Long-term survival and swallowing outcomes in advanced stage oropharyngeal squamous cell carcinomas

Jessica M Clark, Emma M Holmes, Daniel A O'Connell, Jeffrey Harris, Hadi Seikaly, Vincent L Biron, Jessica M Clark, Emma M Holmes, Daniel A O'Connell, Jeffrey Harris, Hadi Seikaly, Vincent L Biron

Abstract

Background: There is a paucity of studies reporting long-term survival outcomes for HPV/p16 positive oropharyngeal squamous cell carcinoma (OPSCC). This study aims to compare long-term outcomes of advanced stage p16 positive and negative OPSCCs, treated by surgical and non-surgical modalities.

Methods: OPSCC patients from 1998 to 2012 were identified through a prospectively collected cancer registry. P16 immunohistochemistry was used as a surrogate marker for HPV-OPSCC. Overall survival (OS) and aspiration free survival (AFS) comparisons were made between patients treated with chemoradiation (CRT) versus primary surgery and radiation/chemoradiation (S+RT/CRT) at 5, 10 and 15 years post-treatment.

Results: A total of 319 patients were included. P16 positive patients and non-smokers had significantly higher long-term (5, 10 and 15-year) OS. Smokers and p16 negative patients treated with S+RT/CRT had improved long-term OS compared to patients who received CRT. Smokers and p16 negative patients had lower long-term AFS. Multivariate analysis showed improved OS was associated with p16 positivity (HR 0.42, 0.28-0.61) and surgery (HR 0.47, 0.32-0.69), whereas lower OS was associated with ECOG ≥ 2 (HR 2.46, 1.61-3.77), smoking (HR 2.37, 1.41-3.99) and higher stage (HR 1.68, 1.05-2.68).

Conclusions: In smokers and p16-negative OPSCC patients, primary surgery may be associated with improved long-term survival and dysphagia-related outcomes.

Copyright © 2018. Published by Elsevier B.V.

Figures

Fig. 1
Fig. 1
Summary of patients included in this study. Patients with no p16 data did not have adequate specimen for tissue microarray construction (1998–2009) or had an inconclusive result clinical pathology (2010–2012). UA, University of Alberta.
Fig. 2
Fig. 2
Long-term survival of patients with oropharyngeal cancer according to p16 and smoking status. Survival up to 18 years follow-up is shown for advanced stage OPSCC patients, stratified by A) p16 status and B) smoking. Patients are classified as smokers with a > 10 pack year tobacco smoking history. Log-rank p-values are show comparing differences pooled over strata. C) 5, 10 and 15-year estimates of overall survival shown for each stratum.
Fig. 3
Fig. 3
Long-term survival of patients with oropharyngeal cancer according to treatment and p16 status. Survival up to 12.5 years follow-up is shown for advanced stage OPSCC patients, stratified according to treatment type in A) p16 positive and B) p16 negative patients. Log-rank p-values are show comparing pairwise differences between strata. C) 5 and 10-year estimates of overall survival shown for each stratum.
Fig. 4
Fig. 4
Long-term survival of patients with oropharyngeal cancer according to treatment and smoking status. Survival up to 12.5 years follow-up is shown for advanced stage OPSCC patients, stratified according to treatment type in A) smokers and B) non-smokers. Log-rank p-values are show comparing pairwise differences between strata. C) 5 and 10-year estimates of overall survival shown for each stratum.
Fig. 5
Fig. 5
Kaplan-Meier Estimates of Aspiration Free Survival in Patients with Oropharyngeal Cancer. The proportion of surviving patients free from aspiration post-treatment is shown stratified according to A) treatment type, B) p16 positivity and C) smoking status. P-value is shown using the Log-rank test comparing pooled differences between groups. D) 5, 10 and 15-year estimates of aspiration free survival are shown for each stratum.
Fig. 6
Fig. 6
Kaplan-Meier Estimates of Aspiration Free Survival in Patients with Oropharyngeal Cancer Stratified Treatment, Smoking and p16 Status. The proportion of surviving patients free from aspiration post-treatment is shown compared to surgical vs non-surgical treatments in A) p16 positive patients, B) p16 negative patients, C) smokers and D) non-smokers. P-value is shown as calculated using the Log-rank test comparing pairwise differences between strata. E) 5 and 10-year estimates of overall survival shown for each stratum.
Fig. 7
Fig. 7
Long-term survival of patients with oropharyngeal cancer stratified by G-tube dependency. Survival up to 12.5 years follow-up is shown for advanced stage OPSCC patients, stratified according to treatment type in A) patients who were free from g-tube > 1 year post-treatment and B) g-tube dependent > 1 year post-treatment. C) 5 and 10-year estimates of overall survival shown for each stratum.

References

    1. Chaturvedi A.K., D'Souza G., Gillison M.L., Katki H.A. Burden of HPV-positive oropharynx cancers among ever and never smokers in the U.S. population. Oral. Oncol. 2016;60:61–67.
    1. Gillison M.L., Restighini C. Anticipation of the impact of human papillomavirus on clinical decision making for the head and neck cancer patient. Hematol. Oncol. Clin. North Am. 2015;29:1045–1060.
    1. Gillison M.L., Chaturvedi A.K., Anderson W.F., Fakhry C. Epidemiology of human papillomavirus-positive head and neck squamous cell carcinoma. Am. Soc. Clin. Oncol. 2015;33:3235–3242.
    1. Sturgis E.M., Ang K.K. The epidemic of HPV-associated oropharyngeal cancer is here: is it time to change our treatment paradigms? J. Natl. Compr. Canc. Netw. 2011;9:665–673.
    1. Xie L., Semenciw R., Mery L. Cancer incidence in Canada: trends and projections (1983–2032) Health Promot. Chronic Dis. Prev. Can. 2015;35(Suppl 1):2–186.
    1. Lin B.M., Wang H., D'Souza G., Zhang Z., Fakhry C., Joseph A.W. Long-term prognosis and risk factors among patients with HPV-associated oropharyngeal squamous cell carcinoma. Cancer. 2013;119:3462–3471.
    1. D'Souza G., Gross N.D., Pai S.I., Haddad R., Anderson K.S., Rajan S. Oral human papillomavirus (HPV) infection in HPV-positive patients with oropharyngeal cancer and their partners. Am. Soc. Clin. Oncol. 2014;32:2408–2415.
    1. Chaturvedi A.K., Engels E.A., Anderson W.F., Gillison M.L. Incidence trends for human papillomavirus-related and -unrelated oral squamous cell carcinomas in the United States. J. Clin. Oncol. 2008;26:612–619. American Society of Clinical Oncology (Available from)
    1. Fakhry C., Andersen K.K., Eisele D.W., Gillison M.L. Oropharyngeal cancer survivorship in Denmark, 1977–2012. Oral. Oncol. 2015;51:982–984.
    1. Patel M.A., Blackford A.L., Rettig E.M., Richmon J.D., Eisele D.W., Fakhry C. Rising population of survivors of oral squamous cell cancer in the United States. Cancer. 2016;122:1380–1387.
    1. Bernier J., Domenge C., Ozsahin M., Matuszewska K., Lefèbvre J.-L., Greiner R.H. Postoperative irradiation with or without concomitant chemotherapy for locally advanced head and neck cancer. N. Engl. J. Med. 2004;(350):1945–1952. Massachusetts Medical Society (Available from)
    1. Boscolo-Rizzo P., Gava A., Baggio V., Marchiori C., Stellin M., Fuson R. Matched survival analysis in patients with locoregionally advanced resectable oropharyngeal carcinoma: platinum-based induction and concurrent chemoradiotherapy versus primary surgical resection. Int. J. Radiat. Oncol.*Biol.*Phys. 2011;80:154–160.
    1. Lacau St Guily J., Rousseau A., Baujat B., Périé S., Schultz P., Barry B. Oropharyngeal cancer prognosis by tumour HPV status in France: the multicentric Papillophar study. Oral. Oncol. 2017;67:29–36. (Available from)
    1. Seikaly H., Biron V.L., Zhang H., O'Connell D.A., Côté D.W.J., Ansari K. Role of primary surgery in the treatment of advanced oropharyngeal cancer. Head Neck. 2016;38(Suppl 1):E571–E579.
    1. Zenga J., Wilson M., Adkins D.R., Gay H.A., Haughey B.H., Kallogjeri D. Treatment outcomes for T4 oropharyngeal squamous cell carcinoma. JAMA Otolaryngol. Head. Neck Surg. 2015;141 (Available from) (1118–10)
    1. Baxi S.S., Pinheiro L.C., Patil S.M., Pfister D.G., Oeffinger K.C., Elkin E.B. Causes of death in long-term survivors of head and neck cancer. Cancer. 2014;120:1507–1513. (7 ed) (Available from)
    1. Hess C.B., Rash D.L., Daly M.E., Farwell D.G., Bishop J., Vaughan A.T. Competing causes of death and medical comorbidities among patients with human papillomavirus–positive vs human papillomavirus–negative oropharyngeal carcinoma and impact on adherence to radiotherapy. JAMA Otolaryngol. Head Neck Surg. 2014;140 (Available from) (312–11)
    1. Funk G.F., Karnell L.H., Christensen A.J. Long-term health-related quality of life in survivors of head and neck cancer. Arch. Otolaryngol. Head. Neck Surg. 2012;138:123–133. American Medical Association (Available from)
    1. Rosenthal D.I., Lewin J.S., Eisbruch A. Prevention and treatment of dysphagia and aspiration after chemoradiation for head and NeckCancer. J. Clin. Oncol. 2006;24:2636–2643. (Available from)
    1. Hutcheson K.A., Lewin J.S., Barringer D.A., Lisec A., Gunn G.B., Moore M.W.S. Vol. 118. 2012. Late dysphagia after radiotherapy-based treatment of head and neck cancer; pp. 5793–5799. (Cancer). (Available from)
    1. Hunter K.U., Lee O.E., Lyden T.H., Haxer M.J., Feng F.Y., Schipper M. Aspiration pneumonia after chemo-intensity-modulated radiation therapy of oropharyngeal carcinoma and its clinical and dysphagia-related predictors. Head Neck. 2013:120–125.
    1. Nguyen N.P., Frank C., Moltz C.C., Vos P., Smith H.J., Bhamidipati P.V. Aspiration rate following chemoradiation for head and neck cancer: an underreported occurrence. Radiother. Oncol. 2006;80:302–306. (Available from)
    1. O'Connell D., Seikaly H., Murphy R., Fung C., Cooper T., Knox A. Primary surgery versus chemoradiotherapy for advanced oropharyngeal cancers: a longitudinal population study. J. Otolaryngol. Head. Neck Surg. BioMed. Cent. 2013;42:31.
    1. Xu C.C., Biron V.L., Puttagunta L., Seikaly H. HPV status and second primary tumours in oropharyngeal squamous cell carcinoma. J. Otolaryngol. Head. Neck Surg. BioMed. Cent. 2013;42:36.
    1. Cooper T., Biron V.L., Adam B., Klimowicz A.C., Puttagunta L., Seikaly H. Association of keratinization with 5-year disease-specific survival in oropharyngeal squamous cell carcinoma. JAMA Otolaryngol. Head. Neck Surg. 2015;141:250–256. American Medical Association.
    1. Cooper T., Biron V., Adam B., Klimowicz A.C., Puttagunta L., Seikaly H. Prognostic utility of basaloid differentiation in oropharyngeal cancer. J. Otolaryngol. Head. Neck Surg. BioMed. Cent. 2013;42:57.
    1. Ang K.K., Harris J., Wheeler R., Weber R., Rosenthal D.I., Nguyen-Tân P.F. Human papillomavirus and survival of patients with oropharyngeal cancer. N. Engl. J. Med. 2010;363:24–35. Massachusetts Medical Society.
    1. Edge S.B., Compton C.C. The American Joint Committee on Cancer: the 7th edition of the AJCC cancer staging manual and the future of TNM. Ann. Surg. Oncol. 7 Ed. 2010;17:1471–1474.
    1. Dziegielewski P.T., O'Connell D.A., Rieger J., Harris J.R., Seikaly H. The lip-splitting mandibulotomy: aesthetic and functional outcomes. Oral. Oncol. 2010;46:612–617.
    1. Dziegielewski P.T., Mlynarek A.M., Dimitry J., Harris J.R., Seikaly H. Vol. 119. Laryngoscope. Wiley Subscription Services, Inc., A Wiley Company; 2009. pp. 2369–2375. (The Mandibulotomy: Friend or Foe? Safety Outcomes and Literature Review).
    1. Biron V.L., O'Connell D.A., Barber B., Clark J.M., Andrews C., Jeffery C.C. Transoral robotic surgery with radial forearm free flap reconstruction: case control analysis. J. Otolaryngol. Head. Neck Surg. BioMed. Cent. 2017;46:20.
    1. Jha N., Harris J., Seikaly H., Jacobs J.R., McEwan A.J.B., Robbins K.T. A phase II study of submandibular gland transfer prior to radiation for prevention of radiation-induced xerostomia in head-and-neck cancer (RTOG 0244) Int. J. Radiat. Oncol. Biol.* Phys. 2012;84:437–442.
    1. Al-Qahtani K., Rieger J., Harris J.R., Mlynarek A., Williams D., Islam T. Treatment of base of tongue cancer, stage III and stage IV with primary surgery: survival and functional outcomes. Eur. Arch. Otorhinolaryngol. 2015;272:2027–2033. Springer Berlin Heidelberg.
    1. Vaz J.A., Côté D.W.J., Harris J.R., Seikaly H. Outcomes of free flap reconstruction in the elderly. Head Neck. 2013;35:884–888.
    1. Seikaly H., Rieger J., O'Connell D., Ansari K., Alqahtani K., Harris J. Beavertail modification of the radial forearm free flap in base of tongue reconstruction: technique and functional outcomes. Head Neck. 2009:213–219.
    1. Seikaly H., Rieger J., Zalmanowitz J., Tang J.L., Alkahtani K., Ansari K. Functional soft palate reconstruction: a comprehensive surgical approach. Head Neck. 2008:1615–1623.
    1. Clark T.G., Bradburn M.J., Love S.B., Altman D.G. Survival analysis part I: basic concepts and first analyses. Br. J. Cancer. 2003:232–238.
    1. Bradburn M.J., Clark T.G., Love S.B., Altman D.G. Survival analysis part II: multivariate data analysis--an introduction to concepts and methods. Br. J. Cancer. 2003:431–436. Nature Publishing Group.
    1. Dale O.T., Sood S., Shah K.A., Han C., Rapozo D., Mehanna H. Long-term survival outcomes in patients with surgically treated oropharyngeal cancer and defined human papilloma virus status. J. Laryngol. Otol. 2016:1048–1053.
    1. Röösli C., Tschudi D.C., Studer G., Braun J., Stoeckli S.J. Outcome of patients after treatment for a squamous cell carcinoma of the oropharynx. Laryngoscope. 2009:534–540.
    1. Preuss S.F., Dinh V., Klussmann J.P., Semrau R., Mueller R.-P., Guntinas-Lichius O. Outcome of multimodal treatment for oropharyngeal carcinoma: a single institution experience. Oral. Oncol. 2007;43:402–407.
    1. Lim Y.C., Hong H.J., Baek S.J., Park J.H., Kim G.E., Lee C.G. Combined surgery and postoperative radiotherapy for oropharyngeal squamous cell carcinoma in Korea: analysis of 110 cases. Int. J. Oral. Maxillofac. Surg. 2008;37:1099–1105.
    1. Zelefsky M.J., Harrison L.B., Armstrong J.G. Long-term treatment results of postoperative radiation therapy for advanced stage oropharyngeal carcinoma. Cancer. 1992;70:2388–2395.
    1. Jones A.S., Fenton J.E., Husband D.J. The treatment of squamous cell carcinoma of the tonsil with neck node metastases. Head Neck. 2003:24–31. Wiley Subscription Services, Inc., A Wiley Company.
    1. Mak-Kregar S., Hilgers F.J., Levendag P.C., Manni J.J., Hart A.A., Visser O. Disease-specific survival and locoregional control in tonsillar carcinoma. Clin. Otolaryngol. Allied Sci. 1996;21:550–556.
    1. Machtay M., Perch S., Markiewicz D., Thaler E., Chalian A., Goldberg A. Combined surgery and postoperative radiotherapy for carcinoma of the base of radiotherapy for carcinoma of the base of tongue: analysis of treatment outcome and prognostic value of margin status. Head. Neck. 1997;19:494–499.
    1. Foote R.L., Olsen K.D., Davis D.L., Buskirk S.J., Stanley R.J., Kunselman S.J. Base of tongue carcinoma: patterns of failure and predictors of recurrence after surgery alone. Head. Neck. 1993;15:300–307.
    1. Hoffmann M., Saleh-Ebrahimi L., Zwicker F., Haering P., Schwahofer A., Debus J. Long term results of postoperative Intensity-Modulated Radiation Therapy (IMRT) in the treatment of Squamous Cell Carcinoma (SCC) located in the oropharynx or oral cavity. Radiat. Oncol. BioMed. Cent. 2015;10:251.
    1. Tiwana M.S., Wu J., Hay J., Wong F., Cheung W., Olson R.A. 25 year survival outcomes for squamous cell carcinomas of the head and neck: population-based outcomes from a Canadian province. Oral. Oncol. 2014;50:651–656.
    1. Bastos de Souza T.R., Pinto C.A.L., da Cunha Mercante A.M., Nishimoto I.N., Brasilino de Carvalho M., Kowalski L.P. Long-term results of surgical treatment for advanced oropharyngeal squamous cell carcinoma. Head Neck. 2014;36:1146–1154. (6 ed)
    1. DeNittis A.S., Liu L., Rosenthal D.I., Machtay M. Nasopharyngeal carcinoma treated with external radiotherapy, brachytherapy, and concurrent/adjuvant chemotherapy. Am. J. Clin. Oncol. 2002;25:93–95.
    1. Poulsen M., Porceddu S.V., Kingsley P.A., Tripcony L., Coman W. Locally advanced tonsillar squamous cell carcinoma: treatment approach revisited. Laryngoscope. 2007:45–50.
    1. Moore E.J., Henstrom D.K., Olsen K.D., Kasperbauer J.L., McGree M.E. Transoral resection of tonsillar squamous cell carcinoma. Laryngoscope. 2009:508–515. Wiley Subscription Services, Inc., A Wiley Company.
    1. Larsen C.G., Jensen D.H., Carlander A.-L.F., Kiss K., Andersen L., Olsen C.H. Novel nomograms for survival and progression in HPV+ and HPV- oropharyngeal cancer: a population-based study of 1,542 consecutive patients. Oncotarget. Impact J. 2016;7:71761–71772.
    1. Biron V.L., Kostiuk M., Isaac A., Puttagunta L., O'Connell D.A., Harris J. Detection of human papillomavirus type 16 in oropharyngeal squamous cell carcinoma using droplet digital polymerase chain reaction. Cancer. 2016;122:1544–1551.
    1. Biron V.L., Mohamed A., Hendzel M.J., Alan Underhill D., Seikaly H. Epigenetic differences between human papillomavirus-positive and -negative oropharyngeal squamous cell carcinomas. J. Otolaryngol. Head. Neck Surg. 2012;41(Suppl 1):S65–S70.
    1. Biron V.L., Côté D.W.J., Seikaly H. Oropharyngeal squamous cell carcinoma and human papillomavirus-associated cancers in women: epidemiologic evaluation of association. J. Otolaryngol. Head. Neck Surg. 2011;40(Suppl 1):S65–S69.
    1. Clark J., Jeffery C.C., Zhang H., Cooper T., O'Connell D.A., Harris J. Correlation of PET-CT nodal SUVmax with p16 positivity in oropharyngeal squamous cell carcinoma. J. Otolaryngol. Head. Neck Surg. BioMed. Cent. 2015;44:37.
    1. Barber B., Dergousoff J., Slater L., Harris J., O'Connell D., El-Hakim H. Depression and survival in patients with head and neck cancer: a systematic review. JAMA Otolaryngol. Head. Neck Surg. 2016;142:284–288. American Medical Association.
    1. Lindsay C., Seikaly H., Biron V.L. Epigenetics of oropharyngeal squamous cell carcinoma: opportunities for novel chemotherapeutic targets. J. Otolaryngol. Head. Neck Surg. BioMed. Cent. 2017;46:9.
    1. Idris S., Lindsay C., Kostiuk M., Andrews C., Côté D.W.J., O'Connell D.A. Investigation of EZH2 pathways for novel epigenetic treatment strategies in oropharyngeal cancer. J. Otolaryngol. Head. Neck Surg. BioMed. Cent. 2016;45:54.
    1. Isaac A., Kostiuk M., Zhang H., Lindsay C., Makki F., O'Connell D.A. Ultrasensitive detection of oncogenic human papillomavirus in oropharyngeal tissue swabs. J. Otolaryngol. Head. Neck Surg. BioMed. Cent. 2017;46:5.
    1. Harris B.N., Biron V.L., Donald P., Farwell D.G., Luu Q.C., Bewley A.F. Primary surgery vs chemoradiation treatment of advanced-stage hypopharyngeal squamous cell carcinoma. JAMA Otolaryngol. Head. Neck Surg. 2015;141:636–640. American Medical Association.
    1. Hanasoge S., Magliocca K.R., Switchenko J.M., Saba N.F., Wadsworth J.T., El-Deiry M.W. Clinical outcomes in elderly patients with human papillomavirus-positive squamous cell carcinoma of the oropharynx treated with definitive chemoradiation therapy. Head Neck. 2016;38:846–851.
    1. Fakhry C., Zhang Q., Nguyen-Tân P.F., Rosenthal D., El-Naggar A., Garden A.S. Human papillomavirus and overall survival after progression of oropharyngeal squamous cell carcinoma. Am. Soc. Clin. Oncol. 2014;32:3365–3373.
    1. Kumar B., Cordell K.G., Lee J.S., Worden F.P., Prince M.E., Tran H.H. EGFR, p16, HPV Titer, Bcl-xL and p53, sex, and smoking as indicators of response to therapy and survival in oropharyngeal cancer. J.Clin. Oncol. 2008;26:3128–3137.
    1. Sharma A., Patel S., Baik F.M., Mathison G., Pierce B.H.G., Khariwala S.S. Survival and gastrostomy prevalence in patients with oropharyngeal cancer treated with transoral robotic surgery vs chemoradiotherapy. JAMA Otolaryngol Head Neck Surg. 2016;142:691–697. (Available from)
    1. Feng F.Y., Kim H.M., Lyden T.H., Haxer M.J., Worden F.P., Feng M. Intensity-modulated chemoradiotherapy aiming to reduce dysphagia in patients with oropharyngeal cancer: clinical and functional results. J. Clin. Oncol. 2010;28:2732–2738. (Available from)
    1. Kraaijenga S.A.C., Oskam I.M., van der Molen L., Hamming-Vrieze O., Hilgers F.J.M., van den Brekel M.W.M. Vol. 51. 2015. Evaluation of long term (10-years+) dysphagia and trismus in patients treated with concurrent chemo-radiotherapy for advanced head and neck cancer; pp. 787–794. (Oral Oncol.). Elsevier (Available from)
    1. Vainshtein J.M., Moon D.H., Feng F.Y., Chepeha D.B., Eisbruch A., Stenmark M.H. Long-term quality of life after swallowing and salivary-sparing chemo-intensity modulated radiation therapy in survivors of human papillomavirus-related oropharyngeal cancer. Int. J. Radiat. Oncol. Biol. Phys. 2015;91:925–933.
    1. Eisbruch A., Kim H.M., Feng F.Y., Lyden T.H., Haxer M.J., Feng M. Chemo-IMRT of oropharyngeal cancer aiming to reduce dysphagia: swallowing organs late complication probabilities and dosimetric correlates. Int. J. Radiat. Oncol.*Biol.*Phys. 2011:e93–e99.
    1. Goepfert R.P., Yom S.S., Ryan W.R., Cheung S.W. Development of a chemoradiation therapy toxicity staging system for oropharyngeal carcinoma. Laryngoscope. 2015;125:869–876.
    1. Owadally W., Hurt C., Timmins H., Parsons E., Townsend S., Patterson J. PATHOS: a phase II/III trial of risk-stratified, reduced intensity adjuvant treatment in patients undergoing transoral surgery for Human papillomavirus (HPV) positive oropharyngeal cancer. BMC Cancer. 2015;15:602. 3rd ed. (BioMed. Central)
    1. N.R.G. HN002. httpsclinicaltrials.govctshowNCTtermhnrank.
    1. ECOG 3311 [Internet]. httpsclinicaltrials.govctshowNCTtermecogrank. [cited 2017 Sep 6]. Available from: .
    1. Nichols A.C., Yoo J., Hammond J.A., Fung K., Winquist E., Read N. Early-stage squamous cell carcinoma of the oropharynx: radiotherapy vs. Trans-Oral Robotic Surgery (ORATOR)--study protocol for a randomized phase II trial. BMC Cancer. 2013;13:133.
    1. Howard J., Masterson L., Dwivedi R.C., Riffat F., Benson R., Jefferies S. Minimally invasive surgery versus radiotherapy/chemoradiotherapy for small-volume primary oropharyngeal carcinoma. In: Howard J., editor. Cochrane Database System Reviews. John Wiley & Sons, Ltd; Chichester, UK: 2016. p. 12.
    1. Dale O.T., Han C., Burgess C.A., Eves S., Harris C.E., White P.L. Long-term functional outcomes in surgically treated patients with oropharyngeal cancer. Laryngoscope. 2015;125:1637–1643.
    1. Chung C.H., Zhang Q., Kong C.S., Harris J., Fertig E.J., Harari P.M. p16 protein expression and human papillomavirus status as prognostic biomarkers of nonoropharyngeal head and neck squamous cell carcinoma. Am. Soc. Clin. Oncol. 2014;32:3930–3938.
    1. Lydiatt W.M., Patel S.G., O'Sullivan B., Brandwein M.S., Ridge J.A., Migliacci J.C. Head and neck cancers-major changes in the American joint Committee on cancer eighth edition cancer staging manual. CA Cancer J. Clin. 2017;67 (7 ed.) (122–37)

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