4,505
Views
65
CrossRef citations to date
0
Altmetric
Review Article

Importance of hemoglobin concentration and its modification for the outcome of head and neck cancer patients treated with radiotherapy

Pages 419-432 | Received 19 Oct 2011, Accepted 22 Dec 2011, Published online: 07 Feb 2012

References

  • Gray LH, Conger AD, Ebert M, Hornsey S, Scott OC. The concentration of oxygen dissolved in tissues at the time of irradiation as a factor in radiotherapy. Br J Radiol 1953; 26:638–48.
  • Dische S. Radiotherapy and anaemia – the clinical experience. Radiother Oncol 1991;20(Suppl 1):35–40.
  • Overgaard J. Sensitization of hypoxic tumour cells – clinical experience. Int J Radiat Biol 1989;56:801–11.
  • Overgaard J. Hypoxic radiosensitization: Adored and ignored. J Clin Oncol 2007;25:4066–74.
  • Overgaard J, Hansen HS, Overgaard M, Bastholt L, Berthelsen A, Specht L, . 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.
  • Hoff CM, Hansen HS, Overgaard M, Grau C, Johansen J, Bentzen J, . The importance of haemoglobin level and effect of transfusion in HNSCC patients treated with radiotherapy – results from the randomized DAHANCA 5 study. Radiother Oncol 2011;98:28–33.
  • 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.
  • Hoff CM, Lassen P, Eriksen JG, Hansen HS, Specht L, Overgaard M, . Does transfusion improve the outcome for HNSCC patients treated with radiotherapy? – Results from the randomized DAHANCA 5 and 7 trial. Acta Oncol 2011;50:1006–14.
  • Moulder JE, Rockwell S. Hypoxic fractions of solid tumors: Experimental techniques, methods of analysis, and a survey of existing data. Int J Radiat Oncol Biol Phys 1984;10: 695–712.
  • IARC [Internet]. GLOBOCAN 2008. [updated 2008; cited 2011 Aug 30]. Available from: http://globocan.iarc.fr/factsheets/populations/factsheet.asp?uno = 900#KEY
  • Ragin CC, Modugno F, Gollin SM. The epidemiology and risk factors of head and neck cancer: A focus on human papillomavirus. J Dent Res 2007;86:104–14.
  • Lassen P. The role of human papillomavirus in head and neck cancer and the impact on radiotherapy outcome. Radiother Oncol 2010;95:371–80.
  • Ang KK, Harris J, Wheeler R, Weber R, Rosenthal DI, Nguyen-Tan PF, . Human papillomavirus and survival of patients with oropharyngeal cancer. N Engl J Med 2010;363:24–35.
  • Nordsmark M, Overgaard M, Overgaard J. Pretreatment oxygenation predicts radiation response in advanced squamous cell carcinoma of the head and neck. Radiother Oncol 1996;41:31–9.
  • Overgaard J, Hansen HS, Specht L, Overgaard M, Grau C, Andersen E, . Five compared with six fractions per week of conventional radiotherapy of squamous-cell carcinoma of head and neck: DAHANCA 6 and 7 randomised controlled trial. Lancet 2003;362:933–40.
  • DAHANCA [Internet]. Retningslinier for strålebehandling af hoved-hals cancer 2004 inkl IMRT. [updated 2004 September 14; cited 2011 Aug 1]. Available from: http://www.dahanca.dk/get_media_file.php?mediaid = 57
  • Overgaard J, Eriksen JG, Nordsmark M, Alsner J, Horsman MR. 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.
  • Grau C, Overgaard J. Significance of hemoglobin concentration for treatment outcome. In: Molls M, Vaupel P, editors. Blood perfusion and microenvironment of human tumors, implications for clinical radiooncology. Berlin: Springer; 1998. p. 101–12.
  • Lumb AB. Oxygen. In: Lumb AB, editor. Nunn's applied respiratory physiology. 6th ed. Philadelphia: Elsevier, Butterworth, Heinemann; 2005. p. 166–200.
  • Beutler E, Waalen J. The definition of anemia: What is the lower limit of normal of the blood hemoglobin concentration? Blood 2006;107:1747–50.
  • Hu K, Harrison LB. Impact of anemia in patients with head and neck cancer treated with radiation therapy. Curr Treat Options Oncol 2005;6:31–45.
  • Calabrich A, Katz A. Management of anemia in cancer patients. Future Oncol 2011;7:507–17.
  • Bohlius J, Schmidlin K, Brillant C, Schwarzer G, Trelle S, Seidenfeld J, . Erythropoietin or Darbepoetin for patients with cancer – meta-analysis based on individual patient data. Cochrane Database Syst Rev 2009; CD007303.
  • Harrison L, Shasha D, Shiaova L, White C, Ramdeen B, Portenoy R. Prevalence of anemia in cancer patients undergoing radiation therapy. Semin Oncol 2001;28:54–9.
  • Caro JJ, Salas M, Ward A, Goss G. Anemia as an independent prognostic factor for survival in patients with cancer: A systemic, quantitative review. Cancer 2001;91: 2214–21.
  • Bron D, Meuleman N, Mascaux C. Biological basis of anemia. Semin Oncol 2001;28:1–6.
  • Miller CB, Jones RJ, Piantadosi S, Abeloff MD, Spivak JL. Decreased erythropoietin response in patients with the anemia of cancer. N Engl J Med 1990;322:1689–92.
  • Hedenus M, Adriansson M, San MJ, Kramer MH, Schipperus MR, Juvonen E, . Efficacy and safety of darbepoetin alfa in anaemic patients with lymphoproliferative malignancies: A randomized, double-blind, placebo-controlled study. Br J Haematol 2003;122:394–403.
  • Ludwig H, Strasser K. Symptomatology of anemia. Semin Oncol 2001;28:7–14.
  • Sobrero A, Puglisi F, Guglielmi A, Belvedere O, Aprile G, Ramello M, . Fatigue: A main component of anemia symptomatology. Semin Oncol 2001;28:15–8.
  • Gafter U, Kalechman Y, Orlin JB, Levi J, Sredni B. Anemia of uremia is associated with reduced in vitro cytokine secretion: Immunopotentiating activity of red blood cells. Kidney Int 1994;45:224–31.
  • Thomlinson RH, Gray LH. The histological structure of some human lung cancers and the possible implications for radiotherapy. Br J Cancer 1955;9:539–49.
  • 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.
  • Overgaard J. The influence of haemoglobin concentration on the response to radiotherapy. Scand J Clin Lab Invest 1988;48:49–53.
  • Hirst DG. Anemia: A problem or an opportunity in radiotherapy? Int J Radiat Oncol Biol Phys 1986;12:2009–17.
  • Evans JC, Bergsjo P. The influence of anemia on the results of radiotherapy in carcinoma of the cervix. Radiology 1965;84:709–17.
  • Pedersen D, Sogaard H, Overgaard J, Bentzen SM. Prognostic value of pretreatment factors in patients with locally advanced carcinoma of the uterine cervix treated by radiotherapy alone. Acta Oncol 1995;34:787–95.
  • Grogan M, Thomas GM, Melamed I, Wong FL, Pearcey RG, Joseph PK, . The importance of hemoglobin levels during radiotherapy for carcinoma of the cervix. Cancer 1999;86:1528–36.
  • Thomas G. The effect of hemoglobin level on radiotherapy outcomes: The Canadian experience. Semin Oncol 2001;28:60–5.
  • Overgaard J, Bentzen SM, Kolstad P, Kjoerstad K, Davy M, Bertelsen K, . Misonidazole combined with radiotherapy in the treatment of carcinoma of the uterine cervix. Int J Radiat Oncol Biol Phys 1989;16:1069–72.
  • Zhao KL, Liu G, Jiang GL, Wang Y, Zhong LJ, Wang Y, . Association of haemoglobin level with morbidity and mortality of patients with locally advanced oesophageal carcinoma undergoing radiotherapy – a secondary analysis of three consecutive clinical phase III trials. Clin Oncol (R Coll Radiol ) 2006;18:621–7.
  • Tannock IF. The relation between cell proliferation and the vascular system in a transplanted mouse mammary tumour. Br J Cancer 1968;22:258–73.
  • Overgaard J, Hansen HS, Jorgensen K, Hjelm HM. Primary radiotherapy of larynx and pharynx carcinoma – an analysis of some factors influencing local control and survival. Int J Radiat Oncol Biol Phys 1986;12:515–21.
  • van Acht MJ, Hermans J, Boks DE, Leer JW. The prognostic value of hemoglobin and a decrease in hemoglobin during radiotherapy in laryngeal carcinoma. Radiother Oncol 1992;23:229–35.
  • Lee WR, Berkey B, Marcial V, Fu KK, Cooper JS, Vikram B, . Anemia is associated with decreased survival and increased locoregional failure in patients with locally advanced head and neck carcinoma: A secondary analysis of RTOG 85 - 27. Int J Radiat Oncol Biol Phys 1998;42: 1069–75.
  • Vaupel P, Mayer A, Hockel M. Impact of hemoglobin levels on tumor oxygenation: The higher, the better? Strahlenther Onkol 2006;182:63–71.
  • Tarnawski R, Skladowski K, Maciejewski B. Prognostic value of hemoglobin concentration in radiotherapy for cancer of supraglottic larynx. Int J Radiat Oncol Biol Phys 1997;38:1007–11.
  • Fyles AW, Milosevic M, Pintilie M, Syed A, Hill RP. Anemia, hypoxia and transfusion in patients with cervix cancer: A review. Radiother Oncol 2000;57:13–9.
  • Vaupel P, Thews O, Mayer A, Hockel S, Hockel M. Oxygenation status of gynecologic tumors: What is the optimal hemoglobin level? Strahlenther Onkol 2002;178:727–31.
  • Vaupel P. Hypoxia and aggressive tumor phenotype: Implications for therapy and prognosis. Oncologist 2008;13(Suppl 3):21–6.
  • Clavo B, Perez JL, Lopez L, Suarez G, Lloret M, Morera J, . Influence of haemoglobin concentration and peripheral muscle pO2 on tumour oxygenation in advanced head and neck tumours. Radiother Oncol 2003;66:71–4.
  • Brizel DM, Dodge RK, Clough RW, Dewhirst MW. Oxygenation of head and neck cancer: Changes during radiotherapy and impact on treatment outcome. Radiother Oncol 1999;53:113–7.
  • Stadler P, Becker A, Feldmann HJ, Hansgen G, Dunst J, Wurschmidt F, . Influence of the hypoxic subvolume on the survival of patients with head and neck cancer. Int J Radiat Oncol Biol Phys 1999;44:749–54.
  • Becker A, Stadler P, Lavey RS, Hansgen G, Kuhnt T, Lautenschlager C, . Severe anemia is associated with poor tumor oxygenation in head and neck squamous cell carcinomas. Int J Radiat Oncol Biol Phys 2000;46:459–66.
  • Nordsmark M, Bentzen SM, Rudat V, Brizel D, Lartigau E, Stadler P, . 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.
  • Nordsmark M, Overgaard J. Tumor hypoxia is independent of hemoglobin and prognostic for loco-regional tumor control after primary radiotherapy in advanced head and neck cancer. Acta Oncol 2004;43:396–403.
  • Vaupel P, Kallinowski F, Okunieff P. Blood flow, oxygen and nutrient supply, and metabolic microenvironment of human tumors: A review. Cancer Res 1989;49:6449–65.
  • Vaupel P, Kelleher DK, Hockel M. Oxygen status of malignant tumors: Pathogenesis of hypoxia and significance for tumor therapy. Semin Oncol 2001;28:29–35.
  • Horsman MR. Measurement of tumor oxygenation. Int J Radiat Oncol Biol Phys 1998;42:701–4.
  • Bayer C, Shi K, Astner ST, Maftei CA, Vaupel P. Acute versus chronic hypoxia: Why a simplified classification is simply not enough. Int J Radiat Oncol Biol Phys 2011; 80:965–8.
  • Hirst DG, Wood PJ. The influence of haemoglobin affinity for oxygen on tumour radiosensitivity. Br J Cancer 1987; 55:487–91.
  • Hirst DG, Wood PJ. The adaptive response of mouse tumours to anaemia and retransfusion. Int J Radiat Biol Relat Stud Phys Chem Med 1987;51:597–609.
  • Hirst DG, Hirst VK, Joiner B, Prise V, Shaffi KM. Changes in tumour morphology with alterations in oxygen availability: Further evidence for oxygen as a limiting substrate. Br J Cancer 1991;64:54–8.
  • Bush RS, Jenkin RD, Allt WE, Beale FA, Bean H, Dembo AJ, . Definitive evidence for hypoxic cells influencing cure in cancer therapy. Br J Cancer Suppl 1978; 3:302–6.
  • Kapp KS, Poschauko J, Geyer E, Berghold A, Oechs AC, Petru E, . Evaluation of the effect of routine packed red blood cell transfusion in anemic cervix cancer patients treated with radical radiotherapy. Int J Radiat Oncol Biol Phys 2002;54:58–66.
  • Sealy R, Jacobs P, Wood L, Levin W, Barry L, Boniaszczuk J, . The treatment of tumors by the induction of anemia and irradiation in hyperbaric oxygen. Cancer 1989;64:646–52.
  • Blajchman MA, Bordin JO. The tumor growth-promoting effect of allogeneic blood transfusions. Immunol Invest 1995;24:311–7.
  • Bentzen SM, Balslev I, Pedersen M, Teglbjaerg PS, Hanberg-Sorensen F, Bone J, . Blood transfusion and prognosis in Dukes’ B and C colorectal cancer. Eur J Cancer 1990;26:457–63.
  • Mortensen FV, Jensen LS, Sorensen HT, Pedersen L. Cause-specific mortality associated with leukoreduced, buffy coat-depleted, or no blood transfusion after elective surgery for colorectal cancer: A posttrial 15-year follow-up study. Transfusion 2011;51:259–63.
  • Blajchman MA. Immunomodulation and blood transfusion. Am J Ther 2002;9:389–95.
  • Jensen LS, Kissmeyer-Nielsen P, Wolff B, Qvist N. Randomised comparison of leucocyte-depleted versus buffy-coat-poor blood transfusion and complications after colorectal surgery. Lancet 1996;348:841–5.
  • Jensen LS, Puho E, Pedersen L, Mortensen FV, Sorensen HT. Long-term survival after colorectal surgery associated with buffy-coat-poor and leucocyte-depleted blood transfusion: A follow-up study. Lancet 2005;365: 681–2.
  • Horsman MR, Khalil AA, Nordsmark M, Grau C, Overgaard J. Relationship between radiobiological hypoxia and direct estimates of tumour oxygenation in a mouse tumour model. Radiother Oncol 1993;28:69–71.
  • Horsman MR, Khalil AA, Siemann DW, Grau C, Hill SA, Lynch EM, . Relationship between radiobiological hypoxia in tumors and electrode measurements of tumor oxygenation. Int J Radiat Oncol Biol Phys 1994;29: 439–42.
  • Horsman MR, Khalil AA, Nordsmark M, Grau C, Overgaard J. Measurement of pO2 in a murine tumour and its correlation with hypoxic fraction. Adv Exp Med Biol 1994;345:493–500.
  • Evans JC, Sanfilippo LJ. Oxygen tension of oral cavity carcinoma. Radiol Clin Biol 1970;39:54–8.
  • Evans JC, Cavanaugh PJ. Clinical trial of atmospheric oxygen breathing during radiotherapy for cancer of the oropharynx. Radiol Clin (Basel) 1975;44:210–3.
  • Rubin P, Hanley J, Keys HM, Marcial V, Brady L. Carbogen breathing during radiation therapy – the Radiation Therapy Oncology Group Study. Int J Radiat Oncol Biol Phys 1979;5:1963–70.
  • Mendenhall WM, Morris CG, Amdur RJ, Mendenhall NP, Siemann DW. Radiotherapy alone or combined with carbogen breathing for squamous cell carcinoma of the head and neck: A prospective, randomized trial. Cancer 2005; 104:332–7.
  • Van den Brenk HA. Hyperbaric oxygen in radiation therapy. An investigation of dose-effect relationships in tumor response and tissue damage. Am J Roentgenol Radium Ther Nucl Med 1968;102:8–26.
  • Tobin DA, Vermund H. A randomized study of hyperbaric oxygen as an adjunct to regularly fractionated radiation therapy for clinical treatment of advanced neoplastic disease. Am J Roentgenol Radium Ther Nucl Med 1971; 111:613–21.
  • Chang CH, Conley JJ, Herbert C, Jr. Radiotherapy of advanced carcinoma of the oropharyngeal region under hyperbaric oxygenation. An interim report. Am J Roentgenol Radium Ther Nucl Med 1973;117:509–16.
  • Berry GH, Dixon B, Ward AJ. The Leeds results for radiotherapy in HBO for carcinoma of the head and neck. Clin Radiol 1979;30:591–2.
  • Sause WT, Plenk HP. Radiation therapy of head and neck tumors: A randomized study of treatment in air vs. treatment in hyperbaric oxygen. Int J Radiat Oncol Biol Phys 1979;5:1833–6.
  • Sealy R, Cridland S, Barry L, Norris R. Irradiation with misonidazole and hyperbaric oxygen: Final report on a randomized trial in advanced head and neck cancer. Int J Radiat Oncol Biol Phys 1986;12:1343–6.
  • Haffty BG, Hurley R, Peters LJ. Radiation therapy with hyperbaric oxygen at 4 atmospheres pressure in the management of squamous cell carcinoma of the head and neck: Results of a randomized clinical trial. Cancer J Sci Am 1999;5:341–7.
  • Henk JM. Late results of a trial of hyperbaric oxygen and radiotherapy in head and neck cancer: A rationale for hypoxic cell sensitizers? Int J Radiat Oncol Biol Phys 1986;12:1339–41.
  • Henk JM, Smith CW. Radiotherapy and hyperbaric oxygen in head and neck cancer. Interim report of second clinical trial. Lancet 1977;2:104–5.
  • 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.
  • Rockwell S. Use of a perfluorochemical emulsion to improve oxygenation in a solid tumor. Int J Radiat Oncol Biol Phys 1985;11:97–103.
  • Teicher BA, Rose CM. Perfluorochemical emulsions can increase tumor radiosensitivity. Science 1984;223:934–6.
  • Teicher BA, Rose CM. Oxygen-carrying perfluorochemical emulsion as an adjuvant to radiation therapy in mice. Cancer Res 1984;44:4285–8.
  • Teicher BA, Herman TS, Hopkins RE, Menon K. Effect of oxygen level on the enhancement of tumor response to radiation by perfluorochemical emulsions or a bovine hemoglobin preparation. Int J Radiat Oncol Biol Phys 1991;21:969–74.
  • Rockwell S. Perfluorochemical emulsions and radiation therapy. Artif Cells Blood Substit Immobil Biotechnol 1994;22:1097–108.
  • Tremper KK, Friedman AE, Levine EM, Lapin R, Camarillo D. The preoperative treatment of severely anemic patients with a perfluorochemical oxygen-transport fluid, Fluosol-DA. N Engl J Med 1982;307:277–83.
  • Rose C, Lustig R, McIntosh N, Teicher B. A clinical trial of Fluosol DA 20% in advanced squamous cell carcinoma of the head and neck. Int J Radiat Oncol Biol Phys 1986;12:1325–7.
  • Lustig R, McIntosh-Lowe N, Rose C, Haas J, Krasnow S, Spaulding M, . Phase I/II study of Fluosol-DA and 100% oxygen as an adjuvant to radiation in the treatment of advanced squamous cell tumors of the head and neck. Int J Radiat Oncol Biol Phys 1989;16:1587–93.
  • Dunst J. The use of epoetin alfa to increase and maintain hemoglobin levels during radiotherapy. Semin Oncol 2001;28:42–8.
  • Glaspy JA. Erythropoietin in cancer patients. Annu Rev Med 2009;60:181–92.
  • Joiner B, Hirst VK, McKeown SR, McAleer JJ, Hirst DG. The effect of recombinant human erythropoietin treatment on tumour radiosensitivity and cancer-associated anaemia in the mouse. Br J Cancer 1993;68:720–6.
  • Kelleher DK, Matthiensen U, Thews O, Vaupel P. Tumor oxygenation in anemic rats: Effects of erythropoietin treatment versus red blood cell transfusion. Acta Oncol 1995; 34:379–84.
  • Thews O, Koenig R, Kelleher DK, Kutzner J, Vaupel P. Enhanced radiosensitivity in experimental tumours following erythropoietin treatment of chemotherapy-induced anaemia. Br J Cancer 1998;78:752–6.
  • Stuben G, Pottgen C, Knuhmann K, Schmidt K, Stuschke M, Thews O, . Erythropoietin restores the anemia-induced reduction in radiosensitivity of experimental human tumors in nude mice. Int J Radiat Oncol Biol Phys 2003;55:1358–62.
  • Lavey RS. Clinical trial experience using erythropoietin during radiation therapy. Strahlenther Onkol 1998; 174(Suppl 4):24–30.
  • Dusenbery KE, McGuire WA, Holt PJ, Carson LF, Fowler JM, Twiggs LB, . Erythropoietin increases hemoglobin during radiation therapy for cervical cancer. Int J Radiat Oncol Biol Phys 1994;29:1079–84.
  • Vijayakumar S, Roach M, III, Wara W, Chan SK, Ewing C, Rubin S, . Effect of subcutaneous recombinant human erythropoietin in cancer patients receiving radiotherapy: Preliminary results of a randomized, open-labeled, phase II trial. Int J Radiat Oncol Biol Phys 1993;26: 721–9.
  • Lavey RS, Dempsey WH. Erythropoietin increases hemoglobin in cancer patients during radiation therapy. Int J Radiat Oncol Biol Phys 1993;27:1147–52.
  • Overgaard J, Hoff CM, Hansen HS, Specht L, Overgaard M, Grau C, . 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 15s):abstr 6007.
  • Overgaard J, Hoff CM, Hansen HS, Specht L, Overgaard M, Grau C, . Randomized study of Aranesp as modifier of radiotherapy in patients with primary squamous cell carcinoma of the head and neck (HNSCC): Final outcome of the DAHANCA 10 trial. Radiother Oncol 2010; 96(Suppl 1):197–8.
  • Wright JR, Ung YC, Julian JA, Pritchard KI, Whelan TJ, Smith C, . Randomized, double-blind, placebo-controlled trial of erythropoietin in non-small-cell lung cancer with disease-related anemia. J Clin Oncol 2007;25: 1027–32.
  • Thomas G, Ali S, Hoebers FJ, Darcy KM, Rodgers WH, Patel M, . Phase III trial to evaluate the efficacy of maintaining hemoglobin levels above 12.0 g/dL with erythropoietin vs above 10.0 g/dL without erythropoietin in anemic patients receiving concurrent radiation and cisplatin for cervical cancer. Gynecol Oncol 2008;108:317–25.
  • Leyland-Jones B, Semiglazov V, Pawlicki M, Pienkowski T, Tjulandin S, Manikhas G, . Maintaining normal hemoglobin levels with epoetin alfa in mainly nonanemic patients with metastatic breast cancer receiving first-line chemotherapy: A survival study. J Clin Oncol 2005;23: 5960–72.
  • Glaser CM, Millesi W, Kornek GV, Lang S, Schull B, Watzinger F, . Impact of hemoglobin level and use of recombinant erythropoietin on efficacy of preoperative chemoradiation therapy for squamous cell carcinoma of the oral cavity and oropharynx. Int J Radiat Oncol Biol Phys 2001;50:705–15.
  • Hoskin PJ, Robinson M, Slevin N, Morgan D, Harrington K, Gaffney C. Effect of epoetin alfa on survival and cancer treatment-related anemia and fatigue in patients receiving radical radiotherapy with curative intent for head and neck cancer. J Clin Oncol 2009;27:5751–6.
  • Henke M, Laszig R, Rube C, Schafer U, Haase KD, Schilcher B, . Erythropoietin to treat head and neck cancer patients with anaemia undergoing radiotherapy: Randomised, double-blind, placebo-controlled trial. Lancet 2003;362:1255–60.
  • Machtay M, Pajak TF, Suntharalingam M, Shenouda G, Hershock D, Stripp DC, . Radiotherapy with or without erythropoietin for anemic patients with head and neck cancer: A randomized trial of the Radiation Therapy Oncology Group (RTOG99 - 03). Int J Radiat Oncol Biol Phys 2007;69:1008–17.
  • Bohlius J, Schmidlin K, Brillant C, Schwarzer G, Trelle S, Seidenfeld J, . Erythropoietin or Darbepoetin for patients with cancer – meta-analysis based on individual patient data. Cochrane Database Syst Rev 2009; CD007303.
  • Bohlius J, Wilson J, Seidenfeld J, Piper M, Schwarzer G, Sandercock J, . Erythropoietin or darbepoetin for patients with cancer. Cochrane Database Syst Rev 2006;3: CD003407.
  • Bohlius J, Schmidlin K, Brillant C, Schwarzer G, Trelle S, Seidenfeld J, . Recombinant human erythropoiesis-stimulating agents and mortality in patients with cancer: A meta-analysis of randomised trials. Lancet 2009;373: 1532–42.
  • Bohlius J, Wilson J, Seidenfeld J, Piper M, Schwarzer G, Sandercock J, . Recombinant human erythropoietins and cancer patients: Updated meta-analysis of 57 studies including 9353 patients. J Natl Cancer Inst 2006;98: 708–14.
  • Lambin P, Ramaekers BL, van Mastrigt GA, Van den Ende P, de JJ, De Ruysscher DK, . Erythropoietin as an adjuvant treatment with (chemo) radiation therapy for head and neck cancer. Cochrane Database Syst Rev 2009; CD006158.
  • Henke M, Mattern D, Pepe M, Bezay C, Weissenberger C, Werner M, . Do erythropoietin receptors on cancer cells explain unexpected clinical findings? J Clin Oncol 2006;24:4708–13.
  • Miller CP, Lowe KA, Valliant-Saunders K, Kaiser JF, Mattern D, Urban N, . Evaluating erythropoietin-associated tumor progression using archival tissues from a phase III clinical trial. Stem Cells 2009;27:2353–61.
  • Agarwal N, Gordeuk VR, Prchal JT. Are erythropoietin receptors expressed in tumors? Facts and fiction – more careful studies are needed. J Clin Oncol 2007;25:1813–4.
  • Jelkmann W, Laugsch M. Problems in identifying functional erythropoietin receptors in cancer tissue. J Clin Oncol 2007;25:1627–8.
  • Della RF, Cucciolla V, Borriello A, Oliva A, Perrotta S. Erythropoietin receptors on cancer cells: A still open question. J Clin Oncol 2007;25:1812–3.
  • Bokemeyer C, Aapro MS, Courdi A, Foubert J, Link H, Osterborg A, . EORTC guidelines for the use of erythropoietic proteins in anaemic patients with cancer: 2006 update. Eur J Cancer 2007;43:258–70.
  • Khuri FR. Weighing the hazards of erythropoiesis stimulation in patients with cancer. N Engl J Med 2007;356: 2445–8.
  • Barbera L, Thomas G. Erythropoiesis stimulating agents, thrombosis and cancer. Radiother Oncol 2010;95:269–76.
  • Spivak JL, Gascon P, Ludwig H. Anemia management in oncology and hematology. Oncologist 2009;14(Suppl 1): 43–56.
  • The European Medicines Agency [Internet]. Press Release EMEA recommends a new warning for epoetins for their use in cancer patients. [updated 2008 June 26; cited 2011 Aug 3]. Available from: http://www.ema.europa.eu/docs/en_GB/document_library/Press_release/2009/11/WC500015069.pdf
  • Siemann DW, Hill RP, Bush RS. Smoking: The influence of carboxyhemoglobin (HbCO) on tumor oxygenation and response to radiation. Int J Radiat Oncol Biol Phys 1978; 4:657–62.
  • Overgaard J, Nielsen JE, Grau C. Effect of carboxyhemoglobin on tumor oxygen unloading capacity in patients with squamous cell carcinoma of the head and neck. Int J Radiat Oncol Biol Phys 1992;22:407–10.
  • Grau C, Khalil AA, Nordsmark M, Horsman MR, Overgaard J. The relationship between carbon monoxide breathing, tumour oxygenation and local tumour control in the C3H mammary carcinoma in vivo. Br J Cancer 1994; 69:50–7.
  • Grau C, Nordsmark M, Khalil AA, Horsman MR, Overgaard J. Effect of carbon monoxide breathing on hypoxia and radiation response in the SCCVII tumor in vivo. Int J Radiat Oncol Biol Phys 1994;29:449–54.
  • Grau C, Horsman MR, Overgaard J. Influence of carboxyhemoglobin level on tumor growth, blood flow, and radiation response in an experimental model. Int J Radiat Oncol Biol Phys 1992;22:421–4.
  • Garces YI, Schroeder DR, Nirelli LM, Croghan GA, Croghan IT, Foote RL, . Second primary tumors following tobacco dependence treatments among head and neck cancer patients. Am J Clin Oncol 2007;30:531–9.
  • Jensen K, Jensen AB, Grau C. Smoking has a negative impact upon health related quality of life after treatment for head and neck cancer. Oral Oncol 2007;43:187–92.
  • Ford MB, Sigurdson AJ, Petrulis ES, Ng CS, Kemp B, Cooksley C, . Effects of smoking and radiotherapy on lung carcinoma in breast carcinoma survivors. Cancer 2003;98:1457–64.
  • van Leeuwen FE, Klokman WJ, Stovall M, Hagenbeek A, van den Belt-Dusebout AW, Noyon R, . Roles of radiotherapy and smoking in lung cancer following Hodgkin's disease. J Natl Cancer Inst 1995;87:1530–7.
  • Browman GP, Wong G, Hodson I, Sathya J, Russell R, McAlpine L, . Influence of cigarette smoking on the efficacy of radiation therapy in head and neck cancer. N Engl J Med 1993;328:159–63.
  • Chen AM, Chen LM, Vaughan A, Farwell DG, Luu Q, Purdy JA, . Head and neck cancer among lifelong never-smokers and ever-smokers: Matched-pair analysis of outcomes after radiation therapy. Am J Clin Oncol 2011; 34:270–5.
  • Chen AM, Chen LM, Vaughan A, Sreeraman R, Farwell DG, Luu Q, . Tobacco smoking during radiation therapy for head-and-neck cancer is associated with unfavorable outcome. Int J Radiat Oncol Biol Phys 2011; 79:414–9.
  • Hoff CM, Grau C, Overgaard J. Effect of smoking on oxygen delivery and outcome in patients treated with radiotherapy for head and neck squamous cell carcinoma – a prospective study. Radiother Oncol 2011 (in press).
  • Hoff CM, Grau C, Overgaard J. A prospective study evaluating the influence of smoking on effective hemoglobin level and outcome in patients with squamous sell carcinoma of the head and neck. Eur J Cancer 2011;47(Suppl 1):544.
  • Fyles A, Voduc D, Syed A, Milosevic M, Pintilie M, Hill R. The effect of smoking on tumour oxygenation and treatment outcome in cervical cancer. Clin Oncol (R Coll Radiol) 2002;14:442–6.
  • Hald J, Overgaard J, Grau C. Evaluation of objective measures of smoking status – a prospective clinical study in a group of head and neck cancer patients treated with radiotherapy. Acta Oncol 2003;42:154–9.
  • Kambam JR, Chen LH, Hyman SA. Effect of short-term smoking halt on carboxyhemoglobin levels and P50 values. Anesth Analg 1986;65:1186–8.
  • Boeje CR, Dalton SO, Kristensen CA, Andersen E, Johansen J, Andersen LJ, . Comorbidity among 13651 head and neck cancer patients from the DAHANCA-database. Radiother Oncol 2011;98(Suppl 1):3.
  • Mortensen LS, Buus S, Nordsmark M, Bentzen L, Munk OL, Keiding S, . Identifying hypoxia in human tumors: A correlation study between 18F-FMISO PET and the Eppendorf oxygen-sensitive electrode. Acta Oncol 2010; 49:934–40.
  • Rischin D, Hicks RJ, Fisher R, Binns D, Corry J, Porceddu S, . 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.
  • Kaanders JH, Wijffels KI, Marres HA, Ljungkvist AS, Pop LA, van den Hoogen FJ, . Pimonidazole binding and tumor vascularity predict for treatment outcome in head and neck cancer. Cancer Res 2002;62:7066–74.
  • Toustrup K, Sorensen BS, Nordsmark M, Busk M, Wiuf C, Alsner J, . 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.
  • Toustrup K, Sorensen BS, Lassen P, Wiuf C, Alsner J, Overgaard J. 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.

Reprints and Corporate Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

To request a reprint or corporate permissions for this article, please click on the relevant link below:

Academic Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

Obtain permissions instantly via Rightslink by clicking on the button below:

If you are unable to obtain permissions via Rightslink, please complete and submit this Permissions form. For more information, please visit our Permissions help page.