HPV and Radiation Sensitivity

  • Anna-Maria De Costa
  • Thorsten Rieckmann
  • Randall J. KimpleEmail author


Human papillomavirus (HPV) is a growing cause of cancers arising in the oropharynx. Patients with HPV-positive head and neck cancers significantly improved outcomes compared to those with traditional tobacco/alcohol associated head and neck cancers. These improved outcomes are likely multifactorial. In this chapter, we review the evidence for increased sensitivity to radiation playing an important role in the improved outcomes of these patients. We discuss how the HPV oncoproteins modulate intrinsic sensitivity to radiation, how differences in the tumor microenvironment may contribute to increased sensitivity to radiation, and how the immune system may play a key role in the response to radiation. Finally, we discuss current efforts aimed at therapeutic de-escalation for this group of patients and highlight future research directions.


Radiation Oropharynx P53 Clinical trials Hypoxia Tumor immunology DNA repair DNA damage Human papillomavirus 


  1. Albers A, Abe K, Hunt J, Wang J, Lopez-Albaitero A, Schaefer C, Gooding W, Whiteside TL, Ferrone S, DeLeo A, Ferris RL (2005) Antitumor activity of human papillomavirus type 16 E7-specific T cells against virally infected squamous cell carcinoma of the head and neck. Cancer Res 65(23):11146–11155. doi: 10.1158/0008-5472.CAN-05-0772 PubMedGoogle Scholar
  2. Anacker DC, Gautam D, Gillespie KA, Chappell WH, Moody CA (2014) Productive replication of human Papillomavirus 31 requires the DNA repair factor Nbs1. J Virol. doi: 10.1128/JVI.00517-14 PubMedCentralPubMedGoogle Scholar
  3. Anderson VE, Walton MI, Eve PD, Boxall KJ, Antoni L, Caldwell JJ, Aherne W, Pearl LH, Oliver AW, Collins I, Garrett MD (2011) CCT241533 is a potent and selective inhibitor of CHK2 that potentiates the cytotoxicity of PARP inhibitors. Cancer Res 71(2):463–472. doi: 10.1158/0008-5472.CAN-10-1252 PubMedGoogle Scholar
  4. Ang KK, Harris J, Wheeler R, Weber R, Rosenthal DI, Nguyen-Tan PF, Westra WH, Chung CH, Jordan RC, Lu C, Kim H, Axelrod R, Silverman CC, Redmond KP, Gillison ML (2010) Human papillomavirus and survival of patients with oropharyngeal cancer. N Engl J Med 363(1):24–35. doi: 10.1056/NEJMoa0912217 PubMedCentralPubMedGoogle Scholar
  5. Ang KK, Zhang QE, Rosenthal DI (2011) A randomized phase III trial (RTOG 0522) of concurrent accelerated radiation plus cisplatin with or without cetuximab for stage III-IV head and neck squamous cell carcinoma (HNC). J Clin Oncol (2011 ASCO annual meeting proceedings (Post-Meeting Addition)) 29(15_suppl (May 20 Suppl)):5500Google Scholar
  6. Apetoh L, Ghiringhelli F, Tesniere A, Obeid M, Ortiz C, Criollo A, Mignot G, Maiuri MC, Ullrich E, Saulnier P, Yang H, Amigorena S, Ryffel B, Barrat FJ, Saftig P, Levi F, Lidereau R, Nogues C, Mira JP, Chompret A, Joulin V, Clavel-Chapelon F, Bourhis J, Andre F, Delaloge S, Tursz T, Kroemer G, Zitvogel L (2007) Toll-like receptor 4-dependent contribution of the immune system to anticancer chemotherapy and radiotherapy. Nat Med 13(9):1050–1059. doi: 10.1038/nm1622 PubMedGoogle Scholar
  7. Arenz A, Ziemann F, Mayer C, Wittig A, Dreffke K, Preising S, Wagner S, Klussmann JP, Engenhart-Cabillic R, Wittekindt C (2014) Increased radiosensitivity of HPV-positive head and neck cancer cell lines due to cell cycle dysregulation and induction of apoptosis. Strahlentherapie und Onkologie: Organ der Deutschen Rontgengesellschaft [et al]. doi: 10.1007/s00066-014-0605-5 Google Scholar
  8. Argiris A, Li S, Ghebremichael M, Egloff AM, Wang L, Forastiere AA, Burtness B, Mehra R (2014) Prognostic significance of human papillomavirus in recurrent or metastatic head and neck cancer: an analysis of Eastern Cooperative Oncology Group trials. Ann Oncol. doi: 10.1093/annonc/mdu167 PubMedCentralPubMedGoogle Scholar
  9. Badoual C, Hans S, Merillon N, Van Ryswick C, Ravel P, Benhamouda N, Levionnois E, Nizard M, Si-Mohamed A, Besnier N, Gey A, Rotem-Yehudar R, Pere H, Tran T, Guerin CL, Chauvat A, Dransart E, Alanio C, Albert S, Barry B, Sandoval F, Quintin-Colonna F, Bruneval P, Fridman WH, Lemoine FM, Oudard S, Johannes L, Olive D, Brasnu D, Tartour E (2013) PD-1-expressing tumor-infiltrating T cells are a favorable prognostic biomarker in HPV-associated head and neck cancer. Cancer Res 73(1):128–138. doi: 10.1158/0008-5472.CAN-12-2606 PubMedGoogle Scholar
  10. Badoual C, Hans S, Rodriguez J, Peyrard S, Klein C, Agueznay Nel H, Mosseri V, Laccourreye O, Bruneval P, Fridman WH, Brasnu DF, Tartour E (2006) Prognostic value of tumor-infiltrating CD4+ T-cell subpopulations in head and neck cancers. Clin Cancer Res 12(2):465–472. doi: 10.1158/1078-0432.CCR-05-1886 PubMedGoogle Scholar
  11. Begg AC, Stewart FA, Vens C (2011) Strategies to improve radiotherapy with targeted drugs. Nat Rev Cancer 11(4):239–253. doi: 10.1038/nrc3007 PubMedGoogle Scholar
  12. Beusterien K, Grinspan J, Tencer T, Brufsky A, Visovsky C (2012) Patient preferences for chemotherapies used in breast cancer. Int J Women’s Health 4:279–287. doi: 10.2147/IJWH.S31331 Google Scholar
  13. Bonner JA, Harari PM, Giralt J, Azarnia N, Shin DM, Cohen RB, Jones CU, Sur R, Raben D, Jassem J, Ove R, Kies MS, Baselga J, Youssoufian H, Amellal N, Rowinsky EK, Ang KK (2006) Radiotherapy plus cetuximab for squamous-cell carcinoma of the head and neck. N Engl J Med 354(6):567–578PubMedGoogle Scholar
  14. Bonner JA, Harari PM, Giralt J, Cohen RB, Jones CU, Sur RK, Raben D, Baselga J, Spencer SA, Zhu J, Youssoufian H, Rowinsky EK, Ang KK (2010) 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 11(1):21–28. doi: 10.1016/S1470-2045(09)70311-0 PubMedGoogle Scholar
  15. Bourhis J, Overgaard J, Audry H, Ang KK, Saunders M, Bernier J, Horiot JC, Le Maitre A, Pajak TF, Poulsen MG, O’Sullivan B, Dobrowsky W, Hliniak A, Skladowski K, Hay JH, Pinto LH, Fallai C, Fu KK, Sylvester R, Pignon JP, Meta-Analysis of Radiotherapy in Carcinomas of H, neck Collaborative G (2006) Hyperfractionated or accelerated radiotherapy in head and neck cancer: a meta-analysis. Lancet 368 (9538):843–854. doi: 10.1016/S0140-6736(06)69121-6 Google Scholar
  16. Brotherston DC, Poon I, Le T, Leung M, Kiss A, Ringash J, Balogh J, Lee J, Wright JR (2013) Patient preferences for oropharyngeal cancer treatment de-escalation. Head Neck 35(2):151–159. doi: 10.1002/hed.22930 PubMedGoogle Scholar
  17. Brunet JF, Denizot F, Luciani MF, Roux-Dosseto M, Suzan M, Mattei MG, Golstein P (1987) A new member of the immunoglobulin superfamily–CTLA-4. Nature 328(6127):267–270. doi: 10.1038/328267a0 PubMedGoogle Scholar
  18. Bryant HE, Schultz N, Thomas HD, Parker KM, Flower D, Lopez E, Kyle S, Meuth M, Curtin NJ, Helleday T (2005) Specific killing of BRCA2-deficient tumours with inhibitors of poly(ADP-ribose) polymerase. Nature 434(7035):913–917. doi: 10.1038/nature03443 PubMedGoogle Scholar
  19. Buckwalter AE, Karnell LH, Smith RB, Christensen AJ, Funk GF (2007) Patient-reported factors associated with discontinuing employment following head and neck cancer treatment. Arch Otolaryngol Head Neck Surg 133(5):464–470PubMedGoogle Scholar
  20. Burnette BC, Liang H, Lee Y, Chlewicki L, Khodarev NN, Weichselbaum RR, Fu YX, Auh SL (2011) The efficacy of radiotherapy relies upon induction of type i interferon-dependent innate and adaptive immunity. Cancer Res 71(7):2488–2496. doi: 10.1158/0008-5472.CAN-10-2820 PubMedCentralPubMedGoogle Scholar
  21. Busch CJ, Kriegs M, Laban S, Tribius S, Knecht R, Petersen C, Dikomey E, Rieckmann T (2013) HPV-positive HNSCC cell lines but not primary human fibroblasts are radiosensitized by the inhibition of Chk1. Radiother Oncol 108(3):495–499. doi: 10.1016/j.radonc.2013.06.035 PubMedGoogle Scholar
  22. Butt AQ, Mills KH (2013) Immunosuppressive networks and checkpoints controlling antitumor immunity and their blockade in the development of cancer immunotherapeutics and vaccines. Oncogene. doi: 10.1038/onc.2013.432 Google Scholar
  23. Bykov VJ, Issaeva N, Shilov A, Hultcrantz M, Pugacheva E, Chumakov P, Bergman J, Wiman KG, Selivanova G (2002) Restoration of the tumor suppressor function to mutant p53 by a low-molecular-weight compound. Nat Med 8(3):282–288. doi: 10.1038/nm0302-282 PubMedGoogle Scholar
  24. Centers for Disease Control and Prevention (2012) National and state vaccination coverage among adolescents aged 13-17 years—United States, 2011. MMWR Morb Mortal Wkly Rep 61:671–677Google Scholar
  25. Centers for Disease Control and Prevention (2013) Trends in Current Cigarette Smoking Among High School Students and Adults, United States, 1965–2011Google Scholar
  26. Chakraborty M, Abrams SI, Camphausen K, Liu K, Scott T, Coleman CN, Hodge JW (2003) Irradiation of tumor cells up-regulates Fas and enhances CTL lytic activity and CTL adoptive immunotherapy. J Immunol 170(12):6338–6347PubMedGoogle Scholar
  27. Chaturvedi AK, Engels EA, Anderson WF, Gillison ML (2008) Incidence trends for human papillomavirus-related and -unrelated oral squamous cell carcinomas in the United States. J Clin Oncol 26(4):612–619. doi: 10.1200/JCO.2007.14.1713 PubMedGoogle Scholar
  28. Chaturvedi AK, Engels EA, Pfeiffer RM, Hernandez BY, Xiao W, Kim E, Jiang B, Goodman MT, Sibug-Saber M, Cozen W, Liu L, Lynch CF, Wentzensen N, Jordan RC, Altekruse S, Anderson WF, Rosenberg PS, Gillison ML (2011) Human papillomavirus and rising oropharyngeal cancer incidence in the United States. J Clin Oncol 29(32):4294–4301. doi: 10.1200/JCO.2011.36.4596 PubMedCentralPubMedGoogle Scholar
  29. Chemnitz JM, Parry RV, Nichols KE, June CH, Riley JL (2004) SHP-1 and SHP-2 associate with immunoreceptor tyrosine-based switch motif of programmed death 1 upon primary human T cell stimulation, but only receptor ligation prevents T cell activation. J Immunol 173(2):945–954PubMedGoogle Scholar
  30. Chen AM, Li BQ, Lau DH, Farwell DG, Luu Q, Stuart K, Newman K, Purdy JA, Vijayakumar S (2010) Evaluating the role of prophylactic gastrostomy tube placement prior to definitive chemoradiotherapy for head and neck cancer. Int J Radiat Oncol Biol Phys 78(4):1026–1032. doi: 10.1016/j.ijrobp.2009.09.036 PubMedGoogle Scholar
  31. Classon M, Harlow E (2002) The retinoblastoma tumour suppressor in development and cancer. Nat Rev Cancer 2(12):910–917. doi: 10.1038/nrc950 PubMedGoogle Scholar
  32. Cmelak A, Li S, Marur S, Zhao W, Westra W, Chung CH, Gillison ML, Gilbert J, Bauman JE, Wagner LI, Ferris RL, Trevarthen DR, Colevas AD, Jahagirdar BN, Burtness B (2014) E1308: reduced-dose IMRT in human papilloma virus (HPV)-associated resectable oropharyngeal squamous carcinomas (OPSCC) after clinical complete response (cCR) to induction chemotherapy (IC). J Clin Oncol 32(5s):(suppl; abstr LBA6006)Google Scholar
  33. Committee on Infectious Diseases (2012) HPV vaccine recommendations. Pediatrics 129:602–605Google Scholar
  34. D’Souza G, Agrawal Y, Halpern J, Bodison S, Gillison ML (2009) Oral sexual behaviors associated with prevalent oral human papillomavirus infection. J Infect Dis 199(9):1263–1269. doi: 10.1086/597755 PubMedGoogle Scholar
  35. D’Souza G, Kreimer AR, Viscidi R, Pawlita M, Fakhry C, Koch WM, Westra WH, Gillison ML (2007) Case-control study of human papillomavirus and oropharyngeal cancer. N Engl J Med 356(19):1944–1956. doi: 10.1056/NEJMoa065497 PubMedGoogle Scholar
  36. D’Souza G, Zhang HH, D’Souza WD, Meyer RR, Gillison ML (2010) Moderate predictive value of demographic and behavioral characteristics for a diagnosis of HPV16-positive and HPV16-negative head and neck cancer. Oral Oncol 46(2):100–104. doi: 10.1016/j.oraloncology.2009.11.004 PubMedCentralPubMedGoogle Scholar
  37. Dahlgren L, Dahlstrand HM, Lindquist D, Hogmo A, Bjornestal L, Lindholm J, Lundberg B, Dalianis T, Munck-Wikland E (2004) Human papillomavirus is more common in base of tongue than in mobile tongue cancer and is a favorable prognostic factor in base of tongue cancer patients. Int J Cancer 112(6):1015–1019. doi: 10.1002/ijc.20490 PubMedGoogle Scholar
  38. Dahlgren L, Mellin H, Wangsa D, Heselmeyer-Haddad K, Bjornestal L, Lindholm J, Munck-Wikland E, Auer G, Ried T, Dalianis T (2003) Comparative genomic hybridization analysis of tonsillar cancer reveals a different pattern of genomic imbalances in human papillomavirus-positive and -negative tumors. Int J Cancer 107(2):244–249. doi: 10.1002/ijc.11371 PubMedGoogle Scholar
  39. de Boer AG, Taskila T, Ojajarvi A, van Dijk FJ, Verbeek JH (2009) Cancer survivors and unemployment: a meta-analysis and meta-regression. JAMA 301(7):753–762. doi: 10.1001/jama.2009.187 PubMedGoogle Scholar
  40. Deboni AL, Giordani AJ, Lopes NN, Dias RS, Segreto RA, Jensen SB, Segreto HR (2012) Long-term oral effects in patients treated with radiochemotherapy for head and neck cancer. Support Care Cancer 20(11):2903–2911. doi: 10.1007/s00520-012-1418-7 PubMedGoogle Scholar
  41. Demaria S, Kawashima N, Yang AM, Devitt ML, Babb JS, Allison JP, Formenti SC (2005) Immune-mediated inhibition of metastases after treatment with local radiation and CTLA-4 blockade in a mouse model of breast cancer. Clin Cancer Res 11(2 Pt 1):728–734PubMedGoogle Scholar
  42. Dewan MZ, Galloway AE, Kawashima N, Dewyngaert JK, Babb JS, Formenti SC, Demaria S (2009) Fractionated but not single-dose radiotherapy induces an immune-mediated abscopal effect when combined with anti-CTLA-4 antibody. Clin Cancer Res 15(17):5379–5388. doi: 10.1158/1078-0432.CCR-09-0265 PubMedCentralPubMedGoogle Scholar
  43. DeWeese TL, Walsh JC, Dillehay LE, Kessis TD, Hedrick L, Cho KR, Nelson WG (1997) Human papillomavirus E6 and E7 oncoproteins alter cell cycle progression but not radiosensitivity of carcinoma cells treated with low-dose-rate radiation. Int J Radiat Oncol Biol Phys 37(1):145–154. doi:S0360301696004488 [pii]Google Scholar
  44. Dillon MT, Good JS, Harrington KJ (2014) Selective targeting of the G2/M cell cycle checkpoint to improve the therapeutic index of radiotherapy. Clin Oncol 26(5):257–265. doi: 10.1016/j.clon.2014.01.009 Google Scholar
  45. Dok R, Kalev P, Van Limbergen EJ, Asbagh LA, Vazquez I, Hauben E, Sablina A, Nuyts S (2014) p16INK4a impairs homologous recombination-mediated DNA repair in human papillomavirus-positive head and neck tumors. Cancer Res 74(6):1739–1751. doi: 10.1158/0008-5472.CAN-13-2479 PubMedGoogle Scholar
  46. Dowthwaite SA, Franklin JH, Palma DA, Fung K, Yoo J, Nichols AC (2012) The role of transoral robotic surgery in the management of oropharyngeal cancer: a review of the literature. ISRN Oncol 2012:945162. doi: 10.5402/2012/945162 PubMedCentralPubMedGoogle Scholar
  47. Eisbruch A (2004) Dysphagia and aspiration following chemo-irradiation of head and neck cancer: major obstacles to intensification of therapy. Ann Oncol 15(3):363–364PubMedGoogle Scholar
  48. Ensley JF, Jacobs JR, Weaver A, Kinzie J, Crissman J, Kish JA, Cummings G, Al-Sarraf M (1984) Correlation between response to cisplatinum-combination chemotherapy and subsequent radiotherapy in previously untreated patients with advanced squamous cell cancers of the head and neck. Cancer 54(5):811–814PubMedGoogle Scholar
  49. Eric A, Juranic Z, Tisma N, Plesinac V, Borojevic N, Jovanovic D, Milovanovic Z, Gavrilovic D, Ilic B (2009) Radiotherapy-induced changes of peripheral blood lymphocyte subpopulations in cervical cancer patients: relationship to clinical response. J Buon 14(1):79–83PubMedGoogle Scholar
  50. Eriksen JG, Maare C, Johansen J, Primdahl H, Evensen JF, Kristensen CA, Andersen L, Overgaard J (2014) DAHANCA19: a randomized phase III study of primary (chemo-) radiotherapy and zalutumumab in head and neck carcinomas. ESTRO 33 (Abstract OC-0372)Google Scholar
  51. Fakhry C, Westra WH, Li S, Cmelak A, Ridge JA, Pinto H, Forastiere A, Gillison ML (2008) Improved survival of patients with human papillomavirus-positive head and neck squamous cell carcinoma in a prospective clinical trial. J Natl Cancer Inst 100(4):261–269. doi: 10.1093/jnci/djn011 PubMedGoogle Scholar
  52. Fei J, Hong A, Dobbins TA, Jones D, Lee CS, Loo C, Al-Ghamdi M, Harnett GB, Clark J, O’Brien CJ, Rose B (2009) Prognostic significance of vascular endothelial growth factor in squamous cell carcinomas of the tonsil in relation to human papillomavirus status and epidermal growth factor receptor. Ann Surg Oncol 16(10):2908–2917. doi: 10.1245/s10434-009-0579-1 PubMedGoogle Scholar
  53. Feng FY, Kim HM, Lyden TH, Haxer MJ, Feng M, Worden FP, Chepeha DB, Eisbruch A (2007) Intensity-modulated radiotherapy of head and neck cancer aiming to reduce dysphagia: early dose-effect relationships for the swallowing structures. Int J Radiat Oncol Biol Phys 68(5):1289–1298. doi:S0360-3016(07)00547-0 [pii] doi: 10.1016/j.ijrobp.2007.02.049
  54. Fischer CA, Zlobec I, Green E, Probst S, Storck C, Lugli A, Tornillo L, Wolfensberger M, Terracciano LM (2010) Is the improved prognosis of p16 positive oropharyngeal squamous cell carcinoma dependent of the treatment modality? Int J Cancer 126(5):1256–1262. doi: 10.1002/ijc.24842 PubMedGoogle Scholar
  55. Freeman GJ, Lombard DB, Gimmi CD, Brod SA, Lee K, Laning JC, Hafler DA, Dorf ME, Gray GS, Reiser H et al (1992) CTLA-4 and CD28 mRNA are coexpressed in most T cells after activation. Expression of CTLA-4 and CD28 mRNA does not correlate with the pattern of lymphokine production. J Immunol 149(12):3795–3801PubMedGoogle Scholar
  56. Friesland S, Mellin H, Munck-Wikland E, Nilsson A, Lindholm J, Dalianis T, Lewensohn R (2001) Human papilloma virus (HPV) and p53 immunostaining in advanced tonsillar carcinoma–relation to radiotherapy response and survival. Anticancer Res 21(1B):529–534PubMedGoogle Scholar
  57. Garnett CT, Palena C, Chakraborty M, Tsang KY, Schlom J, Hodge JW (2004) Sublethal irradiation of human tumor cells modulates phenotype resulting in enhanced killing by cytotoxic T lymphocytes. Cancer Res 64(21):7985–7994. doi: 10.1158/0008-5472.CAN-04-1525 PubMedGoogle Scholar
  58. Gilbert J, Murphy B, Dietrich MS, Henry E, Jordan R, Counsell A, Wirth P, Yarbrough WG, Slebos RJ, Chung CH (2012) Phase 2 trial of oxaliplatin and pemetrexed as an induction regimen in locally advanced head and neck cancer. Cancer 118(4):1007–1013. doi: 10.1002/cncr.26364 PubMedGoogle Scholar
  59. Gillespie KA, Mehta KP, Laimins LA, Moody CA (2012) Human papillomaviruses recruit cellular DNA repair and homologous recombination factors to viral replication centers. J Virol 86(17):9520–9526. doi: 10.1128/JVI.00247-12 PubMedCentralPubMedGoogle Scholar
  60. Gillison ML, Alemany L, Snijders PJ, Chaturvedi A, Steinberg BM, Schwartz S, Castellsague X (2012) Human papillomavirus and diseases of the upper airway: head and neck cancer and respiratory papillomatosis. Vaccine 30(Suppl 5):F34–F54. doi: 10.1016/j.vaccine.2012.05.070 PubMedGoogle Scholar
  61. Gillison ML, D’Souza G, Westra W, Sugar E, Xiao W, Begum S, Viscidi R (2008) Distinct risk factor profiles for human papillomavirus type 16-positive and human papillomavirus type 16-negative head and neck cancers. J Natl Cancer Inst 100(6):407–420. doi: 10.1093/jnci/djn025 PubMedGoogle Scholar
  62. Gillison ML, Koch WM, Capone RB, Spafford M, Westra WH, Wu L, Zahurak ML, Daniel RW, Viglione M, Symer DE, Shah KV, Sidransky D (2000) Evidence for a causal association between human papillomavirus and a subset of head and neck cancers. J Natl Cancer Inst 92(9):709–720PubMedGoogle Scholar
  63. Giralt J, Fortin A, Mesia R, Minn H, Henke M, Ancona A, Cmelak A, Markowitz A, Hotte S, Singh S, Chan AT, Merlano MC, Zhang A, Oliner KS, Vanderwalde AM (2012) A phase II, randomized trial (CONCERT-1) of chemoradiotherapy (CRT) with or without panitumumab (pmab) in patients with unresected, locally advanced squamous cell carcinoma of the head and neck (LASCCHN). J Clin Oncol 30(suppl):abstr 5502Google Scholar
  64. Grabowska AK, Riemer AB (2012) The invisible enemy - how human papillomaviruses avoid recognition and clearance by the host immune system. Open Virol J 6:249–256. doi: 10.2174/1874357901206010249 PubMedCentralPubMedGoogle Scholar
  65. Gubanova E, Brown B, Ivanov SV, Helleday T, Mills GB, Yarbrough WG, Issaeva N (2012) Downregulation of SMG-1 in HPV-positive head and neck squamous cell carcinoma due to promoter hypermethylation correlates with improved survival. Clin Cancer Res 18(5):1257–1267. doi:1078-0432.CCR-11-2058 [pii]  10.1158/1078-0432.CCR-11-2058
  66. Gupta A, Probst HC, Vuong V, Landshammer A, Muth S, Yagita H, Schwendener R, Pruschy M, Knuth A, van den Broek M (2012a) Radiotherapy promotes tumor-specific effector CD8+ T cells via dendritic cell activation. J Immunol 189(2):558–566. doi: 10.4049/jimmunol.1200563 PubMedGoogle Scholar
  67. Gupta A, Sharma A, von Boehmer L, Surace L, Knuth A, van den Broek M (2012b) Radiotherapy supports protective tumor-specific immunity. Oncoimmunology 1(9):1610–1611. doi: 10.4161/onci.21478 PubMedCentralPubMedGoogle Scholar
  68. Haigentz M Jr, Silver CE, Corry J, Genden EM, Takes RP, Rinaldo A, Ferlito A (2009) Current trends in initial management of oropharyngeal cancer: the declining use of open surgery. Eur Arch Otorhinolaryngol 266(12):1845–1855PubMedGoogle Scholar
  69. Hallahan DE, Spriggs DR, Beckett MA, Kufe DW, Weichselbaum RR (1989) Increased tumor necrosis factor alpha mRNA after cellular exposure to ionizing radiation. Proc Natl Acad Sci USA 86(24):10104–10107PubMedCentralPubMedGoogle Scholar
  70. Hampson L, El Hady ES, Moore JV, Kitchener H, Hampson IN (2001) The HPV16 E6 and E7 proteins and the radiation resistance of cervical carcinoma. FASEB J: official publication of the Federation of American Societies for Experimental Biology 15(8):1445–1447Google Scholar
  71. Hayes DN, Grandis JR, El-Naggar AK (2013) The cancer genome Atlas: integrated analysis of genome alterations in squamous cell carcinoma of the head and neck. Proc Am Soc Clin Oncol 31(suppl) (abstr 6009)Google Scholar
  72. Heusinkveld M, Goedemans R, Briet RJ, Gelderblom H, Nortier JW, Gorter A, Smit VT, Langeveld AP, Jansen JC, van der Burg SH (2012) Systemic and local human papillomavirus 16-specific T-cell immunity in patients with head and neck cancer. Int J Cancer 131(2):E74–E85. doi: 10.1002/ijc.26497 PubMedGoogle Scholar
  73. Hitchcock YJ, Tward JD, Szabo A, Bentz BG, Shrieve DC (2009) Relative contributions of radiation and cisplatin-based chemotherapy to sensorineural hearing loss in head-and-neck cancer patients. Int J Radiat Oncol Biol Phys 73(3):779–788. doi: 10.1016/j.ijrobp.2008.05.040 PubMedGoogle Scholar
  74. Hoffmann TK, Arsov C, Schirlau K, Bas M, Friebe-Hoffmann U, Klussmann JP, Scheckenbach K, Balz V, Bier H, Whiteside TL (2006) T cells specific for HPV16 E7 epitopes in patients with squamous cell carcinoma of the oropharynx. Int J Cancer 118(8):1984–1991. doi: 10.1002/ijc.21565 PubMedGoogle Scholar
  75. Hong AM, Dobbins TA, Lee CS, Jones D, Fei J, Clark JR, Armstrong BK, Harnett GB, Milross CG, Tran N, Peculis LD, Ng C, Milne AG, Loo C, Hughes LJ, Forstner DF, O’Brien CJ, Rose BR (2011) Use of cyclin D1 in conjunction with human papillomavirus status to predict outcome in oropharyngeal cancer. Int J Cancer 128(7):1532–1545. doi: 10.1002/ijc.25479 PubMedGoogle Scholar
  76. Hong JH, Chiang CS, Tsao CY, Lin PY, McBride WH, Wu CJ (1999) Rapid induction of cytokine gene expression in the lung after single and fractionated doses of radiation. Int J Radiat Biol 75(11):1421–1427PubMedGoogle Scholar
  77. Hori S, Nomura T, Sakaguchi S (2003) Control of regulatory T cell development by the transcription factor Foxp3. Science 299(5609):1057–1061. doi: 10.1126/science.1079490 PubMedGoogle Scholar
  78. Janot F, de Raucourt D, Benhamou E, Ferron C, Dolivet G, Bensadoun RJ, Hamoir M, Gery B, Julieron M, Castaing M, Bardet E, Gregoire V, Bourhis J (2008) Randomized trial of postoperative reirradiation combined with chemotherapy after salvage surgery compared with salvage surgery alone in head and neck carcinoma. J Clin Oncol 26(34):5518–5523. doi: 10.1200/JCO.2007.15.0102 PubMedGoogle Scholar
  79. Jansen JF, Carlson DL, Lu Y, Stambuk HE, Moreira AL, Singh B, Patel SG, Kraus DH, Wong RJ, Shaha AR, Shah JP, Shukla-Dave A (2012) Correlation of a priori DCE-MRI and (1)H-MRS data with molecular markers in neck nodal metastases: initial analysis. Oral Oncol 48(8):717–722. doi: 10.1016/j.oraloncology.2012.02.001 PubMedCentralPubMedGoogle Scholar
  80. Jung AC, Guihard S, Krugell S, Ledrappier S, Brochot A, Dalstein V, Job S, de Reynies A, Noel G, Wasylyk B, Clavel C, Abecassis J (2013) CD8-alpha T-cell infiltration in human papillomavirus-related oropharyngeal carcinoma correlates with improved patient prognosis. Int J Cancer 132(2):E26–E36. doi: 10.1002/ijc.27776 PubMedGoogle Scholar
  81. Kam MK, Leung SF, Zee B, Chau RM, Suen JJ, Mo F, Lai M, Ho R, Cheung KY, Yu BK, Chiu SK, Choi PH, Teo PM, Kwan WH, Chan AT (2007) Prospective randomized study of intensity-modulated radiotherapy on salivary gland function in early-stage nasopharyngeal carcinoma patients. J Clin Oncol 25(31):4873–4879. doi:25/31/4873 [pii]  10.1200/JCO.2007.11.5501
  82. Kenter GG, Welters MJ, Valentijn AR, Lowik MJ, Berends-van der Meer DM, Vloon AP, Essahsah F, Fathers LM, Offringa R, Drijfhout JW, Wafelman AR, Oostendorp J, Fleuren GJ, van der Burg SH, Melief CJ (2009) Vaccination against HPV-16 oncoproteins for vulvar intraepithelial neoplasia. N Engl J Med 361(19):1838–1847. doi: 10.1056/NEJMoa0810097 PubMedGoogle Scholar
  83. Kimple RJ, Harari PM, Torres AD, Yang RZ, Soriano BJ, Yu M, Armstrong EA, Blitzer GC, Smith MA, Lorenz LD, Lee D, Yang DT, McCulloch TM, Hartig GK, Lambert PF (2013a) Development and characterization of HPV-positive and HPV-negative head and neck squamous cell carcinoma tumorgrafts. Clin Cancer Res 19(4):855–864. doi: 10.1158/1078-0432.CCR-12-2746 PubMedCentralPubMedGoogle Scholar
  84. Kimple RJ, Smith MA, Blitzer GC, Torres AD, Martin JA, Yang RZ, Peet CR, Lorenz LD, Nickel KP, Klingelhutz AJ, Lambert PF, Harari PM (2013b) Enhanced radiation sensitivity in HPV-positive head and neck cancer. Cancer Res 73(15):4791–4800. doi: 10.1158/0008-5472.CAN-13-0587 PubMedCentralPubMedGoogle Scholar
  85. Kong CS, Narasimhan B, Cao H, Kwok S, Erickson JP, Koong A, Pourmand N, Le QT (2009) The relationship between human papillomavirus status and other molecular prognostic markers in head and neck squamous cell carcinomas. Int J Radiat Oncol Biol Phys 74(2):553–561. doi: 10.1016/j.ijrobp.2009.02.015 PubMedCentralPubMedGoogle Scholar
  86. Kostareli E, Holzinger D, Bogatyrova O, Hielscher T, Wichmann G, Keck M, Lahrmann B, Grabe N, Flechtenmacher C, Schmidt CR, Seiwert T, Dyckhoff G, Dietz A, Hofler D, Pawlita M, Benner A, Bosch FX, Plinkert P, Plass C, Weichenhan D, Hess J (2013) HPV-related methylation signature predicts survival in oropharyngeal squamous cell carcinomas. J Clin Invest 123(6):2488–2501. doi: 10.1172/JCI67010 PubMedCentralPubMedGoogle Scholar
  87. Kreimer AR, Clifford GM, Boyle P, Franceschi S (2005) Human papillomavirus types in head and neck squamous cell carcinomas worldwide: a systematic review. Cancer Epidemiol Biomarkers Prev 14(2):467–475. doi:14/2/467 [pii]  10.1158/1055-9965.EPI-04-0551
  88. Lassen P (2010) The role of Human papillomavirus in head and neck cancer and the impact on radiotherapy outcome. Radiother Oncol 95(3):371–380. doi:S0167-8140(10)00278-1 [pii]  10.1016/j.radonc.2010.04.022
  89. Lassen P, Eriksen JG, Hamilton-Dutoit S, Tramm T, Alsner J, Overgaard J (2009a) Effect of HPV-associated p16INK4A expression on response to radiotherapy and survival in squamous cell carcinoma of the head and neck. J Clin Oncol 27(12):1992–1998. doi: 10.1200/JCO.2008.20.2853 PubMedGoogle Scholar
  90. Lassen P, Eriksen JG, Krogdahl A, Therkildsen MH, Ulhoi BP, Overgaard M, Specht L, Andersen E, Johansen J, Andersen LJ, Grau C, Overgaard J, Danish H, Neck Cancer G (2011) The influence of HPV-associated p16-expression on accelerated fractionated radiotherapy in head and neck cancer: evaluation of the randomised DAHANCA 6&7 trial. Radiother Oncol 100(1):49–55. doi: 10.1016/j.radonc.2011.02.010 PubMedGoogle Scholar
  91. Lassen P, Eriksen JG, Tramm T, Hamilton-Dutoit S, Alsner J, Overgaard J (2009b) HPV-associated p16-expression and response to radiobiological modifications of radiotherapy in head and neck cancer: results from the randomized DAHANCA trials. Euro J Cancer Suppl 7(11)Google Scholar
  92. Lee JM, Bernstein A (1993) p53 mutations increase resistance to ionizing radiation. Proc Natl Acad Sci USA 90(12):5742–5746PubMedCentralPubMedGoogle Scholar
  93. Lee N, Chan K, Bekelman JE, Zhung J, Mechalakos J, Narayana A, Wolden S, Venkatraman ES, Pfister D, Kraus D, Shah J, Zelefsky MJ (2007) Salvage re-irradiation for recurrent head and neck cancer. Int J Radiat Oncol Biol Phys 68(3):731–740. doi: 10.1016/j.ijrobp.2006.12.055 PubMedGoogle Scholar
  94. Leonhardt FD, Quon H, Abrahao M, O’Malley BW Jr, Weinstein GS (2012) Transoral robotic surgery for oropharyngeal carcinoma and its impact on patient-reported quality of life and function. Head Neck 34(2):146–154. doi: 10.1002/hed.21688 PubMedGoogle Scholar
  95. Levendag PC, Teguh DN, Voet P, van der Est H, Noever I, de Kruijf WJ, Kolkman-Deurloo IK, Prevost JB, Poll J, Schmitz PI, Heijmen BJ (2007) Dysphagia disorders in patients with cancer of the oropharynx are significantly affected by the radiation therapy dose to the superior and middle constrictor muscle: a dose-effect relationship. Radiother Oncol 85(1):64–73. doi: 10.1016/j.radonc.2007.07.009 PubMedGoogle Scholar
  96. Levy A, Blanchard P, Bellefqih S, Brahimi N, Guigay J, Janot F, Temam S, Bourhis J, Deutsch E, Daly-Schveitzer N, Tao Y (2014) Concurrent use of cisplatin or cetuximab with definitive radiotherapy for locally advanced head and neck squamous cell carcinomas. Strahlentherapie und Onkologie: Organ der Deutschen Rontgengesellschaft [et al]. doi: 10.1007/s00066-014-0626-0 Google Scholar
  97. Licitra L, Perrone F, Bossi P, Suardi S, Mariani L, Artusi R, Oggionni M, Rossini C, Cantu G, Squadrelli M, Quattrone P, Locati LD, Bergamini C, Olmi P, Pierotti MA, Pilotti S (2006) High-risk human papillomavirus affects prognosis in patients with surgically treated oropharyngeal squamous cell carcinoma. J Clin Oncol 24(36):5630–5636. doi:24/36/5630 [pii]  10.1200/JCO.2005.04.6136
  98. Lin BM, Wang H, D’Souza G, Zhang Z, Fakhry C, Joseph AW, Drake VE, Sanguineti G, Westra WH, Pai SI (2013) Long-term prognosis and risk factors among patients with HPV-associated oropharyngeal squamous cell carcinoma. Cancer 119(19):3462–3471. doi: 10.1002/cncr.28250 PubMedCentralPubMedGoogle Scholar
  99. Lindel K, Beer KT, Laissue J, Greiner RH, Aebersold DM (2001) Human papillomavirus positive squamous cell carcinoma of the oropharynx: a radiosensitive subgroup of head and neck carcinoma. Cancer 92(4):805–813. doi: 10.1002/1097-0142(20010815)92:4<805::AID-CNCR1386>3.0.CO;2-9 [pii]
  100. Lindquist D, Nasman A, Tarjan M, Henriksson R, Tot T, Dalianis T, Hedman H (2014) Expression of LRIG1 is associated with good prognosis and human papillomavirus status in oropharyngeal cancer. Br J Cancer 110(7):1793–1800. doi: 10.1038/bjc.2014.87 PubMedCentralPubMedGoogle Scholar
  101. Long A, Ferraro D, Stockler M, Blinman P (2013) Patient versus clinician preferences for chemotherapy in non-small-cell lung cancer. Lung Cancer Manag 2(6):527–536. doi: 10.2217/lmt.13.60 Google Scholar
  102. Loser DA, Shibata A, Shibata AK, Woodbine LJ, Jeggo PA, Chalmers AJ (2010) Sensitization to radiation and alkylating agents by inhibitors of poly(ADP-ribose) polymerase is enhanced in cells deficient in DNA double-strand break repair. Mol Cancer Ther 9(6):1775–1787. doi: 10.1158/1535-7163.MCT-09-1027 PubMedCentralPubMedGoogle Scholar
  103. Lugade AA, Sorensen EW, Gerber SA, Moran JP, Frelinger JG, Lord EM (2008) Radiation-induced IFN-gamma production within the tumor microenvironment influences antitumor immunity. J Immunol 180(5):3132–3139PubMedGoogle Scholar
  104. Lyford-Pike S, Peng S, Young GD, Taube JM, Westra WH, Akpeng B, Bruno TC, Richmon JD, Wang H, Bishop JA, Chen L, Drake CG, Topalian SL, Pardoll DM, Pai SI (2013) Evidence for a role of the PD-1:PD-L1 pathway in immune resistance of HPV-associated head and neck squamous cell carcinoma. Cancer Res 73(6):1733–1741. doi: 10.1158/0008-5472.CAN-12-2384 PubMedCentralPubMedGoogle Scholar
  105. Ma Y, Kepp O, Ghiringhelli F, Apetoh L, Aymeric L, Locher C, Tesniere A, Martins I, Ly A, Haynes NM, Smyth MJ, Kroemer G, Zitvogel L (2010) Chemotherapy and radiotherapy: cryptic anticancer vaccines. Semin Immunol 22(3):113–124. doi: 10.1016/j.smim.2010.03.001 PubMedGoogle Scholar
  106. Marcu LG, Bezak E (2009) Radiobiological modeling of interplay between accelerated repopulation and altered fractionation schedules in head and neck cancer. J Med Phys/Association of Medical Physicists of India 34(4):206–211. doi: 10.4103/0971-6203.56081 Google Scholar
  107. Marur S, Li S, Cmelak A, Gillison ML, Ferris RL, Bauman JE, Zhao W, Westra WH, Chung CH, Wagner LI, Trevarthen DR, Jahagirdar BN, Colevas AD, Burtness B (2013) E 1308: A phase II trial of induction chemotherapy (IC) followed by cetuximab with low dose versus standard dose IMRT in patients with human papilloma virus (HPV)-associated resectable squamous cell carcinoma of the oropharynx (OPSCC). J Clin Oncol (2013 ASCO Annual Meeting Proceedings) 31_suppl (abstr 6005)Google Scholar
  108. Matsumura S, Demaria S (2010) Up-regulation of the pro-inflammatory chemokine CXCL16 is a common response of tumor cells to ionizing radiation. Radiat Res 173(4):418–425. doi: 10.1667/RR1860.1 PubMedCentralPubMedGoogle Scholar
  109. Matsumura S, Wang B, Kawashima N, Braunstein S, Badura M, Cameron TO, Babb JS, Schneider RJ, Formenti SC, Dustin ML, Demaria S (2008) Radiation-induced CXCL16 release by breast cancer cells attracts effector T cells. J Immunol 181(5):3099–3107PubMedCentralPubMedGoogle Scholar
  110. Matsuyama R, Reddy S, Smith TJ (2006) Why do patients choose chemotherapy near the end of life? A review of the perspective of those facing death from cancer. J Clin Oncol 24(21):3490–3496. doi: 10.1200/JCO.2005.03.6236 PubMedGoogle Scholar
  111. Maxwell JH, Kumar B, Feng FY, Worden FP, Lee JS, Eisbruch A, Wolf GT, Prince ME, Moyer JS, Teknos TN, Chepeha DB, McHugh JB, Urba SG, Stoerker J, Walline HM, Kurnit DM, Cordell KG, Davis SJ, Ward PD, Bradford CR, Carey TE (2010) Tobacco use in human papillomavirus-positive advanced oropharynx cancer patients related to increased risk of distant metastases and tumor recurrence. Clin Cancer Res 16(4):1226–1235. doi: 10.1158/1078-0432.CCR-09-2350 PubMedCentralPubMedGoogle Scholar
  112. McQuellon RP, Muss HB, Hoffman SL, Russell G, Craven B, Yellen SB (1995) Patient preferences for treatment of metastatic breast cancer: a study of women with early-stage breast cancer. J Clin Oncol 13(4):858–868PubMedGoogle Scholar
  113. Meinardi MT, Gietema JA, van der Graaf WT, van Veldhuisen DJ, Runne MA, Sluiter WJ, de Vries EG, Willemse PB, Mulder NH, van den Berg MP, Koops HS, Sleijfer DT (2000) Cardiovascular morbidity in long-term survivors of metastatic testicular cancer. J Clin Oncol 18(8):1725–1732PubMedGoogle Scholar
  114. Mellin Dahlstrand H, Lindquist D, Bjornestal L, Ohlsson A, Dalianis T, Munck-Wikland E, Elmberger G (2005) P16(INK4a) correlates to human papillomavirus presence, response to radiotherapy and clinical outcome in tonsillar carcinoma. Anticancer Res 25(6C):4375–4383PubMedGoogle Scholar
  115. Mellin H, Friesland S, Lewensohn R, Dalianis T, Munck-Wikland E (2000) Human papillomavirus (HPV) DNA in tonsillar cancer: clinical correlates, risk of relapse, and survival. Int J Cancer 89(3):300–304PubMedGoogle Scholar
  116. Meng Y, Efimova EV, Hamzeh KW, Darga TE, Mauceri HJ, Fu YX, Kron SJ, Weichselbaum RR (2012) Radiation-inducible immunotherapy for cancer: senescent tumor cells as a cancer vaccine. Mol Ther 20(5):1046–1055. doi: 10.1038/mt.2012.19 PubMedCentralPubMedGoogle Scholar
  117. Meyer RM, Hoppe RT (2012) Point/counterpoint: early-stage Hodgkin lymphoma and the role of radiation therapy. Hematology/the Education Program of the American Society of Hematology American Society of Hematology Education Program 2012:313–321. doi: 10.1182/asheducation-2012.1.313 PubMedGoogle Scholar
  118. Mirghani H, Amen F, Moreau F, Guigay J, Hartl DM, Lacau St Guily J (2014) Oropharyngeal cancers: Relationship between epidermal growth factor receptor alterations and human papillomavirus status. Eur J Cancer 50(6):1100–1111. doi: 10.1016/j.ejca.2013.12.018 PubMedGoogle Scholar
  119. Miyazaki K, Mizutani H, Katabuchi H, Fukuma K, Fujisaki S, Okamura H (1995) Activated (HLA-DR+) T-lymphocyte subsets in cervical carcinoma and effects of radiotherapy and immunotherapy with sizofiran on cell-mediated immunity and survival. Gynecol Oncol 56(3):412–420PubMedGoogle Scholar
  120. Moody CA, Laimins LA (2009) Human papillomaviruses activate the ATM DNA damage pathway for viral genome amplification upon differentiation. PLoS Pathog 5(10):e1000605. doi: 10.1371/journal.ppat.1000605 PubMedCentralPubMedGoogle Scholar
  121. Mortensen LS, Johansen J, Kallehauge J, Primdahl H, Busk M, Lassen P, Alsner J, Sorensen BS, Toustrup K, Jakobsen S, Petersen J, Petersen H, Theil J, Nordsmark M, Overgaard J (2012) 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 105(1):14–20. doi: 10.1016/j.radonc.2012.09.015 PubMedGoogle Scholar
  122. Munoz N, Castellsague X, Berrington de Gonzalez A, Gissmann L (2006) Chapter 1: HPV in the etiology of human cancer. Vaccine 24S3(S3):1–10Google Scholar
  123. Nagy JA, Chang SH, Shih SC, Dvorak AM, Dvorak HF (2010) Heterogeneity of the tumor vasculature. Semin Thromb Hemost 36(3):321–331. doi: 10.1055/s-0030-1253454 PubMedCentralPubMedGoogle Scholar
  124. Nasman A, Andersson E, Marklund L, Tertipis N, Hammarstedt-Nordenvall L, Attner P, Nyberg T, Masucci GV, Munck-Wikland E, Ramqvist T, Dalianis T (2013a) HLA class I and II expression in oropharyngeal squamous cell carcinoma in relation to tumor HPV status and clinical outcome. PLoS ONE 8(10):e77025. doi: 10.1371/journal.pone.0077025 PubMedCentralPubMedGoogle Scholar
  125. Nasman A, Andersson E, Nordfors C, Grun N, Johansson H, Munck-Wikland E, Massucci G, Dalianis T, Ramqvist T (2013b) MHC class I expression in HPV positive and negative tonsillar squamous cell carcinoma in correlation to clinical outcome. Int J Cancer 132(1):72–81. doi: 10.1002/ijc.27635 PubMedGoogle Scholar
  126. Nasman A, Nordfors C, Grun N, Munck-Wikland E, Ramqvist T, Marklund L, Lindquist D, Dalianis T (2013c) Absent/weak CD44 intensity and positive human papillomavirus (HPV) status in oropharyngeal squamous cell carcinoma indicates a very high survival. Cancer Med 2(4):507–518. doi: 10.1002/cam4.90 PubMedCentralPubMedGoogle Scholar
  127. Nasman A, Romanitan M, Nordfors C, Grun N, Johansson H, Hammarstedt L, Marklund L, Munck-Wikland E, Dalianis T, Ramqvist T (2012) Tumor infiltrating CD8+ and Foxp3+ lymphocytes correlate to clinical outcome and human papillomavirus (HPV) status in tonsillar cancer. PLoS ONE 7(6):e38711. doi: 10.1371/journal.pone.0038711 PubMedCentralPubMedGoogle Scholar
  128. NCCN (2013) Head and neck cancer clinical practice guidelinesGoogle Scholar
  129. Nguyen-Tan PF, Pajak TF, Wheeler R (2010) A phase III trial to test accelerated versus standard fractionation in combination with concurrent cisplatin for head and neck carcinomas (RTOG 0129): report of efficacy and toxicity. Multidisciplinary head and neck cancer symposium. Chandler ArizonaGoogle Scholar
  130. Nichols AC, Faquin WC, Westra WH, Mroz EA, Begum S, Clark JR, Rocco JW (2009) HPV-16 infection predicts treatment outcome in oropharyngeal squamous cell carcinoma. Otolaryngol Head Neck Surg 140(2):228–234. doi:S0194-5998(08)01618-5 [pii]  10.1016/j.otohns.2008.11.025
  131. Nichols AC, Finkelstein DM, Faquin WC, Westra WH, Mroz EA, Kneuertz P, Begum S, Michaud WA, Busse PM, Clark JR, Rocco JW (2010) Bcl2 and human papilloma virus 16 as predictors of outcome following concurrent chemoradiation for advanced oropharyngeal cancer. Clin Cancer Res 16(7):2138–2146. doi: 10.1158/1078-0432.CCR-09-3185 PubMedGoogle Scholar
  132. Nordfors C, Grun N, Tertipis N, Ahrlund-Richter A, Haeggblom L, Sivars L, Du J, Nyberg T, Marklund L, Munck-Wikland E, Nasman A, Ramqvist T, Dalianis T (2013) CD8+ and CD4+ tumour infiltrating lymphocytes in relation to human papillomavirus status and clinical outcome in tonsillar and base of tongue squamous cell carcinoma. Eur J Cancer 49(11):2522–2530. doi: 10.1016/j.ejca.2013.03.019 PubMedGoogle Scholar
  133. Nutting CM, Morden JP, Harrington KJ, Urbano TG, Bhide SA, Clark C, Miles EA, Miah AB, Newbold K, Tanay M, Adab F, Jefferies SJ, Scrase C, Yap BK, A’Hern RP, Sydenham MA, Emson M, Hall E, group Ptm (2011) Parotid-sparing intensity modulated versus conventional radiotherapy in head and neck cancer (PARSPORT): a phase 3 multicentre randomised controlled trial. Lancet Oncol 12(2):127–136. doi: 10.1016/S1470-2045(10)70290-4 Google Scholar
  134. O’Rorke MA, Ellison MV, Murray LJ, Moran M, James J, Anderson LA (2012) Human papillomavirus related head and neck cancer survival: a systematic review and meta-analysis. Oral Oncol 48(12):1191–1201. doi: 10.1016/j.oraloncology.2012.06.019 PubMedGoogle Scholar
  135. O’Sullivan B, Huang SH, Siu LL, Waldron J, Zhao H, Perez-Ordonez B, Weinreb I, Kim J, Ringash J, Bayley A, Dawson LA, Hope A, Cho J, Irish J, Gilbert R, Gullane P, Hui A, Liu FF, Chen E, Xu W (2013) Deintensification candidate subgroups in human papillomavirus-related oropharyngeal cancer according to minimal risk of distant metastasis. J Clin Oncol 31(5):543–550. doi: 10.1200/JCO.2012.44.0164 PubMedGoogle Scholar
  136. Obeid M, Panaretakis T, Joza N, Tufi R, Tesniere A, van Endert P, Zitvogel L, Kroemer G (2007) Calreticulin exposure is required for the immunogenicity of gamma-irradiation and UVC light-induced apoptosis. Cell Death Differ 14(10):1848–1850. doi: 10.1038/sj.cdd.4402201 PubMedGoogle Scholar
  137. Overgaard J, Eriksen JG, Nordsmark M, Alsner J, Horsman MR, Danish H, Neck Cancer Study G (2005) 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 6(10):757–764. doi: 10.1016/S1470-2045(05)70292-8 Google Scholar
  138. Overgaard J, Hansen HS, Specht L, Overgaard M, Grau C, Andersen E, Bentzen J, Bastholt L, Hansen O, Johansen J, Andersen L, Evensen JF (2003) 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 362(9388):933–940PubMedGoogle Scholar
  139. Pala M, Odrazka K, Holeckova P, Vitek P, Kubes J, Dvorak J, Podlesak T (2012) Definitive radiochemotherapy with weekly cisplatin in patients with head and neck cancer; single institution outcome analysis. J Buon 17(3):471–477PubMedGoogle Scholar
  140. Pang E, Delic NC, Hong A, Zhang M, Rose BR, Lyons JG (2011) Radiosensitization of oropharyngeal squamous cell carcinoma cells by human papillomavirus 16 oncoprotein E6*I. Int J Radiat Oncol Biol Phys 79(3):860–865. doi: 10.1016/j.ijrobp.2010.06.028 PubMedGoogle Scholar
  141. Petrelli F, Sarti E, Barni S (2014) Predictive value of human papillomavirus in oropharyngeal carcinoma treated with radiotherapy: an updated systematic review and meta-analysis of 30 trials. Head Neck 36(5):750–759. doi: 10.1002/hed.23351 PubMedGoogle Scholar
  142. Pilones KA, Kawashima N, Yang AM, Babb JS, Formenti SC, Demaria S (2009) Invariant natural killer T cells regulate breast cancer response to radiation and CTLA-4 blockade. Clin Cancer Res 15(2):597–606. doi: 10.1158/1078-0432.CCR-08-1277 PubMedCentralPubMedGoogle Scholar
  143. Plummer R, Stephens P, Aissat-Daudigny L, Cambois A, Moachon G, Brown PD, Campone M (2014) Phase 1 dose-escalation study of the PARP inhibitor CEP-9722 as monotherapy or in combination with temozolomide in patients with solid tumors. Cancer Chemother Pharmacol. doi: 10.1007/s00280-014-2486-9 Google Scholar
  144. Posner MR, Lorch JH, Goloubeva O, Tan M, Schumaker LM, Sarlis NJ, Haddad RI, Cullen KJ (2011) Survival and human papillomavirus in oropharynx cancer in TAX 324: a subset analysis from an international phase III trial. Ann Oncol 22(5):1071–1077. doi: 10.1093/annonc/mdr006 PubMedCentralPubMedGoogle Scholar
  145. Postow MA, Callahan MK, Barker CA, Yamada Y, Yuan J, Kitano S, Mu Z, Rasalan T, Adamow M, Ritter E, Sedrak C, Jungbluth AA, Chua R, Yang AS, Roman RA, Rosner S, Benson B, Allison JP, Lesokhin AM, Gnjatic S, Wolchok JD (2012) Immunologic correlates of the abscopal effect in a patient with melanoma. N Engl J Med 366(10):925–931. doi: 10.1056/NEJMoa1112824 PubMedCentralPubMedGoogle Scholar
  146. Pryor DI, Porceddu SV, Burmeister BH, Guminski A, Thomson DB, Shepherdson K, Poulsen M (2009) Enhanced toxicity with concurrent cetuximab and radiotherapy in head and neck cancer. Radiother Oncol 90(2):172–176. doi: 10.1016/j.radonc.2008.09.018 PubMedGoogle Scholar
  147. Ragin CC, Taioli E (2007) Survival of squamous cell carcinoma of the head and neck in relation to human papillomavirus infection: review and meta-analysis. Int J Cancer 121(8):1813–1820. doi: 10.1002/ijc.22851 PubMedGoogle Scholar
  148. Rahimi AS, Wilson DD, Saylor DK, Stelow EB, Thomas CY, Reibel JF, Levine PA, Shonka DC, Jameson MJ, Read PW (2012) p16, Cyclin D1, and HIF-1alpha predict outcomes of patients with oropharyngeal squamous cell carcinoma treated with definitive intensity-modulated radiation therapy. Int J Otolaryngol 2012:685951. doi: 10.1155/2012/685951 PubMedCentralPubMedGoogle Scholar
  149. Rampias T, Sasaki C, Weinberger P, Psyrri A (2009) E6 and e7 gene silencing and transformed phenotype of human papillomavirus 16-positive oropharyngeal cancer cells. J Natl Cancer Inst 101(6):412–423. doi: 10.1093/jnci/djp017 PubMedGoogle Scholar
  150. Reimers N, Kasper HU, Weissenborn SJ, Stutzer H, Preuss SF, Hoffmann TK, Speel EJ, Dienes HP, Pfister HJ, Guntinas-Lichius O, Klussmann JP (2007) Combined analysis of HPV-DNA, p16 and EGFR expression to predict prognosis in oropharyngeal cancer. Int J Cancer 120(8):1731–1738. doi: 10.1002/ijc.22355 PubMedGoogle Scholar
  151. Rieckmann T, Tribius S, Grob TJ, Meyer F, Busch CJ, Petersen C, Dikomey E, Kriegs M (2013) HNSCC cell lines positive for HPV and p16 possess higher cellular radiosensitivity due to an impaired DSB repair capacity. Radiother Oncol 107(2):242–246. doi: 10.1016/j.radonc.2013.03.013 PubMedGoogle Scholar
  152. Rietbergen MM, Martens-de Kemp SR, Bloemena E, Witte BI, Brink A, Baatenburg de Jong RJ, Leemans CR, Braakhuis BJ, Brakenhoff RH (2014) Cancer stem cell enrichment marker CD98: a prognostic factor for survival in patients with human papillomavirus-positive oropharyngeal cancer. Eur J Cancer 50(4):765–773. doi: 10.1016/j.ejca.2013.11.010 PubMedGoogle Scholar
  153. Rischin D, Young RJ, Fisher R, Fox SB, Le QT, Peters LJ, Solomon B, Choi J, O’Sullivan B, Kenny LM, McArthur GA (2010) Prognostic significance of p16INK4A and human papillomavirus in patients with oropharyngeal cancer treated on TROG 02.02 phase III trial. J Clin Oncol 28(27):4142–4148. doi:JCO.2010.29.2904 [pii]  10.1200/JCO.2010.29.2904
  154. Ritchie JM, Smith EM, Summersgill KF, Hoffman HT, Wang D, Klussmann JP, Turek LP, Haugen TH (2003) Human papillomavirus infection as a prognostic factor in carcinomas of the oral cavity and oropharynx. Int J Cancer 104(3):336–344. doi: 10.1002/ijc.10960 PubMedGoogle Scholar
  155. Rosenthal DI, Harari PM, Giralt J, Bell D, Raben D, Liu J, Schulten J, Ang KK, Bonner JA (2014) Impact of p16 status on the results of the phase III cetuximab (cet)/radiotherapy (RT). J Clin Oncol 32(5s):(suppl; abstr 6001)Google Scholar
  156. Ross L, Petersen MA, Johnsen AT, Lundstroem LH, Carlsen K, Groenvold M (2012) Factors associated with Danish cancer patients’ return to work. A report from the population-based study ‘The Cancer Patient’s World’. Cancer epidemiology 36(2):222–229. doi: 10.1016/j.canep.2011.06.001 PubMedGoogle Scholar
  157. Schwartz SR, Yueh B, McDougall JK, Daling JR, Schwartz SM (2001) Human papillomavirus infection and survival in oral squamous cell cancer: a population-based study. Otolaryngol Head Neck Surg 125(1):1–9. doi: 10.1067/mhn.2001.116979 PubMedGoogle Scholar
  158. Sedaghat AR, Zhang Z, Begum S, Palermo R, Best S, Ulmer KM, Levine M, Zinreich E, Messing BP, Gold D, Wu AA, Niparko KJ, Kowalski J, Hirata RM, Saunders JR, Westra WH, Pai SI (2009) Prognostic significance of human papillomavirus in oropharyngeal squamous cell carcinomas. Laryngoscope 119(8):1542–1549. doi: 10.1002/lary.20533 PubMedGoogle Scholar
  159. Seiwert T, Fayette J, Cupissol D (2012) A randomized, open-label, phase II study of afatinib (BIBW 2992) versus cetuximab in recurrent or metastatic squamous cell carcinoma of the head and neck: final data. In: Multidisciplinary head and neck cancer symposium, Phoenix, AZ, 26 Jan 2012Google Scholar
  160. Sewell A, Brown B, Biktasova A, Mills GB, Lu Y, Tyson DR, Issaeva N, Yarbrough WG (2014) Reverse-phase protein array profiling of oropharyngeal cancer and significance of PIK3CA mutations in HPV-associated head and neck cancer. Clin Cancer Res 20(9):2300–2311. doi: 10.1158/1078-0432.CCR-13-2585 PubMedCentralPubMedGoogle Scholar
  161. Slebos RJ, Jehmlich N, Brown B, Yin Z, Chung CH, Yarbrough WG, Liebler DC (2013) Proteomic analysis of oropharyngeal carcinomas reveals novel HPV-associated biological pathways. Int J Cancer 132(3):568–579. doi: 10.1002/ijc.27699 PubMedCentralPubMedGoogle Scholar
  162. Smith EM, Pawlita M, Rubenstein LM, Haugen TH, Hamsikova E, Turek LP (2010) Risk factors and survival by HPV-16 E6 and E7 antibody status in human papillomavirus positive head and neck cancer. Int J Cancer 127(1):111–117. doi: 10.1002/ijc.25015 PubMedGoogle Scholar
  163. Sorensen BS, Busk M, Olthof N, Speel EJ, Horsman MR, Alsner J, Overgaard J (2013) Radiosensitivity and effect of hypoxia in HPV positive head and neck cancer cells. Radiother Oncol 108(3):500–505. doi: 10.1016/j.radonc.2013.06.011 PubMedGoogle Scholar
  164. Spanos WC, Geiger J, Anderson ME, Harris GF, Bossler AD, Smith RB, Klingelhutz AJ, Lee JH (2008) Deletion of the PDZ motif of HPV16 E6 preventing immortalization and anchorage-independent growth in human tonsil epithelial cells. Head Neck 30(2):139–147. doi: 10.1002/hed.20673 PubMedCentralPubMedGoogle Scholar
  165. Spanos WC, Nowicki P, Lee DW, Hoover A, Hostager B, Gupta A, Anderson ME, Lee JH (2009) Immune response during therapy with cisplatin or radiation for human papillomavirus-related head and neck cancer. Arch Otolaryngol Head Neck Surg 135(11):1137–1146. doi: 10.1001/archoto.2009.159 PubMedGoogle Scholar
  166. Stamell EF, Wolchok JD, Gnjatic S, Lee NY, Brownell I (2013) The abscopal effect associated with a systemic anti-melanoma immune response. Int J Radiat Oncol Biol Phys 85(2):293–295. doi: 10.1016/j.ijrobp.2012.03.017 PubMedCentralPubMedGoogle Scholar
  167. Stein AP, Saha S, Yu M, Kimple RJ, Lambert PF (2014) Prevalence of human papillomavirus in oropharyngeal squamous cell carcinoma in the United States across time. Chem Res Toxicol 27(4):462–469. doi: 10.1021/tx500034c PubMedCentralPubMedGoogle Scholar
  168. Strauss L, Bergmann C, Gooding W, Johnson JT, Whiteside TL (2007) The frequency and suppressor function of CD4+ CD25highFoxp3+ T cells in the circulation of patients with squamous cell carcinoma of the head and neck. Clin Cancer Res 13(21):6301–6311. doi: 10.1158/1078-0432.CCR-07-1403 PubMedGoogle Scholar
  169. Strome SE, Savva A, Brissett AE, Gostout BS, Lewis J, Clayton AC, McGovern R, Weaver AL, Persing D, Kasperbauer JL (2002) Squamous cell carcinoma of the tonsils: a molecular analysis of HPV associations. Clin Cancer Res 8(4):1093–1100PubMedGoogle Scholar
  170. Strumberg D, Brugge S, Korn MW, Koeppen S, Ranft J, Scheiber G, Reiners C, Mockel C, Seeber S, Scheulen ME (2002) Evaluation of long-term toxicity in patients after cisplatin-based chemotherapy for non-seminomatous testicular cancer. Ann Oncol 13(2):229–236PubMedGoogle Scholar
  171. Suh Y, Amelio I, Guerrero Urbano T, Tavassoli M (2014) Clinical update on cancer: molecular oncology of head and neck cancer. Cell Death Dis 5:e1018. doi: 10.1038/cddis.2013.548 PubMedCentralPubMedGoogle Scholar
  172. Tai X, Van Laethem F, Pobezinsky L, Guinter T, Sharrow SO, Adams A, Granger L, Kruhlak M, Lindsten T, Thompson CB, Feigenbaum L, Singer A (2012) Basis of CTLA-4 function in regulatory and conventional CD4(+) T cells. Blood 119(22):5155–5163. doi: 10.1182/blood-2011-11-388918 PubMedCentralPubMedGoogle Scholar
  173. Toustrup K, Sorensen BS, Lassen P, Wiuf C, Alsner J, Overgaard J, Danish H, Neck Cancer G (2012) Gene expression classifier predicts for hypoxic modification of radiotherapy with nimorazole in squamous cell carcinomas of the head and neck. Radiother Oncol 102(1):122–129. doi: 10.1016/j.radonc.2011.09.010 PubMedGoogle Scholar
  174. Tseng CW, Trimble C, Zeng Q, Monie A, Alvarez RD, Huh WK, Hoory T, Wang MC, Hung CF, Wu TC (2009) Low-dose radiation enhances therapeutic HPV DNA vaccination in tumor-bearing hosts. Cancer Immunol Immunother 58(5):737–748. doi: 10.1007/s00262-008-0596-0 PubMedCentralPubMedGoogle Scholar
  175. Turksma AW, Bontkes HJ, van den Heuvel H, de Gruijl TD, von Blomberg BM, Braakhuis BJ, Leemans CR, Bloemena E, Meijer CJ, Hooijberg E (2013) Effector memory T-cell frequencies in relation to tumour stage, location and HPV status in HNSCC patients. Oral Dis 19(6):577–584. doi: 10.1111/odi.12037 PubMedGoogle Scholar
  176. Ukpo OC, Thorstad WL, Lewis JS Jr (2013) B7-H1 expression model for immune evasion in human papillomavirus-related oropharyngeal squamous cell carcinoma. Head Neck Pathol 7(2):113–121. doi: 10.1007/s12105-012-0406-z PubMedCentralPubMedGoogle Scholar
  177. van den Belt-Dusebout AW, de Wit R, Gietema JA, Horenblas S, Louwman MW, Ribot JG, Hoekstra HJ, Ouwens GM, Aleman BM, van Leeuwen FE (2007) Treatment-specific risks of second malignancies and cardiovascular disease in 5-year survivors of testicular cancer. J Clin Oncol 25(28):4370–4378. doi: 10.1200/JCO.2006.10.5296 PubMedGoogle Scholar
  178. Vereecque R, Buffenoir G, Gonzalez R, Cambier N, Hetuin D, Bauters F, Fenaux P, Quesnel B (2000) gamma-ray irradiation induces B7.1 expression in myeloid leukaemic cells. Br J Haematol 108(4):825–831PubMedGoogle Scholar
  179. Vermeer DW, Spanos WC, Vermeer PD, Bruns AM, Lee KM, Lee JH (2013) Radiation-induced loss of cell surface CD47 enhances immune-mediated clearance of human papillomavirus-positive cancer. Int J Cancer 133(1):120–129. doi: 10.1002/ijc.28015 PubMedCentralPubMedGoogle Scholar
  180. Vermorken JB, Psyrri A, Mesia R, Peyrade F, Beier F, de Blas B, Celik I, Licitra L (2014) Impact of tumor HPV status on outcome in patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck receiving chemotherapy with or without cetuximab: retrospective analysis of the phase III EXTREME trial. Ann Oncol 25(4):801–807. doi: 10.1093/annonc/mdt574 PubMedCentralPubMedGoogle Scholar
  181. Vermorken JB, Rottey S, Ehrnrooth E, Pelling K, Lahogue A, Wind S, Machiels JP (2013) A phase Ib, open-label study to assess the safety of continuous oral treatment with afatinib in combination with two chemotherapy regimens: cisplatin plus paclitaxel and cisplatin plus 5-fluorouracil, in patients with advanced solid tumors. Ann Oncol 24(5):1392–1400. doi: 10.1093/annonc/mds633 PubMedGoogle Scholar
  182. Walsh L, Gillham C, Dunne M, Fraser I, Hollywood D, Armstrong J, Thirion P (2011) Toxicity of cetuximab versus cisplatin concurrent with radiotherapy in locally advanced head and neck squamous cell cancer (LAHNSCC). Radiother Oncol 98(1):38–41. doi: 10.1016/j.radonc.2010.11.009 PubMedGoogle Scholar
  183. Ward MJ, Thirdborough SM, Mellows T, Riley C, Harris S, Suchak K, Webb A, Hampton C, Patel NN, Randall CJ, Cox HJ, Jogai S, Primrose J, Piper K, Ottensmeier CH, King EV, Thomas GJ (2014) Tumour-infiltrating lymphocytes predict for outcome in HPV-positive oropharyngeal cancer. Br J Cancer 110(2):489–500. doi: 10.1038/bjc.2013.639 PubMedCentralPubMedGoogle Scholar
  184. Watanabe Y, Katou F, Ohtani H, Nakayama T, Yoshie O, Hashimoto K (2010) Tumor-infiltrating lymphocytes, particularly the balance between CD8(+) T cells and CCR4(+) regulatory T cells, affect the survival of patients with oral squamous cell carcinoma. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 109(5):744–752. doi: 10.1016/j.tripleo.2009.12.015 PubMedGoogle Scholar
  185. Weinberger PM, Yu Z, Haffty BG, Kowalski D, Harigopal M, Sasaki C, Rimm DL, Psyrri A (2004) Prognostic significance of p16 protein levels in oropharyngeal squamous cell cancer. Clin Cancer Res 10(17):5684–5691. doi: 10.1158/1078-0432.CCR-04-0448 PubMedGoogle Scholar
  186. Withers HR, Taylor JM, Maciejewski B (1988) The hazard of accelerated tumor clonogen repopulation during radiotherapy. Acta Oncol 27(2):131–146PubMedGoogle Scholar
  187. Xie X, Piao L, Bullock BN, Smith A, Su T, Zhang M, Teknos TN, Arora PS, Pan Q (2014) Targeting HPV16 E6-p300 interaction reactivates p53 and inhibits the tumorigenicity of HPV-positive head and neck squamous cell carcinoma. Oncogene 33(8):1037–1046. doi: 10.1038/onc.2013.25 PubMedCentralPubMedGoogle Scholar
  188. Yang W, Song Y, Lu YL, Sun JZ, Wang HW (2013) Increased expression of programmed death (PD)-1 and its ligand PD-L1 correlates with impaired cell-mediated immunity in high-risk human papillomavirus-related cervical intraepithelial neoplasia. Immunology 139(4):513–522. doi: 10.1111/imm.12101 PubMedCentralPubMedGoogle Scholar
  189. Ye AY, Hay JH, Laskin JJ, Wu JS, Ho CC (2013) Toxicity and outcomes in combined modality treatment of head and neck squamous cell carcinoma: cisplatin versus cetuximab. J Cancer Res Ther 9(4):607–612. doi: 10.4103/0973-1482.126455 PubMedGoogle Scholar
  190. Young RJ, Rischin D, Fisher R, McArthur GA, Fox SB, Peters LJ, Corry J, Lim A, Waldeck K, Solomon B (2011) Relationship between epidermal growth factor receptor status, p16(INK4A), and outcome in head and neck squamous cell carcinoma. Cancer Epidemiol Biomarkers Prev 20(6):1230–1237. doi: 10.1158/1055-9965.EPI-10-1262 PubMedGoogle Scholar
  191. Zache N, Lambert JM, Wiman KG, Bykov VJ (2008) PRIMA-1MET inhibits growth of mouse tumors carrying mutant p53. Cellular Oncol: the official journal of the International Society for Cellular Oncology 30(5):411–418Google Scholar

Copyright information

© Springer International Publishing Switzerland 2015

Authors and Affiliations

  • Anna-Maria De Costa
    • 1
  • Thorsten Rieckmann
    • 2
  • Randall J. Kimple
    • 1
    Email author
  1. 1.Department of Human Oncology, Carbone Comprehensive Cancer Center, School of Medicine and Public HealthUniversity of WisconsinMadisonUSA
  2. 2.Department of Otolaryngology, Laboratory for Radiobiology and Experimental Radiation OncologyUniversity Medical Center Hamburg EppendorfHamburgGermany

Personalised recommendations