Katheryn Wheat, MS IV Advisors: Susan McCammon, MD and Harold Pine, MD University of Texas Medical Branch Department of Otolaryngology Grand Rounds

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1 Katheryn Wheat, MS IV Advisors: Susan McCammon, MD and Harold Pine, MD University of Texas Medical Branch Department of Otolaryngology Grand Rounds Presentation September 30, 2010

2 Outline Background Incidence and Epidemiology Cervical Cancer studies and vaccine approval ABHACUS (Assessing the Burden of HPV-Associated Cancer in the United States) Following incidence Socioeconomic assessment Mathematical modeling Public Policy and Public Health Incidence surveillance results Future studies needed Cost-effectiveness, population targeting, funding

3 Background Squamous cell carcinoma of head and neck 4% of all malignancies in the United States Incidence= 17 per 100,000 persons per year HPV-associated cancers 10.6 per 100,000 people per year Estimated 7360 cases in head and neck region per year Head and neck second only to cervical Majority attributable to HPV 16 and 18 Recurrent Respiratory Papillomatosis HPV6 and 11 Though rare, major morbidity especially in children

4 Oropharyngeal and Oral Cancer 35,000 cases projected for cases per 100,000 persons : 44,160 potentially HPV+ cancers 43.6% tonsillar 38.4% base of tongue 18% other oropharyngeal tumors 35.6% oropharyngeal are HPV+ (87% HPV-16) 23.5% oral cancers are HPV+ (68% HPV-16) Males > females (3-4:1) Defined as overlapping lesion of tongue; lateral wall of oropharynx; overlapping lesion of oropharynx; oropharynx, NOS; pharynx, NOS; overlapping lesion of lip, oral cavity and pharynx. A. Blythe Ryerson, Edward S. Peters, Steven S. Coughlin, Vivien W. Chen, Maura L. Gillison, Marsha E. Reichman, Xiaocheng Wu, Anil K. Chaturvedi, Kelly Kawaoka. Burden of Potentially Human Papillomavirus- associated Cancers of the Oropharynx and Oral Cavity in the US, Cancer 2008;113(10 suppl):

5 Oropharyngeal and Oral Cancer Most common in or after 50 s Race/ethnicity Blacks > whites Non-Hispanics > Hispanics Increase in HPV-associated cancers in this region despite decrease at other sites Decreased tobacco exposure Sexual behavior Increased risk with >6 partners, >4 oral sex partners, earlier age at first intercourse in men

6 Laryngeal Cancer 12,720 cases projected for per 100,000 persons Greatest risk factors: Alcohol, tobacco HPV-association investigated Identified in % of biopsies from separate studies Males > females (5:1) previously 15:1 Peak incidence yrs Blacks > whites

7 Recurrent Respiratory Papillomatosis new cases each year Children 4.3 cases per 100,000 children Peak at 2-3 yrs Often firstborn of young mothers of low economic status Male = female Adults 1.8 per 100,000 in adults Peak at yrs Males > females (4:1)

8 Recurrent Respiratory Papillomatosis HPV 6 and 11 Acquisition Upper aerodigestive tract exposure to mother with HPV infection Some born to mothers with HPV do not acquire RRP Cesarean delivery of child who developed RRP

9 Cervical Cancer Basics HPV as necessary cause of cervical cancer 1995/1996 FUTURE II Study Group phase 3 trial, RCT of 12,167 females, yrs Quadrivalent (HPV6,11,16,18) vaccine had 98% efficacy Quadrivalent and bivalent (HPV16 and 18) FDA-approved Females aged dose schedule starting at age 11 (ideal before sexual contact) Prevention of cervical cancer and genital warts Males 9-26 yrs Quadrivalent approved by FDA March 2010 However, not deemed cost-effective More cost-effective to vaccinate >80% females NOTES: Study to approve bivalent vaccine? Where is the best place for this slide?!?!

10 ABHACUS Assessing the Burden of HPV-Associated Cancer in the United States Goals are to monitor: Age-specific rates of HPV-associated cancers CDC National Program of Cancer Registries (NPRC) NCI Surveillance, Epidemiology and End Results (SEER) Age-specific rates of HPV-associated cancer precursors Distribution of associated HPV types Incidence of carcinoma precursors and invasive carcinoma along with prevalence of vaccination Methods of linking screening and risk factor data that are already being collected by other surveillance data To systematically monitor age-specific rates of invasive cervical cancer and other invasive HPV-associated cancers. To systematically monitor age-specific rates of cervical cancer precursors and precursors for other HPV-associated cancers. To identify the distribution of HPV types associated with HPV-associated carcinoma precursors and invasive carcinoma. To monitor the incidence of carcinoma precursors and invasive carcinoma along with prevalence of vaccination. To explore and evaluate methods of linking screening and risk factor data that are already being collected by other surveillance data.

11 ABHACUS Incidence ( ) 10,800 HPV-associated cervical cancers occurred per yearmore than any other site. Nearly 7,400 potentially HPV-associated cancers of the oral cavity and oropharynx per year; male-to-female ratio 3.3:1. More than 3,000 HPV-associated anal cancers per year. About 2,300 new cases of vulvar cancer each year. Penile cancer relatively rare-- about 800 men each year. About 600 women per year developed vaginal cancers.

12 ABHACUS HPV-associated HPV presence vs. activity vs. oncogenesis Positive PCR amplification cancer Not completely valid assumption but will lead to more studies Additive/synergistic effect of HPV on tobacco or alcohol use Cervical cancer studies ongoing for at least two decades before vaccine trials RRP HPV 6,11 present in more patients than RRP, suggesting additional factors

13 Socioeconomic Status SES important information for allocating resources Oral cavity and oropharyngeal cancer Overall incidence rates: Increased Higher education, low-level to mid-level income, and residence in metropolitan or suburban areas Decreased 10-20% poverty status Female incidence rates: Decreased Hispanics, Asian/Pacific Islanders, rural residence Counties with high school education rates 75% -<85% lower incidence rate than those with >85% high school education

14 Socioeconomic Status Male incidence rates: Decreased Hispanics and those in a county with <85% high school education Increased Higher county smoking prevalence and residence in a county with lower median household income Ethnicity and rural-urban incidence rates: Asian/Pacific Islanders rural > metropolitan areas Whites metropolitan > rural counties Blacks significantly higher incidence rates compared with whites in metropolitan and especially rural areas Asian/Pacific Islanders decreased incidence rate compared with whites in metropolitan areas Current smoking increased incidence rates

15 Years of Potential Life Lost and Productivity Costs Cancer-specific estimates (2003) 45,815 YPLL for oral cavity/oropharyngeal cancer in M (lowest was 3654 YPLL for penile cancer) 17,773 for oral cavity/oropharyngeal in F (range of 5199 YPLL for vaginal cancer to 89,936 YPLL for cervical cancer) Mortality costs (2003) Used data on US mortality, life tables, annual earnings, household services, labor force participation rate $1.1 billion: oral/oropharyngeal cancer in males $270 million: oral/oropharyngeal cancer in females (Cervical cancer highest cost at $1.8 billion)

16 Years of Potential Life Lost and Productivity Costs Total mortality costs of all HPV-associated cancers in white non-hispanics 44.2% cervical cancer 40.9% oral cavity and oropharyngeal cancer 5.8% anal cancer Drawbacks Information on race-specific earnings was not incorporated Pain, suffering, and psychosocial costs were not accounted for Society s value on an individual cannot be calculated Estimates apply to HPV-associated cancers, not the percentage specifically caused by HPV No direct and indirect medical costs, or caregiver costs

17 Public Policy and Public Health Before recommendation and funding for vaccine Incidence surveillance results How long? What is a significant result? RRP Monitor as a separate entity to note change in burden of disease Prospective study in infants difficult, but if no change after administration to mothers, would have to consider at-birth vaccination approval, as in Hepatitis B

18 Public Policy and Public Health Before recommendation and funding for vaccine cont d Cost-effectiveness studies for males and females Resource allocation Determine populations with higher burden Repeat SES studies when HPV causation established? Establish oncogenic causation by HPV in head and neck cancers Laboratory-based assays should include demonstration of the specificity of the viral DNA in tumor cell nuclei, detection of viral oncogene expression, demonstration of a clonal association between virus and tumor (eg, integration, viral load, variant analysis), and dependence of the malignant phenotype upon viral gene expression.

19 Public Policy and Public Health Even if these goals are accomplished Original HPV debate of cost, safety, right to refuse, and moral issues HPV-associated cancers sexual practice issue reminiscent Link to higher number of sex partners and oral sex partners HPV prevalence in cervical tissue, higher rate of oropharyngeal cancer in men Increased rate of tonsillar cancer in men with wives with cervical dysplasia or cancer Some with oropharyngeal cancer report few partners and no oral sex partners What other populations might be at higher risk because of sexual practices?

20 Public Policy and Public Health Funding Vaccine available through Vaccines for Children (VFC) in all 50 states; how will new data change funding through SCHIP, Medicaid; for uninsured and requirements for insurance companies What criteria would make an adult eligible for vaccine coverage Will depend on cost-effectiveness studies Vaccine as a requirement vs. option Washington, DC made vaccine a school requirement in other states with laws for education and funding If it protects against HPV-associated cancers and possibly RRP, should it be required at birth or as part of the vaccination series?

21 Summary Oral cavity and oropharyngeal cancer, laryngeal cancer, RRP are true disease burdens To be monitored after advent of HPV vaccine Further studies on causality of HPV in these cancers Public policy and public health issues Vaccine expansion to boys, adults At-risk populations? Evidence of cost-effectiveness to support funding Legislation on administration

22 References Andrews E, Seaman WT, Webster-Cyriaque J. Oropharyngeal carcinoma in non-smokers and non-drinkers: A role for HPV. Oral Oncology 2009;(45): Benard VB, Johnson CJ, Thompson TD, Roland KB, Lai SM, Cokkinides V, Tangka F, Hawkins NA, Lawon H, Weir HK. Examining the Association Between Socioeconomic Status and Potential Human Papillomavirusassociated Cancers Cancer 2008;113(10 suppl): Brawley OW. Oropharyngeal Cancer, Race, and the Human Papillomavirus. Cancer Prev Res 2009;2(9). Campbell WJ, de la Torre JI. Head and Neck Cancer- Squamous Cell Carcinoma. Emedicine. 30 Sept Website: Center for Disease Control and Prevention. FDA Licensure of Bivalent Human Papillomavirus Vaccine (HPV2, Cervarix) for Use in Females and Updated HPV Vaccination Recommendations from the Advisory Committee on Immunization Practices (ACIP) Weekly (20); Website: Center for Disease Control and Prevention. FDA Licensure of Quadrivalent Human Papillomavirus Vaccine (HPV4, Gardasil) for Use in Males and Guidance from the Advisory Committee on Immunization Practices (ACIP) Weekly 59(20); Website:

23 References Dunne EF, Datta SD, Markowitz LE, A Review of Prophylactic Human Papillomavirus Vaccines: Recommendations and Monitoring in the US. Cancer 2008;113(10 suppl): Ekwueme DU, Chesson HW, Zhang KB, Balamurugan A. Years of Potential Life Lost and Productivity Costs Because of Cancer Mortality and for Specific Cancer Sites Where Human Papillomavirus May Be a Risk Factor for Carcinogenesis. United States, 2003 Cancer 2008;113(10 suppl): FUTURE II Study Group. Quadrivalent Vaccing against Human Pepillomavirus to Prevent High-Grade Cervical Lesions. N Engl J Med 2007;356: Gallagher TQ, Derkay CS. Recurrent respiratory papillomatosis: update Curr Opin Otolaryngo 2008;16: Gillison ML, Chaturvedi AK, Lowy DR. HPV Prophylactic Vaccines and the Potential Prevention of Noncervical Cancers in Both Men and Women Cancer 2008;113(10 suppl): 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:

24 References Hemminki K, Dong C, Frisch M. Tonsillar and other upper aerodigestive tract cancers among cervical cancer patients and their husbands. Eur J Cancer Prev 2000;9: Hennessey PT, Westra WH, Califano JA. Human Papillomavirus and Head and Neck Squamous Cell Carcinoma: Recent Evidence and Clinical Implications. J Dent Res 2009;88(4) Johnson JT, Christopolous A. Caicedo-Granados EE. Malignant Tumors of the Larynx. Emedicine. 7 Jan Website: Kim JJ, Goldie SJ. Cost effectiveness analysis of including boys in a human papillomavirus vaccination programme in the United States. BMJ 2009;339:b3884. Kokot N. Malignant Tumors of the Tonsil, Surgical Treatment. Emedicine. 10 Sept Website: Kreimer AR, Clifford GM, Boyle P, Franceschi S. Human Papillomavirus Types in Head and Neck Squamous Cell Carcinomas Worldwide: A Systematic Review. Cancer Epidemiol Biomarker Prev 2005;14(2):

25 References Luginbuhl A, Sanders M, Spiro JD. Prevalence, Morphology, and Prognosis of Human Ppillomavirus in Tonsillar Cancer. Ann Otol Rhinol Laryngol 2009;118(10): Mammas IN, Sourvinos G, Spandidos DA, Zaravinos A. Vaccination against Human Papilloma Virus (HPV): Epidemiological Evidence of HPV in Non-genital Cancers. Pathol Oncol Res. Epub McClay John E. Recurrent Respiratory Papillomatosis. Emedicine. 28 Oct Website: Marur S, D Souza G, Westra WH, Forastiere AA. HPV-associated head and neck cancer: a virus-related cancer epidemic. Lancet 2010;(11) Mehanna H, Jones T, Gregoire V, Ang K. Oropharyngeal carcinoma related to human papillomavirus. BMJ 2010; 340:c1439. Ryerson AB, Peters ES, Coughlin SS, Chen VW, Gillison ML, Reichman ME, Wu X, Chaturyedi AK, Kawaoka K, Burden of potentially human papillomavirus-associated cancers of the oropharynx and oral cavity in the US, Cancer 2008;113(S10):

26 References Saraiya M, Goodman MT, Dutta SD, Chen VW, Wingo P. Cancer registries and monitoring the impact of prophylactic human papillomavirus vaccines: The potential role. Cancer 2008;113(S10): Sisk J, Schweinfurth JM, Wang XT, Chong K. Presence of Human Papillomavirus DNA in Tonsillectomy Specimens. Laryngoscope 2006;116: Smith EM, Ritchie JM, Summersgill KF, et al. age, sexual behavior and human papillomavirus infection in oral cavity and oropharyngeal cancers. Int J Cancer 2004; 108: Surveillance, Epidemiology and End Results website: Watson M, Saraiya M, Ahmed F, Cardinz CJ, Reichman ME, Weit HK, Richards TB. Using population-based cancer registry data to assess the burden of human papillomariusassocaited cancers in the United States: Overview of methods. Cancer 2008;113(S10):