Methods to overcome radiation resistance in head and neck cancer
- Bruce E Brockstein, MD
Bruce E Brockstein, MD
- Section Editor — Cancer of the Head and Neck
- Clinical Professor of Medicine
- University of Chicago Pritzker School of Medicine
- Everett E Vokes, MD
Everett E Vokes, MD
- John E. Ultmann Professor
- Chairman, Department of Medicine
- Physician-in-Chief, University of Chicago Medicine and Biologic Sciences
- David S Yoo, MD, PhD
David S Yoo, MD, PhD
- Medical Instructor
- Department of Radiation Oncology
- Duke University Medical Center
- Section Editors
- Marshall R Posner, MD
Marshall R Posner, MD
- Section Editor — Cancer of the Head and Neck
- Professor of Gene and Cell Medicine
- The Tisch Cancer Institute
- Icahn School of Medicine at Mount Sinai
- David M Brizel, MD
David M Brizel, MD
- Section Editor — Radiation Therapy
- Leonard R Prosnitz Professor of Radiation Oncology
- Professor of Otolaryngology Head & Neck Surgery
- Duke University Cancer Institute
Radiation therapy (RT) plays a major role in the management of head and neck squamous cell carcinomas. Despite therapeutic and technological advances, some patients will have persistence of irradiated tumor or develop locoregional failure, resulting in significant morbidity and mortality . Radioresistance is a broad term that describes the relative resistance of individual cells, tissues, organs, or entire organisms to the biologic effects of RT .
Mechanisms of radioresistance to RT in head and neck cancer and strategies used to overcome this resistance are discussed here. Concurrent chemoradiotherapy is discussed in detail separately. (See "Locally advanced squamous cell carcinoma of the head and neck: Approaches combining chemotherapy and radiation therapy" and "Definitive radiation therapy for head and neck cancer: Dose and fractionation considerations".)
MECHANISMS OF RADIORESISTANCE
Many factors affect the responsiveness of tumors to radiation therapy (RT). Individual patients with tumors of similar size and stage can respond very differently to RT.
Relevant factors are related to the primary tumor (volume, size, grade, human papillomavirus [HPV] status), the patient (hemoglobin levels, smoking status), and biologic factors (hypoxia, proliferation status, expression of DNA repair genes, and alterations of many other genes).
Clinical factors affecting radiation response
Primary tumor characteristics — The complexity and variability of clinical outcomes in head and neck cancer are reflected in the spectrum of T stage descriptors used in the American Joint Committee on Cancer (AJCC)/Union for International Cancer Control (UICC) tumor, node, metastasis (TNM) staging system for the different primary sites . Larger tumors and/or those with more extensive local invasion have higher T classifications, corresponding to a likely higher malignant cell burden and poorer prognosis. (See "Overview of the diagnosis and staging of head and neck cancer".)To continue reading this article, you must log in with your personal, hospital, or group practice subscription. For more information on subscription options, click below on the option that best describes you:
- Blanchard P, Baujat B, Holostenco V, et al. Meta-analysis of chemotherapy in head and neck cancer (MACH-NC): a comprehensive analysis by tumour site. Radiother Oncol 2011; 100:33.
- Hall EJ, Giaccia AJ. Radiobiology for the radiologist, 6th, Lippincott, Williams and Wilkins, Philadelphia 2006.
- AJCC Cancer Staging Manual, Eighth, Amin, MB (Eds), Springer, Chicago 2017.
- Dinshaw KA, Agarwal JP, Ghosh-Laskar S, et al. Radical radiotherapy in head and neck squamous cell carcinoma: an analysis of prognostic and therapeutic factors. Clin Oncol (R Coll Radiol) 2006; 18:383.
- Hansen O, Overgaard J, Hansen HS, et al. Importance of overall treatment time for the outcome of radiotherapy of advanced head and neck carcinoma: dependency on tumor differentiation. Radiother Oncol 1997; 43:47.
- Gerweck LE, Vijayappa S, Kurimasa A, et al. Tumor cell radiosensitivity is a major determinant of tumor response to radiation. Cancer Res 2006; 66:8352.
- Ogawa K, Boucher Y, Kashiwagi S, et al. Influence of tumor cell and stroma sensitivity on tumor response to radiation. Cancer Res 2007; 67:4016.
- Lee WR, Berkey B, Marcial V, et al. 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.
- Prosnitz RG, Yao B, Farrell CL, et al. Pretreatment anemia is correlated with the reduced effectiveness of radiation and concurrent chemotherapy in advanced head and neck cancer. Int J Radiat Oncol Biol Phys 2005; 61:1087.
- Duffy SA, Ronis DL, McLean S, et al. Pretreatment health behaviors predict survival among patients with head and neck squamous cell carcinoma. J Clin Oncol 2009; 27:1969.
- Compton AH. On the Mechanism of X-Ray Scattering. Proc Natl Acad Sci U S A 1925; 11:303.
- Moeller BJ, Richardson RA, Dewhirst MW. Hypoxia and radiotherapy: opportunities for improved outcomes in cancer treatment. Cancer Metastasis Rev 2007; 26:241.
- Horsman MR. Nicotinamide and other benzamide analogs as agents for overcoming hypoxic cell radiation resistance in tumours. A review. Acta Oncol 1995; 34:571.
- Brizel DM, Sibley GS, Prosnitz LR, et al. Tumor hypoxia adversely affects the prognosis of carcinoma of the head and neck. Int J Radiat Oncol Biol Phys 1997; 38:285.
- 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.
- Silva P, Homer JJ, Slevin NJ, et al. Clinical and biological factors affecting response to radiotherapy in patients with head and neck cancer: a review. Clin Otolaryngol 2007; 32:337.
- 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.
- 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.
- Erler JT, Bennewith KL, Nicolau M, et al. Lysyl oxidase is essential for hypoxia-induced metastasis. Nature 2006; 440:1222.
- Le QT, Harris J, Magliocco AM, et al. Validation of lysyl oxidase as a prognostic marker for metastasis and survival in head and neck squamous cell carcinoma: Radiation Therapy Oncology Group trial 90-03. J Clin Oncol 2009; 27:4281.
- Harada H, Itasaka S, Zhu Y, et al. Treatment regimen determines whether an HIF-1 inhibitor enhances or inhibits the effect of radiation therapy. Br J Cancer 2009; 100:747.
- Tarnawski R, Fowler J, Skladowski K, et al. How fast is repopulation of tumor cells during the treatment gap? Int J Radiat Oncol Biol Phys 2002; 54:229.
- Withers HR, Taylor JM, Maciejewski B. The hazard of accelerated tumor clonogen repopulation during radiotherapy. Acta Oncol 1988; 27:131.
- Marcu L, van Doorn T, Olver I. Modelling of post-irradiation accelerated repopulation in squamous cell carcinomas. Phys Med Biol 2004; 49:3767.
- Bentzen SM, Atasoy BM, Daley FM, et al. Epidermal growth factor receptor expression in pretreatment biopsies from head and neck squamous cell carcinoma as a predictive factor for a benefit from accelerated radiation therapy in a randomized controlled trial. J Clin Oncol 2005; 23:5560.
- Couture C, Raybaud-Diogène H, Têtu B, et al. p53 and Ki-67 as markers of radioresistance in head and neck carcinoma. Cancer 2002; 94:713.
- Baumann M, Krause M, Hill R. Exploring the role of cancer stem cells in radioresistance. Nat Rev Cancer 2008; 8:545.
- Dingli D, Michor F. Successful therapy must eradicate cancer stem cells. Stem Cells 2006; 24:2603.
- Milas L, Hittelman WN. Cancer stem cells and tumor response to therapy: current problems and future prospects. Semin Radiat Oncol 2009; 19:96.
- O'Brien CA, Kreso A, Dick JE. Cancer stem cells in solid tumors: an overview. Semin Radiat Oncol 2009; 19:71.
- Clarke MF, Dick JE, Dirks PB, et al. Cancer stem cells--perspectives on current status and future directions: AACR Workshop on cancer stem cells. Cancer Res 2006; 66:9339.
- Wicha MS, Liu S, Dontu G. Cancer stem cells: an old idea--a paradigm shift. Cancer Res 2006; 66:1883.
- Yaromina A, Krause M, Thames H, et al. Pre-treatment number of clonogenic cells and their radiosensitivity are major determinants of local tumour control after fractionated irradiation. Radiother Oncol 2007; 83:304.
- Eyler CE, Rich JN. Survival of the fittest: cancer stem cells in therapeutic resistance and angiogenesis. J Clin Oncol 2008; 26:2839.
- Heddleston JM, Li Z, Lathia JD, et al. Hypoxia inducible factors in cancer stem cells. Br J Cancer 2010; 102:789.
- Lee HW, Hwang YH, Han JH, et al. High expression of excision repair cross-complementation group 1 protein predicts poor outcome in patients with nasopharyngeal cancer. Oral Oncol 2010; 46:209.
- Guillouf C, Rosselli F, Krishnaraju K, et al. p53 involvement in control of G2 exit of the cell cycle: role in DNA damage-induced apoptosis. Oncogene 1995; 10:2263.
- Jiang G, Ren B, Xu L, et al. Survivin may enhance DNA double-strand break repair capability by up-regulating Ku70 in human KB cells. Anticancer Res 2009; 29:223.
- Seiwert TY, Salama JK, Vokes EE. The concurrent chemoradiation paradigm--general principles. Nat Clin Pract Oncol 2007; 4:86.
- Khosravi Shahi P, Fernández Pineda I. Tumoral angiogenesis: review of the literature. Cancer Invest 2008; 26:104.
- Ang KK, Zhang Q, Rosenthal DI, et al. Randomized phase III trial of concurrent accelerated radiation plus cisplatin with or without cetuximab for stage III to IV head and neck carcinoma: RTOG 0522. J Clin Oncol 2014; 32:2940.
- Moeller BJ, Dreher MR, Rabbani ZN, et al. Pleiotropic effects of HIF-1 blockade on tumor radiosensitivity. Cancer Cell 2005; 8:99.
- Jorgensen TJ. Enhancing radiosensitivity: targeting the DNA repair pathways. Cancer Biol Ther 2009; 8:665.
- Bussink J, van der Kogel AJ, Kaanders JH. Activation of the PI3-K/AKT pathway and implications for radioresistance mechanisms in head and neck cancer. Lancet Oncol 2008; 9:288.
- Seiwert TY, Cohen EE. Targeting angiogenesis in head and neck cancer. Semin Oncol 2008; 35:274.
- 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.
- Brown JM, Wang LH. Tirapazamine: laboratory data relevant to clinical activity. Anticancer Drug Des 1998; 13:529.
- 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.
- Seiwert TY, Salama JK, Vokes EE. The chemoradiation paradigm in head and neck cancer. Nat Clin Pract Oncol 2007; 4:156.
- Bennett MH, Feldmeier J, Smee R, Milross C. Hyperbaric oxygenation for tumour sensitisation to radiotherapy. Cochrane Database Syst Rev 2012; :CD005007.
- Newbold K, Castellano I, Charles-Edwards E, et al. An exploratory study into the role of dynamic contrast-enhanced magnetic resonance imaging or perfusion computed tomography for detection of intratumoral hypoxia in head-and-neck cancer. Int J Radiat Oncol Biol Phys 2009; 74:29.
- Lapi SE, Voller TF, Welch MJ. Positron Emission Tomography Imaging of Hypoxia. PET Clin 2009; 4:39.
- Rischin D, Fisher R, Peters L, et al. Hypoxia in head and neck cancer: studies with hypoxic positron emission tomography imaging and hypoxic cytotoxins. Int J Radiat Oncol Biol Phys 2007; 69:S61.
- Søvik A, Malinen E, Olsen DR. Strategies for biologic image-guided dose escalation: a review. Int J Radiat Oncol Biol Phys 2009; 73:650.
- Flynn RT, Bowen SR, Bentzen SM, et al. Intensity-modulated x-ray (IMXT) versus proton (IMPT) therapy for theragnostic hypoxia-based dose painting. Phys Med Biol 2008; 53:4153.
- 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.
- Hoff CM, Hansen HS, Overgaard M, et al. 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.
- Dunphy FR, Harrison BR, Dunleavy TL, et al. Erythropoietin reduces anemia and transfusions: A randomized trial with or without erythropoietin during chemotherapy. Cancer 1999; 86:1362.
- Dunphy FR, Dunleavy TL, Harrison BR, et al. Erythropoietin reduces anemia and transfusions after chemotherapy with paclitaxel and carboplatin. Cancer 1997; 79:1623.
- Glaser CM, Millesi W, Kornek GV, et al. 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.
- Henke M, Laszig R, Rübe 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.
- 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.
- 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.
- Lambin P, Ramaekers BL, van Mastrigt GA, et al. Erythropoietin as an adjuvant treatment with (chemo) radiation therapy for head and neck cancer. Cochrane Database Syst Rev 2009; :CD006158.
- Bennett CL, Silver SM, Djulbegovic B, et al. Venous thromboembolism and mortality associated with recombinant erythropoietin and darbepoetin administration for the treatment of cancer-associated anemia. JAMA 2008; 299:914.
- Mohyeldin A, Lu H, Dalgard C, et al. Erythropoietin signaling promotes invasiveness of human head and neck squamous cell carcinoma. Neoplasia 2005; 7:537.
- Miller CP, Lowe KA, Valliant-Saunders K, et al. Evaluating erythropoietin-associated tumor progression using archival tissues from a phase III clinical trial. Stem Cells 2009; 27:2353.
- FDA website available online at http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/UCM109375 (Accessed on October 21, 2011).
- Le QT, Kim HE, Schneider CJ, et al. Palifermin reduces severe mucositis in definitive chemoradiotherapy of locally advanced head and neck cancer: a randomized, placebo-controlled study. J Clin Oncol 2011; 29:2808.
- Henke M, Alfonsi M, Foa P, et al. Palifermin decreases severe oral mucositis of patients undergoing postoperative radiochemotherapy for head and neck cancer: a randomized, placebo-controlled trial. J Clin Oncol 2011; 29:2815.
- Jones EL, Oleson JR, Prosnitz LR, et al. Randomized trial of hyperthermia and radiation for superficial tumors. J Clin Oncol 2005; 23:3079.
- Prosnitz LR, Maguire P, Anderson JM, et al. The treatment of high-grade soft tissue sarcomas with preoperative thermoradiotherapy. Int J Radiat Oncol Biol Phys 1999; 45:941.
- van der Zee J, González González D, van Rhoon GC, et al. Comparison of radiotherapy alone with radiotherapy plus hyperthermia in locally advanced pelvic tumours: a prospective, randomised, multicentre trial. Dutch Deep Hyperthermia Group. Lancet 2000; 355:1119.
- Westra A, Dewey WC. Variation in sensitivity to heat shock during the cell-cycle of Chinese hamster cells in vitro. Int J Radiat Biol Relat Stud Phys Chem Med 1971; 19:467.
- TERASIMA T, TOLMACH LJ. Variations in several responses of HeLa cells to x-irradiation during the division cycle. Biophys J 1963; 3:11.
- Gerweck LE, Nygaard TG, Burlett M. Response of cells to hyperthermia under acute and chronic hypoxic conditions. Cancer Res 1979; 39:966.
- Mivechi NF, Miyachi H, Scanlon KJ. Heat radiosensitization and the level of DNA polymerases alpha and beta of human colony-forming unit-granulocyte-macrophage and myeloid leukemias sensitive and resistant to chemotherapeutic agents. Cancer Res 1990; 50:2044.
- Raaphorst GP, Ng CE, Yang DP. Thermal radiosensitization and repair inhibition in human melanoma cells: a comparison of survival and DNA double strand breaks. Int J Hyperthermia 1999; 15:17.
- Brizel DM, Scully SP, Harrelson JM, et al. Radiation therapy and hyperthermia improve the oxygenation of human soft tissue sarcomas. Cancer Res 1996; 56:5347.
- Datta NR, Bose AK, Kapoor HK, Gupta S. Head and neck cancers: results of thermoradiotherapy versus radiotherapy. Int J Hyperthermia 1990; 6:479.
- Valdagni R, Amichetti M. Report of long-term follow-up in a randomized trial comparing radiation therapy and radiation therapy plus hyperthermia to metastatic lymph nodes in stage IV head and neck patients. Int J Radiat Oncol Biol Phys 1994; 28:163.
- MECHANISMS OF RADIORESISTANCE
- Clinical factors affecting radiation response
- - Primary tumor characteristics
- - Inherent tumor cell radioresistance
- Patient factors
- - Hemoglobin
- - Smoking status
- Biological factors determining radiation response
- - Hypoxia
- - Repopulation
- - Inherent tumor cell radioresistance
- - Cancer stem cells
- - Other factors
- STRATEGIES TO OVERCOME RADIORESISTANCE
- Altered fractionation RT
- Concurrent systemic therapy
- - Chemotherapy
- - Molecularly targeted agents
- - Checkpoint inhibitor immunotherapy
- OTHER APPROACHES
- Targeting hypoxia
- - Hypoxic cell sensitizers
- - Hypoxic cell cytotoxins
- - Hyperbaric oxygen
- - Functional imaging
- Correction of anemia
- - Transfusion
- - Erythropoiesis-stimulating agents