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1 A Survey of Primary Care Providers’ Knowledge of HPV-associated Head and Neck Cancers: A focus on clinical characteristics, presentation and outcomes By James Taylor A Master’s Paper submitted to the faculty of the University of North Carolina at Chapel Hill in partial fulfillment of the requirements for the degree of Master of Public Health in the Public Health Leadership Program Chapel Hill 2016 2 Table of Contents Abstract ...........................................................................................................................................3 Introduction ....................................................................................................................................5 Methods ...........................................................................................................................................6 Results .............................................................................................................................................7 Demographics and Response Rates .....................................................................................8 Knowledge of Head and Neck Cancer .................................................................................9 Knowledge of HPV-associated Head and Neck Cancer ......................................................9 Knowledge of HPV Infection ..............................................................................................9 Discussion........................................................................................................................................9 Tables ............................................................................................................................................14 References .....................................................................................................................................20 Appendix .......................................................................................................................................26 Title (2) ..........................................................................................................................................35 Introduction (2) ............................................................................................................................36 Methods (2) ...................................................................................................................................37 Results (2) .....................................................................................................................................39 Discussion (2) ................................................................................................................................42 References (2) ...............................................................................................................................46 Appendix (2) .................................................................................................................................52 3 A Survey of Primary Care Providers’ Knowledge of HPV-associated Head and Neck Cancers: A focus on clinical characteristics, presentation and outcomes Importance: The epidemiology of head and neck cancer has changed in recent years, particularly as related to those associated with human papillomavirus (HPV). Understanding primary care physicians’ (PCPs) current knowledge about HPV-associated head and neck cancers (HNC) will help inform educational efforts on this important topic. Objective: To assess the knowledge and understanding of PCPs towards the rapidly changing clinical characteristics, presentation and outcomes associated with HPV-positive HNCs Design, Setting and Participants: Online survey of primary care physicians (pediatricians, general internists and family medicine physicians) at two tertiary academic medical centers in North Carolina between May and July of 2016. Results: 275 PCPs at two tertiary academic medical centers were invited to participate via email, 95 PCPs completed the survey for a response rate of 34.5%. The majority of respondents were female (67.0%), attending physicians (61.5%), had less than 10 years of practice experience (46.0%), and practiced in an academic setting (85.3%). PCPs correctly answered 56% of knowledge based questions about HPVs causative role in HNC. 79% of PCPs failed to correctly identify the most common clinical presentation of the HPV-positive patient. Further, only 23% of PCPs correctly identified that HPV is associated with a much improved prognosis in HNC. Survey data indicate that PCPs most commonly consider the HPV-positive patient to be an African American male presenting with a persistent sore throat or non-healing ulcer and to have prior tobacco and alcohol consumption. However, PCPs demonstrated a high degree of knowledge on HPV infection correctly answering 91% of questions regarding HPV infection. 4 Conclusions and Relevance: Although knowledgeable about HPV infection, PCPs are less knowledgeable about HPV’s role in head and neck cancer. We demonstrate the need for additional education among PCP physician groups with a focus on the clinical characteristics, presentations, and outcomes of the HPV-positive HNC patient. 5 Introduction Cancer of the head and neck is the sixth most common cancer worldwide with an estimated incidence of 633,000 cases annually.1 Recently in the United States the overall incidence of head and neck cancer (HNC) has declined, paralleling decreases in tobacco use.2 However, despite the overall decline in head and neck cancers, there has been an increase in the incidence of oropharyngeal squamous cell carcinoma (OPSCC) driven by human papillomavirus (HPV) infection.3 It is estimated that the incidence of HPV-associated OPSCC has increased by 225% from 1988-2004.4 Compared to patients with HPV-negative HNCs, patients with HPVpositive HNCs tend to be younger, from higher socioeconomic status, have less tobacco and alcohol exposure, and are more likely to be caucasian.5-6 In addition, HPV-positive disease tends to have superior oncologic outcomes and improved response to therapy.7,8 Due to the substantial differences between patients who present with HPV-positive and HPV-negative HNC, it is imperative that primary care physicians are knowledgeable about the rapidly changing epidemiology, clinical characteristics and outcomes associated with HPV-driven HNC in order to appropriately refer high-risk patients. Currently, a paucity of data exist regarding the knowledge and awareness of HPVassociated HNCs among primary care physicians (PCPs).9 Previous studies have estimated that nearly 20% of chief complaints in primary care involve the head and neck; thus, PCPs have the difficult task of identifying, screening, and referring patients who are at highest risk for HNC and serve a crucial role in primary prevention of these malignancies.10,11 Although questions about tobacco and alcohol use could previously be used to effectively risk-stratify patients with head and neck complaints, these questions may be less sensitive in light of the recent emergence 6 of HPV-related HNC. Overall, the rapid changes associated with HPV-positive HNC pose significant clinical challenges for both PCPs and specialists. The goal of this research is to build upon efforts by the American Head & Neck Society (AHNS) to help educate providers from multiple specialties on the rapidly changing presentation and outcomes associated with HPV-positive head and neck cancers by identifying areas where additional educational resources would benefit PCPs. In order to gain insight into the knowledge of PCPs with respect to HPV-positive HNC, a survey was developed and distributed at two tertiary academic medical centers in North Carolina. Methods We developed a 29-question electronic survey to assess the current knowledge of PCPs in regards to HPV-positive HNC. The survey included a broad assessment of three topics: general knowledge of head and neck cancer, general knowledge about HPV, and specific knowledge about the association of HPV with head and neck cancers. This survey instrument was developed in a collaborative manner with input from head and neck oncology specialists, radiation oncologists, family physicians, and epidemiologists at the University of North Carolina at Chapel Hill (the full survey is located in the appendix). In addition, relevant literature and practice guidelines were searched and incorporated into the development process. Finally, several questions previously used in a survey of AHNS members on awareness of HPVassociated head and neck cancers were included with permission.12 Content and discriminant validity were assessed by a group of 5 physicians and 5 medical students respectively. The final survey was distributed to PCPs, including residents and attending physicians, at the University of North Carolina at Chapel Hill and Wake Forest University in North Carolina. 7 For the purpose of this study, the term “PCPs” included general pediatricians, general internists and family medicine physicians. The survey was made available to these physicians via an online form (Google Forms, Alphabet Inc., Mountain View, CA) between March and July of 2016. No compensation or incentive was provided for participation. The study was approved by the institutional review board at the University of North Carolina at Chapel Hill. Individual scores were calculated as percent for correct overall and for each category of questions and stratified by specialty. Additionally, overall scores were calculated for each knowledge based question. We compared means with either student’s t-test or ANOVA as appropriate with SAS 9.4 (SAS Institute, Cary, NC). Results Demographics and Response Rates The survey had an overall response rate of 34.5% with 95 of 275 PCPs responding and completing the survey. One respondent answered less than 50% of the survey and was excluded from data analysis. Provider characteristics for respondents can be found in Table 1. Over twothirds of respondents were female (67%). Pediatricians had the highest proportion of respondents with a 41.7% response rate, followed by family medicine at 36.4%. The majority of respondents were attending physicians (61%) and were practicing in an academic setting (85%). Of responding attending physicians 46% had less than 10 years of practice experience. Knowledge about Head and Neck Cancer The overall percentage of correctly answered questions about general head and neck cancer knowledge was 68% (Standard Deviation (SD): 18%). Survey questions and answers with 8 percentage of correct responses for general HNC can be found in Table 2. The most commonly missed question was “the incidence of head and neck cancer is decreasing in the United States” with only 19% responding correctly. When stratified by specialty, pediatricians had the average highest percentage of correctly answered questions (72%) followed by family and internal medicine (67% and 64% respectively). Results stratified by question category and specialty can be found in Table 3. Knowledge about HPV’s Causative Role in HNC The percentage of correct responses was relatively low for knowledge regarding HPVdriven HNCs at 56% (SD 15%). The corresponding questions and percent correct can be found in Table 4. Only 61% of respondents correctly identified the oropharynx as the most common site for HPV-positive head and neck cancer to occur. Additionally, only 21% correctly identified that a painless neck mass is the most common presentation for HPV-positive OPSCC. Pediatricians had a 58% correct response rate followed by family medicine and internal medicine at 56% respectively (p-value: 0.77). Knowledge about HPV Infection Overall, accuracy for knowledge about HPV infection was greater than for either general HNC knowledge or knowledge of HPVs causative role in HNC as evidenced by Table 5. Most respondents correctly indicated “most patients with HPV do not experience symptoms of infection” (98%). The average percentage of correctly answered questions on general knowledge of HPV infection was 91% (SD 14%). Although not statistically significant, we found that family physicians were most knowledgeable about HPV infection with a 93% overall correct response rate, followed by internal medicine and pediatrics at 90% and 87%, respectively. 9 Discussion A growing body of literature has demonstrated that patients with HPV-positive OPSCC have distinct risk factors, oncologic outcomes and improved survival compared with non-HPV HNC cancer patients.13 These significant differences between HPV-positive and HPV-negative HNCs indicate that cancers driven by HPV may be biologically and clinically distinct entities from cancers caused by tobacco and alcohol. This rapid change in the incidence of HPV-positive HNCs poses significant clinical challenges. Specifically, for PCPs who are often the first providers to see a patient with various complaints, the presentation of the “classic” head and neck cancer patient is changing. Correctly identifying high-risk patients among the approximately 20% of primary care patients with complaints involving the head and neck will require primary care physicians to be aware of clinical presentations and risk factors for HPVrelated HNC.10,14 To our best knowledge, no previous studies in the United States have been conducted to assess the level of knowledge of PCPs about HPV-associated head and neck cancers. In our study, PCPs correctly answered only 68% of questions assessing general head and neck cancer knowledge. Respondents were most knowledgeable with respect to common risk factors for developing HNC correctly identifying that tobacco and alcohol remain the most important risk factors for HNC. However, as hypothesized, knowledge regarding the HPV-positive HNC patient was lower compared with knowledge about general HNC patients. Overall, PCPs poorly understood the most common demographics and presentation of the HPV-positive patient. Survey data indicate that PCPs most commonly consider the HPV-positive patient to be an African American male presenting with a persistent sore throat or non-healing ulcer and to have prior tobacco and alcohol consumption. In reality the most common clinical picture is a younger 10 Caucasian male presenting with a painless neck mass without a significant alcohol and tobacco history.15,16 This information indicates that PCPs are not fully aware of the demographic differences between the HPV-positive and HPV-negative HNC populations. These misunderstandings hold the potential to lead to delayed initial diagnosis, as well as a decreased likelihood of the providers obtaining a relevant sexual history to evaluate for risk factors for HPV transmission. Additionally, most PCPs believe that HPV-positive patients respond worse to chemoradiotherapy and have worse outcomes overall in regards to morbidity and survival. This is the opposite of the clinical picture associated with HPV-positive patients who have improved response to therapy and clinical outcomes.17 Although a detailed understanding of HPV HNC prognosis and treatment is unnecessary in the context of appropriate primary care, basic awareness of treatment modalities and outcomes can dramatically alter physician approaches to initial patient counseling and referral. For example, the presence of regional lymph node metastasis in HPV-negative HNC patients is considered to be a major indicator of poor prognosis.15 In contrast, HPV-positive OPSCC patients tend to have more extensive lymph node metastasis at time of diagnosis, but this is not associated with major changes in outcome.18 Considering that HNCs can often present with relatively general, insidious symptoms, PCPs are likely to be the first providers to assess many of these patients and play a vital role in preventing diagnostic delay.14 In the absence of national HNC screening guidelines from the United States Preventive Services Task Force (USPSTF), early detection of HNC is even more reliant on the judgment and knowledge of PCPs. Furthermore, errors or delays in diagnosis can have grave consequences as patients diagnosed with late stage disease often require more aggressive treatment and have a poorer prognosis.19 Therefore, education specifically directed 11 towards PCPs to increase awareness of the common clinical characteristics and presentations of HPV-positive HNC patients has the potential to improve outcomes through increased surveillance and early detection. Despite this clear importance of HNC awareness among PCPs, there is evidence that current levels of HNC and otolaryngology knowledge among this group may be sub-optimal. A 2012 survey found that significant portions of PCPs incorrectly identified common presentations of otolaryngology diseases.20 Furthermore, a study conducted by Jackowska et al in Poland found that general practitioners (GPs) were less knowledgeable regarding the association between HPV and head and neck cancer compared with otolaryngologists.9 A similar study of GPs in Italy found that GPs were considerably less knowledgeable about the association of HPV and HNC, compared to HPV’s role in the development of cervical, vulvar and vaginal cancers.21 Overall, when queried, the vast majority of PCPs subjectively desired further education and training about otolaryngology.22 Overall, despite previous studies showing that otolaryngologists are quite knowledgeable about these HPV-related shifts in head and neck oncology, our results clearly indicate that novel and clinically important HPV research is inconsistently being presented to clinicians in primary care fields.12 Furthermore, our study provides evidence about where knowledge gaps exist among PCPs’ understanding of HPV-positive HNC, specifically, the common presentations, risk factors, demographics, and outcomes of this disease. Assessing these awareness gaps objectively allows for specialty societies, such as the American Head and Neck Society, to collaboratively work with family medicine, pediatric, and internal medicine groups to develop educational tools. In fact, a 2013 survey-based study found that 96% of AHNS members support efforts by the AHNS to educate other clinicians about the link between HPV infection and head and neck 12 cancer.12 Overall, we demonstrate the need for increased education among primary care providers with a focus on the HPV-positive patient. The solutions to this challenge will likely be multifold. One potential avenue is addressing the knowledge gaps early by incorporating additional otolaryngology education into medical school curriculums in the United States. Currently, less than 2/3 of American medical schools require any clinical otolaryngology experience.23 This gap likely contributes to the fact that several previous studies have shown insufficient HNC knowledge and physical exam skills among medical students, as well as to ongoing HNC knowledge deficits later in these students’ careers.24-22 Additionally, otolaryngology professional societies should continue to encourage primary care providers to attend otolaryngology conferences or work in unison to organize multispecialty conferences where relevant HNC and HPV research can be presented to both PCP and otolaryngology researchers. Overall, we believe that our study is the first to objectively measure the awareness of HPV-related trends in HNC among PCPs in the United States and builds upon the AHNS’ recent emphasis on education.12 Strengths of our study include a multidisciplinary team of clinicians and researchers who assisted in the survey development process, a high response rate by attending physicians, and survey distribution at two large academic medical centers. Limitations include an overall response rate of 34.5% that could possibly lead to nonresponder bias and limited geographical distribution that could potentially fail to capture a more diverse practice setting. Although relatively low, this response rate is comparable to previous electronic surveys of physicians.25 13 Our study provides evidence that PCPs, although knowledgeable with respect to the “classic” head and neck cancer patient, are less knowledgeable about the HPV-positive head and neck cancer patient. We demonstrate a need for additional education among PCPs with respect to HPV-positive HNCs. Innovative and collaborative efforts, directed at increasing both otolaryngology training in medical education and among active PCPs will be needed in a timely manner to improve current knowledge gaps. Such collaborative efforts should be conducted in a manner that maximizes the role of the primary care physician within the multidisciplinary oncologic treatment team. 14 Table 1. Provider Characteristics Respondents ,% Provider Characteristics (n=95) Sex Male 33.0 Female 67.0 Practice Time (years) Resident/Fellow 41.0 1-10 26.3 11-20 14.8 >20 17.9 Practice Setting Academic 85.3 Clinic or Public Hospital 10.5 Other 4.2 Primary Discipline Internal Medicine 23.4 Pediatrics 26.6 Family Medicine 48.9 Other 1.1 15 Table 2. General Knowledge of HNC Question Answer (True/False) Mean Percent Correct Head and neck cancer patients commonly present with False 92.5% True 88.3% True 86.2% False 52.1% False 19.1% early stage disease Head and neck cancer occurs more commonly in males than females Alcohol and tobacco remain the most important risk factors for head and neck cancer Cancer of the larynx is the most common site for head and neck cancer to occur The incidence of head and neck cancer is decreasing in the United States 16 Table 3. Percent correct by question category and specialty Question Category Mean Percent Correct P-value (SD) General Head and Neck Cancer Pediatrics 72% (17%) Family Medicine 67% (16%) Internal Medicine 64% (19%) 0.26 General HPV Pediatrics 87% (15%) Family Medicine 93% (15%) Internal Medicine 90% (13%) 0.21 HPV-related head and neck cancer 58% (13%) Pediatrics 56% (14%) Family Medicine 56% (19%) Internal Medicine 0.77 17 Table 4. HPV-associated HNC Knowledge Question All types of HPV can lead to head and neck cancer Answer Mean Percent Correct False 86.2% Have a younger 83.0% True False HPV positive vs HPV negative head and neck cancer patients are more likely to? Have a younger mean age at diagnosis mean age at diagnosis Have an older mean age at diagnosis Have a similar mean age at diagnosis Where is the most common site for HPV positive head and Oropharynx 60.6% HPV positive vs HPV negative patients are more likely to Less tobacco and 53.2% have alcohol exposure neck cancer Oral cavity Oropharynx Hypopharynx Oral tounge Greater tobacco and alcohol exposure Less tobacco and alcohol exposure Similar tobacco and alcohol exposure HPV positive vs HPV negative head and neck cancer is False 45.7% 18 more likely to occur in African Americans True False HPV positive head and neck cancers respond worse to False 45.7% True 22.6% Painless neck mass 21.3% chemoradiotherapy True False HPV is associated with a much improved prognosis for patients with head and neck cancer True False What is the most common presenting sign for patient with HPV-positive oropharynx cancer Non healing ulcer Painless neck mass Dysphagia Persistant sore throat 19 Table 5. General knowledge of HPV Infection Question Answer Mean Percent Correct (True/False) Most patients with HPV experience symptoms of the False 97.8% False 95.7% False 94.7% False 74.2% infection Patients with a history of HPV infection should not be offered the HPV vaccination HPV is a relatively uncommon sexually transmitted infection Current HPV vaccinations do not cover serotypes associated with head and neck cancers 20 References 1. Ferlay J, Shin HR, Bray F, Forman D, Mathers C, Parkin DM. Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. Int J Cancer. 2010;127(12):2893-2917. doi:10.1002/ijc.25516. 2. Chai RC, Lambie D, Verma M, Punyadeera C. Current trends in the etiology and diagnosis of HPV-related head and neck cancers. Cancer Med. 2015:n/a - n/a. doi:10.1002/cam4.424. 3. Marur S, D’Souza G, Westra WH, Forastiere AA. HPV-associated head and neck cancer: a virus-related cancer epidemic. Lancet Oncol. 2010;11(8):781-789. doi:10.1016/S14702045(10)70017-6. 4. Chaturvedi AK, Engels EA, Pfeiffer RM, et al. Human Papillomavirus and Rising Oropharyngeal Cancer Incidence in the United States. J Clin Oncol. 2011;29(32):42944301. doi:10.1200/JCO.2011.36.4596. 5. Gillison ML, D’Souza G, Westra W, et al. Distinct risk factor profiles for human papillomavirus type 16-positive and human papillomavirus type 16-negative head and neck cancers. J Natl Cancer Inst. 2008;100(6):407-420. doi:10.1093/jnci/djn025. 6. Ragin CCR, Taioli E. Survival of squamous cell carcinoma of the head and neck in relation to human papillomavirus infection: Review and meta-analysis. Int J Cancer. 2007;121(8):1813-1820. doi:10.1002/ijc.22851. 7. 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 21 Clinical Trial. JNCI J Natl Cancer Inst. 2008;100(4):261-269. doi:10.1093/jnci/djn011. 8. Dayyani F, Etzel CJ, Liu M, Ho C-H, Lippman SM, Tsao AS. Meta-analysis of the impact of human papillomavirus (HPV) on cancer risk and overall survival in head and neck squamous cell carcinomas (HNSCC). Head Neck Oncol. 2010;2:15. doi:10.1186/17583284-2-15. 9. Jackowska J, Bartochowska A, Karlik M, Wichtowski M, Tokarski M, Wierzbicka M. The knowledge of the role of papillomavirus - Related head and neck pathologies among general practitioners, otolaryngologists and trainees. A survey-based study. PLoS One. 2015;10(10):1-10. doi:10.1371/journal.pone.0141003. 10. Griffiths E. Incidence of ENT problems in general practice. J R Soc Med. 1979;72(10):740-742. http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=1437201&tool=pmcentrez&re ndertype=abstract. 11. Rourke T, Tassone P, Philpott C, Bath A. ENT cases seen at a local “walk-in centre”: a one year review. J Laryngol Otol. 2009;123(May 2008):339-342. doi:http://dx.doi.org/10.1017/S0022215108002508. 12. Malloy KM, Ellender SM, Goldenberg D, Dolan RW. A survey of current practices, attitudes, and knowledge regarding human papillomavirus-related cancers and vaccines among head and neck surgeons. JAMA Otolaryngol Head Neck Surg. 2013;139(10):10371042. doi:10.1001/jamaoto.2013.4452. 13. Kian Ang K, Ang KK, Harris J, et al. Human Papillomavirus and Survival of Patients with 22 Oropharyngeal Cancer. N Engl J Med. 2010;363(1):24-35. doi:10.1056/NEJMoa0912217. 14. Emery JD, Shaw K, Williams B, et al. The role of primary care in early detection and follow-up of cancer. Nat Rev Clin Oncol. 2014;11(1):38-48. doi:10.1038/nrclinonc.2013.212. 15. Klozar J, Kratochvil V, Salakova M, et al. HPV status and regional metastasis in the prognosis of oral and oropharyngeal cancer. Eur Arch Oto-Rhino-Laryngology. 2008;265(SUPPL. 1). doi:10.1007/s00405-007-0557-9. 16. Boscolo-Rizzo P, Del Mistro A, Bussu F, et al. New insights into human papillomavirusassociated head and neck squamous cell carcinoma. Acta Otorhinolaryngol Ital organo Uff della Soc Ital di Otorinolaringol e Chir Cerv-facc. 2013;33(2):77-87. http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=3665382&tool=pmcentrez&re ndertype=abstract. 17. O’Rorke MA, Ellison M V., Murray LJ, Moran M, James J, Anderson LA. Human papillomavirus related head and neck cancer survival: A systematic review and metaanalysis. Oral Oncol. 2012;48(12):1191-1201. doi:10.1016/j.oraloncology.2012.06.019. 18. McIlwain WR, Sood AJ, Nguyen S a, Day T a. Initial Symptoms in Patients With HPVPositive and HPV-Negative Oropharyngeal Cancer. JAMA Otolaryngol Head Neck Surg. 2014;140(5):1-7. doi:10.1001/jamaoto.2014.141. 19. Collins R, Flynn A, Melville A, Richardson R, Eastwood A. Effective health care: management of head and neck cancers. Qual Saf Health Care. 2005;14(2):144-148. doi:10.1136/qshc.2005.013961. 23 20. Hu a, Sardesai MG, Meyer TK. A need for otolaryngology education among primary care providers. Med Educ Online. 2012;17:17350. doi:10.3402/meo.v17i0.17350. 21. Signorelli C, Odone A, Pezzetti F, et al. Infezione da Papillomavirus umano e vaccinazione : conoscenze e ruolo dei medici di medicina generale Human Papillomavirus infection and vaccination : knowledge and attitudes of Italian general practitioners. 2014;38(6):3-7. 22. Clamp PJ, Gunasekaran S, Pothier DD, Saunders MW. ENT in general practice: training, experience and referral rates. J Laryngol Otol. 2007;121(6):580-583. doi:10.1017/S0022215106003495. 23. Chawdhary G, Ho EC, Minhas SS. Undergraduate ENT education: What students want. Clin Otolaryngol. 2009;34(6):584-585. doi:10.1111/j.1749-4486.2009.02027.x. 24. Mohyuddin N, Langerman A, LeHew C, et al. Knowledge of Head and Neck Cancer Among Medical Students at 2 Chicago Universities. Arch Otolaryngol Neck Surg. 2008;134(12):1294. doi:10.1001/archotol.134.12.1294. 25. Cunningham CT, Quan H, Hemmelgarn B, et al. Exploring physician specialist response rates to web-based surveys. BMC Med Res Methodol. 2015;15:32. doi:10.1186/s12874015-0016-z. 26. Westra WH. The changing face of head and neck cancer in the 21st century: the impact of HPV on the epidemiology and pathology of oral cancer. Head Neck Pathol. 2009;3(1):7881. doi:10.1007/s12105-009-0100-y. 27. Schlecht NF, Franco EL, Pintos J, Kowalski LP. Effect of smoking cessation and tobacco 24 type on the risk of cancers of the upper aero-digestive tract in Brazil. Epidemiology. 1999;10(4):412-418. doi:00001648-199907000-00009 [pii]. 28. King T, Agulnik M. Head and Neck Cancer: Changing Epidemiology and Public Health Implications. Oncol J. 2010:6-8. www.cancer.gov/.../HeadandNeck-Snapshot.pdf. 29. Chera BS, Amdur RJ, Tepper J, et al. Phase 2 trial of de-intensified chemoradiation therapy for favorable-risk human papillomavirus-associated oropharyngeal squamous cell carcinoma. Int J Radiat Oncol Biol Phys. 2015;93(5):976-985. doi:10.1016/j.ijrobp.2015.08.033. 30. Barnett ML, Song Z, Landon BE. Trends in physician referrals in the United States, 19992009 - with comments. Arch Intern Med. 2012;172(2):163-170. doi:10.1001/archinternmed.2011.722. 31. Scott JR, Wong E, Sowerby LJ. Evaluating the referral preferences and consultation requests of primary care physicians with otolaryngology – head and neck surgery. J Otolaryngol - Head Neck Surg. 2015;44(1):57. doi:10.1186/s40463-015-0114-2. 32. Gillison ML, Koch WM, Capone RB, et al. Evidence for a causal association between human papillomavirus and a subset of head and neck cancers. JNatlCancer Inst. 2000;92(9):709-720. http://www.ncbi.nlm.nih.gov/pubmed/10793107. 33. Malloy KM, Ellender SM, Goldenberg D, Dolan RW. A survey of current practices, attitudes, and knowledge regarding human papillomavirus-related cancers and vaccines among head and neck surgeons. JAMA Otolaryngol Head Neck Surg. 2013;139(10):10371042. doi:10.1001/jamaoto.2013.4452. 25 34. Joseph AW, D’Souza G. Epidemiology of Human Papillomavirus-Related Head and Neck Cancer. Otolaryngol Clin North Am. 2012;45(4):739-764. doi:10.1016/j.otc.2012.04.003. 35. Gregoire V, Lefebvre J-L, Licitra L, Felip E. Squamous cell carcinoma of the head and neck: EHNS-ESMO-ESTRO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2010;21(Supplement 5):v184-v186. doi:10.1093/annonc/mdq185. 26 Appendix Head and Neck Cancer: A Changing Presentation Please tell us about your medical practice. Provider Characteristics Please choose the most appropriate answer by marking in the oval: In what discipline did you receive your primary training? Mark only one oval. o Family Medicine o Internal Medicine o Pediatrics o Other If you answered "other" for the previous question, please provide what you consider your primary discipline: How many years have you been in practice? Mark only one oval. o Resident o Clinical Fellow o 1-5 o 6-10 o 11-15 27 o 16-20 o >20 In which practice setting do you most commonly practice? Mark only one oval. o Private Practice o Academic Setting o Clinic or Public Hospital o Managed Care Organization o Other What gender do you identify with? Mark only one oval. o Male o Female General Knowledge Regarding Head and Neck Cancers Please indicate either True or False: The incidence of head and neck cancer is decreasing in the United States. Mark only one oval. o True o False 28 Cancer of the larynx is the most common site for head and neck cancer to occur. Mark only one oval. o True o False Head and neck cancer patients commonly present with early stage disease. Mark only one oval. o True o False Alcohol and tobacco remain the most important risk factors for head and neck cancer. Mark only one oval. o True o False GENERAL KNOWLEDGE OF HUMAN PAPILLOMAVIRUS AND PREVENTION Please indicate either True or False: All types of Human Papillomavirus (HPV) can lead to head and neck cancer. Mark only one oval. o True o False 29 HPV-positive head and neck cancers respond worse to chemoradiation therapy. Mark only one oval. o True o False HPV is a relatively uncommon sexually transmitted infection. Mark only one oval. o True o False HPV is associated with a much improved prognosis for patients with head and neck cancer. Mark only one oval. o True o False Head and neck cancer occurs more commonly in males than females. Mark only one oval. o True o False Patients with a history of HPV infection should not be offered the HPV vaccination. Mark only one oval. 30 o True o False Most patients with HPV experience symptoms of the infection. Mark only one oval. o True o False Current HPV vaccinations do not cover serotypes associated with head and neck cancers. Mark only one oval. o True o False Knowledge of HPV Head and Neck Cancer Patients Please choose the most appropriate answer: Where is the most common site for HPV positive head and neck cancer? Mark only one oval. o Oral Cavity o Oropharynx o Hypopharynx o Oral Tongue HPV positive vs HPV negative head and neck cancer patients are more likely to: 31 Mark only one oval. o Have a younger mean age at diagnosis. o Have an older mean age at diagnosis. o Have a similar mean age at diagnosis. What is the most common presenting sign for a patient with HPV positive oropharynx cancer? Mark only one oval. o Nonhealing ulcer o Dysphagia o Painless neck mass o Persistent sore throat HPV positive vs HPV negative head and neck cancer is more likely to occur in African Americans. Mark only one oval. o True o False HPV negative vs HPV positive head and neck cancer patients are more likely to have: Mark only one oval. o Greater tobacco and alcohol exposure. o Less tobacco and alcohol exposure. 32 o Similar tobacco and alcohol exposure. Current Practice Trends Please select the most appropriate answer: When you discuss alcohol related diseases with patients, how often do you discuss alcohol as a risk factor for head and neck cancer? Mark only one oval. o Always o Often o Sometimes o Seldom o Never When you discuss smoking related diseases with patients, how often do you discuss smoking as a risk factor for head and neck cancer? Mark only one oval. o Always o Often o Sometimes o Seldom o Never 33 When you discuss smokeless tobacco related diseases with patients, how often do you discuss smokeless tobacco as a risk factor for head and neck cancer? Mark only one oval. o Always o Often o Sometimes o Seldom o Never How often do you recommend the HPV vaccination to eligible female patients? Mark only one oval. o Always o Often o Sometimes o Seldom o Never o N/A How often do you recommend the HPV vaccination to eligible male patients? Mark only one oval. o Always o Often o Sometimes 34 o Seldom o Never o N/A When you discuss the benefits of the HPV vaccination with female patients, how often do you discuss protection from head and neck cancer as a potential benefit? Mark only one oval. o Always o Often o Sometimes o Seldom o Never o N/A When you discuss the benefits of the HPV vaccination with male patients, how often do you discuss protection from head and neck cancer as a potential benefit? Mark only one oval. o Always o Often o Sometimes o Seldom o Never o N/A 35 A Systematic Review of the Knowledge, Attitudes and Beliefs of Primary Care Physicians towards Human Papillomavirus-Positive Head and Neck Cancer 36 Introduction Cancers of the head and neck are a heterogenous group of malignancies that share common anatomical origins.6 Historically, head and neck cancers (HNCs) have been classified based upon their anatomic locations.26 Recently, due to many clinical and biological differences, a subset of HNCs oropharyngeal squamous cell carcinomas (OPSCC) have been further divided based upon their association with Human Papillomavirus (HPV). 1 In the United States, it is estimated that the incidence of HPV-positive OPSCC has increased by 225% from 1988 to 2004.2,27,4 Several theories have been proposed to explain this trend, yet the causative mechanisms underlying this increase have not been fully elucidated.5 Compared with HPVnegative OPSCC, patients with HPV-positive OPSCC have distinct risk factor profiles, treatment strategies, and clinical outcomes.7,28 Additionally, these patients tend to be younger, from higher socioeconomic status, have less tobacco and alcohol exposure, and are more likely to be Caucasian.4 HPV-positive disease may require less aggressive treatments compared with HPVnegative disease and has demonstrated superior oncologic outcomes and improved response to therapy over various treatment modalities.7,29 Due to these substantial differences, it is imperative that primary care physicians (PCPs) are knowledgeable about the rapidly changing clinical picture of the HPV-positive OPSCC patient. Currently, limited data exist that detail the present knowledge, attitudes, and beliefs towards HPV-positive OPSCC among primary care physicians (PCPs).9 PCPs form the backbone of the healthcare system and provide the referral base to head and neck surgeons. Therefore, their knowledge of HPV-positive OPSCC plays a critical role in ensuring the timely referral of patients to head and neck specialists.30,31Additionally, many primary care physicians serve as a patient’s primary medical resource. In this role, primary care physicians seek to educate their 37 patients on preventive health measures, inform their patients of screening recommendations, and aid their patients in shared medical decision making. Additionally, with the advent of the HPV vaccine, there is an added interest in its role in prevention of HPV-positive OPSCC. Therefore, without formal screening guidelines for head and neck cancers, the rapid changing factors associated with HPV-positive OPSCC and the potential for prevention through increased vaccination, it is imperative that PCPs are knowledgeable with respect to this evolving disease. The purpose of this systematic review is to examine the current literature regarding studies which provide insight into the overall knowledge, attitudes, and beliefs of PCPs (and head and neck surgeons) towards HPV-positive OPSCC. The objectives (key principles) of the review are to (1) examine the current level of knowledge among PCPs on HPV-positive OPSCC (2) examine the practice patterns of PCPs towards HPV-positive OPSCC with a focus on risk factor counseling and (3) examine the beliefs of PCPs towards the HPV-vaccination as a method of prevention for OPSCC. Methods Search Criteria A computerized search of PubMed, CINHAL and SCOPUS was performed to identify pertinent articles published between January 1, 2000 and July 2, 2016. The date January 1, 2000 was selected to reflect the Gillison et al. paper which first reported on HPV status in HNSCC patients.32 Prior to 2000, HPV status was not widely reported in head and neck cancer, and it was determined that expanding the search beyond January 1, 2000 would not be relevant for the current study. Additionally, due to limited data on PCPs knowledge of HPV-positive OPSCC, terms for head and neck surgeons were added to the search criteria as several studies contain 38 information comparing head and neck surgeons’ knowledge to that of PCPs. The full search strategy for each database can be found in Table 1. Briefly, we used combinations of key terms to search each database based on database specific criteria. Additionally, to ensure the thoroughness of the search, hand searches were performed on relevant articles returned from the initial search strategy. Articles identified by hand searches were reviewed, critically appraised and, when deemed appropriate, incorporated into the review. Finally, ClinicalTrials.gov was searched to identify any unpublished studies and results. Studies were screened at the abstract level and during full text review. Ultimately, articles were included only if they had relevant information pertaining to (1) oropharyngeal squamous cell carcinoma, (2) head and neck cancer, (3) primary care physicians (pediatricians, internal medicine physicians and family medicine physicians) or head and neck surgeons, (4) contained data commenting on one of the three principles established for the current review and (5) included information from surveys, questionnaires, or focus groups. For details on inclusion and exclusion criteria see Table 2. Studies were excluded if PCPs knowledge, attitudes, and beliefs were modeled (Table 2). Only English language studies were included in the analysis and any studies published from countries outside of the Organisation for Economic Co-Operation and Development (OECD) were excluded. Data Extraction We reviewed all titles and abstracts of studies identified using the defined search strategies. Articles that did not meet inclusion criteria based upon their titles and abstracts were excluded from full text review. We designed and used prespecified structured forms to extract pertinent information from each article, including but not limited to, number of participants 39 (respondents), type of participants, study design, survey (or questionaire) response rates, survey (or questionaire) questions, location where research was conducted, and study outcomes. Assesment of Risk of Bias The quality of each study was assessed by a single reviewer (JT) using a pre-specified critical appraisal and risk of bias template consisting of 15 quality assessment metrics. All studies, regardless of the number of subjects, were considered equally. Due to the types of studies included in the current review (survey based studies), non-responder bias was critically appraised and commented on below. Results As of July 2nd, 2016, the aforementioned search strategy returned 131 citations. After removing 31 studies identified as duplicates, 100 original studies remained (Figure 1. Prisma Flow Diagram). Of these studies, 93 were excluded during abstract and title review because they did not fulfill the defined selection criteria. Following title and abstract review, seven studies remained and were included in the full text review process. Of the remaining studies, five were excluded because they did not fulfill study criteria and were deemed inappropriate for the current review (Table 3.). In total, two articles were included for review. Table 4 lists pertinent information on each included study. The first study entitled “A Survey of Current Practices, Attitudes, and Knowledge Regarding Human Papillomavirus– Related Cancers and Vaccines Among Head and Neck Surgeons” by Malloy et al. was published in JAMA otolaryngology- head and neck surgery and contained information on head and neck surgeons understanding of HPV-positive OPSCC.33 The second study identified by Jackowska et 40 al. was published in PLoS ONE, a free online open access journal, and contained information on general practitioners (GPs) as well as otolaryngologists in Poland.9 The paper published by Malloy et al. had a response rate of 27.5% while the paper by Jackowska et al. had a response rate of only 19.2%. For details on study characteristics and response rates, see Table 5. Key questions, answers, and responses from the study by Malloy et al. can be found in Tables 6 and 7. Lastly, Table 8 includes key information from the paper by Jackowska et al. The tables do not include an exhaustive list of the questions or answers asked from each survey based study, but instead represent key questions that address one or more of the three principles established for the current review. A rating of moderate has been assigned to each study when assessing for risk of bias. This grade was assigned due to low response rates leading to risk of non-responder bias. The study by Malloy and colleagues demonstrates that head and neck surgeons are knowledgeable with respect to HPV and its role in head and neck cancers. Table 6 and Table 7 present the results from knowledge and practice pattern based questions respectively. Furthermore, this study demonstrates that head and neck surgeons are knowledgeable about general aspects of HPV. Importantly, the authors demonstrate that head and neck surgeons in the United States desire to play a larger role in prevention and educational efforts regarding the link between HPV and head and nek cancers. The authors conclude that additional educational efforts led by the American Head & Neck Society would benefit primary care physicians and other specialty groups. In agreement with this statement, the authors suggest that similar surveys of PCPs in the United States be conducted in order to assess their current understanding of the association between HPV and HNC. 41 The paper by Jackowska and colleagues also provides important information into this topic. This survey based study was more in alignment with the goals of the current systematic review. The authors conducted a nationwide survey of GPs, otolaryngologists, and trainees to assess their current knowledge of HPV and head and neck cancer. This study demonstrates that in Poland, otolaryngologists are more knowledgeable with respect to HPV and its association with HNC than are GPs (Table. 8). In addition, the authors also demonstrate that few GPs are knowledgeable about the potential use of the HPV vaccination for the prevention of upper aerodigestive tract tumors (HNCs). When compared with otolaryngologists, PCPs were less aware of a potential benefit of the HPV vaccination for prevention of head and neck cancers. Discussion Currently, few studies exist that detail the knowledge, attitudes, and beliefs of PCPs towards HPV-positive OPSCC, and our study supports this claim. We developed three search strateges each tailored to a specific database to identify studies that would provide insight into this topic. After each database was searched, titles and abstracts were screened, and a full text review was completed, only two articles remained. Despite a low yield, we believe important information can be gained from studying these two physician groups. The study by Malloy and colleagues, although not of PCPs, provides evidence that specialists are knowledgeable with respect to this rapidly changing disease. More importantly, specialists in the United States desire a greater role in educating other groups of physicians on the changes associated with HPV-positive OPSCC. We believe this will be an important step in increasing awareness on the changing aspects of head and neck cancer. Currently, over 90% of all OPSCC is associated with HPV, and it is predicted that the incidence of HPV-positive 42 OPSCC will surpass the incidence of HPV-positive cervical cancer by 2020.34,35 These rapid changes demand that innovative solutions are developed to increase awareness among PCPs and the general population. Increasing educational efforts to PCPs has the potential to improve patient outcomes through increased vaccination efforts, early detection, and timely referral of patients presenting with early signs of malignancy The paper by Jackowska et al. found that in Poland, GPs are less knowledgeable about HPV and its role in head and neck cancers. Although this study was not conducted in the United States, we believe it demonstrates an important issue; GPs who have the ability to act in a preventive manner through vaccination efforts were less knowledgeable about the potential use of the HPV vaccination for the prevention of HNCs. Although we expect specialists to be more knowledgeable, they are less able to play a preventive role due to most commonly only seeing patients after diseases have developed. Increasing vaccination efforts is predicated upon a strong knowledge base among GPs who have the ability to offer vaccinations to patients at appropriate ages and before diseases have developed. As in the United States, increasing the knowledge base of PCPs may have the largest effect on HPV-positive OPSCC through increased prevention, surveillance, and early detection. Both studies conclude that additional targeted education strategies are needed to increase awareness of HPV and its role in head and neck cancer. The results of our systematic review are in agreement with these points. We were unable to identify a single English language article that addresses the current knowledge of HPV-positive OPSCC among primary care physicians in the United States or other OECD countries. A first step in developing targeted educational resources for PCPs is to develop a greater understanding of the current level of knowledge among these physicians groups. This process allows knowledge gaps to be identified, which informs the 43 development of educational resources tailored to address these gaps. By identifying areas where knowledge gaps exist and directing resources to address these gaps, educational programs can be maximized. Our study is limited by the low yield from the search strategy and the potential of nonresponder bias to have driven the results of each study. Although we acknowledge these studies may suffer from non-responder bias, similar low response rates for surveys have recently been reported among physicians.25,14. Additionally, title, abstract, and full text review was done by a single author. This could potentially bias the results by failing to include studies that may have been included if dual review was used. Finally, limiting the search to English language articles only could have missed studies published from OECD countries that did not have English translations. Furthermore, our study has several strengths, including a comprehensive search strategy collaboratively developed with the assistance of a professional librarian. Additionally, we searched three databases through two separate electronic libraries to ensure the thoroughness of the search. Although the yield was small and only single review was used, we believe the thoroughness of the search ensures that the majority of relevant articles were assessed. In conclusion, we have identified a need for additional studies of key physician groups, including pediatricians, internal medicine physicians, and family medicine physicians in the United States to provide insight into this important topic. The goal of such future reseach should be to identify where knowledge gaps exist in the presentation, outcomes, and prevention of HPVpositive OPSCC in order to inform the development of educational resources to address these gaps. Due to the rapid changes in presentation and outcomes associated with HPV-positive OPSCC patients, these studies should be performed in a timely manner. By increasing the 44 knowledge base of the primary care network, the role of the PCP can be maximized and patient outcomes improved through preventive measures, early detection, and timely referral. 45 References 1. Ferlay J, Shin HR, Bray F, Forman D, Mathers C, Parkin DM. Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. Int J Cancer. 2010;127(12):2893-2917. doi:10.1002/ijc.25516. 2. Chai RC, Lambie D, Verma M, Punyadeera C. Current trends in the etiology and diagnosis of HPV-related head and neck cancers. Cancer Med. 2015:n/a - n/a. doi:10.1002/cam4.424. 3. 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A survey of current practices, attitudes, and knowledge regarding human papillomavirus-related cancers and vaccines among head and neck surgeons. JAMA Otolaryngol Head Neck Surg. 2013;139(10):10371042. doi:10.1001/jamaoto.2013.4452. 50 34. Joseph AW, D’Souza G. Epidemiology of Human Papillomavirus-Related Head and Neck Cancer. Otolaryngol Clin North Am. 2012;45(4):739-764. doi:10.1016/j.otc.2012.04.003. 35. Gregoire V, Lefebvre J-L, Licitra L, Felip E. Squamous cell carcinoma of the head and neck: EHNS-ESMO-ESTRO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2010;21(Supplement 5):v184-v186. doi:10.1093/annonc/mdq185. Appendix 51 Figure 1. Prisma Diagram detailing article selection process from the three searched databases Table 1. Database Specific Search Strategies 52 Database PubMed Key Terms (connected with Expansion Terms (connected “AND”) with “OR”) Carcinoma, Squamous Otolaryngeal cell Head and Neck Neoplasm Alphapapillomavirus Neoplasms Head and Neck Cancers Human papillomavirus Papillomavirus infections Human Papillomaviruses Primary Care Physicians HPV HPV-6 Education Early Detection of Cancer Practice Patterns, Physicians Health Knowledge, Attitudes, Practice 53 Attitudes of Health Personnel CINHAL SCOPUS Healthcare Surveys Specialists Surgical Carcinoma, Squamous Neoplasms Cell Malignancy Human Papillomavirus HPV Papillomavirus Alphapapillomavirus Pediatricians Family medicine Internal medicine surgery Medical Surveys Knowledge Attitudes Beliefs Practice Patterns Malignancy Cancer Head and neck oropharyngeal Primary Care Physicians Surveys Neoplasms 54 Human Papillomavirus Primary Care Providers Medical Surveys HPV Alphapapillomavirus Family medicine Internal medicine pediatrics Surveys Table 2. Key Inclusion and Exclusion Criteria Key Inclusion and Exclusion Criteria Key Inclusion Information pertaining to HPV-Positive: Key Exclusion Information pertaining to HPV-negative OPSCC OPSCC HNC HNC Information obtained from PCPs Studies Using Modeling to Predict PCPs: Knowledge Pediatricians Practice Patterns Inernal Medicine Physicians Attitudes Family Medicine Physicians Beliefs Head and Neck Surgeons Included 1 of the following 3 key principles: Knowledge of PCPs Practice Patterns of PCPs 55 Beliefs of PCPs Information Obtained From: Information not obtained from: Surveys Surveys Focus Groups Focus Groups Questionnaires Questionnaires English Language Only Non-English Language Articles Published in an OECD Country Published outside of an OECD Country Table 3. Studies excluded during full text review with reasons for exclusion Study Title Reason for Exclusion North American Survey on HPV-DNA and p- Survey results did not fulfill one of the 3 key 16 testing for head and neck carcinoma principles of the current review Human Papillomavirus infection and Non-English Language Article vaccination: knowledge and attitudes of Italian general practitioners Cancers That U.S. Physicians Believe that the Did not include oropharynx or head and neck HPV Vaccine Prevents: Findings from a cancer Physician Survey , 2009 Educational value of a medical student-led Did not include PCPs or head and neck head and neck cancer screening event surgeons Awareness and knowledge of human Did not include PCPs or head and neck papillomavirus-related diseases are still surgeons 56 dramatically insufficient in the era of highcoverage vaccination programs Table 4. Article Specifics Study Authors Journal Study Design Date Published Malloy et al. JAMA Online Electronic August 29,2013 otolaryngology- head Survey and neck surgery Jackowska et al. Plos ONE Online Electronic October 26, 2015 Survey Table 5. Study Survey Response Rates Study Authors Study Population Physicians surveyed Responses (Response Rate) Malloy et al. American Head & Head and Neck Neck Society Surgeons 297 (27.5%) Members Jackowska et al. Poland Physicians Head and Neck 404 (19.2%) 57 Surgeons, General Practitioners and Trainees Table 6. Key knowledge questions from Malloy et al. Question Answer Percent Correct HPV is associated with a True 94.9% False 42.4% False 99.0% False 96.3% False 95.6% much improved response for patients with head and neck cancer Patients with a history of HPV infection should not be offered the HPV vaccine Most patients with HPV experience symptoms of infection The oral tongue is the principal head and neck cancer site associated with HPV HPV is a relatively uncommon sexually transmitted infection 58 All types of HPV can lead to False 96.3% head and neck cancer Table 7. Key practice questions from Malloy et al. Question Options with response percentages I Strongly Agree Pediatricians should remain the sole I I somewhat somewhat I strongly Disagree Agree Disagree 8.8% 22.9% 24.6% 44.3% 23.2% 33.0% 23.2% 20.5% 16.5% 43.1% 28.3% 12.1% 9.1% 22.2% 36.7% 32.0% appropriate source of information regarding the HPV vaccine It is necessary to discuss issues of sexuality before recommending HPV vaccines to patients The efficacy and safety of new vaccines can only be sufficiently established after the vaccine has been on the market for 5 to 10 years. My patients are sufficiently informed of the risks of becoming infected with HPV and the 59 potential consequences of such an infection. Table 8. Key questions and answers from Jackowska et al. Question Answer with Response Percentage General Practitioners Have you heard about the Otolaryngologists Yes 100.0% No 0.0% Yes 100.0% No 0.0% Yes 23.4% No 76.6% Yes 44.4% NO 55.6% Yes 93.0% No 7.0% Yes 80.0% No 20.0% impact of vaccination on the reduction of cervical cancer incidence? Have you heard about the potential value of HPV vaccination in preventing oropharyngeal cancer? Have you heard about the association between HPV and upper aerodigestive tract tumors? 60