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Increased exposure likely driving ‘epidemic’ of HPV-associated cancers
Comprehensive data from the CDC, NCI and the North American Association of Central Cancer Registries continue to show a decline in both incidence and mortality rates for most cancers in the United States.
There are three notable exceptions: oropharyngeal, anal and vulvar cancers related to HPV.
The most dramatic increase is among cancers of the oropharynx, the region of the throat that includes the tonsils, uvula and the base of the tongue.
A SEER registry review conducted by Jemal and colleagues, published earlier this year in the Journal of the National Cancer Institute, showed HPV DNA was detected in 71.7% of oropharyngeal tumors diagnosed between 2000 and 2004. That figure is more than four times higher than the 16.3% prevalence rate reported between 1984 and 1989. Incidence rates also have increased in Canada and several European countries.
The increase is most significant among white men and women, although reasons are unclear.
“There are no data on the natural history of oral HPV infection or on changes in the prevalence of infection over time among the general population, or among oropharyngeal cancer patients by race and ethnicity,” Jemal and colleagues wrote.
Meanwhile, rates of oropharyngeal cancers attributable to other common causes — including smoking and alcohol consumption — are on the decline, according to NCI.
HemOnc Today discussed the trend with several researchers. Most agreed that changing sexual behaviors among Americans likely contribute to the increase in oropharyngeal cancers, but the specific connection has yet to be clearly defined.
HPV vaccines, given as a series of three shots over 6 months, protect against anal, vulvar, cervical and vaginal cancers. It is too early to tell whether the recommendation that all teens undergo HPV vaccination will affect incidence rates of HPV-associated cancers, but slower-than-expected uptake rates for vaccinations among both girls and boys have many in the field concerned.
There is some encouraging news: Data suggest the prognosis is good for patients with HPV-associated oropharyngeal cancers. Shifting trends in self-examination and screening may play a role, but even that is the subject of speculation.
David Adelstein, MD, a staff physician in the department of solid tumor oncology at Cleveland Clinic’s Taussig Cancer Institute, said it is unclear why patients with HPV-associated oropharyngeal cancers have a better prognosis than patients with HPV-negative tumors.
Source: Photo courtesy of Cleveland Clinic, ©Russell Lee 2011.
“The expectation is that the vaccines will prevent oropharyngeal cancers in future, but we are not there yet,” David Adelstein, MD, a staff physician in the department of solid tumor oncology at Cleveland Clinic’s Taussig Cancer Institute, told HemOnc Today. “The improved prognosis for these patients is independent of better performance status and other risk factors, but it is still unclear as to why.”
Changing sexual habits
The oropharyngeal cancer patient population — traditionally composed of older men and women who were heavy smokers or drinkers — has evolved to include a higher percentage of nonsmokers and nondrinkers in their mid-40s and early 50s.
“They present with stage IV oropharynx cancer, the vast majority of which are linked to HPV16,” Robert I. Haddad, MD, the disease center leader in the head and neck oncology program at Dana-Farber Cancer Institute, said in an interview.
The infection is transmitted orally, and oral sex is one of the easiest ways of transmitting cancer of the oropharynx.
“The increase may be attributed to changing sexual habits coinciding with an epidemic of this virus,” Carol L. Brown, MD, director of the office of diversity programs in clinical care, research and training at Memorial Sloan-Kettering Cancer Center, told HemOnc Today.
Maura L. Gillison
Maura L. Gillison, MD, PhD, professor of medicine, epidemiology and otolaryngology and Jeg Coughlin Chair of cancer research at The Ohio State University Comprehensive Cancer Center — Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, summarized the issue in more clinical terms.
“The fact is that more people are getting exposed. Therefore, more cancers are developing,” Gillison said. “There is no evidence that the infection is becoming more virulent because this has proven to be a very stable virus, so we must begin looking at how exposure has changed.”
Traditionally, oropharyngeal cancers have been prevalent among smokers and drinkers.
Bert W. O’Malley Jr., MD, chair of the department of otorhinolaryngology at the University of Pennsylvania, said most of the HPV-positive patients he sees neither smoke nor drink, and recent evidence supports this trend.
Jain and colleagues conducted a population-based study of 64,673 patients with head and neck squamous cell cancer to determine secondary primary malignancy risk.
Study results — published earlier this year in Cancer — showed the head and neck carried the highest risk, with a standard incidence ratio of 41.4. The esophagus was associated with an incidence ratio of 21.8, followed by the lung at 7.4.
The risk for synchronous secondary primary malignancy has evolved over time, Jain and colleagues wrote.
In the 1970s and 1980s, oropharyngeal cancers were linked to the highest risk for secondary primary malignancy. A decline was observed in the 1990s, and now these cancers have the lowest risk for synchronous primary malignancy.
“The current data are consistent with the etiologic shift of oropharyngeal [head and neck squamous cell carcinoma], from a primarily tobacco-associated malignancy associated with significant field cancerization of the upper aerodigestive mucosa, to a malignancy primarily caused by oncogenic human papillomavirus,” Jain and colleagues concluded.
These data drive home the importance of preventing the spread of HPV infection.
“One of the biggest issues we deal with in the clinic is risk to the partner,” Haddad said. “This is a delicate discussion, one that can have a profound effect on relationship or marriage. At the moment, we are not seeing an increased risk for cancer in the partner, but the data may show us that eventually.”
Still, efforts to reduce sexual transmission of the virus may be unrealistic, and it is also just a small piece of the puzzle, Adelstein said.
“The likelihood that fear of oropharyngeal cancer will alter sexual practices is nonexistent,” he said. “Where you can intervene is with the use of the vaccination.”
The vaccination conversation
It is far too early to tell how significant the effect of vaccinations will be on incidence of HPV-associated cancers. The HPV vaccine became available for teenage girls in 2006 and teenage boys in 2009, and those who have been vaccinated since then will not begin to be at risk for these cancers for decades.
However, the clinicians who spoke with HemOnc Today agreed the vaccination rates are abysmal.
The study by Jain and colleagues revealed that just 32% (95% CI, 30.3-33.6) of girls aged 13 to 17 years received the full three-dose course of the HPV vaccine in 2010. Rates were as low as 14.1% (95% CI, 9.4-20.6) among the uninsured.
The researchers reported vaccination rates of 20% in Alabama and Mississippi, two states with the highest cervical cancer rates and lowest Pap testing rates.
HPV vaccination rates for boys remain in the single digits, Amy E. Leader, PhD, assistant professor in the department of medical oncology at Thomas Jefferson University, said in an interview.
“For the boys, it is somewhat understandable because, practically speaking, the vaccine has really only been around for a year or so,” Leader said. “But what we have heard from parents is that their teenagers are ‘too young to be having discussions about sex.’ The reality is that we want them to be vaccinated before they have sex. Parents don’t see that connection.”
Brown agreed.
“It is frustrating to know what these kids are looking at every day on TV and on the Internet, and yet many parents can’t bring themselves to have a conversation about sexually transmitted diseases and cancer risks that could potentially impact their lives,” Brown said.
The challenge for clinicians is helping parents view the HPV vaccination in a manner similar to other disease prevention efforts.
Martin C. Mahoney
“People have no problem getting their children vaccinated for pertussis or meningococcal disease, but the sexual nature of HPV can make everyone involved uncomfortable,” said Martin C. Mahoney, MD, PhD, associate professor in the departments of health behavior and medicine at Roswell Park Cancer Institute. “Many physicians don’t want to broach the subject of HPV vaccine because it’s sexualized, and parents and teenagers are happy to avoid the subject for the same reason. This has to change.”
Although the fact that HPV is transmitted sexually cannot — and should not — be ignored, the cancer prevention component must be part of the message, Mahoney said.
“We are vaccinating now to prevent cervical cancer among women in their 40s and 50s,” he said. “If parents understand this a little more clearly, it may influence their decision-making process.”
There also may have been a missed opportunity to minimize the sexual implications of the vaccine at the time it was introduced, Brown said.
“There is no avoiding the fact that HPV is an STD,” she said. “But if the initial message emphasized the fact that the vaccine may prevent you from getting cancer when you get older, we might be looking at some different numbers right now.”
Many teens fail to complete the three-dose series, Leader added.
“Most get one of their doses, and they don’t come back to get second or third,” she said. “We need to drive home the message of follow through.”
Improving uptake
Darden and colleagues, who analyzed data from the National Immunization Survey of Teens, found the number of parents who are worried about the safety of the HPV vaccine rose from 4.5% in 2008 to 16.4% in 2010. The results, published in March in Pediatrics, showed 40% of parents surveyed in 2010 said they did not intend to have their teenage daughters vaccinated.
The researchers observed no similar patterns for other vaccines recommended for adolescents.
Clinicians may not have time to bring up the HPV vaccine when other more pressing health concerns exist, Leader said.
“They are also concerned about what the parents may say,” she said. “Providers need to be more proactive in having this discussion.”
Denise Galloway
Despite current trends, successful HPV vaccination is possible, said Denise Galloway, PhD, a researcher in the human biology division at Fred Hutchinson Cancer Research Center.
“We have seen 80% vaccination rates in countries where school-based programs are used,” she said. “With this kind of coverage, we can achieve herd immunity. That is not happening in the United States — not even close.”
Hopkins and colleagues conducted a study of trends in HPV vaccination programs worldwide.
“School-based opt-out [programs] consistently achieve highest coverage, [while] countries and regions without systematic vaccination schemes have low coverage,” the researchers wrote in the study, published in Vaccine. “In all countries, the success of vaccination [programs] is dependent on the support of the public and health care professionals.”
Hopkins and colleagues said there are multiple factors that play into public acceptance of vaccination programs, but physician recommendation is the common denominator for successful uptake.
“Worryingly, it appears that a proportion of clinicians still have significant reservations about promoting vaccination, particularly for younger age groups,” they wrote. “A commitment now, to fully educating both the public and clinicians, has the potential to make a dramatic future impact.”
The researchers also offered other suggestions to increase uptake of the vaccine, including legislative mandate.
“Insurance reimbursement is an issue in some situations, so if we can deal with that, we may see some success,” Adelstein said. “But education is really the major issue. There is all kinds of misinformation out there regarding autism [and the] risk of severe reactions. We need to educate parents.”
Part of the problem is that the vaccine was introduced through a marketing campaign rather than through providers, Gillison said.
“We have seen time and again — even in remote villages in Africa — if you educate the provider, and then the provider advocates in the community, everyone lines up their daughters to get the vaccine,” Gillison said. “A marketing campaign is a different story.”
The key is to frame the recommendation as a public health issue.
“If you tell parents that the vaccine prevents cancer, they respond,” Gillison said. “Telling them it prevents an STD is not as impactful.”
The gender-specific recommendation at the time the vaccine was introduced also may have contributed to confusion among parents and the public, Mahoney said. Although guidelines issued in 2009 recommend the HPV vaccination for boys, confusion remains.
“When there is this kind of confusion, as there was in 2006 when the vaccine was first recommended [for girls], people tend to avoid the issue altogether and move onto something else,” Mahoney said. “This is reflected in the uptake levels.”
There is misinformation about the vaccine even among providers, Gillison said.
“We have heard pediatricians tell parents that their daughters do not weigh enough to receive the vaccine, which is incorrect,” she said. “Another provider said he would not give the vaccine because the daughter was not yet menstruating, which is also incorrect. The message needs to be more consistent, even in the health care community.”
Still, more evidence is required to determine whether the vaccine prevents oropharyngeal cancers.
“If we see that it does, we can push it harder,” Brown said.
Screening and early detection
As the vaccine debate continues, issues regarding screening also have sparked debate.
“In the United States, we are seeing firsthand in cervical cancer how primary prevention with a vaccination and secondary prevention with a screening program can work,” Gillison said. “We are seeing a clear public health benefit in reduced cervical cancer incidence rates. The challenge is to apply this to other HPV-related cancers.”
However, screening methods for HPV-related oropharyngeal cancers remain uncertain.
“We don’t know what the precursor lesions are like,” she said. “We can’t make a visual identification because they are not on the surface. Figuring out how to detect and eliminate the precursors is critical. It is possible because this is what we do on the cervix, but we are not there yet in the oropharynx.”
The incidence of genital warts may be a predictor for how the HPV vaccination will prevent cancers in the future, Galloway said.
“Countries that have been efficient in vaccinating have seen a decrease in genital warts, which takes 6 months to 2 years for the infection to develop,” she said. “By monitoring warts, we may see trends in what will happen with HPV.”
Removing the tonsils may be another simpler alternative, O’Malley said.
“If we could come up with a test to show that a patient has HPV — and that the gene still resides in the back of the throat — removing the tonsils, in theory, could reduce their risk of cancer,” he said. “We can prevent it regardless of their vaccine status.”
New diagnostics also are in development.
“Researchers are looking at saliva for genetic markers,” O’Malley said. “This could be a promising tool.”
Prognosis and treatment
Despite the dramatic increase in incidence of HPV-associated oropharyngeal cancers, prognosis for this patient population generally is good.
Ang and colleagues performed a retrospective analysis that examined tumor HPV status and survival of 323 patients with stage III or IV oropharyngeal squamous cell carcinoma.
The researchers determined that 63.8% of patients had HPV-positive tumors.
Three-year OS among those patients was 82.4% vs. 57.1% among patients with HPV-negative tumors.
Ang and colleagues concluded that tumor HPV status is a strong and independent prognostic factor for survival among patients with oropharyngeal cancer.
“Unfortunately, we don’t have a good explanation for this phenomenon,” Haddad said.
The simple answer may be that the patients are younger and are less likely to smoke and drink, O’Malley said.
Emerging treatments — and tumor responses to them — are under investigation.
Tumors in the throat, tonsils and base of the tongue can be a technical challenge to reach and have traditionally been removed through surgeries requiring a large neck incision and cutting of the bottom jaw. These types of surgeries often require long hospital stays, extensive rehabilitation and may result in difficulty in swallowing and speaking.
“We are seeing decent cure rates in these patients; however, the radical chemoradiation therapy being used to achieve these rates is causing significant and debilitating long-term side effects,” O’Malley said.
Robotic surgery, which allows tumors to be removed from surrounding tissue safely with fewer complications, has become more widely available in the past few years.
A national trial designed to determine if and how the rigors of treatment can be reduced is under way, O’Malley said.
Allen M. Chen, MD, an associate professor in the department of radiation oncology at UC Davis, and colleagues used CT scans to compare the responses of HPV-positive and HPV-negative oropharyngeal tumors during radiation treatment. None of the patients smoked.
Within 2 weeks of the start of radiation, gross tumor volume decreased by 33% among HPV-positive patients vs. 10% among HPV-negative patients, according to findings published in January in The Laryngoscope.
By the end of a 7-week regimen, total tumor shrinkage was nearly the same in both patient groups.
“[However], the dramatic early response observed in the HPV-positive patients strongly implies that these tumors behave distinctly from a biological standpoint and could be approached as a separate disease process,” Chen said in a press release.
Even with more encouraging baseline characteristics and advanced procedures, oropharyngeal cancers are more difficult to treat than cervical cancers, Brown said.
“This emphasizes the importance of prevention,” she said.
And prevention, in turn, can help ensure that the incidence rates of HPV-associated oropharyngeal cancers do not continue to increase significantly.
“HPV-related cancers represent about 3% of the overall cancer burden,” Mahoney said. “Compared with other malignancies, this is a relatively small number. We need to pay attention to the information we have in order to keep it that way.” – by Rob Volansky
References:
Ang KK. N Engl J Med. 2010; 363:24-35.
Chen AM. Laryngoscope. 2013;123:152-157.
Darden PM. Pediatrics. 2013;131:645-661.
Hopkins TG. Vaccine. 2013;31:1673-1679.
Jain KS. Cancer. 2013;doi:10.1002/cncr.27988.
Jemal A. J Natl Cancer Inst. 2013;105:175-201.
For more information:
David Adelstein, MD, can be reached at Cleveland Clinic Main Campus, Mail Code R35, 9500 Euclid Ave., Cleveland, OH 44195.
Carol L. Brown, MD, can be reached Memorial Sloan-Kettering Cancer Center, 1275 York Ave., New York, NY 10065.
Denise Galloway, PhD, can be reached at Fred Hutchinson Cancer Research Center, 1100 Fairview Ave. N., P.O. Box 19024, Seattle, WA 98109.
Maura L. Gillison, MD, PhD, can be reached at 690 Tzagournis Research Facility, 410 W. 10th Ave., Columbus, OH 43210.
Robert I. Haddad, MD, can be reached at Dana-Farber Cancer Institute, 450 Brookline Ave., Boston, MA 02215.
Amy E. Leader, PhD, can be reached at Jefferson Medical College, 834 Chestnut St., Suite 314, Philadelphia, PA 19107.
Martin C. Mahoney, MD, PhD, can be reached at Roswell Park Cancer Institute, Elm and Carton streets, Buffalo, NY 14263.
Bert W. O’Malley Jr., MD, can be reached at University of Pennsylvania Health System, Department of Otorhinolaryngology — Head and Neck Surgery, 5 Ravdin, 3400 Spruce St., Philadelphia, PA 19104.
Disclosure: Gillison serves as a consultant to GlaxoSmithKline, and previously worked as a consultant to and received research funding from Merck. Mahoney serves as a consultant to and speakers’ bureau member for Merck, and he is a former consultant to and speakers’ bureau member for GlaxoSmithKline. Adelstein, Brown, Galloway, Haddad, Leader and O’Malley report no relevant financial disclosures.
Do HPV-related oropharyngeal cancers have better prognoses because of tumor biology or patient lifestyle?
Ezra Cohen
Biology likely defines the improved prognosis.
HPV-positive oropharynx cancers are rising dramatically in incidence, and they have become the most common subtype of head and neck cancers seen in North America and many other countries.
The silver lining of this disease is that it carries a better prognosis than its HPV-negative counterpart.
Until large data sets were analyzed, there was controversy whether this improved outcome was due to the favorable demographics associated with HPV-positive cancers. These patients tend to be younger, nonsmokers, and they also tend to have fewer comorbidities. Moreover, the disease is more likely to present with smaller tumors but with early lymph node involvement.
However, with retrospective examination of large randomized trials that could account for these factors in multivariate analysis, it is apparent that patient or disease characteristics could not account for the improved outcome.
HPV-positive cancers fare better based on the fact they are HPV positive. The solution to this observation comes from deciphering the molecular biology of HPV-positive cancers. From gene expression and exome sequencing data, it is clear that HPV-positive cancers harbor fewer mutations in general than their negative counterparts, and they almost never carry alterations in critical tumor suppressor genes associated with aggressive behavior, such as p53 or p16.
Therefore, it is almost certainly the intrinsic biology of HPV-positive cancers that defines their better prognosis. Now we must meet the challenge of treating these patients with approaches tailored to that difference in biology and improve outcomes even further.
Ezra Cohen, MD, FRCPC, is an associate professor in the department of medicine, co-director of the Head and Neck Cancer Program, program director of the Hematology/Oncology Fellowship Program and associate director for education at the University of Chicago Comprehensive Cancer Center. He also is editor-in-chief of Oral Oncology. He can be reached at 900 E. 57th St., Room 7146, Chicago, IL 60637; email: ecohen@medicine.bsd.uchicago.edu. Disclosure: Cohen reports no relevant financial disclosures.
Laura S. Rozek
Tumor biology and lifestyle both likely contribute.
These cancers don’t appear to be staged all that much earlier than HPV-negative malignancies. We tend to see them staged at III or IV.
There certainly are differences in the biology of HPV-negative and HPV-positive tumors. Although patients generally have a profound history of alcohol and/or tobacco use or other associated carcinogens in HPV-negative tumors, there is a different tumor phenotype. Smoking is more prevalent among patients with HPV-negative tumors. This, in turn, is associated with different genetic changes than we see in HPV-positive tumors. The HPV-positive tumors come from a viral etiology, and those patients tend to have better health behaviors.
That said, in our research, we often ask ourselves whether it is the healthy lifestyles of these patients that lead to the improved tumor biology and better prognosis, or whether it is the underlying biology of the tumor itself.
The answer, likely, is both. In our data, patients with HPV-positive tumors are more likely to be married, have healthier diets and have a higher BMI, which helps them withstand the rigors of therapy associated with head and neck cancers.
Undoubtedly, both lifestyle and tumor biology are so intertwined that it is probably a little bit of both. There is a lot of interplay over the life span of these tumors.
Laura S. Rozek, PhD, is assistant professor in environmental health sciences at the University of Michigan School of Public Health. She can be reached at 6630 SPH Tower, 1415 Washington Heights, Ann Arbor, MI 48109-2029; email: rozekl@umich.edu. Disclosure: Rozek reports no relevant financial disclosures.