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The role of human papillomavirus on the prognosis and treatment of oropharyngeal carcinoma

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Abstract

Human papillomavirus positive oropharyngeal cancer (HPV-positive OPC) is a distinct subtype of head and neck carcinoma (HNC) distinguished from HPV-negative HNC by its risk factor profile, clinical behavior, and molecular biology. Compared to HPV-negative HNC, HPV-positive OPC exhibits significantly better prognosis and an enhanced response to treatment. Recognition of the survival benefit of HPV-positive tumors has led to therapeutic de-intensification strategies aiming to mitigate treatment-related toxicities while maintaining high response rates. In this review, we summarize key aspects of oral HPV infection and the molecular mechanisms of HPV-related carcinogenesis. We review the clinical and molecular characteristics of HPV-positive OPC that contribute to its improved prognosis compared to HPV-negative HNC. We also discuss current and emerging treatment strategies, emphasizing potential mechanisms of treatment sensitivity and the role of therapeutic de-intensification in HPV-positive OPC. Lastly, we examine literature on the management and prognosis of recurrent/metastatic HPV-positive OPC with a focus on the role of salvage surgery in its management.

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References

  1. Torre, L. A., Bray, F., Siegel, R. L., Ferlay, J., Lortet-Tieulent, J., & Jemal, A. (2015). Global cancer statistics, 2012. CA: a Cancer Journal for Clinicians, 65(2), 87–108. doi:10.3322/caac.21262.

    Google Scholar 

  2. Siegel, R. L., Miller, K. D., & Jemal, A. (2016). Cancer statistics, 2016. CA: a Cancer Journal for Clinicians, 66(1), 7–30. doi:10.3322/caac.21332.

    Google Scholar 

  3. Parkin, D. M., Bray, F., Ferlay, J., & Pisani, P. (2005). Global cancer statistics, 2002. CA: a Cancer Journal for Clinicians, 55(2), 74–108.

    Google Scholar 

  4. Ferlay, J., Soerjomataram, I., Dikshit, R., Eser, S., Mathers, C., Rebelo, M., et al. (2015). Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. International Journal of Cancer, 136(5), E359–E386. doi:10.1002/ijc.29210.

    Article  CAS  PubMed  Google Scholar 

  5. Shield, K. D., Ferlay, J., Jemal, A., Sankaranarayanan, R., Chaturvedi, A. K., Bray, F., et al. (2017). The global incidence of lip, oral cavity, and pharyngeal cancers by subsite in 2012. CA: a Cancer Journal for Clinicians, 67(1), 51–64. doi:10.3322/caac.21384.

    Google Scholar 

  6. Cancer, A. J. C. o (2017). AJCC cancer staging manual. Springer.

  7. Do, K. A., Johnson, M. M., Doherty, D. A., Lee, J. J., Wu, X. F., Dong, Q., et al. (2003). Second primary tumors in patients with upper aerodigestive tract cancers: joint effects of smoking and alcohol (United States). Cancer Causes & Control, 14(2), 131–138.

    Article  Google Scholar 

  8. Blot, W. J., McLaughlin, J. K., Winn, D. M., Austin, D. F., Greenberg, R. S., Preston-Martin, S., et al. (1988). Smoking and drinking in relation to oral and pharyngeal cancer. Cancer Research, 48(11), 3282–3287.

    CAS  PubMed  Google Scholar 

  9. IARC Working Group on the Evaluation of Carcinogenic Risks to Humans. Meeting (2004: Lyon, F., & Cancer., I. A. f. R. o. (2007). Smokeless tobacco and some tobacco-specific N-nitrosamines. 626.

  10. Dal Maso, L., Torelli, N., Biancotto, E., Di Maso, M., Gini, A., Franchin, G., et al. (2016). Combined effect of tobacco smoking and alcohol drinking in the risk of head and neck cancers: a re-analysis of case-control studies using bi-dimensional spline models. European Journal of Epidemiology, 31(4), 385–393. doi:10.1007/s10654-015-0028-3.

    Article  CAS  PubMed  Google Scholar 

  11. Sturgis, E. M., & Cinciripini, P. M. (2007). Trends in head and neck cancer incidence in relation to smoking prevalence: an emerging epidemic of human papillomavirus-associated cancers? Cancer, 110(7), 1429–1435. doi:10.1002/cncr.22963.

    Article  PubMed  Google Scholar 

  12. Marur, S., D'Souza, G., Westra, W. H., & Forastiere, A. A. (2010). HPV-associated head and neck cancer: a virus-related cancer epidemic. The Lancet Oncology, 11(8), 781–789. doi:10.1016/S1470-2045(10)70017-6.

    Article  PubMed  PubMed Central  Google Scholar 

  13. de Sanjose, S., Quint, W. G., Alemany, L., Geraets, D. T., Klaustermeier, J. E., Lloveras, B., et al. (2010). Human papillomavirus genotype attribution in invasive cervical cancer: a retrospective cross-sectional worldwide study. The Lancet Oncology, 11, 1048–1056. doi:10.1016/S1470-2045(10)70230-8.

    Article  PubMed  CAS  Google Scholar 

  14. D’Souza, G., Kreimer, A. R., Viscidi, R., Pawlita, M., Fakhry, C., Koch, W. M., et al. (2007). Case–control study of human papillomavirus and oropharyngeal cancer. New England Journal of Medicine, 356, 1944–1956. doi:10.1056/NEJMoa065497.

    Article  PubMed  Google Scholar 

  15. Kreimer, A. R., Clifford, G. M., Boyle, P., & Franceschi, S. (2005). Human papillomavirus types in head and neck squamous cell carcinomas worldwide: a systematic review. Cancer Epidemiology, Biomarkers & Prevention, 14(2), 467–475. doi:10.1158/1055-9965.EPI-04-0551.

    Article  CAS  Google Scholar 

  16. Ndiaye, C., Mena, M., Alemany, L., Arbyn, M., Castellsagué, X., Laporte, L., et al. (2014). HPV DNA, E6/E7 mRNA, and p16INK4a detection in head and neck cancers: a systematic review and meta-analysis. The Lancet Oncology, 15, 1319–1331. doi:10.1016/S1470-2045(14)70471-1.

    Article  CAS  PubMed  Google Scholar 

  17. Gillison, M. L., Koch, W. M., Capone, R. B., Spafford, M., Westra, W. H., Wu, L., et al. (2000). Evidence for a causal association between human papillomavirus and a subset of head and neck cancers. Journal of the National Cancer Institute, 92(9), 709–720.

    Article  CAS  PubMed  Google Scholar 

  18. Gillison, M. L., D’Souza, G., Westra, W., Sugar, E., Xiao, W., Begum, S., et al. (2008). Distinct risk factor profiles for human papillomavirus type 16-positive and human papillomavirus type 16-negative head and neck cancers. Journal of the National Cancer Institute, 100, 407–420. doi:10.1093/jnci/djn025.

    Article  PubMed  Google Scholar 

  19. Schwartz, S. M., Daling, J. R., Doody, D. R., Wipf, G. C., Carter, J. J., Madeleine, M. M., et al. (1998). Oral cancer risk in relation to sexual history and evidence of human papillomavirus infection. Journal of the National Cancer Institute, 90, 1626–1636.

    Article  CAS  PubMed  Google Scholar 

  20. Applebaum, K. M., Furniss, C. S., Zeka, A., Posner, M. R., Smith, J. F., Bryan, J., et al. (2007). Lack of association of alcohol and tobacco with HPV16-associated head and neck cancer. Journal of the National Cancer Institute, 99, 1801–1810. doi:10.1093/jnci/djm233.

    Article  PubMed  Google Scholar 

  21. Smith, E. M., Ritchie, J. M., Summersgill, K. F., Hoffman, H. T., Wang, D. H., Haugen, T. H., et al. (2004). Human papillomavirus in oral exfoliated cells and risk of head and neck cancer. Journal of the National Cancer Institute, 96, 449–455.

    Article  PubMed  Google Scholar 

  22. D’Souza, G., Westra, W. H., Wang, S. J., van Zante, A., Wentz, A., Kluz, N., et al. (2016). Differences in the prevalence of human papillomavirus (HPV) in head and neck squamous cell cancers by sex, race, anatomic tumor site, and HPV detection method. JAMA Oncology. doi:10.1001/jamaoncol.2016.3067.

  23. Sun, C., Bennett, N., Tran, P., Tang, K., Lim, Y., Frazer, I., et al. (2017). A pilot study into the association between oral health status and human papillomavirus—16 infection. Diagnostic, 7, 11. doi:10.3390/diagnostics7010011.

    Article  Google Scholar 

  24. Anantharaman, D., Muller, D. C., Lagiou, P., Ahrens, W., Holcatova, I., Merletti, F., et al. (2016). Combined effects of smoking and HPV16 in oropharyngeal cancer. International Journal of Epidemiology, 45(3), 752–761. doi:10.1093/ije/dyw069.

    Article  PubMed  Google Scholar 

  25. Smith, E. M., Rubenstein, L. M., Haugen, T. H., Pawlita, M., & Turek, L. P. (2012). Complex etiology underlies risk and survival in head and neck cancer human papillomavirus, tobacco, and alcohol: a case for multifactor disease. Journal of Oncology, 2012, 1–9. doi:10.1155/2012/571862.

    Article  Google Scholar 

  26. Seiwert, T. Y., Zuo, Z., Keck, M. K., Khattri, A., Pedamallu, C. S., Stricker, T., et al. (2015). Integrative and comparative genomic analysis of HPV-positive and HPV-negative head and neck squamous cell carcinomas. Clinical Cancer Research, 21, 632–641. doi:10.1158/1078-0432.CCR-13-3310.

    Article  CAS  PubMed  Google Scholar 

  27. Biron, V. L., Mohamed, A., Hendzel, M. J., Alan Underhill, D., & Seikaly, H. (2012). Epigenetic differences between human papillomavirus-positive and -negative oropharyngeal squamous cell carcinomas. Journal of otolaryngology - head & neck surgery = Le Journal d'oto-rhino-laryngologie et de chirurgie cervico-faciale, 41(Suppl 1), S65–S70.

    Google Scholar 

  28. Lawrence, M. S., Sougnez, C., Lichtenstein, L., Cibulskis, K., Lander, E., Gabriel, S. B., et al. (2015). Comprehensive genomic characterization of head and neck squamous cell carcinomas. Nature, 517, 576–582. doi:10.1038/nature14129.

    Article  CAS  Google Scholar 

  29. Argiris, A., Li, S., Ghebremichael, M., Egloff, A. M., Wang, L., Forastiere, A. A., et al. (2014). Prognostic significance of human papillomavirus in recurrent or metastatic head and neck cancer: an analysis of Eastern Cooperative Oncology Group trials. Annals of Oncology, 25(7), 1410–1416. doi:10.1093/annonc/mdu167.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Fakhry, C., Westra, W. H., Li, S., Cmelak, A., Ridge, J. A., Pinto, H., et al. (2008). Improved survival of patients with human papillomavirus-positive head and neck squamous cell carcinoma in a prospective clinical trial. Journal of the National Cancer Institute, 100(4), 261–269. doi:10.1093/jnci/djn011.

    Article  CAS  PubMed  Google Scholar 

  31. Ang, K. K., Harris, J., Wheeler, R., Weber, R., Rosenthal, D. I., Nguyen-Tân, P. F., et al. (2010). Human papillomavirus and survival of patients with oropharyngeal cancer. New England Journal of Medicine, 363, 24–35. doi:10.1056/NEJMoa0912217.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Nguyen-Tan, P. F., Zhang, Q., Ang, K. K., Weber, R. S., Rosenthal, D. I., Soulieres, D., et al. (2014). Randomized phase III trial to test accelerated versus standard fractionation in combination with concurrent cisplatin for head and neck carcinomas in the radiation therapy oncology group 0129 trial: long-term report of efficacy and toxicity. Journal of Clinical Oncology, 32(34), 3858–3866. doi:10.1200/JCO.2014.55.3925.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Ward, M. J., Thirdborough, S. M., Mellows, T., Riley, C., Harris, S., Suchak, K., et al. (2014). Tumour-infiltrating lymphocytes predict for outcome in HPV-positive oropharyngeal cancer. British Journal of Cancer, 110(2), 489–500. doi:10.1038/bjc.2013.639.

    Article  CAS  PubMed  Google Scholar 

  34. Chakravarthy, A., Henderson, S., Thirdborough, S. M., Ottensmeier, C. H., Su, X., Lechner, M., et al. (2016). Human papillomavirus drives tumor development throughout the head and neck: improved prognosis is associated with an immune response largely restricted to the oropharynx. Journal of Clinical Oncology, 34(34), 4132–4141.

    Article  PubMed  PubMed Central  Google Scholar 

  35. Wood, O., Woo, J., Seumois, G., Savelyeva, N., McCann, K. J., Singh, D., et al. (2016). Gene expression analysis of TIL rich HPV-driven head and neck tumors reveals a distinct B-cell signature when compared to HPV independent tumors. Oncotarget, 7, 56781–56797. doi:10.18632/oncotarget.10788.

    Article  PubMed  PubMed Central  Google Scholar 

  36. Ottensmeier, C. H., Perry, K. L., Harden, E. L., Stasakova, J., Jenei, V., Fleming, J., et al. (2016). Upregulated glucose metabolism correlates inversely with CD8+ t-cell infiltration and survival in squamous cell carcinoma. Cancer Research, 76(14), 4136–4148. doi:10.1158/0008-5472.CAN-15-3121.

    Article  CAS  PubMed  Google Scholar 

  37. Lesseur, C., Diergaarde, B., Olshan, A. F., Wunsch-Filho, V., Ness, A. R., Liu, G., et al. (2016). Genome-wide association analyses identify new susceptibility loci for oral cavity and pharyngeal cancer. Nature Genetics, 48(12), 1544–1550. doi:10.1038/ng.3685.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Westra, W. H., Taube, J. M., Poeta, M. L., Begum, S., Sidransky, D., & Koch, W. M. (2008). Inverse relationship between human papillomavirus-16 infection and disruptive p53 gene mutations in squamous cell carcinoma of the head and neck. Clinical Cancer Research, 14(2), 366–369. doi:10.1158/1078-0432.CCR-07-1402.

    Article  CAS  PubMed  Google Scholar 

  39. Cancer Genome Atlas, N. (2015). Comprehensive genomic characterization of head and neck squamous cell carcinomas. Nature, 517(7536), 576–582. doi:10.1038/nature14129.

    Article  CAS  Google Scholar 

  40. Zheng, Z. M., & Baker, C. C. (2006). Papillomavirus genome structure, expression, and post-transcriptional regulation. Frontiers in Bioscience, 11, 2286–2302.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Burd, E. M. (2003). Human papillomavirus and cervical cancer. Clinical Microbiology Reviews, 16(1), 1–17.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Howley, P. M. (1986). On human papillomaviruses. The New England Journal of Medicine, 315(17), 1089–1090. doi:10.1056/NEJM198610233151710.

    Article  CAS  PubMed  Google Scholar 

  43. Arbyn, M., de Sanjose, S., Saraiya, M., Sideri, M., Palefsky, J., Lacey, C., et al. (2012). EUROGIN 2011 roadmap on prevention and treatment of HPV-related disease. International Journal of Cancer, 131(9), 1969–1982. doi:10.1002/ijc.27650.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Roberts, J. N., Buck, C. B., Thompson, C. D., Kines, R., Bernardo, M., Choyke, P. L., et al. (2007). Genital transmission of HPV in a mouse model is potentiated by nonoxynol-9 and inhibited by carrageenan. Nature Medicine, 13(7), 857–861. doi:10.1038/nm1598.

    Article  CAS  PubMed  Google Scholar 

  45. Westra, W. H. (2012). The morphologic profile of HPV-related head and neck squamous carcinoma: implications for diagnosis, prognosis, and clinical management. Head and Neck Pathology, 6(Suppl 1), S48–S54. doi:10.1007/s12105-012-0371-6.

    Article  PubMed  Google Scholar 

  46. Doorbar, J. (2005). The papillomavirus life cycle. Journal of Clinical Virology, 32(Suppl 1), S7–15. doi:10.1016/j.jcv.2004.12.006.

    Article  CAS  PubMed  Google Scholar 

  47. Vinokurova, S., Wentzensen, N., Kraus, I., Klaes, R., Driesch, C., Melsheimer, P., et al. (2008). Type-dependent integration frequency of human papillomavirus genomes in cervical lesions. Cancer Research, 68(1), 307–313. doi:10.1158/0008-5472.CAN-07-2754.

    Article  CAS  PubMed  Google Scholar 

  48. Lim, M. Y., Dahlstrom, K. R., Sturgis, E. M., & Li, G. (2016). Human papillomavirus integration pattern and demographic, clinical, and survival characteristics of patients with oropharyngeal squamous cell carcinoma. Head & Neck, 38(8), 1139–1144. doi:10.1002/hed.24429.

    Article  Google Scholar 

  49. Jeon, S., Allen-Hoffmann, B. L., & Lambert, P. F. (1995). Integration of human papillomavirus type 16 into the human genome correlates with a selective growth advantage of cells. Journal of Virology, 69(5), 2989–2997.

    CAS  PubMed  PubMed Central  Google Scholar 

  50. Jeon, S., & Lambert, P. F. (1995). Integration of human papillomavirus type 16 DNA into the human genome leads to increased stability of E6 and E7 mRNAs: implications for cervical carcinogenesis. Proceedings of the National Academy of Sciences of the United States of America, 92(5), 1654–1658.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Akagi, K., Li, J., Broutian, T. R., Padilla-Nash, H., Xiao, W., Jiang, B., et al. (2014). Genome-wide analysis of HPV integration in human cancers reveals recurrent, focal genomic instability. Genome Research, 24(2), 185–199. doi:10.1101/gr.164806.113.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Sherman, L., Jackman, A., Itzhaki, H., Stoppler, M. C., Koval, D., & Schlegel, R. (1997). Inhibition of serum- and calcium-induced differentiation of human keratinocytes by HPV16 E6 oncoprotein: role of p53 inactivation. Virology, 237(2), 296–306. doi:10.1006/viro.1997.8778.

    Article  CAS  PubMed  Google Scholar 

  53. Scheffner, M., Werness, B. A., Huibregtse, J. M., Levine, A. J., & Howley, P. M. (1990). The E6 oncoprotein encoded by human papillomavirus types 16 and 18 promotes the degradation of p53. Cell, 63(6), 1129–1136.

    Article  CAS  PubMed  Google Scholar 

  54. Taylor, W. R., & Stark, G. R. (2001). Regulation of the G2/M transition by p53. Oncogene, 20(15), 1803–1815. doi:10.1038/sj.onc.1204252.

    Article  CAS  PubMed  Google Scholar 

  55. Boyer, S. N., Wazer, D. E., & Band, V. (1996). E7 protein of human papilloma virus-16 induces degradation of retinoblastoma protein through the ubiquitin-proteasome pathway. Cancer Research, 56(20), 4620–4624.

    CAS  PubMed  Google Scholar 

  56. Thomas, M., Pim, D., & Banks, L. (1999). The role of the E6-p53 interaction in the molecular pathogenesis of HPV. Oncogene, 18(53), 7690–7700. doi:10.1038/sj.onc.1202953.

    Article  CAS  PubMed  Google Scholar 

  57. Werness, B. A., Levine, A. J., & Howley, P. M. (1990). Association of human papillomavirus types 16 and 18 E6 proteins with p53. Science, 248(4951), 76–79.

    Article  CAS  PubMed  Google Scholar 

  58. Castellsague, X., Alemany, L., Quer, M., Halec, G., Quiros, B., Tous, S., et al. (2016). HPV involvement in head and neck cancers: comprehensive assessment of biomarkers in 3680 patients. J Natl Cancer Inst, 108(6), djv403. doi:10.1093/jnci/djv403.

    Article  PubMed  Google Scholar 

  59. Munger, K., Werness, B. A., Dyson, N., Phelps, W. C., Harlow, E., & Howley, P. M. (1989). Complex formation of human papillomavirus E7 proteins with the retinoblastoma tumor suppressor gene product. The EMBO Journal, 8(13), 4099–4105.

    CAS  PubMed  PubMed Central  Google Scholar 

  60. Barbosa, M. S., Edmonds, C., Fisher, C., Schiller, J. T., Lowy, D. R., & Vousden, K. H. (1990). The region of the HPV E7 oncoprotein homologous to adenovirus E1a and Sv40 large T antigen contains separate domains for Rb binding and casein kinase II phosphorylation. The EMBO Journal, 9(1), 153–160.

    CAS  PubMed  PubMed Central  Google Scholar 

  61. Serrano, M., Hannon, G. J., & Beach, D. (1993). A new regulatory motif in cell-cycle control causing specific inhibition of cyclin D/CDK4. Nature, 366(6456), 704–707. doi:10.1038/366704a0.

    Article  CAS  PubMed  Google Scholar 

  62. Ang, K. K., Harris, J., Wheeler, R., Weber, R., Rosenthal, D. I., Nguyen-Tan, P. F., et al. (2010). Human papillomavirus and survival of patients with oropharyngeal cancer. The New England Journal of Medicine, 363(1), 24–35. doi:10.1056/NEJMoa0912217.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Chung, C. H., Zhang, Q., Kong, C. S., Harris, J., Fertig, E. J., Harari, P. M., et al. (2014). p16 protein expression and human papillomavirus status as prognostic biomarkers of nonoropharyngeal head and neck squamous cell carcinoma. Journal of Clinical Oncology, 32(35), 3930–3938. doi:10.1200/JCO.2013.54.5228.

    Article  PubMed  PubMed Central  Google Scholar 

  64. Egawa, N., Egawa, K., Griffin, H., & Doorbar, J. (2015). Human papillomaviruses; epithelial tropisms, and the development of neoplasia. Virus, 7(7), 3863–3890. doi:10.3390/v7072802.

    Article  CAS  Google Scholar 

  65. Haller, O., Kochs, G., & Weber, F. (2006). The interferon response circuit: induction and suppression by pathogenic viruses. Virology, 344(1), 119–130. doi:10.1016/j.virol.2005.09.024.

    Article  CAS  PubMed  Google Scholar 

  66. Nees, M., Geoghegan, J. M., Hyman, T., Frank, S., Miller, L., & Woodworth, C. D. (2001). Papillomavirus type 16 oncogenes downregulate expression of interferon-responsive genes and upregulate proliferation-associated and NF-κB-responsive genes in cervical keratinocytes. Journal of Virology, 75(9), 4283–4296. doi:10.1128/JVI.75.9.4283-4296.2001.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Scott, M., Nakagawa, M., & Moscicki, A. B. (2001). Cell-mediated immune response to human papillomavirus infection. Clinical and Diagnostic Laboratory Immunology, 8(2), 209–220. doi:10.1128/CDLI.8.2.209-220.2001.

    CAS  PubMed  PubMed Central  Google Scholar 

  68. Stanley, M. A. (2012). Epithelial cell responses to infection with human papillomavirus. Clinical Microbiology Reviews, 25(2), 215–222. doi:10.1128/CMR.05028-11.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Lydiatt, W. M., Patel, S. G., O'Sullivan, B., Brandwein, M. S., Ridge, J. A., Migliacci, J. C., et al. (2017). Head and neck cancers-major changes in the American joint committee on cancer eighth edition cancer staging manual. CA: a Cancer Journal for Clinicians, 67(2), 122–137. doi:10.3322/caac.21389.

    Google Scholar 

  70. Kelly, J. R., Husain, Z. A., & Burtness, B. (2016). Treatment de-intensification strategies for head and neck cancer. European Journal of Cancer, 68, 125–133. doi:10.1016/j.ejca.2016.09.006.

    Article  PubMed  Google Scholar 

  71. 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. International Journal of Cancer, 89(3), 300–304.

    Article  CAS  PubMed  Google Scholar 

  72. Rischin, D., Young, R. J., Fisher, R., Fox, S. B., Le, Q. T., Peters, L. J., et al. (2010). Prognostic significance of p16INK4A and human papillomavirus in patients with oropharyngeal cancer treated on TROG 02.02 phase III trial. Journal of Clinical Oncology, 28(27), 4142–4148. doi:10.1200/JCO.2010.29.2904.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. O'Rorke, M. A., Ellison, M. V., Murray, L. J., Moran, M., James, J., & Anderson, L. A. (2012). Human papillomavirus related head and neck cancer survival: a systematic review and meta-analysis. Oral Oncology, 48(12), 1191–1201. doi:10.1016/j.oraloncology.2012.06.019.

    Article  PubMed  Google Scholar 

  74. Hafkamp, H. C., Manni, J. J., Haesevoets, A., Voogd, A. C., Schepers, M., Bot, F. J., et al. (2008). Marked differences in survival rate between smokers and nonsmokers with HPV 16-associated tonsillar carcinomas. International Journal of Cancer, 122(12), 2656–2664. doi:10.1002/ijc.23458.

    Article  CAS  PubMed  Google Scholar 

  75. Gillison, M. L., Zhang, Q., Jordan, R., Xiao, W., Westra, W. H., Trotti, A., et al. (2012). Tobacco smoking and increased risk of death and progression for patients with p16-positive and p16-negative oropharyngeal cancer. Journal of Clinical Oncology, 30(17), 2102–2111. doi:10.1200/JCO.2011.38.4099.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Maxwell, J. H., Kumar, B., Feng, F. Y., Worden, F. P., Lee, J. S., Eisbruch, A., et al. (2010). Tobacco use in human papillomavirus-positive advanced oropharynx cancer patients related to increased risk of distant metastases and tumor recurrence. Clinical Cancer Research, 16(4), 1226–1235. doi:10.1158/1078-0432.CCR-09-2350.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Marks, S. C. (1999). Surgical management of head and neck cancer. Hematology/Oncology Clinics of North America, 13(4), 655–678 v.

    Article  CAS  PubMed  Google Scholar 

  78. The Department of Veterans Affairs Laryngeal Cancer Study Group. (1991). Induction chemotherapy plus radiation compared with surgery plus radiation in patients with advanced laryngeal cancer. The New England Journal of Medicine, 324(24), 1685–1690. doi:10.1056/NEJM199106133242402.

  79. Forastiere, A. A., Goepfert, H., Maor, M., Pajak, T. F., Weber, R., Morrison, W., et al. (2003). Concurrent chemotherapy and radiotherapy for organ preservation in advanced laryngeal cancer. The New England Journal of Medicine, 349(22), 2091–2098. doi:10.1056/NEJMoa031317.

    Article  CAS  PubMed  Google Scholar 

  80. Denis, F., Garaud, P., Bardet, E., Alfonsi, M., Sire, C., Germain, T., et al. (2004). Final results of the 94-01 French head and neck oncology and radiotherapy group randomized trial comparing radiotherapy alone with concomitant radiochemotherapy in advanced-stage oropharynx carcinoma. Journal of Clinical Oncology, 22(1), 69–76. doi:10.1200/JCO.2004.08.021.

    Article  PubMed  Google Scholar 

  81. Pignon, J. P., le Maitre, A., Maillard, E., Bourhis, J., & Group, M.-N. C. (2009). Meta-analysis of chemotherapy in head and neck cancer (MACH-NC): an update on 93 randomised trials and 17,346 patients. Radiotherapy and Oncology, 92(1), 4–14. doi:10.1016/j.radonc.2009.04.014.

    Article  PubMed  Google Scholar 

  82. Adelstein, D. J., Li, Y., Adams, G. L., Wagner Jr., H., Kish, J. A., Ensley, J. F., et al. (2003). An intergroup phase III comparison of standard radiation therapy and two schedules of concurrent chemoradiotherapy in patients with unresectable squamous cell head and neck cancer. Journal of Clinical Oncology, 21(1), 92–98. doi:10.1200/JCO.2003.01.008.

    Article  PubMed  Google Scholar 

  83. Bentzen, S. M., & Trotti, A. (2007). Evaluation of early and late toxicities in chemoradiation trials. Journal of Clinical Oncology, 25(26), 4096–4103. doi:10.1200/JCO.2007.13.3983.

    Article  CAS  PubMed  Google Scholar 

  84. Bernier, J., Domenge, C., Ozsahin, M., Matuszewska, K., Lefebvre, J. L., Greiner, R. H., et al. (2004). Postoperative irradiation with or without concomitant chemotherapy for locally advanced head and neck cancer. The New England Journal of Medicine, 350(19), 1945–1952. doi:10.1056/NEJMoa032641.

    Article  CAS  PubMed  Google Scholar 

  85. Cooper, J. S., Pajak, T. F., Forastiere, A. A., Jacobs, J., Campbell, B. H., Saxman, S. B., et al. (2004). Postoperative concurrent radiotherapy and chemotherapy for high-risk squamous-cell carcinoma of the head and neck. The New England Journal of Medicine, 350(19), 1937–1944. doi:10.1056/NEJMoa032646.

    Article  PubMed  Google Scholar 

  86. Calais, G., Alfonsi, M., Bardet, E., Sire, C., Germain, T., Bergerot, P., et al. (1999). Randomized trial of radiation therapy versus concomitant chemotherapy and radiation therapy for advanced-stage oropharynx carcinoma. Journal of the National Cancer Institute, 91(24), 2081–2086.

    Article  CAS  PubMed  Google Scholar 

  87. Weinstein, G. S., O'Malley Jr., B. W., Cohen, M. A., & Quon, H. (2010). Transoral robotic surgery for advanced oropharyngeal carcinoma. Archives of Otolaryngology – Head & Neck Surgery, 136(11), 1079–1085. doi:10.1001/archoto.2010.191.

    Article  Google Scholar 

  88. White, H., Ford, S., Bush, B., Holsinger, F. C., Moore, E., Ghanem, T., et al. (2013). Salvage surgery for recurrent cancers of the oropharynx: comparing TORS with standard open surgical approaches. JAMA Otolaryngology. Head & Neck Surgery, 139(8), 773–778. doi:10.1001/jamaoto.2013.3866.

    Article  Google Scholar 

  89. Cleary, C., Leeman, J. E., Higginson, D. S., Katabi, N., Sherman, E., Morris, L., et al. (2016). Biological features of human papillomavirus-related head and neck cancers contributing to improved response. Clinical Oncology (Royal College of Radiologists), 28(7), 467–474. doi:10.1016/j.clon.2016.03.001.

    Article  CAS  Google Scholar 

  90. Rieckmann, T., Tribius, S., Grob, T. J., Meyer, F., Busch, C. J., Petersen, C., et al. (2013). HNSCC cell lines positive for HPV and p16 possess higher cellular radiosensitivity due to an impaired DSB repair capacity. Radiotherapy and Oncology, 107(2), 242–246. doi:10.1016/j.radonc.2013.03.013.

    Article  CAS  PubMed  Google Scholar 

  91. Pang, E., Delic, N. C., Hong, A., Zhang, M., Rose, B. R., & Lyons, J. G. (2011). Radiosensitization of oropharyngeal squamous cell carcinoma cells by human papillomavirus 16 oncoprotein E6 *I. International Journal of Radiation Oncology, Biology, Physics, 79(3), 860–865. doi:10.1016/j.ijrobp.2010.06.028.

    Article  CAS  PubMed  Google Scholar 

  92. Dok, R., Kalev, P., Van Limbergen, E. J., Asbagh, L. A., Vazquez, I., Hauben, E., et al. (2014). p16INK4a impairs homologous recombination-mediated DNA repair in human papillomavirus-positive head and neck tumors. Cancer Research, 74(6), 1739–1751. doi:10.1158/0008-5472.CAN-13-2479.

    Article  CAS  PubMed  Google Scholar 

  93. Lechner, M., Frampton, G. M., Fenton, T., Feber, A., Palmer, G., Jay, A., et al. (2013). Targeted next-generation sequencing of head and neck squamous cell carcinoma identifies novel genetic alterations in HPV+ and HPV- tumors. Genome Medicine, 5(5), 49. doi:10.1186/gm453.

    Article  PubMed  PubMed Central  Google Scholar 

  94. Braakhuis, B. J., Snijders, P. J., Keune, W. J., Meijer, C. J., Ruijter-Schippers, H. J., Leemans, C. R., et al. (2004). Genetic patterns in head and neck cancers that contain or lack transcriptionally active human papillomavirus. Journal of the National Cancer Institute, 96(13), 998–1006.

    Article  CAS  PubMed  Google Scholar 

  95. Kimple, R. J., Smith, M. A., Blitzer, G. C., Torres, A. D., Martin, J. A., Yang, R. Z., et al. (2013). Enhanced radiation sensitivity in HPV-positive head and neck cancer. Cancer Research, 73(15), 4791–4800. doi:10.1158/0008-5472.CAN-13-0587.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Rockwell, S., Dobrucki, I. T., Kim, E. Y., Marrison, S. T., & Vu, V. T. (2009). Hypoxia and radiation therapy: past history, ongoing research, and future promise. Current Molecular Medicine, 9(4), 442–458.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Mortensen, L. S., Johansen, J., Kallehauge, J., Primdahl, H., Busk, M., Lassen, P., et al. (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. Radiotherapy and Oncology, 105(1), 14–20. doi:10.1016/j.radonc.2012.09.015.

    Article  PubMed  Google Scholar 

  98. Machtay, M., Moughan, J., Trotti, A., Garden, A. S., Weber, R. S., Cooper, J. S., et al. (2008). Factors associated with severe late toxicity after concurrent chemoradiation for locally advanced head and neck cancer: an RTOG analysis. Journal of Clinical Oncology, 26(21), 3582–3589. doi:10.1200/JCO.2007.14.8841.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Chera, B. S., Amdur, R. J., Tepper, J., Qaqish, B., Green, R., Aumer, S. L., et al. (2015). Phase 2 trial of de-intensified Chemoradiation therapy for favorable-risk human papillomavirus-associated oropharyngeal squamous cell carcinoma. International Journal of Radiation Oncology, Biology, Physics, 93(5), 976–985. doi:10.1016/j.ijrobp.2015.08.033.

    Article  PubMed  Google Scholar 

  100. Marur, S., Li, S., Cmelak, A. J., Gillison, M. L., Zhao, W. J., Ferris, R. L., et al. (2016). E1308: phase II trial of induction chemotherapy followed by reduced-dose radiation and weekly cetuximab in patients with HPV-associated resectable squamous cell carcinoma of the oropharynx- ECOG-ACRIN Cancer Research Group. J Clin Oncol. doi:10.1200/JCO.2016.68.3300.

  101. Gildener-Leapman, N., Kim, J., Abberbock, S., Choby, G. W., Mandal, R., Duvvuri, U., et al. (2016). Utility of up-front transoral robotic surgery in tailoring adjuvant therapy. Head & Neck, 38(8), 1201–1207. doi:10.1002/hed.24390.

    Article  Google Scholar 

  102. Hoffmann, T. K., Sonkoly, E., Hauser, U., van Lierop, A., Whiteside, T. L., Klussmann, J. P., et al. (2008). Alterations in the p53 pathway and their association with radio- and chemosensitivity in head and neck squamous cell carcinoma. Oral Oncology, 44(12), 1100–1109. doi:10.1016/j.oraloncology.2008.02.006.

    Article  CAS  PubMed  Google Scholar 

  103. Funaoka, K., Shindoh, M., Yamashita, T., Fujinaga, K., Amemiya, A., & Totsuka, Y. (1996). High-risk HPV-positive human cancer cell lines show different sensitivity to cisplatin-induced apoptosis correlated with the p21Waf1/Cip1 level. Cancer Letters, 108(1), 15–23.

    Article  CAS  PubMed  Google Scholar 

  104. Veena, M. S., Wilken, R., Zheng, J. Y., Gholkar, A., Venkatesan, N., Vira, D., et al. (2014). p16 protein and gigaxonin are associated with the ubiquitination of NFκB in cisplatin-induced senescence of cancer cells. The Journal of Biological Chemistry, 289(50), 34921–34937. doi:10.1074/jbc.M114.568543.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  105. Bonner, J. A., Harari, P. M., Giralt, J., Azarnia, N., Shin, D. M., Cohen, R. B., et al. (2006). Radiotherapy plus cetuximab for squamous-cell carcinoma of the head and neck. The New England Journal of Medicine, 354(6), 567–578. doi:10.1056/NEJMoa053422.

    Article  CAS  PubMed  Google Scholar 

  106. Sepiashvili, L., Bruce, J. P., Huang, S. H., O'Sullivan, B., Liu, F. F., & Kislinger, T. (2015). Novel insights into head and neck cancer using next-generation “omic” technologies. Cancer Research, 75(3), 480–486. doi:10.1158/0008-5472.CAN-14-3124.

    Article  CAS  PubMed  Google Scholar 

  107. Mehanna, H. M., Haider, S., Rapozo, D. C., von Zeidler, S., Harrington, K., Winter, S., Jones, T., Pring, M., West, C., Golusinski, P., Sloan, P., Thavaraj, S., Odell, E. W., Hunter, K., Shah, K. A., Thomas, G., & Robinson, M. (2017). Developing and validating a multivariable predictive biomarker for treatment selection for oropharyngeal squamous cell carcinoma: the PREDICTR-OPC study. Journal of Clinical Oncology, 35(suppl), abstr 6004.

    Google Scholar 

  108. Fakhry, C., Qualliotine, J. R., Zhang, Z., Agrawal, N., Gaykalova, D. A., Bishop, J. A., et al. (2016). Serum antibodies to HPV16 early proteins warrant investigation as potential biomarkers for risk stratification and recurrence of HPV-associated oropharyngeal cancer. Cancer Prevention Research (Philadelphia, Pa.), 9(2), 135–141. doi:10.1158/1940-6207.CAPR-15-0299.

    Article  CAS  Google Scholar 

  109. Nichols, A. C., Finkelstein, D. M., Faquin, W. C., Westra, W. H., Mroz, E. A., Kneuertz, P., et al. (2010). Bcl2 and human papilloma virus 16 as predictors of outcome following concurrent chemoradiation for advanced oropharyngeal cancer. Clinical Cancer Research, 16(7), 2138–2146. doi:10.1158/1078-0432.CCR-09-3185.

    Article  CAS  PubMed  Google Scholar 

  110. Rainsbury, J. W., Ahmed, W., Williams, H. K., Roberts, S., Paleri, V., & Mehanna, H. (2013). Prognostic biomarkers of survival in oropharyngeal squamous cell carcinoma: systematic review and meta-analysis. Head & Neck, 35(7), 1048–1055. doi:10.1002/hed.22950.

    Article  Google Scholar 

  111. De Meulenaere, A., Vermassen, T., Aspeslagh, S., Vandecasteele, K., Rottey, S., & Ferdinande, L. (2016). TILs in head and neck cancer: ready for clinical implementation and why (not)? Head and Neck Pathology. doi:10.1007/s12105-016-0776-8.

  112. Rios Velazquez, E., Hoebers, F., Aerts, H. J., Rietbergen, M. M., Brakenhoff, R. H., Leemans, R. C., et al. (2014). Externally validated HPV-based prognostic nomogram for oropharyngeal carcinoma patients yields more accurate predictions than TNM staging. Radiotherapy and Oncology, 113(3), 324–330. doi:10.1016/j.radonc.2014.09.005.

    Article  PubMed  Google Scholar 

  113. Larsen, C. G., Jensen, D. H., Carlander, A. F., Kiss, K., Andersen, L., Olsen, C. H., et al. (2016). Novel nomograms for survival and progression in HPV+ and HPV- oropharyngeal cancer: a population-based study of 1,542 consecutive patients. Oncotarget, 7(44), 71761–71772. doi:10.18632/oncotarget.12335.

    PubMed  PubMed Central  Google Scholar 

  114. Shoultz-Henley, S., Garden, A. S., Mohamed, A. S., Sheu, T., Kroll, M. H., Rosenthal, D. I., et al. (2016). Prognostic value of pretherapy platelet elevation in oropharyngeal cancer patients treated with chemoradiation. International Journal of Cancer, 138(5), 1290–1297. doi:10.1002/ijc.29870.

    Article  CAS  PubMed  Google Scholar 

  115. Fakhry, C., Zhang, Q., Nguyen-Tân, P. F., Rosenthal, D. I., Weber, R. S., Lambert, L., et al. (2017). Development and validation of nomograms predictive of overall and progression-free survival in oropharyngeal cancer patients. J Clin Oncol. doi:10.1200/JCO.2016.72.0748. 

  116. Weinberger, P. M., Yu, Z., Haffty, B. G., Kowalski, D., Harigopal, M., Brandsma, J., et al. (2006). Molecular classification identifies a subset of human papillomavirus–associated oropharyngeal cancers with favorable prognosis. Journal of Clinical Oncology, 24(5), 736–747. doi:10.1200/JCO.2004.00.3335.

    Article  CAS  PubMed  Google Scholar 

  117. Huang, S. H., Perez-Ordonez, B., Weinreb, I., Hope, A., Massey, C., Waldron, J. N., et al. (2013). Natural course of distant metastases following radiotherapy or chemoradiotherapy in HPV-related oropharyngeal cancer. Oral Oncology, 49(1), 79–85. doi:10.1016/j.oraloncology.2012.07.015.

    Article  PubMed  Google Scholar 

  118. Posner, M. R., Lorch, J. H., Goloubeva, O., Tan, M., Schumaker, L. M., Sarlis, N. J., et al. (2011). Survival and human papillomavirus in oropharynx cancer in TAX 324: a subset analysis from an international phase III trial. Annals of Oncology, 22(5), 1071–1077. doi:10.1093/annonc/mdr006.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Faraji, F., Eisele, D. W., & Fakhry, C. (2017). Emerging insights into recurrent and metastatic human papillomavirus-related oropharyngeal squamous cell carcinoma. Laryngoscope Investigative Otolaryngology, 2, 10–18. doi:10.1002/lio2.37.

    Article  PubMed  PubMed Central  Google Scholar 

  120. Fakhry, C., Zhang, Q., Nguyen-Tan, P. F., Rosenthal, D., El-Naggar, A., Garden, A. S., et al. (2014). Human papillomavirus and overall survival after progression of oropharyngeal squamous cell carcinoma. Journal of Clinical Oncology, 32(30), 3365–3373. doi:10.1200/JCO.2014.55.1937.

    Article  PubMed  PubMed Central  Google Scholar 

  121. Vermorken, J. B., Stohlmacher-Williams, J., Davidenko, I., Licitra, L., Winquist, E., Villanueva, C., et al. (2013). Cisplatin and fluorouracil with or without panitumumab in patients with recurrent or metastatic squamous-cell carcinoma of the head and neck (SPECTRUM): an open-label phase 3 randomised trial. The Lancet Oncology, 14(8), 697–710. doi:10.1016/S1470-2045(13)70181-5.

    Article  CAS  PubMed  Google Scholar 

  122. Vermorken, J. B., Psyrri, A., Mesia, R., Peyrade, F., Beier, F., de Blas, B., et al. (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. Annals of Oncology, 25(4), 801–807. doi:10.1093/annonc/mdt574.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Lassen, P., Primdahl, H., Johansen, J., Kristensen, C. A., Andersen, E., Andersen, L. J., et al. (2014). Impact of HPV-associated p16-expression on radiotherapy outcome in advanced oropharynx and non-oropharynx cancer. Radiotherapy and Oncology, 113(3), 310–316. doi:10.1016/j.radonc.2014.11.032.

    Article  PubMed  Google Scholar 

  124. Fakhry, C., Westra, W. H., Wang, S. J., van Zante, A., Zhang, Y., Rettig, E. M., et al. (2017). The prognostic role of sex, race, and human papillomavirus in oropharyngeal and nonoropharyngeal head and neck squamous cell cancer. Cancer, 123, 1566–1575.

    Article  CAS  PubMed  Google Scholar 

  125. Jordan, R. C., Lingen, M. W., Perez-Ordonez, B., He, X., Pickard, R., Koluder, M., et al. (2012). Validation of methods for oropharyngeal cancer HPV status determination in US cooperative group trials. The American Journal of Surgical Pathology, 36(7), 945–954. doi:10.1097/PAS.0b013e318253a2d1.

    Article  PubMed  Google Scholar 

  126. Schache, A. G., Liloglou, T., Risk, J. M., Filia, A., Jones, T. M., Sheard, J., et al. (2011). Evaluation of human papilloma virus diagnostic testing in oropharyngeal squamous cell carcinoma: sensitivity, specificity, and prognostic discrimination. Clinical Cancer Research, 17(19), 6262–6271. doi:10.1158/1078-0432.CCR-11-0388.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Misiukiewicz, K., Camille, N., Gupta, V., Bakst, R., Teng, M., Miles, B., et al. (2014). The role of HPV status in recurrent/metastatic squamous cell carcinoma of the head and neck. Clinical Advances in Hematology & Oncology, 12(12), 812–819.

    Google Scholar 

  128. Fakhry, C., Zhang, Q., Nguyen-Tan, P. F., Rosenthal, D., El-Naggar, A. K., Garden, A. S., et al. (2015). Reply to B. O’Sullivan et al. Journal of Clinical Oncology, 33(15), 1708–1709. doi:10.1200/JCO.2014.60.3555.

    Article  PubMed  Google Scholar 

  129. O'Sullivan, B., Adelstein, D. L., Huang, S. H., Koyfman, S. A., Thorstad, W., Hope, A. J., et al. (2015). First site of failure analysis incompletely addresses issues of late and unexpected metastases in p16-positive oropharyngeal cancer. Journal of Clinical Oncology, 33(15), 1707–1708. doi:10.1200/JCO.2014.58.2700.

    Article  PubMed  Google Scholar 

  130. Pfister, D. G., Baxi, S. S., Dunn, L. A., & Fury, M. G. (2015). Reply to B. O'Sullivan et al. J Clin Oncol, 33(15), 1710. doi:10.1200/JCO.2014.60.3563.

    Article  PubMed  Google Scholar 

  131. Daly, M. E., Le, Q. T., Maxim, P. G., Loo Jr., B. W., Kaplan, M. J., Fischbein, N. J., et al. (2010). Intensity-modulated radiotherapy in the treatment of oropharyngeal cancer: clinical outcomes and patterns of failure. International Journal of Radiation Oncology, Biology, Physics, 76(5), 1339–1346. doi:10.1016/j.ijrobp.2009.04.006.

    Article  PubMed  Google Scholar 

  132. Ruzevick, J., Olivi, A., & Westra, W. H. (2013). Metastatic squamous cell carcinoma to the brain: an unrecognized pattern of distant spread in patients with HPV-related head and neck cancer. Journal of Neuro-Oncology, 112(3), 449–454. doi:10.1007/s11060-013-1075-9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Muller, S., Khuri, F. R., Kono, S. A., Beitler, J. J., Shin, D. M., & Saba, N. F. (2012). HPV positive squamous cell carcinoma of the oropharynx. Are we observing an unusual pattern of metastases? Head and Neck Pathology, 6(3), 336–344. doi:10.1007/s12105-012-0355-6.

    Article  PubMed  PubMed Central  Google Scholar 

  134. Huang, S. H., Perez-Ordonez, B., Liu, F. F., Waldron, J., Ringash, J., Irish, J., et al. (2012). Atypical clinical behavior of p16-confirmed HPV-related oropharyngeal squamous cell carcinoma treated with radical radiotherapy. International Journal of Radiation Oncology, Biology, Physics, 82(1), 276–283. doi:10.1016/j.ijrobp.2010.08.031.

    Article  PubMed  Google Scholar 

  135. Guo, T., Rettig, E., & Fakhry, C. (2016). Understanding the impact of survival and human papillomavirus tumor status on timing of recurrence in oropharyngeal squamous cell carcinoma. Oral Oncology, 52, 97–103. doi:10.1016/j.oraloncology.2015.10.016.

    Article  PubMed  Google Scholar 

  136. Zafereo, M. E., Hanasono, M. M., Rosenthal, D. I., Sturgis, E. M., Lewin, J. S., Roberts, D. B., et al. (2009). The role of salvage surgery in patients with recurrent squamous cell carcinoma of the oropharynx. Cancer, 115(24), 5723–5733. doi:10.1002/cncr.24595.

    Article  PubMed  Google Scholar 

  137. Jayaram, S. C., Muzaffar, S. J., Ahmed, I., Dhanda, J., Paleri, V., & Mehanna, H. (2016). Efficacy, outcomes, and complication rates of different surgical and nonsurgical treatment modalities for recurrent/residual oropharyngeal carcinoma: a systematic review and meta-analysis. Head & Neck, 38(12), 1855–1861. doi:10.1002/hed.24531.

    Article  Google Scholar 

  138. Patel, S. N., Cohen, M. A., Givi, B., Dixon, B. J., Gilbert, R. W., Gullane, P. J., et al. (2016). Salvage surgery for locally recurrent oropharyngeal cancer. Head & Neck, 38(Suppl 1), E658–E664. doi:10.1002/hed.24065.

    Article  Google Scholar 

  139. Joseph, A. W., Guo, T., Hur, K., Xie, Y., Yin, L., Califano, J. A., et al. (2016). Disease-free survival after salvage therapy for recurrent oropharyngeal squamous cell carcinoma. Head & Neck, 38(Suppl 1), E1501–E1509. doi:10.1002/hed.24268.

    Article  Google Scholar 

  140. Ganly, I., Patel, S., Matsuo, J., Singh, B., Kraus, D., Boyle, J., et al. (2005). Postoperative complications of salvage total laryngectomy. Cancer, 103(10), 2073–2081. doi:10.1002/cncr.20974.

    Article  PubMed  Google Scholar 

  141. Pang, L., Jeannon, J. P., & Simo, R. (2011). Minimizing complications in salvage head and neck oncological surgery following radiotherapy and chemo-radiotherapy. Current Opinion in Otolaryngology & Head and Neck Surgery, 19(2), 125–131. doi:10.1097/MOO.0b013e3283440ee3.

    Article  Google Scholar 

  142. Sewnaik, A., Keereweer, S., Al-Mamgani, A., Baatenburg de Jong, R. J., Wieringa, M. H., Meeuwis, C. A., et al. (2012). High complication risk of salvage surgery after chemoradiation failures. Acta Oto-Laryngologica, 132(1), 96–100. doi:10.3109/00016489.2011.617779.

    Article  PubMed  Google Scholar 

  143. Grant, D. G., Salassa, J. R., Hinni, M. L., Pearson, B. W., Hayden, R. E., & Perry, W. C. (2008). Transoral laser microsurgery for recurrent laryngeal and pharyngeal cancer. Otolaryngology and Head and Neck Surgery, 138(5), 606–613. doi:10.1016/j.otohns.2007.12.046.

    Article  Google Scholar 

  144. Rettig, E. M., Wentz, A., Posner, M. R., Gross, N. D., Haddad, R. I., Gillison, M. L., et al. (2015). Prognostic implication of persistent human papillomavirus type 16 DNA detection in oral rinses for human papillomavirus-related oropharyngeal carcinoma. JAMA Oncology, 1(7), 907–915. doi:10.1001/jamaoncol.2015.2524.

    Article  PubMed  Google Scholar 

  145. Ahn, S. M., Chan, J. Y., Zhang, Z., Wang, H., Khan, Z., Bishop, J. A., et al. (2014). Saliva and plasma quantitative polymerase chain reaction-based detection and surveillance of human papillomavirus-related head and neck cancer. JAMA Otolaryngology. Head & Neck Surgery, 140(9), 846–854. doi:10.1001/jamaoto.2014.1338.

    Article  Google Scholar 

  146. Wang, Y., Springer, S., Mulvey, C. L., Silliman, N., Schaefer, J., Sausen, M., et al. (2015). Detection of somatic mutations and HPV in the saliva and plasma of patients with head and neck squamous cell carcinomas. Sci Transl Med, 7(293), 293ra104. doi:10.1126/scitranslmed.aaa8507.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  147. Zhang, Y., Waterboer, T., Haddad, R. I., Miles, B. A., Wentz, A., Gross, N. D., et al. (2017). Human papillomavirus (HPV) 16 antibodies at diagnosis of HPV-related oropharyngeal cancer and antibody trajectories after treatment. Oral Oncology, 67, 77–82. doi:10.1016/j.oraloncology.2017.02.004.

    Article  PubMed  CAS  Google Scholar 

  148. Dahlstrom, K. R., Li, G., Hussey, C. S., Vo, J. T., Wei, Q., Zhao, C., et al. (2015). Circulating human papillomavirus DNA as a marker for disease extent and recurrence among patients with oropharyngeal cancer. Cancer, 121(19), 3455–3464. doi:10.1002/cncr.29538.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  149. Liang, C., Marsit, C. J., McClean, M. D., Nelson, H. H., Christensen, B. C., Haddad, R. I., et al. (2012). Biomarkers of HPV in head and neck squamous cell carcinoma. Cancer Research, 72(19), 5004–5013. doi:10.1158/0008-5472.CAN-11-3277.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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  1. Nicholas Fung and Farhoud Faraji equally contributed to this work.

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  1. Department of Otolaryngology-Head and Neck Surgery, Johns Hopkins University School of Medicine, 601 N. Caroline Street, Sixth Floor, Baltimore, MD, 21287, USA

    Nicholas Fung, Farhoud Faraji & Carole Fakhry

  2. Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA

    Hyunseok Kang

  3. Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA

    Carole Fakhry

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Fung, N., Faraji, F., Kang, H. et al. The role of human papillomavirus on the prognosis and treatment of oropharyngeal carcinoma. Cancer Metastasis Rev 36, 449–461 (2017). https://doi.org/10.1007/s10555-017-9686-9

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