Skip to main content
SpringerLink
Log in

Hypoxia in Head and Neck Cancers: Clinical Relevance and Treatment

  • Chapter
  • First Online:
Head and Neck Cancer

  • 2410 Accesses

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 (HIF) family of transcription factors. There are several approaches for detecting tumor hypoxia in head and neck cancer (HNC). 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 such as positron emission tomography (PET) scan with 18F-FMISO and 18F-FAZA. Hypoxia gene signature is a promising strategy for characterizing the hypoxic status of tumor. Hypoxia appears to be prognostic for outcome in HNC. Several studies have shown that low PO2 in tumor, HIF-1, Glut-1 and CA-IX expression, and serum level of osteopontin correlated with treatment outcomes in HNC patients treated with radiotherapy or chemoradiotherapy. The correlation of human papillomavirus and hypoxia needs to be further clarified.

Several strategies have been used to overcome hypoxia-induced treatment resistance in HNC, such as hyperbaric oxygen treatment, accelerated radiotherapy with carbogen and nicotinamide (ARCON), and hypoxic cell radiosensitizers—nitroimidazoles, erythropoietin manipulation, and hypoxic cell cytotoxin. More recently, new approaches such as vascular normalization, HIF-1 targeting or integrating FMISO-PET information for adaptive radiotherapy appeared also very promising.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 219.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 279.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 279.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

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  CAS  PubMed  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  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  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  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  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  CAS  PubMed  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  CAS  PubMed  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.

    Article  CAS  PubMed  PubMed Central  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  CAS  PubMed  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  CAS  PubMed  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.

    CAS  PubMed  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.

    CAS  PubMed  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.

    CAS  PubMed  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.

    CAS  PubMed  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  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  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.

    CAS  PubMed  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  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  22. Okamoto S, Shiga T, Yasuda K, et al. High reproducibility of tumor hypoxia evaluated by 18F-fluoromisonidazole PET for head and neck cancer. J Nucl Med. 2013;54:201–7.

    Article  CAS  PubMed  Google Scholar 

  23. Sato J, Kitagawa Y, Yamazaki Y, et al. 18F-fluoromisonidazole PET uptake is correlated with hypoxia-inducible factor-1alpha expression in oral squamous cell carcinoma. J Nucl Med. 2013;54:1060–5.

    Article  CAS  PubMed  Google Scholar 

  24. Halmos GB, Bruine de Bruin L, Langendijk JA, et al. Head and neck tumor hypoxia imaging by 18F-fluoroazomycin-arabinoside (18F-FAZA)-PET: a review. Clin Nucl Med. 2014;39:44–8.

    Article  PubMed  Google Scholar 

  25. 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;59:971–82.

    Article  PubMed  Google Scholar 

  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;49:1944–51.

    Article  PubMed  Google Scholar 

  27. 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 USA. 2011;108:14620–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. 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.

    Article  PubMed  Google Scholar 

  29. 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;33:1096–102.

    Article  CAS  PubMed  Google Scholar 

  30. Kositwattanarerk A, Oh M, Kudo T, et al. Different distribution of (62) Cu ATSM and (18)F-FDG in head and neck cancers. Clin Nucl Med. 2012;37:252–7.

    Article  PubMed  Google Scholar 

  31. Grassi I, Nanni C, Cicoria G, et al. Usefulness of 64Cu-ATSM in head and neck cancer: a preliminary prospective study. Clin Nucl Med. 2014;39:e59–63.

    Article  PubMed  Google Scholar 

  32. Toustrup K, Sorensen BS, Nordsmark M, et al. Development of a hypoxia gene expression classifier with predictive impact for hypoxic modification of radiotherapy in head and neck cancer. Cancer Res. 2011;71:5923–31.

    Article  CAS  PubMed  Google Scholar 

  33. Toustrup K, Sorensen BS, Alsner J, et al. Hypoxia gene expression signatures as prognostic and predictive markers in head and neck radiotherapy. Semin Radiat Oncol. 2012;22:119–27.

    Article  PubMed  Google Scholar 

  34. Toustrup K, Sorensen BS, Lassen P, et al. Gene expression classifier predicts for hypoxic modification of radiotherapy with nimorazole in squamous cell carcinomas of the head and neck. Radiother Oncol. 2012;102:122–9.

    Article  CAS  PubMed  Google Scholar 

  35. Eustace A, Mani N, Span PN, et al. A 26-gene hypoxia signature predicts benefit from hypoxia-modifying therapy in laryngeal cancer but not bladder cancer. Clin Cancer Res. 2013;19:4879–88.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. 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  CAS  PubMed  Google Scholar 

  37. 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  CAS  PubMed  Google Scholar 

  38. 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  CAS  PubMed  Google Scholar 

  39. 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 

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

    Article  CAS  PubMed  Google Scholar 

  41. 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 

  42. 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  CAS  PubMed  Google Scholar 

  43. 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  CAS  PubMed  Google Scholar 

  44. 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.

    CAS  PubMed  Google Scholar 

  45. 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  CAS  PubMed  Google Scholar 

  46. 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.

    CAS  PubMed  Google Scholar 

  47. 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.

    CAS  PubMed  Google Scholar 

  48. Hong A, Zhang M, Veillard AS, et al. The prognostic significance of hypoxia inducing factor 1-alpha in oropharyngeal cancer in relation to human papillomavirus status. Oral Oncol. 2013;49:354–9.

    Article  CAS  PubMed  Google Scholar 

  49. 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  CAS  PubMed  Google Scholar 

  50. 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  CAS  PubMed  Google Scholar 

  51. 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  CAS  PubMed  Google Scholar 

  52. 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  CAS  PubMed  Google Scholar 

  53. Eckert AW, Lautner MH, Schutze A, et al. Coexpression of hypoxia-inducible factor-1alpha and glucose transporter-1 is associated with poor prognosis in oral squamous cell carcinoma patients. Histopathology. 2011;58:1136–47.

    Article  PubMed  Google Scholar 

  54. 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  PubMed Central  CAS  Google Scholar 

  55. 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  CAS  PubMed  Google Scholar 

  56. 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  CAS  PubMed  Google Scholar 

  57. Douglas CM, Bernstein JM, Ormston VE, et al. Lack of prognostic effect of carbonic anhydrase-9, hypoxia inducible factor-1alpha and bcl-2 in 286 patients with early squamous cell carcinoma of the glottic larynx treated with radiotherapy. Clin Oncol (R Coll Radiol). 2013;25:59–65.

    Article  CAS  Google Scholar 

  58. 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  CAS  PubMed  Google Scholar 

  59. Lim AM, Rischin D, Fisher R, et al. Prognostic significance of plasma osteopontin in patients with locoregionally advanced head and neck squamous cell carcinoma treated on TROG 02.02 phase III trial. Clin Cancer Res. 2012;18:301–7.

    Article  CAS  PubMed  Google Scholar 

  60. 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. 2012;105:21–8.

    Article  PubMed  Google Scholar 

  61. Sato J, Kitagawa Y, Yamazaki Y, et al. Advantage of FMISO-PET over FDG-PET for predicting histological response to preoperative chemotherapy in patients with oral squamous cell carcinoma. Eur J Nucl Med Mol Imaging. 2014;41(11): 2031–41.

    Google Scholar 

  62. Minagawa Y, Shizukuishi K, Koike I, 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. 2011;25:339–45.

    Article  PubMed  Google Scholar 

  63. Ang KK, Harris J, Wheeler R, et al. Human papillomavirus and survival of patients with oropharyngeal cancer. N Engl J Med. 2010;363:24–35.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Lassen P, Eriksen JG, Hamilton-Dutoit S, et al. HPV-associated p16-expression and response to hypoxic modification of radiotherapy in head and neck cancer. Radiother Oncol. 2010;94:30–5.

    Article  CAS  PubMed  Google Scholar 

  65. Rischin D, Young RJ, Fisher R, et al. Prognostic significance of p16INK4A and human papillomavirus in patients with oropharyngeal cancer treated on TROG 02.02 phase III trial. J Clin Oncol. 2010;28:4142–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Sorensen BS, Busk M, Olthof N, et al. Radiosensitivity and effect of hypoxia in HPV positive head and neck cancer cells. Radiother Oncol. 2013;108:500–5.

    Article  PubMed  Google Scholar 

  67. Trinkaus ME, Hicks RJ, Young RJ, et al. Correlation of p16 status, hypoxic imaging using [18F]-misonidazole positron emission tomography and outcome in patients with loco-regionally advanced head and neck cancer. J Med Imaging Radiat Oncol. 2014;58:89–97.

    Article  PubMed  Google Scholar 

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

    Google Scholar 

  69. 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  CAS  PubMed  Google Scholar 

  70. 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  CAS  PubMed  Google Scholar 

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

    PubMed  Google Scholar 

  72. 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 

  73. 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 

  74. 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 

  75. 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;30:1777–83.

    Article  CAS  PubMed  Google Scholar 

  76. Janssens GO, Rademakers SE, Terhaard CH, et al. Improved recurrence-free survival with ARCON for anemic patients with laryngeal cancer. Clin Cancer Res. 2014;20:1345–54.

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  78. 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 

  79. 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;45:91–93.

    Google Scholar 

  80. 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  CAS  PubMed  Google Scholar 

  81. 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 oncology group (RTOG 99-03). Int J Radiat Oncol Biol Phys. 2007;69:1008–17.

    Article  CAS  PubMed  Google Scholar 

  82. Overgaard J, Hoff CM, Hansen HS, et al. Randomized study of darbepoetin alfa as modifier of radiotherapy in patients with primary squamous cell carcinoma of the head and neck (HNSCC): final outcome of the DAHANCA 10 trial. J Clin Oncol. 2009;27 Suppl; abstr 6007.

    Google Scholar 

  83. 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  CAS  PubMed  Google Scholar 

  84. 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  CAS  PubMed  Google Scholar 

  85. 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  CAS  PubMed  Google Scholar 

  86. 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  CAS  PubMed  Google Scholar 

  87. Overgaard J. Hypoxic modification of radiotherapy in squamous cell carcinoma of the head and neck—a systematic review and meta-analysis. Radiother Oncol. 2011;100:22–32.

    Article  PubMed  Google Scholar 

  88. Thomson D, Yang H, Baines H, et al. NIMRAD – a phase III trial to investigate the use of nimorazole hypoxia modification with intensity-modulated radiotherapy in head and neck cancer. Clin Oncol (R Coll Radiol). 2014;26:344–7.

    Article  CAS  Google Scholar 

  89. 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 

  90. 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. 1997;15:268–76.

    CAS  PubMed  Google Scholar 

  91. 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  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  93. 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  CAS  PubMed  Google Scholar 

  94. 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.

    CAS  PubMed  Google Scholar 

  95. 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  CAS  PubMed  Google Scholar 

  96. 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 

  97. 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;28:2989–95.

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  100. 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.

    CAS  PubMed  Google Scholar 

  101. 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  CAS  PubMed  Google Scholar 

  102. 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  CAS  PubMed  PubMed Central  Google Scholar 

  103. 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  CAS  PubMed  Google Scholar 

  104. Fury MG, Lee NY, Sherman E, et al. A phase 2 study of bevacizumab with cisplatin plus intensity-modulated radiation therapy for stage III/IVB head and neck squamous cell cancer. Cancer. 2012;118:5008–14.

    Article  CAS  PubMed  Google Scholar 

  105. Lee NY, Zhang Q, Pfister DG, et al. Addition of bevacizumab to standard chemoradiation for locoregionally advanced nasopharyngeal carcinoma (RTOG 0615): a phase 2 multi-institutional trial. Lancet Oncol. 2012;13:172–80.

    Article  CAS  PubMed  Google Scholar 

  106. 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  CAS  PubMed  PubMed Central  Google Scholar 

  107. 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  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  109. Bonner JA, Harari PM, Giralt J, et al. Radiotherapy plus cetuximab for locoregionally advanced head and neck cancer: 5-year survival data from a phase 3 randomised trial, and relation between cetuximab-induced rash and survival. Lancet Oncol. 2009;11:21–8.

    Article  PubMed  CAS  Google Scholar 

  110. Fury MG, Lee NY, Sherman E, et al. A phase 1 study of everolimus + weekly cisplatin + intensity modulated radiation therapy in head-and-neck cancer. Int J Radiat Oncol Biol Phys. 2013;87:479–86.

    Article  CAS  PubMed  Google Scholar 

  111. 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 

  112. 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  CAS  PubMed  Google Scholar 

  113. Tao Y, Daly-Schveitzer N, Lusinchi A, et al. Advances in radiotherapy of head and neck cancers. Curr Opin Oncol. 2010;22:194–9.

    Article  PubMed  Google Scholar 

  114. Dirix P, Vandecaveye V, De Keyzer F, 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. 2009;50:1020–7.

    Article  PubMed  Google Scholar 

  115. 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 

  116. Duprez F, De Neve W, De Gersem W, et al. Adaptive dose painting by numbers for head-and-neck cancer. Int J Radiat Oncol Biol Phys. 2011;80:1045–55.

    Article  PubMed  Google Scholar 

  117. Olteanu LA, Berwouts D, Madani I, et al. Comparative dosimetry of three-phase adaptive and non-adaptive dose-painting IMRT for head-and-neck cancer. Radiother Oncol. 2014;111:348–53.

    Article  PubMed  Google Scholar 

  118. Hendrickson K, Phillips M, Smith W, et al. Hypoxia imaging with [F-18] FMISO-PET in head and neck cancer: potential for guiding intensity modulated radiation therapy in overcoming hypoxia-induced treatment resistance. Radiother Oncol. 2011;101:369–75.

    Article  PubMed  PubMed Central  Google Scholar 

  119. Lee N, Nehmeh S, Schoder H, 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. 2009;75:101–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. 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  PubMed Central  Google Scholar 

  121. Bourhis J, Sire C, Graff P, et al. Concomitant chemoradiotherapy versus acceleration of radiotherapy with or without concomitant chemotherapy in locally advanced head and neck carcinoma (GORTEC 99-02): an open-label phase 3 randomised trial. Lancet Oncol. 2012;13:145–53.

    Article  PubMed  Google Scholar 

  122. 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 

  123. Mizoe JE, Hasegawa A, Jingu K, et al. Results of carbon ion radiotherapy for head and neck cancer. Radiother Oncol. 2012;103:32–7.

    Article  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Radiotherapy, Institut Gustave-Roussy, Villejuif, France

    Yungan Tao MD, PhD

  2. Department of Radiation Oncology, CHUV – Lausanne University Hospital, 46 Bugnon Street, Lausanne, 1011, Switzerland

    Jean Bourhis PhD

Authors
  1. Yungan Tao MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jean Bourhis PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Jean Bourhis PhD .

Editor information

Editors and Affiliations

  1. Department of Radio-Oncology, Genolier Swiss Medical Network, Genolier, Switzerland

    Jacques Bernier

Rights and permissions

Reprints and permissions

Copyright information

© 2016 Springer International Publishing Switzerland

About this chapter

Cite this chapter

Tao, Y., Bourhis, J. (2016). Hypoxia in Head and Neck Cancers: Clinical Relevance and Treatment. In: Bernier, J. (eds) Head and Neck Cancer. Springer, Cham. https://doi.org/10.1007/978-3-319-27601-4_12

Download citation

  • DOI: https://doi.org/10.1007/978-3-319-27601-4_12

  • Published:

  • Publisher Name: Springer, Cham

  • Print ISBN: 978-3-319-27599-4

  • Online ISBN: 978-3-319-27601-4

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation