Targeting hypoxia to overcome radiation resistance in head & neck cancers: real challenge or clinical fairytale?

References

• Semenza GL. The hypoxic tumor microenvironment: a driving force for breast cancer progression. Biochim Biophys Acta. 2015. pii:S0167-4889(15)00192-5. doi:10.1016/j.bbamcr.2015.05.036.
   Web of Science ®Google Scholar
• Vaupel P, Mayer A. Hypoxia in tumors: pathogenesis-related classification, characterization of hypoxia subtypes, and associated biological and clinical implications. Adv Exp Med Biol. 2014;812:19–24.
   PubMed Web of Science ®Google Scholar
• Ejtehadifar M, Shamsasenjan K, Movassaghpour A, et al. The effect of hypoxia on mesenchymal stem cell biology. Adv Pharm Bull. 2015;5:141–149.
   PubMed Web of Science ®Google Scholar
• Hawkins KE, Sharp TV, McKay TR. The role of hypoxia in stem cell potency and differentiation. Regen Med. 2013;8:771–782.
   PubMed Web of Science ®Google Scholar
• Imanirad P, Dzierzak E. Hypoxia and HIFs in regulating the development of the hematopoietic system. Blood Cells Mol Dis. 2013;51:256–263.
   PubMed Web of Science ®Google Scholar
• Nombela-Arrieta C, Silberstein LE. The science behind the hypoxic niche of hematopoietic stem and progenitors. Hematology Am Soc Hematol Educ Program. 2014;2014:542–547.
   PubMedGoogle Scholar
• Höckel M, Vaupel P. Tumor hypoxia: definitions and current clinical, biologic, and molecular aspects. J Natl Cancer Inst. 2001;93:266–267.
   PubMed Web of Science ®Google Scholar
• Vaupel P, Kallinowski F, Okunieff P. Blood flow, oxygen and nutrient supply, and metabolic microenvironment of human tumors: a review. Cancer Res. 1989;49:6449–6465.
   PubMed Web of Science ®Google Scholar
• Peitzsch C, Perrin R, Hill RP, et al. Hypoxia as a biomarker for radioresistant cancer stem cells. Int J Radiat Biol. 2014;90:636–652.
   PubMed Web of Science ®Google Scholar
• Qin C, Chen X, Bai Q, et al. Factors associated with radiosensitivity of cervical cancer. Anticancer Res. 2014;34:4649–4656.
   PubMed Web of Science ®Google Scholar
• Höckel M, Knoop C, Schlenger K, et al. Intratumoral pO2 predicts survival in advanced cancer of the uterine cervix. Radiother Oncol. 1993;26:45–50.
   PubMed Web of Science ®Google Scholar
• Nordsmark M, Bentzen SM, Overgaard J. Measurement of human tumour oxygenation status by a polarographic needle electrode. An analysis of inter- and intratumour heterogeneity. Acta Oncol. 1994;33:383–389.
   PubMed Web of Science ®Google Scholar
• 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.
   PubMed Web of Science ®Google Scholar
• 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 multicenter study. Radiother Oncol. 2005;77:18–24.
   PubMed Web of Science ®Google Scholar
• Stadler P, Becker A, Feldmann HJ, et al. Influence of the hypoxic subvolume on the survival of patients with head and neck cancer. Int J Radiat Oncol Biol Phys. 1999;44:749–754.
   PubMed Web of Science ®Google Scholar
• Dhani N, Fyles A, Hedley D, et al. The clinical significance of hypoxia in human cancers. Semin Nucl Med. 2015;45:110–121.
   PubMed Web of Science ®Google Scholar
• Graeber TG, Osmanian C, Jacks T, et al. Hypoxia-mediated selection of cells with diminished apoptotic potential in solid tumours. Nature. 1996;379:88–91.
   PubMed Web of Science ®Google Scholar
• Zhao J, Du F, Luo Y, et al. The emerging role of hypoxia-inducible factor-2 involved in chemo/radioresistance in solid tumors. Cancer Treat Rev. 2015;41:623–633.
   PubMed Web of Science ®Google Scholar
• Mayer A, Vaupel P. Hypoxia, lactate accumulation, and acidosis: siblings or accomplices driving tumor progression and resistance to therapy? Adv Exp Med Biol. 2013;789:203–209.
   PubMed Web of Science ®Google Scholar
• Ostheimer C, Bache M, Güttler A, et al. A pilot study on potential plasma hypoxia markers in the radiotherapy of non-small cell lung cancer. Osteopontin, carbonic anhydrase IX and vascular endothelial growth factor. Strahlenther Onkol. 2014;190:276–282.
   PubMed Web of Science ®Google Scholar
• Overgaard J, Eriksen JG, Nordsmark M, et al.; Danish Head and Neck Cancer Study Group. 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;6:757–764.
   PubMed Web of Science ®Google Scholar
• Bollineni VR, Koole MJB, Pruim J, et al. Dynamics of tumor hypoxia assessed by 18F-FAZA PET/CT in head and neck and lung cancer patients during chemoradiation: possible implications for radiotherapy treatment planning strategies. Radiother Oncol. 2014;113:198–203.
   PubMed Web of Science ®Google Scholar
• Bredholt G, Mannelqvist M, Stefansson IM, et al. Tumor necrosis is an important hallmark of aggressive endometrial cancer and associates with hypoxia, angiogenesis and inflammation responses. Oncotarget. 2015. doi:10.18632/oncotarget.5344.
   PubMed Web of Science ®Google Scholar
• Fleming IN, Manavaki R, Blower PJ, et al. Imaging tumour hypoxia with positron emission tomography. Br J Cancer. 2015;112:238–250.
   PubMed Web of Science ®Google Scholar
• Henriques de Figueiredo B, Zacharatou C, Galland-Girodet S, et al. Hypoxia imaging with [18F]-FMISO-PET for guided dose escalation with intensity-modulated radiotherapy in head-and-neck cancers. Strahlenther Onkol. 2015;191:217–224.
   PubMed Web of Science ®Google Scholar
• Kelada OJ, Carlson DJ. Molecular imaging of tumor hypoxia with positron emission tomography. Radiat Res. 2014;181:335–349.
   PubMed Web of Science ®Google Scholar
• Kuhnt T, Mueller AC, Pelz T, et al. Impact of tumor control and presence of visible necrosis in head and neck cancer patients treated with radiotherapy or radiochemotherapy. J Cancer Res Clin Oncol. 2005;131:758–764.
   PubMed Web of Science ®Google Scholar
• Matsuo M, Matsumoto S, Mitchell JB, et al. Magnetic resonance imaging of the tumor microenvironment in radiotherapy: perfusion, hypoxia, and metabolism. Semin Radiat Oncol. 2014;24:210–217.
   PubMed Web of Science ®Google Scholar
• 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.
   PubMed Web of Science ®Google Scholar
• Overgaard J, Horsman MR. Modification of hypoxia-induced radioresistance in tumors by the use of oxygen and sensitizers. Sem Radiat Oncol. 1996;6:10–21.
   PubMed Web of Science ®Google Scholar
• Thews O, Vaupel P. Spatial oxygenation profiles in tumors during normo- and hyperbaric hyperoxia. Strahlenther Onkol. 2015;191:875–882.
   PubMed Web of Science ®Google Scholar
• Nijkamp MM, Span PN, Terhaard CHJ, et al. Epidermal growth factor receptor expression in laryngeal cancer predicts the effect of hypoxia modification as an additive to accelerated radiotherapy in a randomised controlled trial. Eur J Cancer. 2013;49:3202–3209.
   PubMed Web of Science ®Google Scholar
• Janssens GO, Rademakers SE, Terhaard CH, et al. Improved recurrence-free survival with ARCON for anemic patients with laryngeal cancer. Clin Cancer Res. 2014;20:1345–1354.
   PubMed Web of Science ®Google Scholar
• Becker A, Stadler P, Lavey R, et al. Severe anemia is associated with poor tumor oxygenation in head and neck squamous cell carcinoma. Int J Radiat Oncol Biol Phys. 2000;46:459–466.
   PubMed Web of Science ®Google Scholar
• Vaupel P, Kelleher DK, Thews O. Modulation of tumor oxygenation. Int J Radiat Oncol Biol Phys. 1998;42:843–848.
   PubMed Web of Science ®Google Scholar
• Grogan M, Thomas GM, Melamed I, et al. The importance of hemoglobin levels during radiotherapy for carcinoma of the cervix. Cancer. 1999;86:1528–1536.
   PubMed Web of Science ®Google Scholar
• Hoff CM, Lassen P, Eriksen JG, et al. Does transfusion improve the outcome for HNSCC patients treated with radiotherapy? Results from the randomized DAHANCA 5 and 7 trials. Acta Oncol. 2011;50:1006–1014.
   PubMed Web of Science ®Google Scholar
• Blohmer JU, Paepke S, Sehouli J, et al. Randomized phase III trial of sequential adjuvant chemoradiotherapy with or without erythropoietin Alfa in patients with high-risk cervical cancer: results of the NOGGO-AGO intergroup study. J Clin Oncol. 2011;29:3791–3797.
   PubMed Web of Science ®Google Scholar
• Henke M, Laszig R, Ruebe C, et al. Erythropoietin to treat head and neck cancer patients with anaemia undergoing radiotherapy: randomised, double-blind, placebo-controlled trial. Lancet. 2003;362:1255–1260.
   PubMed Web of Science ®Google Scholar
• Jiang XD, Qiao Y, Dai P, et al. Preliminary clinical study of weekly recombinant human endostatin as a hypoxic tumour cell radiosensitiser combined with radiotherapy in the treatment of NSCLC. Clin Transl Oncol. 2012;14:465–470.
   PubMed Web of Science ®Google Scholar
• Shenouda G, Zhang Q, Ang KK, et al. Long-term results of radiation therapy oncology group 9903: a randomized phase 3 trial to assess the effect of erythropoietin on local-regional control in anemic patients treated with radiation therapy for squamous cell carcinoma of the head and neck. Int J Radiat Oncol Biol Phys. 2015;91:907–915.
   PubMed Web of Science ®Google Scholar
• Jain RK. Normalizing tumor vasculature with anti-angiogenic therapy: a new paradigm for combination therapy. Nat Med. 2001;7:987–989.
   PubMed Web of Science ®Google Scholar
• Borg C, André T, Mantion G, et al. Pathological response and safety of two neoadjuvant strategies with bevacizumab in MRI-defined locally advanced T3 resectable rectal cancer: a randomized, noncomparative phase II study. Ann Oncol. 2014;25:2205–2210.
   PubMed Web of Science ®Google Scholar
• Dellas K, Höhler T, Reese T, et al. Phase II trial of preoperative radiochemotherapy with concurrent bevacizumab, capecitabine and oxaliplatin in patients with locally advanced rectal cancer. Radiat Oncol. 2013;8:90.
   PubMed Web of Science ®Google Scholar
• Lee CG, Heijn M, di Tomaso E, et al. Anti-vascular endothelial growth factor treatment augments tumor radiation response under normoxic or hypoxic conditions. Cancer Res. 2000;60:5565–5570.
   PubMed Web of Science ®Google Scholar
• Nyflot MJ, Kruser TJ, Traynor AM, et al. Phase 1 trial of bevacizumab with concurrent chemoradiation therapy for squamous cell carcinoma of the head and neck with exploratory functional imaging of tumor hypoxia, proliferation, and perfusion. Int J Radiat Oncol Biol Phys. 2015;91:942–951.
   PubMed Web of Science ®Google Scholar
• Overgaard J. Clinical evaluation of nitroimidazoles as modifiers of hypoxia in solid tumors. Oncol Res. 1994;6:509–518.
   PubMed Web of Science ®Google Scholar
• 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;46:135–146.
   PubMed Web of Science ®Google Scholar
• Bentzen J, Toustrup K, Eriksen JG, et al. Locally advanced head and neck cancer treated with accelerated radiotherapy, the hypoxic modifier nimorazole and weekly cisplatin. Results from the DAHANCA 18 phase II study. Acta Oncol. 2015;1:1–7.
   Google Scholar
• Hassan Metwally MA, Ali R, Kuddu M, et al.; IAEA-HypoX. A randomized multicenter study of the hypoxic radiosensitizer nimorazole concomitant with accelerated radiotherapy in head and neck squamous cell carcinoma. Radiother Oncol. 2015;116:15–20.
   PubMed Web of Science ®Google Scholar
• Budach V, Stromberger C, Poettgen C, et al. Hyperfractionated accelerated radiation therapy (HART) of 70.6 Gy with concurrent 5-FU/Mitomycin C is superior to HART of 77.6 Gy alone in locally advanced head and neck cancer: long-term results of the ARO 95-06 randomized phase III trial. Int J Radiat Oncol Biol Phys. 2015;91:916–924.
   PubMed Web of Science ®Google Scholar
• Foehrenbacher A, Secomb TW, Wilson WR, et al. Design of optimized hypoxia-activated prodrugs using pharmacokinetic/pharmacodynamic modeling. Front Oncol. 2013;3:314.
   PubMedGoogle Scholar
• Borad MJ, Reddy SG, Bahary N, et al. Randomized phase II trial of gemcitabine plus TH-302 versus gemcitabine in patients with advanced pancreatic cancer. J Clin Oncol. 2015;33:1475–1487.
   PubMed Web of Science ®Google Scholar
• TH-302. Available from: https://clinicaltrials.gov/ct2/show/NCT02598687?term=radiotherapy&cond=hypoxia&rank=22
   Google Scholar
• Mandl M, Lieberum M, Dunst J, et al. The expression level of the transcription factor Aryl hydrocarbon receptor nuclear translocator (ARNT) determines cellular survival after radiation treatment. Radiat Oncol. 2015;10:229.
   PubMed Web of Science ®Google Scholar
• Conforti F, Wang Y, Rodriguez JA, et al. Molecular pathways: anticancer activity by inhibition of nucleocytoplasmic shuttling. Clin Cancer Res. 2015;21:4508–4513.
   PubMed Web of Science ®Google Scholar
• Askoxylakis V, Dinkel J, Eichinger M, et al. Multimodal hypoxia imaging and intensity modulated radiation therapy for unresectable non-small-cell lung cancer: the HIL trial. Radiat Oncol. 2012;7:157.
   PubMed Web of Science ®Google Scholar
• Even AJG, van der Stoep J, Zegers CML, et al. PET-based dose painting in non-small cell lung cancer: comparing uniform dose escalation with boosting hypoxic and metabolically active sub-volumes. Radiother Oncol. 2015;116:281–286.
   PubMed Web of Science ®Google Scholar
• Servagi-Vernat S, Differding S, Sterpin E, et al. Hypoxia-guided adaptive radiation dose escalation in head and neck carcinoma: a planning study. Acta Oncol. 2015;54:1008–1016.
   PubMed Web of Science ®Google Scholar
• Zschaeck S, Haase R, Abolmaali N, et al. Spatial distribution of FMISO in head and neck squamous cell carcinomas during radio-chemotherapy and its correlation to pattern of failure. Acta Oncol. 2015;54:1355–1363.
   PubMed Web of Science ®Google Scholar
• Coleman CN, Mitchell JB, Camphausen K. Tumor hypoxia: chicken, egg, or a piece of the farm? J Clin Oncol. 2002;20:610–615.
   PubMed Web of Science ®Google Scholar
• Lewis A, Kang R, Levine A, et al. The new face of head and neck cancer: the HPV epidemic. Oncology. 2015;29:616–626.
   PubMed Web of Science ®Google Scholar