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Hypoxia in Head and Neck Cancers: Clinical Relevance and Treatment

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Head and Neck Cancer

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Abstract

Tumor hypoxia, or the condition of low oxygen, is a key factor for tumor progression and treatment resistance. Hypoxic areas arise as a result of an imbalance between the supply and consumption of oxygen. Cellular responses to hypoxia are orchestrated through activation of the hypoxia-inducible factor family of transcription factors (HIFs). There are several approaches for detecting tumor hypoxia in head and neck cancers (HNC). Direct oxygen measurements in tissues with Eppendorf-pO2 histography have been used, but this method is invasive. Recent studies have focused on molecular markers of hypoxia, such as HIF-1 and carbonic anhydrase isozyme IX (CA-IX), and on developing noninvasive imaging techniques. Hypoxia appears to be prognostic for outcome in HNC. Several studies have shown that low pO2 in tumor, high HIF-1, Glut-1 and CA-IX expression, serum level of osteopontin correlated with treatment outcomes in HNC patients treated with RT or chemoradiotherapy. Several strategies have been used to overcome hypoxia-induced treatment resistance in HNC, such as hyperbaric oxygen treatment, accelerated radiotherapy with carbogen and nicotinamide, hypoxic cell radiosensitizers: nitroimi-dazoles, erythropoietin manipulation, and hypoxic cell cytotoxin. More recently, Micro-Environment-Vascular Normalization, HIF-1 Targeting and 18F-FMISO positron emission tomography-based intensity-modulated radiotherapy are promising methods.

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References

  1. Bourhis J. Hypoxia response pathways and radiotherapy for head and neck cancer. J Clin Oncol. 2006;24:725–6.

    Article  PubMed  Google Scholar 

  2. Vaupel P, Mayer A. Hypoxia in cancer: significance and impact on clinical outcome. Cancer Metastasis Rev. 2007;26:225–39.

    Article  PubMed  CAS  Google Scholar 

  3. Moeller BJ, Richardson RA, Dewhirst MW. Hypoxia and radiotherapy: opportunities for improved outcomes in cancer treatment. Cancer Metastasis Rev. 2007;26:241–8.

    Article  PubMed  CAS  Google Scholar 

  4. Brown JM, Wilson WR. Exploiting tumour hypoxia in cancer treatment. Nat Rev Cancer. 2004;4:437–47.

    Article  PubMed  CAS  Google Scholar 

  5. Tannock IF. Conventional cancer therapy: promise broken or promise delayed? Lancet. 1998;351 Suppl 2:SII9–16.

    Article  PubMed  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  7. Semenza GL. Targeting HIF-1 for cancer therapy. Nat Rev Cancer. 2003;3:721–32.

    Article  PubMed  CAS  Google Scholar 

  8. Giaccia A, Siim BG, Johnson RS. HIF-1 as a target for drug development. Nat Rev Drug Discov. 2003;2:803–11.

    Article  PubMed  CAS  Google Scholar 

  9. Wouters BG, Koritzinsky M. Hypoxia signalling through mTOR and the unfolded protein response in cancer. Nat Rev Cancer. 2008;8:851–64.

    Article  PubMed  CAS  Google Scholar 

  10. Schneider A, Younis RH, Gutkind JS. Hypoxia-induced energy stress inhibits the mTOR pathway by activating an AMPK/REDD1 signaling axis in head and neck squamous cell carcinoma. Neoplasia. 2008;10:1295–302.

    PubMed  CAS  Google Scholar 

  11. Tatum JL, Kelloff GJ, Gillies RJ, et al. Hypoxia: importance in tumor biology, noninvasive measurement by imaging, and value of its measurement in the management of cancer therapy. Int J Radiat Biol. 2006;82:699–757.

    Article  PubMed  CAS  Google Scholar 

  12. Stone HB, Brown JM, Phillips TL, et al. Oxygen in human tumors: correlations between methods of measurement and response to therapy. Summary of a workshop held November 19–20, 1992, at the National Cancer Institute, Bethesda, Maryland. Radiat Res. 1993;136:422–34.

    Article  PubMed  CAS  Google Scholar 

  13. Le QT, Sutphin PD, Raychaudhuri S, et al. Identification of osteopontin as a prognostic plasma marker for head and neck squamous cell carcinomas. Clin Cancer Res. 2003;9:59–67.

    PubMed  CAS  Google Scholar 

  14. Raleigh JA, Calkins-Adams DP, Rinker LH, et al. Hypoxia and vascular endothelial growth factor expression in human squamous cell carcinomas using pimonidazole as a hypoxia marker. Cancer Res. 1998;58:3765–8.

    PubMed  CAS  Google Scholar 

  15. Evans SM, Hahn S, Pook DR, et al. Detection of hypoxia in human squamous cell carcinoma by EF5 binding. Cancer Res. 2000;60:2018–24.

    PubMed  CAS  Google Scholar 

  16. Varghese AJ, Gulyas S, Mohindra JK. Hypoxia-dependent reduction of 1-(2-nitro-1-imidazolyl)-3-methoxy-2-propanol by Chinese hamster ovary cells and KHT tumor cells in vitro and in vivo. Cancer Res. 1976;36:3761–5.

    PubMed  CAS  Google Scholar 

  17. Ljungkvist AS, Bussink J, Kaanders JH, et al. Dynamics of tumor hypoxia measured with bioreductive hypoxic cell markers. Radiat Res. 2007;167:127–45.

    Article  PubMed  CAS  Google Scholar 

  18. Evans SM, Koch CJ. Prognostic significance of tumor oxygenation in humans. Cancer Lett. 2003;195:1–16.

    Article  PubMed  CAS  Google Scholar 

  19. Kaanders JH, Wijffels KI, Marres HA, et al. Pimonidazole binding and tumor vascularity predict for treatment outcome in head and neck cancer. Cancer Res. 2002;62:7066–74.

    PubMed  CAS  Google Scholar 

  20. Lee NY, Le QT. New developments in radiation therapy for head and neck cancer: intensity-modulated radiation therapy and hypoxia targeting. Semin Oncol. 2008;35:236–50.

    Article  PubMed  Google Scholar 

  21. Krohn KA, Link JM, Mason RP. Molecular imaging of hypoxia. J Nucl Med. 2008;49(2):129S–48.

    Article  PubMed  CAS  Google Scholar 

  22. Nordsmark M, Overgaard J. A confirmatory prognostic study on oxygenation status and loco-regional control in advanced head and neck squamous cell carcinoma treated by radiation therapy. Radiother Oncol. 2000;57:39–43.

    Article  PubMed  CAS  Google Scholar 

  23. Rudat V, Stadler P, Becker A, et al. Predictive value of the tumor oxygenation by means of pO2 histography in patients with advanced head and neck cancer. Strahlenther Onkol. 2001;177:462–8.

    Article  PubMed  CAS  Google Scholar 

  24. Brizel DM, Dodge RK, Clough RW, et al. Oxygenation of head and neck cancer: changes during radiotherapy and impact on treatment outcome. Radiother Oncol. 1999;53:113–7.

    Article  PubMed  CAS  Google Scholar 

  25. Brizel DM, Prosnitz RG, Hunter S, et al. Necessity for adjuvant neck dissection in setting of concurrent chemoradiation for advanced head-and-neck cancer. Int J Radiat Oncol Biol Phys. 2004;58:1418–23.

    Article  PubMed  Google Scholar 

  26. Terris DJ. Head and neck cancer: the importance of oxygen. Laryngoscope. 2000;110:697–707.

    Article  PubMed  CAS  Google Scholar 

  27. Nordsmark M, Bentzen SM, Rudat V, 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;77:18–24.

    Article  PubMed  Google Scholar 

  28. Koukourakis MI, Giatromanolaki A, Sivridis E, et al. Hypoxia-inducible factor (HIF1A and HIF2A), angiogenesis, and chemoradiotherapy outcome of squamous cell head-and-neck cancer. Int J Radiat Oncol Biol Phys. 2002;53:1192–202.

    Article  PubMed  CAS  Google Scholar 

  29. Kyzas PA, Stefanou D, Batistatou A, et al. Hypoxia-induced tumor angiogenic pathway in head and neck cancer: an in vivo study. Cancer Lett. 2005;225:297–304.

    Article  PubMed  CAS  Google Scholar 

  30. Beasley NJ, Leek R, Alam M, et al. Hypoxia-inducible factors HIF-1alpha and HIF-2alpha in head and neck cancer: relationship to tumor biology and treatment outcome in surgically resected patients. Cancer Res. 2002;62:2493–7.

    PubMed  CAS  Google Scholar 

  31. Silva P, Slevin NJ, Sloan P, et al. Prognostic significance of tumor hypoxia inducible factor-1alpha expression for outcome after radiotherapy in oropharyngeal cancer. Int J Radiat Oncol Biol Phys. 2008;72:1551–9.

    Article  PubMed  CAS  Google Scholar 

  32. Aebersold DM, Burri P, Beer KT, et al. Expression of hypoxia-inducible factor-1alpha: a novel predictive and prognostic parameter in the radiotherapy of oropharyngeal cancer. Cancer Res. 2001;61:2911–6.

    PubMed  CAS  Google Scholar 

  33. Hui EP, Chan AT, Pezzella F, et al. Coexpression of hypoxia-inducible factors 1alpha and 2alpha, carbonic anhydrase IX, and vascular endothelial growth factor in nasopharyngeal carcinoma and relationship to survival. Clin Cancer Res. 2002;8:2595–604.

    PubMed  CAS  Google Scholar 

  34. Winter SC, Shah KA, Han C, et al. The relation between hypoxia-inducible factor (HIF)-1alpha and HIF-2alpha expression with anemia and outcome in surgically treated head and neck cancer. Cancer. 2006;107:757–66.

    Article  PubMed  CAS  Google Scholar 

  35. Jonathan RA, Wijffels KI, Peeters W, et al. The prognostic value of endogenous hypoxia-related markers for head and neck squamous cell carcinomas treated with ARCON. Radiother Oncol. 2006;79:288–97.

    Article  PubMed  CAS  Google Scholar 

  36. Oliver RJ, Woodwards RT, Sloan P, et al. Prognostic value of facilitative glucose transporter Glut-1 in oral squamous cell carcinomas treated by surgical resection; results of EORTC Translational Research Fund studies. Eur J Cancer. 2004;40:503–7.

    Article  PubMed  CAS  Google Scholar 

  37. Kunkel M, Reichert TE, Benz P, et al. Overexpression of Glut-1 and increased glucose metabolism in tumors are associated with a poor prognosis in patients with oral squamous cell carcinoma. Cancer. 2003;97:1015–24.

    Article  PubMed  CAS  Google Scholar 

  38. De Schutter H, Landuyt W, Verbeken E, et al. The prognostic value of the hypoxia markers CA IX and GLUT 1 and the cytokines VEGF and IL 6 in head and neck squamous cell carcinoma treated by radiotherapy +/− chemotherapy. BMC Cancer. 2005;5:42.

    Article  PubMed  Google Scholar 

  39. Koukourakis MI, Bentzen SM, Giatromanolaki A, 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;24:727–35.

    Article  PubMed  CAS  Google Scholar 

  40. Schrijvers ML, van der Laan BF, de Bock GH, et al. Overexpression of intrinsic hypoxia markers HIF1alpha and CA-IX predict for local recurrence in stage T1–T2 glottic laryngeal carcinoma treated with radiotherapy. Int J Radiat Oncol Biol Phys. 2008;72:161–9.

    Article  PubMed  CAS  Google Scholar 

  41. Overgaard J, Eriksen JG, Nordsmark M, et al. 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. 2005;6:757–64.

    Article  PubMed  CAS  Google Scholar 

  42. Report of a Medical Research Council Working Party. Radiotherapy and hyperbaric oxygen. Lancet. 1978;2:881–4.

    Google Scholar 

  43. Dische S, Anderson PJ, Sealy R, et al. Carcinoma of the cervix – anaemia, radiotherapy and hyperbaric oxygen. Br J Radiol. 1983;56:251–5.

    Article  PubMed  CAS  Google Scholar 

  44. Henk JM, Kunkler PB, Smith CW. Radiotherapy and hyperbaric oxygen in head and neck cancer. Final report of first controlled clinical trial. Lancet. 1977;2:101–3.

    Article  PubMed  CAS  Google Scholar 

  45. Bennett M, Feldmeier J, Smee R et al. Hyperbaric oxygenation for tumour sensitisation to radiotherapy. Cochrane Database Syst Rev. 2005;4:CD005007.

    Google Scholar 

  46. Overgaard J, Horsman MR. Modification of hypoxia-induced radioresistance in tumors by the use of oxygen and sensitizers. Semin Radiat Oncol. 1996;6:10–21.

    Article  PubMed  Google Scholar 

  47. Kaanders JH, Pop LA, Marres HA, et al. ARCON: experience in 215 patients with advanced head-and-neck cancer. Int J Radiat Oncol Biol Phys. 2002;52:769–78.

    Article  PubMed  Google Scholar 

  48. Kaanders JH, Bussink J, van der Kogel AJ. ARCON: a novel biology-based approach in radiotherapy. Lancet Oncol. 2002;3:728–37.

    Article  PubMed  Google Scholar 

  49. Evans JC, Bergsjo P. The influence of anemia on the results of radiotherapy in carcinoma of the cervix. Radiology. 1965;84:709–17.

    PubMed  CAS  Google Scholar 

  50. Denis F, Garaud P, Bardet E, et al. Final results of the 94-01 French Head and Neck Oncology and Radiotherapy Group randomized trial comparing radiotherapy alone with concomitant radiochemotherapy in advanced-stage oropharynx carcinoma. J Clin Oncol. 2004;22:69–76.

    Article  PubMed  Google Scholar 

  51. Rades D. Erythropoietin administration during radiotherapy in anaemic head-and-neck cancer patients: is it still a reasonable option or too dangerous? Oral Oncol. 2009;45:91–3.

    Article  PubMed  CAS  Google Scholar 

  52. Henke M, Laszig R, Rube C, et al. Erythropoietin to treat head and neck cancer patients with anaemia undergoing radiotherapy: randomised, double-blind, placebo-controlled trial. Lancet. 2003;362:1255–60.

    Article  PubMed  CAS  Google Scholar 

  53. Machtay M, Pajak TF, Suntharalingam M, et al. Radiotherapy with or without erythropoietin for anemic patients with head and neck cancer: a randomized trial of the Radiation Therapy Onco-logy Group (RTOG 99-03). Int J Radiat Oncol Biol Phys. 2007;69:1008–17.

    Article  PubMed  CAS  Google Scholar 

  54. Henke M, Mattern D, Pepe M, et al. Do erythropoietin receptors on cancer cells explain unexpected clinical findings? J Clin Oncol. 2006;24:4708–13.

    Article  PubMed  CAS  Google Scholar 

  55. Bokemeyer C, Aapro MS, Courdi A, et al. EORTC guidelines for the use of erythropoietic proteins in anaemic patients with cancer: 2006 update. Eur J Cancer. 2007;43:258–70.

    Article  PubMed  CAS  Google Scholar 

  56. Overgaard J, Hansen HS, Andersen AP, et al. Misonidazole combined with split-course radiotherapy in the treatment of invasive carcinoma of larynx and pharynx: report from the DAHANCA 2 study. Int J Radiat Oncol Biol Phys. 1989;16:1065–8.

    Article  PubMed  CAS  Google Scholar 

  57. Overgaard J, Hansen HS, Overgaard M, et al. A randomized double-blind phase III study of nimorazole as a hypoxic radiosensitizer of primary radiotherapy in supraglottic larynx and pharynx carcinoma. Results of the Danish Head and Neck Cancer Study (DAHANCA) Protocol 5-85. Radiother Oncol. 1998;46:135–46.

    Article  PubMed  CAS  Google Scholar 

  58. De Ridder M, Van Esch G, Engels B, et al. Hypoxic tumor cell radiosensitization: role of the iNOS/NO pathway. Bull Cancer. 2008;95:282–91.

    PubMed  Google Scholar 

  59. Haffty BG, Son YH, Papac R, et al. Chemotherapy as an adjunct to radiation in the treatment of squamous cell carcinoma of the head and neck: results of the Yale Mitomycin Randomized Trials. J Clin Oncol. 1007;15:268–76.

    Google Scholar 

  60. Dobrowsky W, Naude J, Widder J, et al. Continuous hyperfractionated accelerated radiotherapy with/without mitomycin C in head and neck cancer. Int J Radiat Oncol Biol Phys. 1998;42:803–6.

    Article  PubMed  CAS  Google Scholar 

  61. Dobrowsky W, Naude J. Continuous hyperfractionated accelerated radiotherapy with/without mitomycin C in head and neck cancers. Radiother Oncol. 2000;57:119–24.

    Article  PubMed  CAS  Google Scholar 

  62. Gandara DR, Lara Jr PN, Goldberg Z, et al. Tirapazamine: prototype for a novel class of therapeutic agents targeting tumor hypoxia. Semin Oncol. 2002;29:102–9.

    Article  PubMed  CAS  Google Scholar 

  63. Rischin D, Peters L, Hicks R, et al. Phase I trial of concurrent tirapazamine, cisplatin, and radiotherapy in patients with advanced head and neck cancer. J Clin Oncol. 2001;19:535–42.

    PubMed  CAS  Google Scholar 

  64. Rischin D, Peters L, Fisher R, et al. Tirapazamine, Cisplatin, and Radiation versus Fluorouracil, Cisplatin, and Radiation in patients with locally advanced head and neck cancer: a randomized phase II trial of the Trans-Tasman Radiation Oncology Group (TROG 98.02). J Clin Oncol. 2005;23:79–87.

    Article  PubMed  CAS  Google Scholar 

  65. 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;24:2098–104.

    Article  PubMed  Google Scholar 

  66. Le QT, Taira A, Budenz S, et al. Mature results from a randomized Phase II trial of cisplatin plus 5-fluorouracil and radiothe-rapy with or without tirapazamine in patients with resectable Stage IV head and neck squamous cell carcinomas. Cancer. 2006;106:1940–9.

    Article  PubMed  CAS  Google Scholar 

  67. Jain RK. Normalization of tumor vasculature: an emerging concept in antiangiogenic therapy. Science. 2005;307:58–62.

    Article  PubMed  CAS  Google Scholar 

  68. Winkler F, Kozin SV, Tong RT, et al. Kinetics of vascular normalization by VEGFR2 blockade governs brain tumor response to radiation: role of oxygenation, angiopoietin-1, and matrix metalloproteinases. Cancer Cell. 2004;6:553–63.

    PubMed  CAS  Google Scholar 

  69. Jain RK, Duda DG, Clark JW, et al. Lessons from phase III clinical trials on anti-VEGF therapy for cancer. Nat Clin Pract Oncol. 2006;3:24–40.

    Article  PubMed  CAS  Google Scholar 

  70. Bozec A, Sudaka A, Fischel JL, et al. Combined effects of bevacizumab with erlotinib and irradiation: a preclinical study on a head and neck cancer orthotopic model. Br J Cancer. 2008;99:93–9.

    Article  PubMed  CAS  Google Scholar 

  71. Seiwert TY, Haraf DJ, Cohen EE, et al. Phase I study of bevacizumab added to fluorouracil- and hydroxyurea-based concomitant chemoradiotherapy for poor-prognosis head and neck cancer. J Clin Oncol. 2008;26:1732–41.

    Article  PubMed  CAS  Google Scholar 

  72. Cohen EE, Davis DW, Karrison TG, et al. Erlotinib and bevacizumab in patients with recurrent or metastatic squamous-cell carcinoma of the head and neck: a phase I/II study. Lancet Oncol. 2009;10:247–57.

    Article  PubMed  CAS  Google Scholar 

  73. Elser C, Siu LL, Winquist E, et al. Phase II trial of sorafenib in patients with recurrent or metastatic squamous cell carcinoma of the head and neck or nasopharyngeal carcinoma. J Clin Oncol. 2007;25:3766–73.

    Article  PubMed  CAS  Google Scholar 

  74. Melillo G. Targeting hypoxia cell signaling for cancer therapy. Cancer Metastasis Rev. 2007;26:341–52.

    Article  PubMed  CAS  Google Scholar 

  75. Christian N, Lee JA, Bol A, et al. The limitation of PET imaging for biological adaptive-IMRT assessed in animal models. Radiother Oncol. 2009;91:101–6.

    Article  PubMed  Google Scholar 

  76. 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;49:1171–82.

    Article  PubMed  CAS  Google Scholar 

  77. 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.

    Article  PubMed  Google Scholar 

  78. Lee N, Nehmeh S, Schoder H, et al. Prospective trial incorpo-rating pre-/mid-treatment [(18)F]-misonidazole positron emission tomography for head-and-neck cancer patients undergoing concurrent chemoradiotherapy. Int J Radiat Oncol Biol Phys. 2009;75:101–8.

    Article  PubMed  CAS  Google Scholar 

  79. Lin Z, Mechalakos J, Nehmeh S, et al. The influence of changes in tumor hypoxia on dose-painting treatment plans based on 18F-FMISO positron emission tomography. Int J Radiat Oncol Biol Phys. 2008;70:1219–28.

    Article  PubMed  Google Scholar 

  80. Bourhis J, Lapeyre M, Tortochaux J, et al. Phase III randomized trial of very accelerated radiation therapy compared with conventional radiation therapy in squamous cell head and neck cancer: a GORTEC trial. J Clin Oncol. 2006;24:2873–8.

    Article  PubMed  Google Scholar 

  81. Bourhis J, Overgaard J, Audry H, et al. Hyperfractionated or accelerated radiotherapy in head and neck cancer: a meta-analysis. Lancet. 2006;368:843–54.

    Article  PubMed  Google Scholar 

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  1. Radiotherapy Department, Institut Gustave Roussy, 39 Rue Camille-Desmoulins, Villejuif, 94805, France

    Jean Bourhis

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  1. Yungan Tao
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  1. , Dept of Radio-Oncology, Genolier Swiss Medical Network, 4 Route du Muids, Genolier, CH-1272, Switzerland

    Jacques Bernier

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Tao, Y., Bourhis, J. (2011). Hypoxia in Head and Neck Cancers: Clinical Relevance and Treatment. In: Bernier, J. (eds) Head and Neck Cancer. Springer, New York, NY. https://doi.org/10.1007/978-1-4419-9464-6_10

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