HPV and the Rise of Head and Neck Cancers

Human papillomavirus is perhaps best known as the main cause of cervical cancer, but if recent trends continue, by 2020 HPV will cause more cases of oropharyngeal cancer each year than cervical cancer. Changes in public perceptions of the virus, as well as in sexual habits, are necessary to slow the spread of HPV-positive head and neck cancer, and experts are calling for widespread HPV vaccination of boys as well as girls, despite the lack of clinical trial evidence to support HPV vaccination for head and neck cancers.

Human papillomavirus (HPV) is the most common sexually transmitted infection, with more than 100 different strains and approximately 6.2 million new infections reported in the United States each year, according to the Centers for Disease Control and Prevention (CDC). Although less than 1% of infections lead to cancer, HPV is responsible for thousands of new cases of cervical, vulvar, vaginal, and anal cancers each year, and is the leading cause of cervical cancer, according to the CDC.

Experts have long suspected a link between HPV and oropharyngeal cancer, and an increasing body of evidence supports this association. A study of 100 patients with newly diagnosed oropharyngeal cancer and 200 matched case controls, published in 2007 in The New England Journal of Medicine, found that the HPV 16 strain was present in 72% of cancerous tumors. [D’Souza G et al. N Engl J Med. 2007;356:1944-1956.] Prior HPV infection increased the risk of oropharyngeal cancer by a factor of 32—more than the 3-fold increase in risk for smoking and the 2.5-fold increase for drinking. Oral-genital contact was strongly associated with oropharyngeal cancer, suggesting oral sex as the main route of transmission for oral HPV infection.

The incidence of oropharyngeal cancers has been rising for nearly 40 years, and a study in a recent issue of the Journal of Clinical Oncology provided empirical evidence linking the increase to HPV infection. Researchers determined HPV status for 271 oropharyngeal cancers, from 1984 to 2004, collected by the 3 population-based cancer registries in the Surveillance, Epidemiology, and End Results (SEER) Residual Tissue Repositories Program [Chaturvedi AK et al. J Clin Oncol. 2011;29:4294-4301.]. The population-level incidence of HPV-positive oropharyngeal cancers increased by 225% (95% CI, 208%-242%) from 1988 to 2004 (from 0.8 per 100,000 to 2.6 per 100,000). At the same time, the incidence of HPV-negative cancers declined by 50% (95% CI, 47%-53%; from 2.0 per 100,000 to 1.0 per 100,000), a trend that parallels the decline in smoking—a risk factor for head and neck cancer—in the United States.

The researchers predicted that, should these incidence trends continue, by 2020 the number of HPV-positive oropharyngeal cancers will surpass cervical cancers. In addition, they expect that HPV-positive oropharyngeal cancers will constitute the majority of head and neck cancers in the United States in the next 20 years.

HPV Vaccines, Oropharyngeal Cancer, and Public Health Implications

The increasing incidence of HPV-related head and neck cancers has important public health implications. Two vaccines are currently available for the prevention of HPV infection. Gardasil [human papillomavirus quadrivalent (Types 6, 11, 16, and 18) vaccine, recombinant], manufactured by Merck, was approved by the FDA in 2006 for use in females ages 9 to 26 years for the prevention of certain diseases caused by HPV, including cervical, vulvar, vaginal, and anal cancers. Three years after the initial approval for use in girls, Gardasil was later approved for use in males ages 9 to 26 years for the prevention of anal cancer, genital warts, and associated precancerous lesions due to HPV. Cervarix [human papillomavirus bivalent (types 16 and 18) vaccine, recombinant], manufactured by GlaxoSmithKline, was approved by the FDA in 2009 for similar indications for girls and women ages 10 through 25 years.

In an editorial accompanying the Chaturvedi study in the Journal of Clinical Oncology, Mroz and colleagues note that because currently available HPV vaccines are only effective before infection has been established, it is up to primary care providers to inform parents of boys (not just girls) about the risks of HPV-associated tumors and the likely reduction in risk provided by vaccination. [Mroz EA et al. J Clin Oncol. 2011;29:4222-4223.] Such efforts, however, are impeded by several issues.

First, there is the perception among the public, as well as among some healthcare providers, that the vaccine is not appropriate for boys. This may be due in part to efforts by Merck to lobby state legislatures for mandatory vaccinations for 11- and 12-year-old girls. However, the lobbying effort was dropped in 2007 amidst a storm of controversy that mostly centered around whether mandatory vaccination was implicitly sanctioning sexual activity in this young population.

HPV vaccination has not been readily accepted for use in girls. As of September 2011, an estimated 40 million doses of HPV vaccine had been administered. That represents approximately 12.9% of the population being vaccinated even though people under the age of 18 make up approximately 24% of the population, according to the US Census Bureau. In order to expand the number of vaccinations performed, in October 2011, the CDC’s Advisory Committee on Immunization Practices recommended that boys between the ages of 9 to 26 years should receive the HPV vaccine.

“Male vaccination is most cost effective when coverage of females is low, and unfortunately here in the US, coverage of females is currently low,” said Anne Schuchat, MD, director of the CDC’s National Center for Immunization and Respiratory Diseases in a press conference that accompanied the announcement of the recommendation. Insurance coverage also impacts vaccinations rates. Gardasil, for example, costs approximately $390 per patient for 3 doses of the vaccine, according to the CDC. However, Merck, the manufacturer of Gardasil, offers an insurance assistance program, and many providers cover a portion of the cost if administered to a patient in the recommended age range.

According to Ezra E. W. Cohen, MD, co-director of the Head and Neck Cancer Program at the University of Chicago Medical Center in Illinois, the recommendation to vaccinate boys is an important step in the right direction. Cohen noted that the CDC’s recommendation more heavily promotes the safety and efficacy of the vaccine for both boys and girls. “It’s the right move by the CDC,” Cohen said. “I think it’s a long time coming.”

HPV Vaccinations for Head and Neck Cancer: A Need for Clinical Trial Data?

A study published in The New England Journal of Medicine in October 2011 has shown Gardasil to be effective in preventing other forms of cancer in men. The phase III clinical trial of 602 healthy men who have sex with men ages 16 to 26 years found that Gardasil was 77.5% effective in reducing the rates of anal intraepithelial neoplasia associated with HPV types 6, 11, 16, and 18 [Palefsky JM et al. N Engl J Med. 2011;365(17)1576-1585].

A number of clinical trials are currently enrolling to assess the impact of HPV and its links to oropharyngeal cancer. Likewise, trials are underway to assess the effectiveness of HPV vaccines in preventing more cases of oropharyngeal cancer, and a number of studies are investigating cisplatin, cetuximab, and other forms of chemotherapy and radiation therapy, to test their efficacy in treating patients with HPV-positive cases of oropharyngeal cancer.

Preventing Head and Neck Cancers

While oncologists believe that more widespread HPV vaccination could help stem the spread of HPV-associated head and neck cancers, many also believe that head and neck cancer rates will continue to rise for the next 20 to 30 years.

“Even if vaccinations were made mandatory, we will not see the effects on cancer rates for decades,” Cohen said. However, since vaccinations are not being made mandatory, Cohen said he believes that the rising cases could be even greater, and making the vaccinations mandatory would prevent the numbers from rising any higher.

Part of the problem is that many factors contributing to HPV-positive oropharyngeal cancers are not yet fully understood, according to Marshall Posner, MD, director of the Head and Neck Oncology Program at Mt. Sinai School of Medicine in New York City. Posner said that more needs to be understood in terms of how HPV is transmitted, whether genetic risk factors predispose patients to developing oropharyngeal cancer if exposed to the virus, the risks associated with specific strains of the virus, and what diagnostic techniques are available. However, Posner said many of these studies are focusing on the link between HPV and cervical cancer, and so these questions are not being addressed when it comes to oropharyngeal cancers.

“There is no screening test for HPV-related oropharynx cancer in men or women, and this presents a very important [issue] that we have to address,” Posner said.

Posner said that about 25% of teenage girls have been infected with HPV, and the exposure increases dramatically as these girls reach their mid-20s. Because the disease is spread through sexual contact, it’s safe to assume that the virus is spreading to any men that infected women have had contact with. Although Posner stressed the importance of investing more resources into developing treatment for HPV-positive oropharyngeal cancer, people across the country need to embrace the CDC’s recommendations for vaccination.

“Right now, only vaccinating women is not a solution,” Posner said. “Men get this cancer. Young boys are exposed to the virus…In my opinion, every young boy and girl in this country should be vaccinated for this virus.”