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Patients with head and neck cancer positive for human papillomavirus (HPV) have a better response to chemotherapy and chemoradiation and better overall survival than patients with HPV-negative cancers. This result, from one of the first prospective studies to investigate this association, confirms previous findings from retrospective analyses and shows that HPV-positive head and neck cancer is more sensitive to therapy.

he authors, who report their findings in the February 12 issue of the Journal of the National Cancer Institute, say that stratification for HPV status should be included in clinical trials being conducted in head and neck cancer.

"Tumor HPV status is an important molecular biomarker of response to chemotherapy and chemoradiation for patients with head and neck cancer. The improved response is likely responsible, at least in part, for the improved disease control and survival of patients with this type [HPV positive] of cancer," said lead researcher Maura Gillison MD, PhD, from the John Hopkins Kimmel Cancer Center, in Baltimore, Maryland.

"Tumor HPV status does not currently affect treatment decisions regarding standard-of-care therapy," Dr. Gillison told Medscape Oncology. "However, in the future it probably will."

The treatment of local–regionally advanced head and neck cancer has intensified over time quite recently," she explained, "from surgical therapy with or without adjuvant radiation to intensive induction chemotherapy with concurrent chemoradiation. This therapy is associated with significant short- and long-term toxicity. Given that patients with HPV-positive cancer are young and largely expected to survive their cancer, we must ask whether the current treatment paradigms of increasingly intense multimodality therapy are appropriate for this patient population. A risk–benefit analysis may favor a deintensification of therapy for this group to minimize long-term morbidities of therapy."

"For now, we offer classification of tumor HPV status to our patients because of the prognostic significance of the result and to determine their eligibility for clinical trials specific to the HPV-positive patient," Dr. Gillison said.

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May 19, 2009 —Oropharyngeal cancer is a distinct disease entity when it is positive for human papillomavirus (HPV), with a better prognosis than oropharyngeal cancer that is HPV negative. Although these findings have been suggested in smaller trials, evidence now comes from the largest and most definitive study of the subject to date, in which patients were randomized according to HPV status.

The results were previewed in a presscast on May 14 and will be presented at the upcoming 2009 Annual Meeting of the American Society of Clinical Oncologists.

"HPV status may have important prognostic implications," said lead author Maura Gillison, MD, PhD, professor of medicine, epidemiology and otolaryngology at the Ohio State University in Columbus.

Tumor HPV status should now be part of the routine assessment of oropharyngeal cancer patients, she added.

Investigators are already using this information in designing clinical trials and are stratifying patients by HPV status, Dr. Gillison said. In the future, this might also guide treatment decisions, she noted, because it appears that patients with HPV-positive status have better outcomes with whatever therapy they receive. The National Cancer Institute is requesting proposals for trials to address this issue, she added.
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August 18, 2009 — The benefit of vaccinating against human papilloma virus (HPV) to prevent cervical cancer is questioned in an editorial in the Journal of the American Medical Association.

"The theory behind the vaccine is sound: if HPV infection can be prevented, cancer will not occur," writes editorialist Charlotte Haug, MD, PhD, from the Journal of the Norwegian Medical Association. "But in practice, the issue is more complex."

HPV is the most prevalent sexually transmitted infection, "but the virus does not appear to be very harmful because almost all HPV infections are cleared by the immune system," she explains. In a few women, the HPV infection persists, and some women may develop precancerous cervical lesions and eventually cancer, Dr. Haug writes, "but it is currently impossible to predict in which women this will occur."


"The net benefit of the HPV vaccine to a woman is uncertain," Dr. Haug comments. "Even if persistently infected with HPV, a woman most likely will not develop cancer if she is regularly screened [with cervical smear tests]."

Dr. Haug has spoken out against HPV vaccination previously. Last year, she urged caution over widespread vaccination programs in an editorial in the New England Journal of Medicine (2008;359:861–862), as reported by Medscape Oncology at the time.

This latest editorial accompanies 2 articles published in the same issue of JAMA. One of the articles is critical of the marketing of the HPV vaccine Gardasil (Merck & Co) in the United States, and the other details adverse events that have been reported with the vaccine since it was launched there in 2006.

Dr. Haug comments that, in view of the uncertain benefit from the HPV vaccine, "only a small risk of harmful effects from the vaccine" is acceptable.

The balance between the risks and benefits of HPV vaccination should rest only on medical and scientific evidence, Dr. Haug states.

However, she warns that this balance is "easily skewed" if other matters weigh in; for example, profit for a company or gains for physicians — issues that are explored in the article on marketing.

"The balance will also tilt if adverse events are not calculated correctly," Dr. Haug comments, and her editorial points out limitations of the system used for collecting adverse event reports, detailed in the other article.

Criticism of Gardasil Marketing

The article discussing the marketing of Gardasil in the United States was authored by Sheila Rothman, PhD, from sociomedical sciences and David Rothman, PhD, from social medicine, both at the Columbia College of Physicians and Surgeons, New York City.

Merck & Co promoted Gardasil primarily to "guard" against cervical cancer, rather than promoting it as a vaccine against HPV viruses or sexually transmitted diseases, the authors note. (The vaccine is active against 4 virus subtypes: HPV-6, HPV-11, HPV-16, and HPV-18; HPV-16 and HPV-18 are responsible for about 70% of cervical cancers worldwide and can also cause other anogenital cancers, whereas HPV-6 and HPV-11 are the most common causes of genital warts).

The marketing was so successful that in its first year, Gardasil was named in the industry journal Pharmaceutical Executive as the "brand of the year" for building a "market out of thin air," the authors point out.

"By making this vaccine's target disease cervical cancer, the sexual transmission of HPV was minimized, the threat of cervical cancer to all adolescents maximized, and the subpopulations most at risk practically ignored," they write.

"Rather than concentrating on populations in geographical areas with excess cervical cancer mortality, including African Americans in the South, Latinos along the Texas-Mexico border, and whites in Appalachia, the marketing campaign posited that every girl was at equal risk," Dr. Rothman and Dr. Rothman write.

"That these arguments were delivered by professional medical associations (PMAs) is cause for concern," they add. Merck & Co funded activities at the American College of Obstetricians and Gynecologists, the American Society for Colposcopy and Cervical Pathology, the Society for Gynecologic Oncologists, and the American College Health Association.

Among the company-funded activities were speaker lecture kits and education resource panels, with sample answers to patient questions, as well sample press releases and sample letters to parents and students explaining why they should have the vaccine. The authors detail specific instances in which the message being promulgated by PMAs was influenced by Merck & Co.

Approached for comment, Diane Harper, MD, from the University of Missouri- Kansas City School of Medicine, Kansas City, Missouri, commented to Medscape Oncology that the PMAs "must confess to both their memberships and to the women whose health they serve that they were overtly exuberant in their hopefulness for vaccination and are guilty of presenting essentially only the information that Merck wanted presented."

She added, "In order to move on from this mistake, PMAs need to work with researcher clinicians to develop informed consents that include detailed risks and benefits of vaccination and screening." Dr. Harper also said that, now that serious adverse events have been documented, full disclosure of benefits and risks must be presented in all educational lectures.

Dr. Harper is professor and vice-chair, Obstetrics and Gynecology, Community and Family Medicine and Informatics and Personalized Medicine, and she conducted the phase 2 and phase 3 trials for Gardasil, authoring their publications. She has spoken out previously about the HPV vaccine and its marketing, and to Medscape Oncology, she expressed her concern over how the message about the need for regular cervical smears was overshadowed by "aggressive and inappropriate promotion of the vaccine."

Dr. Harper also commented that nowhere in any of the information about Gardasil has it been pointed out that in developed countries such as the United States, which have Papanicolaou (Pap) screening programs in place, the HPV vaccine will do little to decrease the already very small cancer rate but mostly will allow screening intervals to be extended safely.

Also approached by Medscape Oncology for comment, Maurie Markman, MD, professor of gynecologic medical oncology at the M.D. Anderson Cancer Center, Houston, Texas, questioned the credibility of the article on marketing, which is published as a "special communication." The authors are social scientists, he points out, and they "quote opinions from editorials as if they equate to facts." He emphasized the need to distinguish opinion from data and pointed out that there was no reference to any of the extensive peer-reviewed research articles on the HPV vaccine, which have accumulated data from thousands of patients.

Dr. Markman said he cannot comment directly about the claims made in the article, but added that he would be concerned if there were any truth to the idea that PMAs were not acting appropriately.

However, he strongly disagreed with one of the main points made in the article — the implied criticism of Merck & Co for promoting the vaccine for the prevention of cervical cancer. "I can't say how strongly I disagree with this — in fact, I am appalled," Dr. Markman told Medscape Oncology.

This vaccine does prevent cervical cancer, he emphasized, on the basis of all the data that are available, and "you cannot get better studies or a better strategy," he added. He acknowledges that there is no proof, as yet, but "it will take another 30 years or so to have that proof, and in the meantime, thousands of women will have died from cervical cancer."

"This paper is opinion masquerading as data," Dr. Markman said, and he added that it was "potentially harmful, as it may make people who have already received the vaccine think that they made a mistake."

(In fact, Gardasil is licensed for the prevention of cancer and is only the second vaccine to have this indication, point out the authors from the other article, all of who are from either the Centers for Disease Control and Prevention [CDC] or the US Food and Drug Administration. The first was the hepatitis B vaccine against liver cancer, which is also marketed by Merck & Co. Dr. Rothman and Dr. Rothman suggest that the company learned valuable lessons in the marketing of this first vaccine, which helped it make the marketing of Gardasil so successful.)

Dr. Harper says that HPV vaccination has a role to play in the prevention of cervical cancer. However, she emphasizes the need for regular cervical smears and points out that even women who are vaccinated need to have regular smears, as otherwise they are still at risk for developing cancer. In addition, women who do not receive the vaccine can still protect themselves equally well by undergoing regular Pap tests.

HPV vaccination will prevent more cervical cancers in populations that do not have access to cervical cancer screening, she continued. Some developing countries without screening have an incidence of cervical cancer that is 5 to 12 times higher than that seen in the United States. Because the death rate from cervical cancer is so much higher in these populations, they may also tolerate a high rate of serious adverse events, including death, that have been associated with Gardasil, Dr. Harper commented.

However, in the United States, the usefulness of the vaccine is to increase the chance that a woman's next Pap test will be normal, Dr. Harper commented. Women must still have Pap tests after vaccination, and vaccination alone in the United States will only incrementally reduce the rate of cervical cancer, with its greatest benefit being to increase the screening interval between screens, and hence being a cost-saving device, she added. In fact, if women who are vaccinated stop going for Pap smears, the incidence rate for cervical cancer would increase, she said.

In the United States, the death rate from cervical cancer (3/100,000 women by statistics from the CDC) is at present similar to the rate of reported serious adverse events from Gardasil (3.4/100,000 doses distributed), Dr. Harper pointed out. "This is a sobering reality," she commented. "Would a parent accept such a rate of serious adverse events if the same cancer prevention can occur with continued Pap screening? Is there any acceptable level of risk of serious adverse events, including death, to prevent genital warts?" she asked, referring to one of the vaccine's other benefits.

Latest Adverse Event Data

The latest data on adverse events with Gardasil, published in the same issue of the journal, comes from the US Vaccine Adverse Event Reporting System (VAERS). In total, 12,424 adverse events after immunization were reported to in United States between June 2006 and December 2008, during which an estimated 23 million doses had been distributed (with a course of 3 doses per person recommended). This represents a reporting rate of 53.9 reports per 100,000 doses distributed.

Of these, 772 reports (6.2% of the total) were described as serious, including 32 reports of death.

The authors, headed by Barbara Slade, MD, from the CDC, comment that most of the rates of adverse events after immunization were "not greater than the background rates compared with other vaccines," with the exception of syncope and venous thromboembolic events, which were higher for the HPV vaccine.

These 2 events, syncope and thromboembolic events, were also reported for the HPV vaccine at a higher rate during this postlicensure period than they had been in clinical trials before marketing, the authors note.

Syncope or syncope vasovagal was mentioned in 1896 reports, and dizziness was mentioned in 1572 and nausea in 1164 reports. The reporting rate was 8.2 cases per 100,000 doses distributed. The majority (>90% – 95%) of these reports were classified as nonserious, the authors note. However, some of the reports mentioned falls, and some of these led to fractures, concussions, hemorrhages, and lacerations.

Venous thromboembolic events were mentioned in 56 reports, giving a reporting rate of 0.2 cases per 100,000 doses distributed. Of these, 19 cases involved pulmonary embolism, and 4 of these resulted in death.

Other adverse events included local site reactions (reporting rate, 7.5 cases per 100,000 doses distributed), headache (4.1 cases per 100,000 doses distributed), hypersensitivity reactions (3.1 cases per 100,000 doses distributed), urticaria (2.6 cases per 100,000 doses distributed), autoimmune reactions (0.2 cases per 100,000 doses distributed), Guillain-Barré syndrome (0.2 cases per 100,000 doses distributed), anaphylaxis (0.1 cases per 100,000 doses distributed), death (0.1 cases per 100,000 doses distributed), transverse myelitis (0.04 cases per 100,000 doses distributed), pancreatitis (0.04 cases per 100,000 doses distributed), and motor neuron disease (0.009).

Dr. Markman commented to Medscape Oncology that he saw nothing very new or surprising in this article and said that the surveillance shows that the vaccine is "generally quite safe."

Dr. Harper agreed that "HPV vaccination is generally safe for most girls or women," but she also commented that the adverse events reported are "quite significant."

However, Dr. Harper was critical of the system in which the reports were collected. "VAERS, by all accounts, is an inadequate reporting system whose function in this form is biased towards not showing causality," she said. The definition of the denominator (those exposed to the vaccine) is very broad — if this figure was divided by 3 for women who received all 3 doses, then the reporting rate would be increased, she added.

"If a statistical association is shown with this level of inaccuracy, then it is truly there," Dr. Harper commented. "But conversely, if no statistical association is seen, one cannot conclude that there is no association."

This point is also made by Dr. Haug in her editorial. She points out limitations of the VAERS reporting system, which the authors themselves emphasize by saying that the "data must be interpreted cautiously and cannot generally be used to infer causal association." Dr. Haug, however, adds that "these limitations work both ways: it is also difficult to conclude that a serious event is not caused by the vaccine."

Dr. Harper also highlighted another concern about the VAERS data. The majority of the reports (68%) were submitted by the manufacturer (Merck & Co), which the authors say compares with a rate of 40% from manufacturers of other vaccines. But for nearly 90% of these reports, Merck & Co would not provide the CDC with any follow-up information to investigate possible statistical causality link. As the authors pointed out in the article, this is unusual behavior for a pharmaceutical company, Dr. Harper comments. During the same reporting period, manufacturers reported only 14.5% of the adverse events associated with Menactra (a meningitis vaccine from sanofi pasteur) and only 7.5% of the adverse events associated with Adacel (a polio vaccine from sanofi pasteur), she points out.

"Why would Merck make a concentrated effort at reporting nearly 70% of the adverse events for Gardasil if they did not want to control the information?" Dr. Harper comments. "Legislation needs to be enacted to require adverse events reported to pharma to include medical and contact information for potential follow-up by the CDC."

The editorialist and the authors of both articles have disclosed no relevant financial relationships. Dr. Harper reports having received honoraria from Merck & Co and GlaxoSmithKline, and institutions at which she has worked have received funding from both companies to support clinical trials on HPV vaccines. Dr. Markman reports having received grants for educational activities from Eli Lilly and serving as an advisor or consultant for Genentech, Celgene Corporation, Tibotec, and Boehringer Ingelheim.

JAMA. 2009;302:750–757, 795–796, 781–786.

Zosia Chustecka is news editor for Medscape Hematology-Oncology and prior news editor of jointandbone.org, a Web site acquired by WebMD. A veteran medical journalist based in London, UK, she has won a prize from the British Medical Journalists Association and is a pharmacology graduate. She has written for a wide variety of publications aimed at the medical and related health professions.
Medscape Medical News © 2009 Medscape, LLC

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INTERPRETATION: Our findings show excellent long-term efficacy, high and sustained immunogenicity, and favourable safety of the HPV-16/18 AS04-adjuvanted vaccine up to 6.4 years.

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What are human papillomaviruses, and how are they transmitted?

Human papillomaviruses (HPVs) are a group of more than 100 related viruses. They are called papillomaviruses because certain types may cause warts, or papillomas, which are benign (noncancerous) tumors. The HPVs that cause the common warts which grow on hands and feet are different from those that cause growths in the throat or genital area. Some types of HPV are associated with certain types of cancer (1). These are called high-risk, oncogenic, or carcinogenic HPVs.

Genital HPV infections are very common and are sexually transmitted. Of the more than 100 types of HPV, more than 30 types can be passed from one person to another through sexual contact. Although HPVs are usually transmitted sexually, doctors cannot say for certain when infection occurred. Most HPV infections occur without any symptoms and go away without any treatment over the course of a few years. However, HPV infection sometimes persists for many years, with or without causing cell abnormalities. This can increase a woman’s risk of developing cervical cancer.

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HPV Status Is Prognostic in Oropharyngeal Cancer

June 16, 2010 (Chicago, Illinois) — The human papillomavirus (HPV) status of a tumor is a "strong and independent" prognostic factor for survival in patients with oropharyngeal cancer.

This was the conclusion of a new study presented here at the American Society of Clinical Oncology 2010 Annual Meeting and simultaneously published online June 7 in the New England Journal of Medicine.

The median 3-year rate of overall survival was 82.4% for patients with HPV-positive tumors (n = 206) and 57.1% for patients with HPV-negative tumors (n = 117; P < .001).

The patients all had stage 3 or 4 oropharyngeal squamous cell carcinoma and were randomized to 2 different radiotherapies, each combined with cisplatin therapy. There was no significant difference in survival between the 2 radiotherapy groups.

The American investigators found that the HPV-positive patients had a 58% reduction in the risk for death (hazard ratio (hr), 0.42; 95% confidence interval [CI], 0.27 - 0.66); the hazard ratio was calculated after controlling for age, race, tumor and nodal stage, tobacco exposure, and which radiotherapy a patient underwent in the trial.

As an outgrowth of their study, the investigators developed a novel risk model for oropharyngeal cancer patients.

"A combination of tumor HPV status, pack-years of tobacco smoking, and cancer stage may be used to classify patients as having a low, intermediate, or high risk of death," write the study authors, including senior author Maura Gillison, MD, PhD, from the Ohio State University Comprehensive Cancer Center in Columbus.

They also ask a provocative question about low-risk patients and their need for chemoradiotherapy — given the enduring adverse effects such as xerostomia and dysphagia.

"Whether patients with HPV-positive tumors who are considered to be in the low-risk category can be spared the long-term complications of intensive, multimodal therapy without compromising their survival is now a highly relevant clinical question," the authors write.

A More Definitive Finding

Previous studies have shown that, in this setting, patients with HPV-positive tumors have better survival than those with HPV-negative tumors, write Dr. Gillison and her coauthors.

However, because of small study samples in those studies, "other favorable prognostic factors associated with tumor HPV status (e.g., early tumor stage or young age) could not be ruled out as an explanation for the observed difference in survival," they write.

The size of the study, with its 323 patients, "enable the authors to control for many variables and to conclude that HPV status was a critical independent prognostic determinant," notes Douglas Lowy, MD, and Karl Munger, MD, in an editorial that accompanies the study.

Dr. Lowy is from the Center for Cancer Research of the National Institutes of Health and Dr. Munger is from Harvard Medical School in Boston, Massachusetts.

The new study is an analysis performed within a randomized clinical trial conducted by the Radiation Therapy Oncology Group (RTOG 0129), which examined whether accelerated fractionation radiotherapy is superior to standard fractionation radiotherapy when each therapy is combined with concurrent cisplatin.

To be eligible in the trial, which enrolled 743 patients from 2002 to 2005, patients had to have had a squamous cell carcinoma of the oral cavity, oropharynx, hypopharynx, or larynx. The analysis focused only on the patients with oropharyngeal cancers.

Same But Different

In their editorial, Drs. Lowy and Munger observe that the 2 classes of oropharyngeal squamous cell carcinoma seem to have "distinct causes."

The HPV-positive cases are associated with sex-related risk factors (increased likelihood of orogenital activity) and the HPV-negative cases are associated with tobacco and alcohol consumption, they write.

However, data from the study suggest that smoking has a negative effect on prognosis in both HPV-positive and HPV-negative cases, Drs. Lowy and Munger point out.

The editorialists also note that "clear cut molecular differences" between the 2 classes of carcinoma have been identified.

Nearly all HPV-positive cases express the viral E6 and E7 oncoproteins, which "may render the HPV-positive tumors more immunogenic than the HPV-negative tumors," they write.

Serologic assays detect anti-E6 or anti-E7 antibodies in many patients with HPV-positive tumors, note the editorialists. Also, a higher proportion of patients with HPV-positive tumors have partial or complete responses to treatment.

In summary, it seems clear that HPV-positive and the HPV-negative oropharyngeal squamous cell carcinomas are "distinct entities."

The study authors believe that this means that future clinical trials "should be designed specifically for patients with HPV-positive or HPV-negative squamous cell carcinoma of the head and neck."

Reanalysis of existing clinical trial data is also in order, say Dr. Gillison and colleagues, because it might uncover some "therapeutic implications" for patients with the different HPV types.

Different Levels of Risks: Can Some Patients Forgo Treatment?

The investigators report that HPV status was the major determinant of survival, followed by pack-years of tobacco smoking (<10 vs >10), then nodal stage (n0 to N2a vs N2b to N3) for HPV-positive tumors and tumor stage (T2 or T3 vs T4) for HPV-negative tumors.

Using a recursive partitioning analysis, they classified the patients in the study into 3 categories with respect to risk for death:

• Low risk had a 3-year survival rate of 93%
• Intermediate risk had a 3-year survival rate of 70.8% (HR for the comparison with low risk, 3.54; 95% CI, 1.91 - 6.57)
• High risk had a 3-year survival rate of 46.2% (HR for the comparison with low risk, 7.16; 95% CI, 3.97 - 12.93).

All HPV-positive patients were considered low risk unless they were smokers with a high nodal stage (N2b to N3) — then they were considered intermediate risk.

All HPV-negative patients were considered high risk unless they were nonsmokers with stage T2 or T3 tumors — then they were considered intermediate risk.

Currently, there is no evidence to guide treatment decisions for individual patients on the basis of HPV status, note the study authors. However, they see their study as a basis for future clinical research, including the possibility, as noted above, that low-risk patients might not receive radiotherapy, given its serious adverse effects.

Dr. Gillison has disclosed no relevant financial relationships. Dr. Lowy reports receiving royalties from Merck and GlaxoSmithKline for technology related to the HPV vaccine licensed by the National Institutes of Health to the companies. Dr. Munger reports being a consultant to Arbor Vita and on the Merck speakers bureau.

N Engl J Med. Published online June 7,2010, presented at American Society of Clinical Oncology (ASCO) 2010 Annual Meeting: Abstract 5507 on June 7, 2010

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A drastic increase in the number of HPV-associated oropharynx cancers, particularly those of the tonsil and base of tongue, has captured the attention of head and neck oncologists worldwide.
In February, at the Multidisciplinary Head and Neck Cancer Symposium in Chandler, Ariz., Maura Gillison, MD, PhD, professor and Jeg Coughlin Chair of Cancer Research at The Ohio State University in Columbus, presented data that showed that the proportion of all head and neck squamous cell cancers that were of the oropharynx — which are most commonly HPV-positive cancers — increased from 18% in 1973 to 32% in 2005.

Maura Gillison, MD, PhD, Jeg Coughlin Chair of Cancer Research at The Ohio State University, said screening for HPV in the head and neck is years behind cervical screening for HPV.

In addition, studies from the United States, Europe, Denmark and Australia indicate that HPV-positive patients have a more than twofold increased cancer survival than HPV-negative patients, according to Gillison.
With the rising incidence of HPV-related oropharynx cancers, it will soon be the predominant type of cancer in the oral or head and neck region, according to Andy Trotti, MD, director of radiation oncology clinical research, H. Lee Moffitt Cancer Center & Research Institute, in Tampa, Fla.

“We should be focusing on HPV-related oropharyngeal cancer because it will dominate the field of head and neck cancers for many years,” he said during an interview with HemOnc Today . “It is certainly an important population for which to continue to conduct research.”
Because HPV-associated oropharyngeal cancer is emerging as a distinct biological entity, the recent rise in incidence will significantly affect treatment, and prevention and screening techniques, essentially reshaping current clinical practice.
Social change driving incidence

In the analysis performed by Gillison and colleagues, trends demonstrated that change in the rates of head and neck cancers was largely due to birth cohort effects, meaning that one of the greatest determinants of risk was the year in which patients were born.
The increased incidence of HPV-related oropharyngeal squamous cell carcinoma started to occur in birth cohorts born after 1935, indicating that people who were aged in their teens and twenties in the 1960s were demonstrating increased incidence, Gillison said.
“Two important and probably related events happened in the 1960s. In 1964, the surgeon general published a report citing smoking as a risk factor for lung cancer, and public health policy began promoting smoking cessation along with encouragement not to start smoking,” she told HemOnc Today.

If you were 40 years old between 2000 and 2005, your risk for having HPV-related cancer is more than someone who was between the age of 40 and 45 years in 1970, according to Gillison. Social changes that occurred among people born after 1935, for example, a reduction in the number of smokers, is consistent with the increasing proportion of oropharyngeal cancers that were HPV-related.
“The rates for HPV-related cancers began to increase and the rates for HPV-unrelated cancers started to decline, consistent with the known decline in tobacco use in the U.S. population,” she said.

Now, most cases of head and neck squamous cell carcinoma in non-smokers are HPV-related; however, oral HPV infection is common and is a cause of oropharyngeal cancer in both smokers and non-smokers, research shows.

In addition to a decrease in tobacco use reducing HPV-unrelated oral cavity cancers, the number of sexual partners may have increased during this time and have helped to increase HPV-related oropharyngeal cancers, according to Gillison.

Determining the cause of the elevated incidence is only a small piece of the puzzle. Screening, establishing who is at risk, and weighing vaccination and treatment options are all relevant issues that must be addressed.

Screening is problematic
A critical area for examination and research is the issue of screening for oral cancers. In contrast to cervical cancer, there is no accepted screening that has been shown to reduce incidence or death from oropharyngeal cancer, according to Gillison.
Not many studies have examined the issue of screening for HPV-unrelated oral cancers, and the few that have, tend to include design flaws.
Gillison said there is a hope that dentists would examine the oral cavity and palpate the lymph nodes in the neck as a front-line screen for oral cancer; however, in her experience, and from her perspective as a scientist, this has never been shown to provide benefit for oral cancer as a whole.

Another caveat with regard to HPV detection is that head and neck HPV screening is about 20 years behind the cervical field.
“Clinicians screening for HPV in the field of gynecology were incredibly fortunate because Pap smear screening was already an accepted cervical cancer screening method before HPV was even identified,” she said. “There was already a treatment algorithm: If there were cytologic abnormalities, patients were referred to the gynecologist, who in turn did a colposcopy and biopsy.”

A similar infrastructure does not exist for oropharyngeal cancer. People with HPV16 oral infection are at a 15-fold higher risk for oropharynx cancer and a 50-fold increased risk for HPV-positive head and neck cancer, yet there is no algorithm for treatment and management of these at-risk individuals, Gillison said.

In 2007, WHO said there was sufficient evidence to conclude that HPV16 was the cause of oropharynx cancer, but with no clinical algorithm already established, progress in this area is much further behind.

Another problematic aspect of HPV-related oropharyngeal cancer screening is that the site where the cancer arises is not accessible to a brush sampling, according to Gillison.

“To try to find this incredibly small lesion in the submucosal area that you cannot see and cannot get access to with a brush, highlights that we need to develop new techniques, new technologies and new approaches,” she said.

The near future consists of establishing the actual rates of infection in the oral cavity and oropharynx, and then screening for early diagnosis, according to Erich Madison Sturgis, MD, MPH, associate professor in the department of head and neck surgery and the department of epidemiology at The University of Texas M.D. Anderson Cancer Center.

“I am not extremely hopeful because the oropharyngeal anatomy makes screening complicated, and these cancers likely begin in small areas within the tonsils and the base of the tongue,” Sturgis told HemOnc Today. “I am hopeful, however, that preventive vaccines will eventually, at a population level, start to prevent these cancers by helping people avoid initial infection by immunity through vaccination earlier in life.”

Much of the currently known information surrounding the issue of HPV-related oral cancers is new, so researchers continue to conduct research in various relevant areas. One key question to answer is who may be at higher risk for HPV-related oropharynx cancers.

Who is at risk?
As mentioned earlier, the number of oral sex partners seems to play a role in the risk for contracting the HPV virus.

In one study published in The New England Journal of Medicine in 2007, findings demonstrated that a high lifetime number of oral sex partners (at least six partners) was associated with an increased risk for oropharyngeal cancer (OR=3.4; 95% CI, 1.3-8.8).

In addition to a higher number of oral sex partners, other still unknown factors may be contributing to risk. This is an area that needs further research, according to Barbara Burtness, MD, chief of head and neck oncology, and professor of medical oncology at Fox Chase Cancer Center in Philadelphia.

The effect of smoking status is another area that needs further research. According to Burtness, smokers with HPV-associated oropharynx cancer have less favorable outcomes.

When discussing the prognosis of HPV-associated cancers, Sturgis said low risk is defined as low or no tobacco exposure and positive HPV status, and intermediate risk is defined as significant tobacco exposure but an HPV-positive tumor, and the highest risk group appears to be the HPV-negative group.

Although HPV-negative cancers are overwhelmingly tobacco-related cancers and tend to have multiple mutations, it appears that HPV-positive cancers, particularly those in patients with low tobacco and alcohol exposure, tend to lack mutations and to have a better prognosis, and this may ultimately help to guide treatment practices, according to Sturgis. Yet, there is still much to learn about HPV-related oropharyngeal cancers on various fronts.
Vaccination a hopeful ally

In HPV-related head and neck cancer, particularly oropharynx cancers, more than 90% of patients who have an HPV-type DNA identified, have type 16, according to Sturgis.

The two current HPV vaccines, Gardasil (Merck) and Cervarix (GlaxoSmithKline), which are approved for cervical cancers, include HPV types 16 and 18; therefore, in theory, they should be protective against the development of infections in the oropharynx and protective at preventing these HPV-associated cancers from occurring.

The presumption is that if there was a population-wide vaccination against HPV, there would be less person-to-person transmission, and this would lead to fewer oropharynx cancers, according to Burtness, who said this theory still needs further research.

There is excitement at the possibility that therapeutic vaccines could be developed, and various groups are investigating this, Burtness added.

“There is reason to think that the vaccines may be helpful; however, when HPV infects the tonsillar tissues, it exerts control in the host cells by making two proteins: E6 and E7; so another potentially exciting therapeutic avenue would be to target those specific viral proteins,” she told HemOnc Today.

Anxiety about protection from the HPV virus is palpable, according to Sturgis. He described the worry that many patients experience about contracting and transmitting HPV infection.

“Many patients are concerned they will put their spouses and/or children at risk in ways such as kissing them; and we need to tone down those worries until we have better data,” he said.

Screening and vaccination are fundamental aspects of current ongoing research, but of equal importance is determining what clinicians should do to treat a population of patients with HPV-related oropharyngeal cancers.

HPV status may influence treatment
With rates of HPV-related cancers escalating, determining the appropriate treatment for these patients is crucial.
During the past 10 years, findings from retrospective studies have shown that patients with HPV-related cancers have a much better prognosis than patients who test negative for HPV. Findings from several retrospective analyses from clinical trials conducted during the past 2 years have come to the same conclusion, according to Gillison: HPV-positive patients have half the risk for death compared with patients negative for HPV.

Therefore, there may be several alternative treatment options, including the possibility of reducing the dose of radiation given to patients after chemotherapy, thereby reducing toxicity.

Comparing HPV-negative and HPV-positive patients may not be enough to determine proper treatment, researchers said. Data between different cohorts of HPV-positive patients also needs to be examined. Smoking, for example, may play a role in patient outcome.
In a prospective Radiation Therapy Oncology Group clinical trial (RTOG 0129), presented by Gillison at the 2009 ASCO Annual Meeting and recently published in The New England Journal of Medicine (see page 53), researchers conducted a subanalysis of the effect of smoking on outcome in uniformly staged and treated HPV-positive and HPV-negative patients while accounting for a number of potential confounders. HPV-positive patients who were never smokers had a 3-year OS of 93% compared with heavy smoking HPV-negative patients who had an OS of 46%.
The study found that smoking was independently associated with OS and PFS. Patients had a 1% increased risk for death and cancer relapse for each additional pack-year of smoking. This risk was evident in both HPV-positive and HPV-negative patients. Gillison said smoking data must be paid attention to, and she encouraged cooperative group research on the topic.

Most of the findings demonstrate improved outcomes for patients with HPV-positive oropharyngeal cancers vs. patients with HPV-negative oropharyngeal cancers, according to the experts interviewed by HemOnc Today.

Dose de-intensification for less toxicity
To date, there is no evidence that HPV-related cancers should be managed differently than HPV-unrelated cancers, but it is a hot topic among clinicians in the field, according to Burtness.

The superior outcomes for HPV-associated oropharynx cancer have suggested the possibility of treatment de-intensification. The use of effective induction chemotherapy may permit definitive treatment with a lower total radiation dose. In theory, this would reduce the severity of late toxic effects of radiation, such as swallowing dysfunction. Such a trial is being conducted by the Eastern Cooperative Oncology Group. Burtness said this is currently pure research question.

“There is still much research that needs to be done before clinicians can safely reduce the dose of radiation administered to HPV-positive patients,” Burtness said.

Currently, she and colleagues in the ECOG are conducting a study of patients with HPV-associated stage III or IV oropharynx cancers to examine the possibility of tailoring therapy to these patients. Patients are assigned to one of two groups: low-dose intensity-modulated radiotherapy 5 days per week for 5 weeks (27 fractions) plus IV cetuximab (Erbitux, ImClone) once weekly for 6 weeks, or standard-dose intensity-modulated radiotherapy 5 days per week for 6 weeks (33 fractions) plus IV cetuximab once weekly for 7 weeks.

If patients have a very good clinical response to chemotherapy, which is likely to happen with HPV-associated cancers, they are eligible to receive a reduced dose of radiation, and hopefully, they would experience less adverse effects, Burtness said.

“Patients who are treated with the full course of radiation for head and neck cancer are now getting 70 Gy, and they are often left with dry mouth, and speech and swallowing difficulty,” she said. “We are hopeful that if these particular cancers are treatment responsive to chemotherapy, we may be able to spare the patient the last 14 Gy of radiation.”

Immunotherapy a viable treatment
Another possible treatment technique that may benefit patients with HPV-related cancers is immunotherapy. One form of immunotherapy uses lymphocytes collected from the patient, and training the cells in the laboratory to recognize in this case a virus that is associated with a tumor and consequently attack it. This approach potentially may be used to treat HPV-related oropharynx cancers, according to Carlos A. Ramos, MD, assistant professor at the Center for Cell and Gene Therapy at Baylor College of Medicine, Houston.

“With some infections that lead to cancer, even though the virus is present in the tumor cells, the proteins shown to the immune system are limited; therefore, they do not drive a very strong immune response,” Ramos told HemOnc Today. “Training the immune system cells, T lymphocytes, may make them respond better to antigens.”

Data from ongoing trials that are taking T lymphocytes from patients and educating them to recognize antigens in patients with the Epstein-Barr virus associated tumors have shown some activity against them, according to Ramos. This adoptive transfer appears to be safe and may have the same effect on the HPV virus associated tumors. Immunotherapy does not cause the usual toxicities associated with chemotherapy, he said.

“There are currently no trials showing whether we can prevent more recurrences with this approach, but the results of trials examining viruses such as Epstein-Barr are good so far, in both patients who have no evidence of disease and in those who still have disease,” he said.
Even patients with active disease who have not responded to other therapies have responded to this therapy, Ramos said. He and colleagues are working toward compiling preclinical data to study the possibility of using immunotherapy to treat patients with HPV-related cancers.

Journey is just beginning
Much of what is known about risk, screening, prevention and treatment of HPV-related oropharynx cancers is in the early stages of discovery and much is still theoretical, according to Sturgis.

“As far as we can tell, these infections are transmitted sexually; the hope is that as we have better vaccines for prevention of cervical dysplasia, the downstream effect will help prevent other HPV-related cancers, such as anal cancers and penile cancers and oropharyngeal cancers,” he said.

Several recent studies examining new therapies that may reduce the intensity of traditional treatments while maintaining survival rates would have a major effect on the field, according to Sturgis.

Gillison said the rise in the number of cases of HPV-related cancers is changing the patient population considered to be at risk, and more research is vital.

“The most important thing for clinicians to do is be aware that trials are being developed and strongly encourage their patients to participate,” she said.

quote:

HPV is presenting itself as a new dominant cause of mouth cancer.

That's according to Dr Vinod Joshi, founder of the Mouth Cancer Foundation.

In light of this, Dr Joshi has produced a new Human Papillomava Virus (HPV) leaflet launching for Mouth Cancer Awareness Week, which takes place 14-20 November to coincide with Mouth Cancer Action Month.

quote:

The dental practitioner has a responsibility to examine and assess the oral tissue status of all patients. Usually, we are happy to report that the tissue is healthy and no further treatment is necessary. Ethically, our role in assessment is both an understood practice as well as a legal one each time we interact with our patients.


Figure 1: Tonsillar cancer. Courtesy of: Dr. Martin T. Tyler, McGill University Health Center.

Within your practice, what is the expected role in assessing and relaying advice/recommendations to our patients? Do we rely strictly on scientific evidence with evidence-based protocol? Do we trust the developers/promoters of dental products to provide information to us? Do we relay personal opinion from colleagues, or do we reject opinion-based information? Do we search the scientific literature for current information, or call our colleagues and company representatives and obtain a consensus of what the best options may be for dissemination of information?

We have all been in these situations. With busy practices, it is very time consuming to sit down and evaluate all the literature. Anyone who has been faced with a medical decision for a loved one or ourselves may actually feel exhausted while trying to sort through all of the options, treatments, and advice – some of which may even be at odds within specific group specialties in the way treatment is rendered. It can be very daunting, draining us both mentally and physically. So how do we approach this dilemma?

For some time, we have known about the detrimental effects of alcohol and tobacco products and the role of both in the etiology of oral cancer. Counseling a patient on discontinuing these products has become commonplace. Most of the population knows that these products are detrimental, but we still try to provide both current and factual information to our patients. Recently, considerable information has been published about the human papillomavirus (HPV) status of the patient. Both hygienists and dentists are being asked about HPV (specifically HPV 16) and its connection to oral cancer. HPV has been correlated with cancer at the base of the tongue, the oropharynx, and tonsil. Although we know that the correlation is present and oral exams are performed periodically, these areas are difficult to assess and do not appear as the typical oral tissue changes that we have been able to detect during oral cancer exams. These cancers are not easily detected through visual exams, palpation in early development, and by using some of the early cancer detection devices on the market while in early stage. Most of these cancers are detected in a late stage because the tonsillar tissue, particularly the tonsillar crypts, have many crevices and tissue surfaces that are hidden from the practitioner's view. Some individuals have disease states hidden in the tissues.

By the time the problem is observed and detectable changes are observed in the lymph nodes, the stage is much higher and usually at a Stage III or IV. Although it is so important to check the posterior areas of the mouth, it is not uncommon to find that tonsillar regions are neglected.

For many years, dentistry did not even consider this "their area of expertise or responsibility" and the examination was left to the medical community. Students now are taught to check this area thoroughly while in dental schools, and we now know that the tissue in this area of the mouth is highly linked to HPV. Because of the lack of clear visible oral lesions, the palpation of cervical lymph nodes and close examination of these areas is crucial.

An excellent oral exam video has been produced by Dr. Michael Siegel and Dr. Valerie Murrah (see references). Dr. Siegel and Dr. Murrah demonstrate the exam with a thorough focus on the cervical lymph nodes and the oropharynx.

What do we really know about HPV?
A recently published letter written by Dr. Mark W. Lingen (2010) addressed the issue associated with the saliva test that is being offered in dental offices with on-site training by representatives of the company manufacturing the test. In the paper, he states that it appears that this test "is a test looking for a disease." He additionally questions whether knowing if one is HPV positive really means anything that is clinically significant for the patient.

Most of the time HPV is cleared from the body through its own immune system. If the person is tested again at a later date, the results in most cases will be negative. Some individuals who have ongoing positive results could be more susceptible to oral cancer.

Essentially, we really do not know very much as to how this entity behaves in all individuals. We cannot predict in whom the virus will persist.

Overall, we do know that some individuals are more susceptible to certain disease states and cancers. As an example, we know that some individuals in their eighties and nineties have smoked all their lives, and yet they do not develop oral or lung cancer. Why is one individual affected and not another? Clearly, there are multiple factors playing a role in the development of disease states, and this may be genetically and environmentally influenced. Dr. Lingen also suggests that those reading his article may want to peruse a published article by Dr. Jaeschke et al. on a user's guide to the medical literature. It is instructive in how to use an article promoting a diagnostic test (see references).

With the continued rise of oral cancer in the under 40-year-old age group without known risk factors, what do we really know about HPV?

We know that we are seeing oral cancer in the younger age groups (under 40 years old) with no historic risk factors, such as tobacco and alcohol.
We are finding posterior of the mouth cancer at advanced stages with often occult primary lesions in the oropharynx, base of the tongue, and tonsillar tissue. Most of the time these do not produce the historic surface lesions we are accustomed to finding. Neck palpation for hard, painless, fixed nodes is becoming increasingly important as a component of the oral exam.

• The CDC estimates that 20 million Americans are currently infected with HPV. This number is constantly changing as new data becomes available.
  
• 50% of sexually active adults will be infected with HPV in their lifetime.
  
• The National Cancer Institute estimates 36,540 oral cancers in 2010 with 7,880 subsequent deaths within the United States. These numbers vary with some of the large research institutes conducting current research.

I recently presented a seminar on mucosal diseases at a national meeting and introduced some ideas of my own. I found that I really could not even answer my own questions based on the research I read. Consequently, I then turned to open dialogue with those whom I knew had studied the literature on the subject. Unfortunately, I was less clear after assessing the information than I was at the start of my search. If I was not completely clear, what would I tell patients or students who asked the following?

• Does kissing transfer the HPV and make the other person susceptible to oral cancer? How much of a deep passionate kiss do you need to transfer the HPV? How would you even begin to test this assumption?
  
• Is a child at risk if the mother is HPV positive?
  Can HPV be transferred if the mother tastes her baby's food before giving it to the child? Since this is a rather common practice, should we be concerned about contagion? This is always a question that a patient will ask when diagnosed with any disease state.
  
• Is an HPV positive person more at risk if he/she uses tobacco and alcohol together? Or, is one more of a risk than the other? Is a person who may be genetically susceptible to cancer more affected by the trio of alcohol, tobacco, or HPV?
  
• Is the HPV an entity that can be harbored for years and then reappear? If you are in a relationship, does this open up the questions of fidelity? And, how do you help the patient answer this question, or can you possibly provide any answers?
  
• Do you test all patients, or just some known high-risk groups? Do you check adolescents who may or may not admit to sexual activity? Do you talk to the parent first before even asking? What would be the reaction of a parent? As you know, adolescents and even some much older individuals do not consider oral sex to be "true" sex, so your phrasing and communication is crucial.
  
• Do you recheck a positive patient again and at what intervals?
  
• Who should talk with the patient? How confidential is the information?
  
• Do you check the entire family for HPV? Do you check at intervals?
  
• Do you test patients for HPV who have had a previous oral cancer at every appointment?
  
• Does the constant bleaching of teeth (practiced by many under 40 years of age) affect the oral tissues in some individuals, and does HPV affect this tissue after or during bleaching?
  
• Does GERD and frequent heartburn make the tissues more susceptible to HPV in some individuals – possibly those with a genetic predisposition?

Finding the answers to our questions about HPV
I have pondered these questions for several months now and discussed all these questions with many colleagues who have expertise in oral medicine and pathology. I don't know the answers to these questions in the depth needed to make clear recommendations. Frankly, I am amazed at how fast the dental/dental hygiene community has embraced the addition of promoting HPV testing in the dental office without knowing the answers to many important questions related to HPV.

We must do our own critical thinking about new information and the ramifications of that information for our patients. It is clearly never a sound idea to automatically discount information because it is new and maybe not in line with our current thoughts or those of our trusted fellow professionals. Progress in research is based on innovation, analysis, and critical thinking.

I, for one, believe that we have in some ways lost touch with the promotion of innovation and critical thinking. They are intertwined. Most people who are in research and education have a strong innovative side and those people who go into specialty areas in dentistry often have an investigative/innovative side as well. So what are we to accept and to believe and how do we assess new information? And, when is there enough evidence-based information to suggest new protocol to our patients?

Steven Berlin Johnson, in his new book, "Where Good Ideas Start," states that alcohol was used as a "cure all" in early English history. We know that there is a depressant effect to alcohol. As time progressed, it was found that the new coffeehouses in England provided not only the stimulant brew of coffee, but it was determined that the arousal of ideas was prevalent as well. I am not suggesting that we all drink coffee and sit around discussing our ideas, but open pathways for discussion are key.

This promotion of discussion and sharing ideas goes back to early years when Ben Franklin led discussion sessions and the "Junto Groups" of like-minded craftsmen and townspeople came together to discuss the topics of the day.

Any time you have a group of people who gather and discuss ideas, new information is shared and new ideas flourish. The Internet has provided the opportunity in which discussion board participants post questions, relevant ideas can be debated, and critical thinking is promoted. This is true for many of us in the dental community where it is so easy to accept ideas from others in our profession. But we need to raise these questions, listen to other views, and critically analyze information. The Internet has provided a sounding board where patients, researchers, practitioners, and family members come together, ask questions, and discuss areas of concern.

An Internet site and discussion board was founded by Brian Hill of the Oral Cancer Foundation, Inc., and Brian is an oral cancer survivor himself. His organization provides educational materials, lectures and discussion postings for those who have been diagnosed with oral cancer. The group also supports family members dealing with oral cancer.

Brian has been instrumental in calling attention to the screening process and the importance of the oral exam, along with its role in early detection. He has been instrumental in the discussion of the role of HPV in oral cancer and calling attention to the risk factors for oral cancer with the distribution of educational materials. The Web site for the foundation is: http://www.oralcancer.org", and a section of the site is devoted to HPV.

It is interesting that so little time is spent trying to provide information on nutrition and lifestyle modifications that clearly impact the health of all patients. Yet, dental personnel are being asked to counsel patients about sexual practices and personal medical information with regard to HPV status. If we do provide this counseling, what are the long-term ramifications?

A phenomenon in the medical field is known as "white coat syndrome." Patients experience and test very high for blood pressure readings when they enter a medical office. Cardiologists are aware of this phenomenon, even among regular patients. We know how powerful the mind is, and there is no doubt that some disease states can actually develop due to prolonged stress and are termed "health anxiety." The mind-body connection is very strong. Are we really ready to deal with all the psychological problems that may develop in our patients when given test results for HPV status? And, as Dr. Lingen so eloquently stated, do we really have enough information and what do the results really mean anyway?

Lastly, are we creating more problems than we are attempting to solve? Asking questions, discussing issues, and assessing the evidence is always necessary.

Keep asking good questions and always listen to your patients!

quote:

Head and neck cancer in Australia between 1982 and 2005 show increasing incidence of potentially HPV-associated oropharyngeal cancers.
Hocking JS, Stein A, Conway EL, Regan D, Grulich A, Law M, Brotherton JM.
Centre for Women's Health, Gender and Society, University of Melbourne, 2/723 Swanston Street, Carlton 3053, Victoria, Australia.

Abstract

• Background:
  Although tobacco- and alcohol-associated head and neck cancers are declining in the developed world, potentially human papillomavirus (HPV)-associated oropharnygeal cancers are increasing.
  
• Methods: We analysed oropharyngeal and oral cavity cancer rates in Australia in 1982-2005. Cancers from the oropharynx (base of tongue, tonsil and other specific oropharyngeal sites) were classified as potentially HPV associated (n=8844); cancers in other oral cavity and oropharyngeal sites not previously associated with HPV were classified as comparison (n=28 379).
  
• Results: In 2000-2005, an average of 219, 159 and 110 cancers of the tonsil, base of tongue and other oropharyngeal sites were diagnosed annually, with incidences of 1.09 (95% CI: 1.03, 1.15), 0.79 (95% CI: 0.74, 0.84) and 0.55 (95% CI: 0.50, 0.59) per 100 000, respectively. An average of 1242 comparison cancers were diagnosed annually (6.17 (95% CI: 6.03, 6.31) per 100 000). In 1982-2005, there were significant annual increases in tonsil (1.39% (95% CI: 0.88, 1.92%)) and base of tongue cancers in males (3.02% (95% CI: 2.27, 3.78%)) and base of tongue cancer in females (3.45% (95% CI: 2.21, 4.70%)). There was a significant decrease in comparison cancers in men (-1.69% (95% CI: -1.96, -1.42%)), but not in females.
  
• Conclusion: Potentially HPV-associated oropharyngeal cancer in Australia is increasing; the impact of HPV vaccination on these cancers should be monitored.

quote:

More than 16 million Americans - seven per cent - now have oral HPV, a sexually transmitted virus more commonly linked with both cervical cancer and mouth cancer.

According to the first nationwide estimate, the human papilloma virus is increasingly recognized as a major cause of oral cancers affecting the back of the tongue and tonsil area.
Smoking and heavy drinking are also key causes.

Until now, it was not known how many people have oral HPV infections.

The nationally representative study is based on 30-second gargle tests given to about 5,500 people in a 2009 to 2010 government health survey. Their mouthwash samples were tested for HPV. The results were published online on Thursday in the Journal of the American Medical Association.

Overall, seven per cent of Americans aged 14 to 69 are infected, the study found. But the results are not cause for alarm. While mouth cancers are on the rise – probably from oral sex – most people with oral HPV will never develop cancer. There are many types of HPV, but one in particular, known as HPV-16, is most strongly linked with oral cancer and also is a common cause of cervical cancer. That form was found in about one per cent of people studied, translating to about two million Americans. So most don't have the kind most strongly linked to cancer.

Tests for oral HPV are costly and mainly used in research. Still, experts say the study provides important information for future research that could increase knowledge about who is most at risk for oral cancer and ways to prevent the disease.

Dr Maura Gillison, the lead author and a researcher at Ohio State University, said the study 'provides us some reassurance' that most people with oral HPV will not get oral cancer. Millions may have oral HPV, but fewer than 15,000 Americans get HPV-linked oral cancer each year. She said the study should prompt research into whether the existing vaccines for cervical cancer protect against oral HPV, too. Dr Gillison has consulted with Merck & Co., and GlaxoSmithKline, makers of HPV vaccines. Ohio State, Merck and the National Cancer Institute helped pay for the study.

Dr Ezra Cohen, a head and neck cancer specialist at the University of Chicago, said the study provides important information confirming similarities in risk factors for HPV oral infections and oral cancer. For example, oral HPV was more common in men than women – ten per cent versus almost four per cent, in smokers, and in people who had many sexual partners. People aged 55 to 59 were most at risk. Sexual activity was a strong risk factor, including oral sex. Oral HPV infection rates were much lower than previous estimates for HPV affecting the cervix and other genital areas, suggesting that the mouth might somehow be more resistant to infection, according to a journal editorial.

Dr Hans Schlecht , the editorial author and an infectious disease specialist at Drexel University in Philadelphia, said the study provides fodder for researching how some infections lead to cancer and identifying ways to detect and treat HPV-related oral lesions before they turn into cancer. Unlike non-HPV cancers easily seen in the front of the mouth, HPV-linked tumors in the rear tongue and tonsil area are often hard to detect. Schlecht emphasized the importance of knowing symptoms of these cancers, which can include a sore throat, difficulty swallowing, ear pain and swollen lymph nodes in the neck.