NCCN Guidelines® Insights: Head and Neck Cancers, Version 1.2022

Featured Updates to the NCCN Guidelines

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Jimmy J. Caudell Moffitt Cancer Center;

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Maura L. Gillison The University of Texas MD Anderson Cancer Center;

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Ellie Maghami City of Hope National Medical Center;

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Sharon Spencer O'Neal Comprehensive Cancer Center at UAB;

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David G. Pfister Memorial Sloan Kettering Cancer Center;

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Douglas Adkins Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine;

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Andrew C. Birkeland UC Davis Comprehensive Cancer Center;

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David M. Brizel Duke Cancer Institute;

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Paul M. Busse Massachusetts General Hospital Cancer Center;

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Anthony J. Cmelak Vanderbilt-Ingram Cancer Center;

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A. Dimitrios Colevas Stanford Cancer Institute;

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David W. Eisele The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins;

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Thomas Galloway Fox Chase Cancer Center;

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Jessica L. Geiger Case Comprehensive Cancer Center/University Hospitals Seidman Cancer Center and Cleveland Clinic Taussig Cancer Institute;

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Robert I. Haddad Dana-Farber/Brigham and Women’s Cancer Center;

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Wesley L. Hicks Jr Roswell Park Comprehensive Cancer Center;

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Ying J. Hitchcock Huntsman Cancer Institute at the University of Utah;

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Antonio Jimeno University of Colorado Cancer Center;

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Debra Leizman Case Comprehensive Cancer Center/University Hospitals Seidman Cancer Center and Cleveland Clinic Taussig Cancer Institute;

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Loren K. Mell UC San Diego Moores Cancer Center;

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Bharat B. Mittal Robert H. Lurie Comprehensive Cancer Center of Northwestern University;

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Harlan A. Pinto Stanford Cancer Institute;

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James W. Rocco The Ohio State University Comprehensive Cancer Center – James Cancer Hospital and Solove Research Institute;

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Cristina P. Rodriguez Fred Hutchinson Cancer Research Center/Seattle Cancer Care Alliance;

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Panayiotis S. Savvides Mayo Clinic Cancer Center;

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David Schwartz St. Jude Children’s Research Hospital/The University of Tennessee Health Science Center;

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Jatin P. Shah Memorial Sloan Kettering Cancer Center;

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David Sher UT Southwestern Simmons Comprehensive Cancer Center;

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Maie St. John UCLA Jonsson Comprehensive Cancer Center;

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Randal S. Weber The University of Texas MD Anderson Cancer Center;

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Gregory Weinstein Abramson Cancer Center at the University of Pennsylvania;

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Frank Worden University of Michigan Rogel Cancer Center;

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Justine Yang Bruce University of Wisconsin Carbone Cancer Center;

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Sue S. Yom UCSF Helen Diller Family Comprehensive Cancer Center;

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Weining Zhen Fred & Pamela Buffett Cancer Center; and

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Jennifer L. Burns National Comprehensive Cancer Network.

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Susan D. Darlow National Comprehensive Cancer Network.

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The NCCN Guidelines for Head and Neck Cancers address tumors arising in the oral cavity (including mucosal lip), pharynx, larynx, and paranasal sinuses. Occult primary cancer, salivary gland cancer, and mucosal melanoma (MM) are also addressed. The specific site of disease, stage, and pathologic findings guide treatment (eg, the appropriate surgical procedure, radiation targets, dose and fractionation of radiation, indications for systemic therapy). The NCCN Head and Neck Cancers Panel meets at least annually to review comments from reviewers within their institutions, examine relevant new data from publications and abstracts, and reevaluate and update their recommendations. These NCCN Guidelines Insights summarize the panel’s most recent recommendations regarding management of HPV-positive oropharynx cancer and ongoing research in this area.

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  • 1.

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  • 2.

    Chaturvedi AK, Engels EA, Pfeiffer RM, et al. Human papillomavirus and rising oropharyngeal cancer incidence in the United States. J Clin Oncol 2011;29:42944301.

  • 3.

    Gillison ML, Broutian T, Pickard RK, et al. Prevalence of oral HPV infection in the United States, 2009-2010. JAMA 2012;307:693703.

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    Näsman A, Attner P, Hammarstedt L, et al. Incidence of human papillomavirus (HPV) positive tonsillar carcinoma in Stockholm, Sweden: an epidemic of viral-induced carcinoma? Int J Cancer 2009;125:362366.

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  • 5.

    Mehanna H, Beech T, Nicholson T, et al. Prevalence of human papillomavirus in oropharyngeal and nonoropharyngeal head and neck cancer--systematic review and meta-analysis of trends by time and region. Head Neck 2013;35:747755.

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    Snow AN, Laudadio J. Human papillomavirus detection in head and neck squamous cell carcinomas. Adv Anat Pathol 2010;17:394403.

  • 7.

    D’Souza G, Zhang HH, D’Souza WD, et al. Moderate predictive value of demographic and behavioral characteristics for a diagnosis of HPV16-positive and HPV16-negative head and neck cancer. Oral Oncol 2010;46:100104.

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  • 8.

    Lu DJ, Luu M, Mita A, et al. Human papillomavirus-associated oropharyngeal cancer among patients aged 70 and older: Dramatically increased prevalence and clinical implications. Eur J Cancer 2018;103:195204.

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  • 9.

    Tota JE, Best AF, Zumsteg ZS, et al. Evolution of the oropharynx cancer epidemic in the United States: moderation of increasing incidence in younger individuals and shift in the burden to older individuals. J Clin Oncol 2019;37:15381546.

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  • 10.

    Gillison ML, Alemany L, Snijders PJ, et al. Human papillomavirus and diseases of the upper airway: head and neck cancer and respiratory papillomatosis. Vaccine 2012;30(Suppl 5):F3454.

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    Gillison ML, Koch WM, Capone RB, et al. Evidence for a causal association between human papillomavirus and a subset of head and neck cancers. J Natl Cancer Inst 2000;92:709720.

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  • 12.

    Ndiaye C, Mena M, Alemany L, et al. HPV DNA, E6/E7 mRNA, and p16INK4a detection in head and neck cancers: a systematic review and meta-analysis. Lancet Oncol 2014;15:13191331.

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  • 13.

    Agalliu I, Gapstur S, Chen Z, et al. Associations of oral alpha-, beta-, and gamma-human papillomavirus types with risk of incident head and neck cancer. JAMA Oncol 2016;2:599606.

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  • 14.

    LeConte BA, Szaniszlo P, Fennewald SM, et al. Differences in the viral genome between HPV-positive cervical and oropharyngeal cancer. PLoS One 2018;13:e0203403.

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    Steinau M, Saraiya M, Goodman MT, et al. Human papillomavirus prevalence in oropharyngeal cancer before vaccine introduction, United States. Emerg Infect Dis 2014;20:822828.

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    da Silva RL, da Silva Batista Z, Bastos GR, et al. Role of HPV 16 variants among cervical carcinoma samples from Northeastern Brazil. BMC Womens Health 2020;20:162.

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    Gillison ML, Akagi K, Xiao W, et al. Human papillomavirus and the landscape of secondary genetic alterations in oral cancers. Genome Res 2019;29:117.

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    Chaturvedi AK, Graubard BI, Broutian T, et al. Effect of prophylactic human papillomavirus (HPV) vaccination on oral HPV infections among young adults in the United States. J Clin Oncol 2018;36:262267.

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  • 19.

    Chaturvedi AK, Graubard BI, Broutian T, et al. Prevalence of oral HPV infection in unvaccinated men and women in the United States, 2009-2016. JAMA 2019;322:977979.

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    FUTURE II Study Group. Quadrivalent vaccine against human papillomavirus to prevent high-grade cervical lesions. N Engl J Med 2007;356:19151927.

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    Beachler DC, Kreimer AR, Schiffman M, et al. Multisite HPV16/18 vaccine efficacy against cervical, anal, and oral HPV infection. J Natl Cancer Inst 2015;108:108.

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    Lei J, Ploner A, Elfström KM, et al. HPV vaccination and the risk of invasive cervical cancer. N Engl J Med 2020;383:13401348.

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    Ang KK, Harris J, Wheeler R, et al. Human papillomavirus and survival of patients with oropharyngeal cancer. N Engl J Med 2010;363:2435.

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    Rischin D, Young RJ, Fisher R, et al. Prognostic significance of p16INK4A and human papillomavirus in patients with oropharyngeal cancer treated on TROG 02.02 phase III trial. J Clin Oncol 2010;28:41424148.

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  • 25.

    Fakhry C, Zhang Q, Nguyen-Tan PF, et al. Human papillomavirus and overall survival after progression of oropharyngeal squamous cell carcinoma. J Clin Oncol 2014;32:33653373.

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  • 26.

    Posner MR, Lorch JH, Goloubeva O, et al. Survival and human papillomavirus in oropharynx cancer in TAX 324: a subset analysis from an international phase III trial. Ann Oncol 2011;22:10711077.

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  • 27.

    Fakhry C, Zhang Q, Nguyen-Tân PF, et al. Development and validation of nomograms predictive of overall and progression-free survival in patients with oropharyngeal cancer. J Clin Oncol 2017;35:40574065.

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  • 28.

    Fullerton ZH, Butler SS, Mahal BA, et al. Short-term mortality risks among patients with oropharynx cancer by human papillomavirus status. Cancer 2020;126:14241433.

  • 29.

    Ren J, Yang W, Su J, et al. Human papillomavirus and p16 immunostaining, prevalence and prognosis of squamous carcinoma of unknown primary in the head and neck region. Int J Cancer 2019;145:14651474.

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  • 30.

    Fakhry C, Westra WH, Li S, et al. Improved survival of patients with human papillomavirus-positive head and neck squamous cell carcinoma in a prospective clinical trial. J Natl Cancer Inst 2008;100:261269.

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  • 31.

    Lassen P, Eriksen JG, Hamilton-Dutoit S, et al. Effect of HPV-associated p16INK4A expression on response to radiotherapy and survival in squamous cell carcinoma of the head and neck. J Clin Oncol 2009;27:19921998.

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  • 32.

    Coordes A, Lenz K, Qian X, et al. Meta-analysis of survival in patients with HNSCC discriminates risk depending on combined HPV and p16 status. Eur Arch Otorhinolaryngol 2016;273:21572169.

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  • 33.

    Jordan RC, Lingen MW, Perez-Ordonez B, et al. Validation of methods for oropharyngeal cancer HPV status determination in US cooperative group trials. Am J Surg Pathol 2012;36:945954.

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  • 34.

    Gillison ML, Zhang Q, Jordan R, et al. Tobacco smoking and increased risk of death and progression for patients with p16-positive and p16-negative oropharyngeal cancer. J Clin Oncol 2012;30:21022111.

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  • 35.

    Sinha P, Lewis JS Jr, Piccirillo JF, et al. Extracapsular spread and adjuvant therapy in human papillomavirus-related, p16-positive oropharyngeal carcinoma. Cancer 2012;118:35193530.

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  • 36.

    Lassen P, Lacas B, Pignon JP, et al. Prognostic impact of HPV-associated p16-expression and smoking status on outcomes following radiotherapy for oropharyngeal cancer: the MARCH-HPV project. Radiother Oncol 2018;126:107115.

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  • 37.

    Spector ME, Gallagher KK, Light E, et al. Matted nodes: poor prognostic marker in oropharyngeal squamous cell carcinoma independent of HPV and EGFR status. Head Neck 2012;34:17271733.

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  • 38.

    O’Sullivan B, Huang SH, Siu LL, et al. Deintensification candidate subgroups in human papillomavirus-related oropharyngeal cancer according to minimal risk of distant metastasis. J Clin Oncol 2013;31:543550.

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  • 39.

    Vainshtein JM, Spector ME, Ibrahim M, et al. Matted nodes: high distant-metastasis risk and a potential indication for intensification of systemic therapy in human papillomavirus-related oropharyngeal cancer. Head Neck 2016;38(Suppl 1):E805814.

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  • 40.

    Huang SH, O’Sullivan B, Su J, et al. Prognostic importance of radiologic extranodal extension in HPV-positive oropharyngeal carcinoma and its potential role in refining TNM-8 cN-classification. Radiother Oncol 2020;144:1322.

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  • 41.

    Weinberger PM, Yu Z, Haffty BG, et al. Molecular classification identifies a subset of human papillomavirus--associated oropharyngeal cancers with favorable prognosis. J Clin Oncol 2006;24:736747.

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  • 42.

    Cantley RL, Gabrielli E, Montebelli F, et al. Ancillary studies in determining human papillomavirus status of squamous cell carcinoma of the oropharynx: a review. Pathol Res Int 2011;2011:138469.

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  • 43.

    Prigge ES, Arbyn M, von Knebel Doeberitz M, et al. Diagnostic accuracy of p16INK4a immunohistochemistry in oropharyngeal squamous cell carcinomas: a systematic review and meta-analysis. Int J Cancer 2017;140:11861198.

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  • 44.

    Lang Kuhs KA, Wood CB, Wiggleton J, et al. Transcervical sonography and human papillomavirus 16 E6 antibodies are sensitive for the detection of oropharyngeal cancer. Cancer 2020;126:26582665.

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  • 45.

    Singhi AD, Westra WH. Comparison of human papillomavirus in situ hybridization and p16 immunohistochemistry in the detection of human papillomavirus-associated head and neck cancer based on a prospective clinical experience. Cancer 2010;116:21662173.

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  • 46.

    Thavaraj S, Stokes A, Guerra E, et al. Evaluation of human papillomavirus testing for squamous cell carcinoma of the tonsil in clinical practice. J Clin Pathol 2011;64:308312.

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  • 47.

    Begum S, Gillison ML, Nicol TL, et al. Detection of human papillomavirus-16 in fine-needle aspirates to determine tumor origin in patients with metastatic squamous cell carcinoma of the head and neck. Clin Cancer Res 2007;13:11861191.

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  • 48.

    Lewis JS Jr, Beadle B, Bishop JA, et al. Human papillomavirus testing in head and neck carcinomas: guideline from the College of American Pathologists. Arch Pathol Lab Med 2018;142:559597.

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  • 49.

    Kaczmar JM, Tan KS, Heitjan DF, et al. HPV-related oropharyngeal cancer: risk factors for treatment failure in patients managed with primary transoral robotic surgery. Head Neck 2016;38:5965.

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  • 50.

    Dahlstrom KR, Garden AS, William WN Jr, et al. Proposed staging system for patients with HPV-related oropharyngeal cancer based on nasopharyngeal cancer N categories. J Clin Oncol 2016;34:18481854.

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    Gillison ML. Human papillomavirus and oropharyngeal cancer stage. J Clin Oncol 2016;34:18331835.

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    Mehra R, Ang KK, Burtness B. Management of human papillomavirus-positive and human papillomavirus-negative head and neck cancer. Semin Radiat Oncol 2012;22:194197.

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    Psyrri A, Rampias T, Vermorken JB. The current and future impact of human papillomavirus on treatment of squamous cell carcinoma of the head and neck. Ann Oncol 2014;25:21012115.

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    Mehanna H. Update on de-intensification and intensification studies in HPV. Recent Results Cancer Res 2017;206:251256.

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    Mehanna H, Rischin D, Wong SJ, et al. De-escalation after DE-ESCALATE and RTOG 1016: a Head and Neck Cancer InterGroup Framework for future de-escalation studies. J Clin Oncol 2020;38:25522557.

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    Quon H, Forastiere AA. Controversies in treatment deintensification of human papillomavirus-associated oropharyngeal carcinomas: should we, how should we, and for whom? J Clin Oncol 2013;31:520522.

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    Masterson L, Moualed D, Masood A, et al. De-escalation treatment protocols for human papillomavirus-associated oropharyngeal squamous cell carcinoma. Cochrane Database Syst Rev 2014;2:CD010271.

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    Kofler B, Laban S, Busch CJ, et al. New treatment strategies for HPV-positive head and neck cancer. Eur Arch Otorhinolaryngol 2014;271:18611867.

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    Adelstein DJ, Ridge JA, Brizel DM, et al. Transoral resection of pharyngeal cancer: summary of a National Cancer Institute Head and Neck Cancer Steering Committee Clinical Trials Planning Meeting, November 6-7, 2011, Arlington, Virginia. Head Neck 2012;34:16811703.

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    Li RJ, Richmon JD. Transoral endoscopic surgery: new surgical techniques for oropharyngeal cancer. Otolaryngol Clin North Am 2012;45:823844.

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    Cracchiolo JR, Baxi SS, Morris LG, et al. Increase in primary surgical treatment of T1 and T2 oropharyngeal squamous cell carcinoma and rates of adverse pathologic features: National Cancer Data Base. Cancer 2016;122:15231532.

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    Nichols AC, Theurer J, Prisman E, et al. Radiotherapy versus transoral robotic surgery and neck dissection for oropharyngeal squamous cell carcinoma (ORATOR): an open-label, phase 2, randomised trial. Lancet Oncol 2019;20:13491359.

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    Nichols AC, Theurer J, Prisman E, et al. Randomized trial of radiotherapy versus transoral robotic surgery for oropharyngeal squamous cell carcinoma: long-term results of the ORATOR trial [published online January 7, 2022]. J Clin Oncol, doi:10.1200/JCO.21.01961

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    Palma D, Nichols A. A phase II randomized trial of treatment de-escalation for HPV associated oropharyngeal squamous cell carcinoma: radiotherapy vs trans-oral surgery (ORATOR 2). Presented at the 2021 American Society for Radiation Oncology Annual Meeting; October 24–27, 2021; Chicago, Illinoi. Abstract LBA-2.

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  • 67.

    Marur S, Li S, Cmelak AJ, et al. 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 2017;35:490497.

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    Chen AM, Felix C, Wang PC, et al. Reduced-dose radiotherapy for human papillomavirus-associated squamous-cell carcinoma of the oropharynx: a single-arm, phase 2 study. Lancet Oncol 2017;18:803811.

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    Chera BS, Amdur RJ, Tepper JE, et al. Mature results of a prospective study of deintensified chemoradiotherapy for low-risk human papillomavirus-associated oropharyngeal squamous cell carcinoma. Cancer 2018;124:23472354.

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    Chera BS, Amdur RJ, Green R, et al. Phase II trial of de-intensified chemoradiotherapy for human papillomavirus-associated oropharyngeal squamous cell carcinoma. J Clin Oncol 2019;37:26612669.

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    Ma DJ, Price KA, Moore EJ, et al. Phase II evaluation of aggressive dose de-escalation for adjuvant chemoradiotherapy in human papillomavirus-associated oropharynx squamous cell carcinoma. J Clin Oncol 2019;37:19091918.

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    Yom SS, Torres-Saavedra P, Caudell JJ, et al. Reduced-dose radiation therapy for HPV-associated oropharyngeal carcinoma (NRG Oncology HN002). J Clin Oncol 2021;39:956965.

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    Hegde JV, Shaverdian N, Daly ME, et al. Patient-reported quality-of-life outcomes after de-escalated chemoradiation for human papillomavirus-positive oropharyngeal carcinoma: findings from a phase 2 trial. Cancer 2018;124:521529.

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    Ferris RL, Flamand Y, Weinstein GS, et al. Phase II randomized trial of transoral surgery and low-dose intensity modulated radiation therapy in resectable p16+ locally advanced oropharynx cancer: an ECOG-ACRIN Cancer Research Group Trial (E3311). J Clin Oncol 2022;40:138149.

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    Cooper JS, Pajak TF, Forastiere AA, et al. Postoperative concurrent radiotherapy and chemotherapy for high-risk squamous-cell carcinoma of the head and neck. N Engl J Med 2004;350:19371944.

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