence, A. M. et al. Regional hypoxia in glioblastoma multiforme quantified with [18F]fluoromisonidazole positron emission tomography before radiotherapy: correlation with time to progression and survival. Clin. Cancer Res. 14, 2623–2630 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Dirix, P. et al. Dose painting in radiotherapy for head and neck squamous cell carcinoma: value of repeated functional imaging with (18)F-FDG PET, (18)F-fluoromisonidazole PET, diffusion-weighted MRI, and dynamic contrast-enhanced MRI. J. Nucl. Med. 50, 1020–1027 (2009).

    Article  PubMed  Google Scholar 

  59. Lee, N. et al. Prospective trial incorporating pre-/mid-treatment [18F]-misonidazole positron emission tomography for head-and-neck cancer patients undergoing concurrent chemoradiotherapy. Int. J. Radiat. Oncol. Biol. Phys. 75, 101–108 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Li, L. et al. Comparison of 18F-fluoroerythronitroimidazole and 18F-fluorodeoxyglucose positron emission tomography and prognostic value in locally advanced non-small-cell lung cancer. Clin. Lung Cancer 11, 335–340 (2010).

    Article  PubMed  Google Scholar 

  61. Kikuchi, M. et al. 18F-fluoromisonidazole positron emission tomography before treatment is a predictor of radiotherapy outcome and survival prognosis in patients with head and neck squamous cell carcinoma. Ann. Nucl. Med. 25, 625–633 (2011).

    Article  CAS  PubMed  Google Scholar 

  62. Mortensen, L. S. 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. doi:10.1016/j.radonc.2012.09.015

  63. Yue, J. et al. Measuring tumor hypoxia with 18F-FETNIM PET in esophageal squamous cell carcinoma: a pilot clinical study. Dis. Esophagus 25, 54–61 (2012).

    Article  CAS  PubMed  Google Scholar 

  64. Zips, D. et al. Exploratory prospective trial of hypoxia imaging during radiochemotherapy in patients with locally advanced head-and-neck cancer. Radiother. Oncol. doi:10.1016/j.radonc.2012.08.019.

  65. Dearling, J. L. et al. Design of hypoxia-targeting radiopharmaceuticals: selective uptake of copper-64 complexes in hypoxic cells in vitro. Eur. J. Nucl. Med. 25, 788–792 (1998).

    Article  CAS  PubMed  Google Scholar 

  66. Vävere, A. L. & Lewis, J. S. Cu-ATSM: a radiopharmaceutical for the PET imaging of hypoxia. Dalton Trans. 4893–4902 (2007).

  67. Lewis, J. S. & Welch, M. J. PET imaging of hypoxia. Q. J. Nucl. Med. 45, 183–188 (2001).

    CAS  PubMed  Google Scholar 

  68. O'Donoghue, J. A. et al. Assessment of regional tumor hypoxia using 18F-fluoromisonidazole and 64Cu(II)-diacetyl-bis(N4-methylthiosemicar-bazone) positron emission tomography: comparative study featuring microPET imaging, Po2 probe measurement, autoradiography, and fluorescent microscopy in the R3327-AT and FaDu rat tumor models. Int. J. Radiat. Oncol. Biol. Phys. 61, 1493–1502 (2005).

    Article  CAS  PubMed  Google Scholar 

  69. Dence, C. S., Ponde, D. E., Welch, M. J. & Lewis, J. S. Autoradiographic and small-animal PET comparisons between (18)F-FMISO, (18)F-FDG, (18)F-FLT and the hypoxic selective (64)Cu-ATSM in a rodent model of cancer. Nucl. Med. Biol. 35, 713–720 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Dehdashti, F. et al. In vivo assessment of tumor hypoxia in lung cancer with 60Cu-ATSM. Eur. J. Nucl. Med. Mol. Imaging 30, 844–850 (2003).

    Article  CAS  PubMed  Google Scholar 

  71. Dehdashti, F. et al. Assessing tumor hypoxia in cervical cancer by PET with 60Cu-labeled diacetyl-bis(N4-methylthiosemicarbazone). J. Nucl. Med. 49, 201–205 (2008).

    Article  CAS  PubMed  Google Scholar 

  72. Dietz, D. W. et al. Tumor hypoxia detected by positron emission tomography with 60Cu-ATSM as a predictor of response and survival in patients undergoing neoadjuvant chemoradiotherapy for rectal carcinoma: a pilot study. Dis. Colon Rectum 51, 1641–1648 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  73. Minagawa, Y. et al. Assessment of tumor hypoxia by 62Cu-ATSM PET/CT as a predictor of response in head and neck cancer: a pilot study. Ann. Nucl. Med. 25, 339–345 (2011).

    Article  PubMed  Google Scholar 

  74. Yuan, H. et al. Intertumoral differences in hypoxia selectivity of the PET imaging agent 64Cu(II)-diacetyl-bis(N4-methylthiosemicarbazone). J. Nucl. Med. 47, 989–998 (2006).

    CAS  PubMed  Google Scholar 

  75. Busk, M. et al. Aerobic glycolysis in cancers: implications for the usability of oxygen-responsive genes and fluorodeoxyglucose-PET as markers of tissue hypoxia. Int. J. Cancer 122, 2726–2734 (2008).

    Article  CAS  PubMed  Google Scholar 

  76. Rajendran, J. G. et al. Hypoxia and glucose metabolism in malignant tumors: evaluation by [18F]fluoromisonidazole and [18F]fluorodeoxyglucose positron emission tomography imaging. Clin. Cancer Res. 10, 2245–2252 (2004).

    Article  CAS  PubMed  Google Scholar 

  77. Christian, N. et al. Is 18F-FDG a surrogate tracer to measure tumor hypoxia? Comparison with the hypoxic tracer 14C-EF3 in animal tumor models. Radiother. Oncol. 97, 183–188 (2010).

    Article  CAS  PubMed  Google Scholar 

  78. Gagel, B. 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 7, 113 (2007).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  79. Vera, P. et al. Simultaneous positron emission tomography (PET) assessment of metabolism with 18F-fluoro-deoxy-D-glucose (FDG), proliferation with 18F-fluoro-thymidine (FLT), and hypoxia with 18F-fluoro-misonidazole (F-miso) before and during radiotherapy in patients with non-small-cell lung cancer (NSCLC): a pilot study. Radiother. Oncol. 98, 109–116 (2011).

    Article  CAS  PubMed  Google Scholar 

  80. Bussink, J., Kaanders, J. H. A. M. & van der Kogel, A. J. Tumor hypoxia at the micro-regional level: clinical relevance and predictive value of exogenous and endogenous hypoxic cell markers. Radiother. Oncol. 67, 3–15 (2003).

    Article  PubMed  Google Scholar 

  81. Hoeben, B. A. et al. PET of hypoxia with 89Zr-labeled cG250-F(ab')2 in head and neck tumors. J. Nucl. Med. 51, 1076–1083 (2010).

    Article  CAS  PubMed  Google Scholar 

  82. Dubois, L. et al. Imaging of CA IX with fluorescent labelled sulphonamides distinguishes hypoxic and (re)-oxygenated cells in a xenograft tumour model. Radiother. Oncol. 92, 423–428 (2009).

    Article  CAS  PubMed  Google Scholar 

  83. Asakawa, C. et al. Radiosynthesis of three [11C]ureido-substituted benzenesulfonamides as PET probes for carbonic anhydrase IX in tumors. Bioorg. Med. Chem. Lett. 21, 7017–7020 (2011).

    Article  CAS  PubMed  Google Scholar 

  84. Sørensen, B. S., Alsner, J., Overgaard, J. & Horsman, M. R. Hypoxia induced expression of endogenous markers in vitro is highly influenced by pH. Radiother. Oncol. 83, 362–366 (2007).

    Article  PubMed  CAS  Google Scholar 

  85. Komar, G. et al. 18F-EF5: a new PET tracer for imaging hypoxia in head and neck cancer. J. Nucl. Med. 49, 1944–1951 (2008).

    Article  PubMed  Google Scholar 

  86. Ng, C. S. et al. Tumor blood flow measured by perfusion computed tomography and 15O-labeled water positron emission tomography: a comparison study. J. Comput. Assist. Tomogr. 33, 460–465 (2009).

    Article  PubMed  Google Scholar 

  87. Hermans, R. et al. Tumoural perfusion as measured by dynamic computed tomography in head and neck carcinoma. Radiother. Oncol. 53, 105–111 (1999).

    Article  CAS  PubMed  Google Scholar 

  88. Bisdas, S. et al. Outcome prediction after surgery and chemoradiation of squamous cell carcinoma in the oral cavity, oropharynx, and hypopharynx: use of baseline perfusion CT microcirculatory parameters vs. tumor volume. Int. J. Radiat. Oncol. Biol. Phys. 73, 1313–1318 (2009).

    Article  PubMed  Google Scholar 

  89. Truong, M. T. et al. Prediction of locoregional control in head and neck squamous cell carcinoma with serial CT perfusion during radiotherapy. AJNR Am. J. Neuroradiol. 32, 1195–1201 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Newbold, K. et al. An exploratory study into the role of dynamic contrast-enhanced magnetic resonance imaging or perfusion computed tomography for detection of intratumoral hypoxia in head-and-neck cancer. Int. J. Radiat. Oncol. Biol. Phys. 74, 29–37 (2009).

    Article  PubMed  Google Scholar 

  91. Pacheco-Torres, J., López-Larrubia, P., Ballesteros, P. & Cerdán, S. Imaging tumor hypoxia by magnetic resonance methods. NMR Biomed. 24, 1–16 (2011).

    Article  CAS  PubMed  Google Scholar 

  92. Cooper, R. A. et al. Tumour oxygenation levels correlate with dynamic contrast-enhanced magnetic resonance imaging parameters in carcinoma of the cervix. Radiother. Oncol. 57, 53–59 (2000).

    Article  CAS  PubMed  Google Scholar 

  93. Donaldson, S. B. et al. Perfusion estimated with rapid dynamic contrast-enhanced magnetic resonance imaging correlates inversely with vascular endothelial growth factor expression and pimonidazole staining in head-and-neck cancer: a pilot study. Int. J. Radiat. Oncol. Biol. Phys. 81, 1176–1183 (2011).

    Article  PubMed  Google Scholar 

  94. Swanson, K. R. et al. Complementary but distinct roles for MRI and 18F-fluoromisonidazole PET in the assessment of human glioblastomas. J. Nucl. Med. 50, 36–44 (2009).

    Article  PubMed  Google Scholar 

  95. Jansen, J. F. A. et al. Noninvasive assessment of tumor microenvironment using dynamic contrast-enhanced magnetic resonance imaging and 18F-fluoromisonidazole positron emission tomography imaging in neck nodal metastases. Int. J. Radiat. Oncol. Biol. Phys. 77, 1403–1410 (2010).

    Article  PubMed  Google Scholar 

  96. Hoskin, P. J. et al. Hypoxia in prostate cancer: correlation of BOLD-MRI with pimonidazole immunohistochemistry–initial observations. Int. J. Radiat. Oncol. Biol. Phys. 68, 1065–1071 (2007).

    Article  CAS  PubMed  Google Scholar 

  97. Loncaster, J. A. et al. Prediction of radiotherapy outcome using dynamic contrast enhanced MRI of carcinoma of the cervix. Int. J. Radiat. Oncol. Biol. Phys. 54, 759–767 (2002).

    Article  PubMed  Google Scholar 

  98. Mayr, N. A. et al. Longitudinal changes in tumor perfusion pattern during the radiation therapy course and its clinical impact in cervical cancer. Int. J. Radiat. Oncol. Biol. Phys. 77, 502–508 (2010).

    Article  PubMed  Google Scholar 

  99. Andersen, E. K. F. et al. Dynamic contrast-enhanced MRI of cervical cancers: temporal percentile screening of contrast enhancement identifies parameters for prediction of chemoradioresistance. Int. J. Radiat. Oncol. Biol. Phys. 82, e485–e492 (2012).

    Article  PubMed  Google Scholar 

  100. Seddon, B. M. et al. A phase I study of SR-4554 via intravenous administration for noninvasive investigation of tumor hypoxia by magnetic resonance spectroscopy in patients with malignancy. Clin. Cancer Res. 9, 5101–5112 (2003).

    CAS  PubMed  Google Scholar 

  101. Zhao, D., Jiang, L., Hahn, E. W. & Mason, R. P. Tumor physiologic response to combretastatin A4 phosphate assessed by MRI. Int. J. Radiat. Oncol. Biol. Phys. 62, 872–880 (2005).

    Article  CAS  PubMed  Google Scholar 

  102. Urtasun, R. C. et al. Measurement of hypoxia in human tumours by non-invasive spect imaging of iodoazomycin arabinoside. Br. J. Cancer 74 (Suppl. XXVII), 209–212 (1996).

    Google Scholar 

  103. Hoebers, F. J. P. et al. Phase 1 study to identify tumour hypoxia in patients with head and neck cancer using technetium-99m BRU 59–21L. Eur. J. Nucl. Med. Mol. Imaging 29, 1206–1211 (2002).

    Article  CAS  PubMed  Google Scholar 

  104. Li, L. et al. Serial hypoxia imaging with 99mTc-HL91 SPECT to predict radiotherapy response in non small cell lung cancer. Am. J. Clin. Oncol. 29, 628–633 (2006).

    Article  PubMed  Google Scholar 

  105. Krishna, M. C. et al. Electron paramagnetic resonance imaging of tumor pO2 . Radiat. Res. 177, 376–386 (2012).

    Article  CAS  PubMed  Google Scholar 

  106. Swartz, H. M. et al. Clinical applications of EPR: overview and perspectives. NMR Biomed. 17, 335–351 (2004).

    Article  CAS  PubMed  Google Scholar 

  107. Yaromina, A. et al. Exploratory study of the prognostic value of microenvironmental parameters during fractionated irradiation in human squamous cell carcinoma xenografts. Int. J. Radiat. Oncol. Biol. Phys. 80, 1205–1213 (2011).

    Article  PubMed  Google Scholar 

  108. Nehmeh, S. A. et al. Reproducibility of intratumor distribution of 18F-fluoromisonidazole in head and neck cancer. Int. J. Radiat. Oncol. Biol. Phys. 70, 235–242 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Lassen, P. et al. HPV-associated p16-expression and response to hypoxic modification of radiotherapy in head and neck cancer. Radiother. Oncol. 94, 30–35 (2010).

    Article  CAS  PubMed  Google Scholar 

  110. Horsman, M. R. Nicotinamide and other benzamide analogs as agents for overcoming hypoxic cell radiation resistance in tumors: a review. Acta Oncol. 34, 571–587 (1995).

    Article  CAS  PubMed  Google Scholar 

  111. Horsman, M. R. Measurement of tumor oxygenation. Int. J. Radiat. Oncol. Biol. Phys. 42, 701–704 (1998).

    Article  CAS  PubMed  Google Scholar 

  112. Abolmaali, N. et al. Two or four hour [(1)(8)F]FMISO-PET in HNSCC. When is the contrast best? Nuklearmedizin 50, 22–27 (2011).

    Article  CAS  PubMed  Google Scholar 

  113. Evans, S. M. et al. Noninvasive detection of tumor hypoxia using the 2 nitroimidazole [18F] EF1. J. Nucl. Med. 41, 327–336 (2000).

    CAS  PubMed  Google Scholar 

  114. Dubois, L. et al. [18F]EF3 is not superior to [18F]FMISO for PET-based hypoxia evaluation as measured in a rat rhabdomyosarcoma tumour model. Eur. J. Nucl. Med. Mol. Imaging 36, 209–218 (2009).

    Article  PubMed  Google Scholar 

  115. Eskola, O. et al. Tracer level electrophilic synthesis and pharmacokinetics of the hypoxia tracer [(18)F]EF5. Mol. Imaging Biol. 14, 205–212 (2012).

    Article  PubMed  Google Scholar 

  116. Koch, C. J. et al. Biodistribution and dosimetry of (18)F-EF5 in cancer patients with preliminary comparison of (18)F-EF5 uptake versus EF5 binding in human glioblastoma. Eur. J. Nucl. Med. Mol. Imaging 37, 2048–2059 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Rasey, J. S., Hofstrand, P. D., Chin, L. K. & Tewson, T. J. Characterization of [18F]fluoroetanidazole, a new radiopharmaceutical for detecting tumor hypoxia. J. Nucl. Med. 40, 1072–1079 (1999).

    CAS  PubMed  Google Scholar 

  118. Barthel, H. et al. In vivo evaluation of [18F]fluoroetanidazole as a new marker for imaging tumour hypoxia with positron emission tomography. Br. J. Cancer 90, 2232–2242 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Gronroos, T. et al. Comparison of the biodistribution of two hypoxia markers [18F]FETNIM and [18F]FMISO in an experimental mammary carcinoma. Eur. J. Nucl. Med. Mol. Imaging 31, 513–520 (2004).

    Article  PubMed  CAS  Google Scholar 

  120. Gronroos, T. et al. Pharmacokinetics of [18F]FETNIM: a potential marker for PET. J. Nucl. Med. 42, 1397–1404 (2001).

    CAS  PubMed  Google Scholar 

  121. Piert, M. et al. Hypoxia-specific tumor imaging with 18F-fluoroazomycin arabinoside. J. Nucl. Med. 46, 106–113 (2005).

    PubMed  Google Scholar 

  122. Sorger, D. et al. 18F-Fluoroazomycinarabino-furanoside (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. 30, 317–326 (2003).

    Article  CAS  PubMed  Google Scholar 

  123. Doss, M. et al. Biodistribution and radiation dosimetry of the hypoxia marker 18F-HX4 in monkeys and humans determined by using whole-body PET/CT. Nucl. Med. Commun. 31, 1016–1024 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  124. Kaneta, T. et al. Initial evaluation of dynamic human imaging using 18F-FRP170 as a new PET tracer for imaging hypoxia. Ann. Nucl. Med. 21, 101–107 (2007).

    Article  CAS  PubMed  Google Scholar 

  125. Riedl, C. C. et al. Tumor hypoxia imaging in orthotopic liver tumors and peritoneal metastasis: a comparative study featuring dynamic 18F-MISO and 124I-IAZG PET in the same study cohort. Eur. J. Nucl. Med. Mol. Imaging 35, 39–46 (2008).

    Article  PubMed  Google Scholar 

Download references

Acknowledgements

The authors would like to thank the following organizations for financial support: the Danish Agency for Science Technology & Innovation; the Danish Cancer Society; the EC FP7 project METOXIA (project no. 222741); and CIRRO—the Lundbeck Foundation Center for Interventional Research in Radiation Oncology & the Danish Council for Strategic Research.

Author information

Authors and Affiliations

  1. Department of Experimental Clinical Oncology, Aarhus University Hospital, Nørrebrogade 44, Aarhus, DK-8000, Denmark

    Michael R. Horsman, Lise Saksø Mortensen, Morten Busk & Jens Overgaard

  2. Department of Medical Physics, Aarhus University Hospital, Nørrebrogade 44, Aarhus, DK-8000, Denmark

    Jørgen B. Petersen

Authors
  1. Michael R. Horsman
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Lise Saksø Mortensen
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jørgen B. Petersen
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Morten Busk
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Jens Overgaard
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

All authors researched the data for the article, provided a substantial contribution to discussions of the content, wrote the article, and reviewed and edited the manuscript before submission.

Corresponding author

Correspondence to Jens Overgaard.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Horsman, M., Mortensen, L., Petersen, J. et al. Imaging hypoxia to improve radiotherapy outcome. Nat Rev Clin Oncol 9, 674–687 (2012). https://doi.org/10.1038/nrclinonc.2012.171

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrclinonc.2012.171

This article is cited by

Search

Advanced search

Quick links

Nature Briefing: Cancer

Sign up for the Nature Briefing: Cancer newsletter — what matters in cancer research, free to your inbox weekly.

Get what matters in cancer research, free to your inbox weekly. Sign up for Nature Briefing: Cancer