COSM14: HPV Status and Prognosis for Oropharyngeal Cancers

An array of experts came together in the panel discussion “HPV in Different Subsites—Clinical Importance and Effect on Therapy” to shed light on a variety of topics concerning human papillomavirus (HPV) status, including risk factors, the effectiveness of vaccinations, the use of biomarkers to predict response to cancer treatment, and guidance on treatment of adults.

Panel moderator Dinesh K. Chhetri, MD, head of the Swallowing Disorders Center at the University of California at Los Angeles, said the discussion provided an up-to-date overview of a topic that’s growing in importance. “I think we should be making physicians aware of this rising HPV epidemic … how it’s changing the landscape of the diseases affected, and how we should change our management as our understanding of the HPV-related diseases increases,” he said.

The prevalence of HPV infections among the healthy U.S. population is only 1%, according to National Health and Nutrition Examination Survey data. But oropharyngeal cancer among men is on the rise, due largely to a rise in HPV-positive cancers, said Carole Fakhry, MD, MPH, assistant professor of otolaryngology-head and neck surgery at Johns Hopkins University in Baltimore.

The incidence of cervical cancer cases, which are largely caused by HPV infections as well, is on the decline and is expected to dip below cases of HPV-positive male and female oropharyngeal cancer cases in approximately 2025, Dr. Fakhry said.

Whom the Vaccine Helps

The incidence of HPV infection rises with a person’s number of sex partners, including oral sex partners (JAMA. 2012; 307:693-703). Those most at risk of oropharyngeal cancer tend to be younger, white, married, non-smokers, and college educated.

The clearest explanation for this is that younger individuals tend to report having had oral sex at the time of their first sex act, and older age groups are less likely to report this. Additionally, whites are more likely to have performed oral sex and have more oral sex partners than other races. “The oral HPV infection [rate] is related to sexual behaviors,” Dr. Fakhry said. “It’s a very low prevalence, though, in the United States. Natural history studies are just starting.”

The main vaccine target group in the U.S. is 11- to 12-year-old girls who have not yet become sexually active. The Advisory Committee on Immunization Practices for the Centers for Disease Control, as of October 2011, also recommends routine vaccination of boys between nine and 21 years old.

Quadrivalent HPV vaccines are highly effective at preventing infections, but more effort needs to be put into encouraging parents to get their children vaccinated to further prevent recurrent respiratory papillomatosis (RRP), said Craig Derkay, MD, director of pediatric otolaryngology at Eastern Virginia Medical School in Norfolk.

At up to five years of follow-up, the vaccines were 100% effective at preventing the HPV 6- and 11-types, which are responsible for causing RRP. Data suggest that the vaccine provides long-term protection, with VLP [virus-like particle] antibody titer levels that plateau at about 18 months following the vaccination course, suggesting no need for future booster doses, Dr. Derkay added.

Two recent papers suggest that the vaccine could have some therapeutic value for treating RRP. In one of the studies, in which 11 adults with RRP were given the vaccine, six of them were disease-free at one year, three of them had fewer recurrences, and two had no change (International Papillomavirus Conference 2011. OP-236). Moreover, the vaccine will protect against the most common HPV subtypes responsible for causing oropharyngeal cancer.

Despite the evidence that vaccines work, Dr. Derkay noted that vaccine uptake rates have not changed since 2011, requiring an increased effort by otolaryngologists to promote vaccination among the families they treat. “There is an anti-vaccine movement in the United States,” in part because some think the vaccines will lead to earlier sexual behavior, he said. “I think that’s a fallacy in the same way that encouraging seat belt use encourages you to drive drunk.”

Treatment Courses

James Rocco, MD, PhD, director of head and neck cancer research at Massachusetts General Hospital (MGH) and the Daniel Miller Associate Professor of Otology and Laryngology at Harvard Medical School in Boston, delved into new ways of assessing how well different patients with HPV-positive oropharyngeal cancer will respond to different treatments. “There are lots of different treatment options, and we really have no way to know which are best in terms of survival and function,” he said, even though it’s known that some patients are being overtreated and are thus at unnecessary risk of serious side effects.

Published work has stratified the risk of death of oropharyngeal cancers by HPV status and the amount of smoking by patients, with HPV-negative patients who have 10 or more pack years having the worst risk. HPV-positive patients can be stratified into low- and high-risk groups through the combined use of both pack years and nodal status (N Engl J Med. 2010:363:24-35).

Dr. Rocco then discussed biomarkers that can go beyond nodal status and smoking history as poor prognostic markers in HPV-positive oropharyngeal cancer. Based on his prior work demonstrating that high expression of the anti-apoptotic BCL-2 protein is related to worse outcome, he presented the clinical application of these findings as part of an ongoing prospective study at the Massachusetts Eye and Ear Infirmary (MEEI) and the MGH Cancer Center to assess how “full” the BCL-2 tank is (Clin Cancer Res. 2010;16:2138-2146).

The technique, known as BH3 profiling, involves single-cell suspensions and adding peptides that mimic all the anti-cell death and pro-cell death molecules in the cell to predict the patient’s response at the time of primary tumor biopsy. The result is an assessment of a patient’s tumor cells’ propensity toward apoptosis in response to cytotoxic therapy like chemoradiation. It also lays the groundwork for future clinical trials of BCL-2 inhibitors. Prospective trials are now underway to see how well this knowledge can be used to ascertain the best treatment course in patients.

Dr. Rocco also described how multiple subpopulations of cancer cells within a tumor also can lead to resistance to treatment: The fewer the number of subpopulations of alleles, the lower probability of resistance to treatment; the more subpopulations, the higher the likelihood of resistance. Researchers in Dr. Rocco’s lab developed a way, called mutant-allele tumor heterogeneity (MATH), to measure this intratumor heterogeneity, and showed that high tumor heterogeneity predicts a worse outcome in head and neck cancer (Cancer. 2013;119:3034-3042). Prospective studies are now underway at MEEI and the MGH Cancer Center to see how well this knowledge can be used to ascertain the best treatment course in patients.

Treatment for Adults

Michael M. Johns III, MD, associate professor of otolaryngology-head and neck surgery at Emory University School of Medicine and director of the Emory Voice Center in Atlanta, highlighted the differences between adult and pediatric RRP. In adults, it usually presents as a voice problem and typically has a much slower growth rate than in children.

Treatment has shifted toward awake procedures, prompted largely by growing use of the fiber-based KTP laser. The treatment goals should be to preserve the voice, prolong the time between treatments, and avoid using general anesthesia, he said.

Surgical precision is of utmost importance, Dr. Johns added. The digital AcuBlade scanning micromanipulator, used under general anesthesia, is his favorite tool because of its precision. He urged caution in using fiber-based CO2 lasers on superficial disease on the free vocal fold edge, because they will “inherently” have instability.

Dr. Johns advised monitoring patients with RRP for dysplasia. At Emory, physicians assessed 85 consecutive patients and found that dysplasia was present in 28% percent of them. All patients had either HPV 6 or 11, and none had HPV 16 or 18. “[Dysplasia] is fairly common, and it warrants periodic surveillance,” he said. “As we’re treating more and more of these awake, we often are not biopsying them.”

Advocacy

Dr. Chhetri said he hopes the panel’s presentations result in better patient care. “The main thing is to realize that HPV status makes a difference for prognosis in oropharyngeal cancer, and we should always make sure that’s part of the diagnostic algorithm,” he said. “Can we treat these patients differently to minimize treatment complications? That’s going to be important in the future.”

Advocating HPV vaccinations, he said, is an important endeavor for all otolaryngologists. “We ourselves haven’t really talked about it very much. I think now we need to go further and we really need to advocate to our pediatric and other medical colleagues, saying, ‘Hey, we encourage you to encourage all of your eligible patients to be vaccinated,’ because the truth is, vaccination is the most effective strategy to prevent HPV-related disease.”