Top

15-08-2017 | Head and neck cancers | Article

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

Journal: Cancer and Metastasis Reviews

Authors: Nicholas Fung, Farhoud Faraji, Hyunseok Kang, Carole Fakhry

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.

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.

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.

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

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.PubMedCrossRef

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.

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

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.CrossRef

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.PubMed

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.PubMedCrossRef

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.PubMedCrossRef

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.PubMedPubMedCentralCrossRef

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.PubMedCrossRef

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.PubMedCrossRef

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.CrossRef

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.PubMedCrossRef

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.PubMedCrossRef

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.PubMedCrossRef

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.PubMedCrossRef

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.PubMedCrossRef

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.PubMedCrossRef

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.CrossRef

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.PubMedCrossRef

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.CrossRef

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.PubMedCrossRef

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.

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.CrossRef

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.PubMedPubMedCentralCrossRef

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.PubMedCrossRef

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.PubMedPubMedCentralCrossRef

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.PubMedPubMedCentralCrossRef

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.PubMedCrossRef

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.PubMedPubMedCentralCrossRef

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.PubMedPubMedCentralCrossRef

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.PubMedCrossRef

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.PubMedPubMedCentralCrossRef

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.PubMedCrossRef

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.CrossRef

40.

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

41.

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

42.

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

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.PubMedPubMedCentralCrossRef

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.PubMedCrossRef

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.PubMedCrossRef

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.PubMedCrossRef

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.PubMedCrossRef

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.CrossRef

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.PubMedPubMedCentral

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.PubMedPubMedCentralCrossRef

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.PubMedPubMedCentralCrossRef

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.PubMedCrossRef

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.PubMedCrossRef

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.PubMedCrossRef

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.PubMed

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.PubMedCrossRef

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.PubMedCrossRef

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.PubMedCrossRef

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.PubMedPubMedCentral

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.PubMedPubMedCentral

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.PubMedCrossRef

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.PubMedPubMedCentralCrossRef

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.PubMedPubMedCentralCrossRef

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.CrossRef

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.PubMedCrossRef

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.PubMedPubMedCentralCrossRef

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.PubMedPubMedCentral

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.PubMedPubMedCentralCrossRef

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.

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.PubMedCrossRef

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.PubMedCrossRef

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.PubMedPubMedCentralCrossRef

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.PubMedCrossRef

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.PubMedCrossRef

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.PubMedPubMedCentralCrossRef

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.PubMedPubMedCentralCrossRef

77.

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

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.PubMedCrossRef

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.PubMedCrossRef

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.PubMedCrossRef

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.PubMedCrossRef

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.PubMedCrossRef

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.PubMedCrossRef

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.PubMedCrossRef

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.PubMedCrossRef

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.CrossRef

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.CrossRef

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.CrossRef

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.PubMedCrossRef

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.PubMedCrossRef

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.PubMedCrossRef

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.PubMedPubMedCentralCrossRef

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.PubMedCrossRef

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.PubMedPubMedCentralCrossRef

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.PubMedPubMedCentralCrossRef

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.PubMedCrossRef

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.PubMedPubMedCentralCrossRef

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.PubMedCrossRef

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.CrossRef

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.PubMedCrossRef

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.PubMedCrossRef

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.PubMedPubMedCentralCrossRef

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.PubMedCrossRef

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.PubMedCrossRef

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.

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.CrossRef

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.PubMedCrossRef

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.CrossRef

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.PubMedCrossRef

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.PubMedPubMedCentral

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.PubMedCrossRef

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.PubMedCrossRef

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.PubMedCrossRef

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.PubMedPubMedCentralCrossRef

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.PubMedPubMedCentralCrossRef

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.PubMedPubMedCentralCrossRef

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.PubMedCrossRef

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.PubMedPubMedCentralCrossRef

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.PubMedCrossRef

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.PubMedCrossRef

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.PubMedCrossRef

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.PubMedPubMedCentralCrossRef

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.

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.PubMedCrossRef

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.PubMedCrossRef

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.PubMedCrossRef

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.PubMedCrossRef

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.PubMedPubMedCentralCrossRef

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.PubMedPubMedCentralCrossRef

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.PubMedCrossRef

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.PubMedCrossRef

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.PubMedCrossRef

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.CrossRef

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.CrossRef

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.CrossRef

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.PubMedCrossRef

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.CrossRef

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.PubMedCrossRef

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.CrossRef

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.PubMedCrossRef

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.CrossRef

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.PubMedPubMedCentralCrossRef

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.PubMedCrossRef

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.PubMedPubMedCentralCrossRef

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.PubMedPubMedCentralCrossRef

Medicine Matters Oncology

Abstract