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.