At the start of his presentation for the Eye & Ear Foundation’s August 9 webinar, “HPV and the Changing Epidemiology of Head and Neck Cancer,” José P. Zevallos, MD, MPH, FACS, and the Eugene N. Myers, MD Chair of Otolaryngology at the University of Pittsburgh Medical Center (UPMC), said he was going to talk about a topic that has become more mainstream in terms of understanding. The internationally recognized expert on the epidemiology and genomics of HPV-associated oropharyngeal cancer thinks there is a lot of room to continue to educate people about HPV and how it impacts head and neck cancer.
Head and Neck Anatomy
A common question is, “What are we actually talking about when we talk about head and neck cancer (HNC)?” We are not talking about cancer of the brain or spinal cord, but the upper digestive tract. This includes the nose, pharynx, back of the throat (which is divided into three parts: the nasal pharynx, the part behind the nose, and the oral pharynx). The webinar’s focus is behind the mouth. Oropharyngeal anatomy means the tonsils, base of the tongue, lateral and posterior pharyngeal walls, and the soft palate.
A unique aspect about this part of the throat – comprised of lymphoid tissue – is that the tissues look like tonsil tissue in many ways. This is not seen in other parts of the throat, which might be why there are unique cancers in this area.
Head and Neck Squamous Cell Carcinoma
- Heterogeneous anatomic sites
- Traditional risk factors: tobacco and alcohol
- Other risk factors: paan, mate, poor oral health, radiation, EBV
- “New” risk factors: sexually transmitted infection – HPV
Over the past 20-30 years, it became obvious that patients did not have the traditional risk factors. Patients who did not smoke or drink were developing cancer in this area.
Human Papillomavirus (HPV)
- Small, circular DNA viruses
- Over 130 unique types
- “High” and “low” risk types
- Integrated into cervical cancer screening algorithm
These patients were not necessarily associated with smoking and drinking. They also had better outcomes as they responded better to therapy. Over time, it became evident through discovery that these cancers were in fact being caused by HPV.
HPV+ Oropharyngeal Squamous Cell Carcinoma
- >50,000 new OPSCC annually in the US
- 90% HPV positive
- 40-59 year age range (30 year latency)
- Tonsil>base of tongue (BOT)
- Nonsmokers
- Excellent oncologic outcomes
“What’s really interesting about this cancer and virus is the 30-year latency period between infection and onset,” Dr. Zevallos said. This means that most people get infected with HPV in their late teens and early 20s when they become sexually active. Most people who are infected and have an acute infection are able to get rid of it completely. If they are tested again six or nine months later, it can’t be found it in their saliva.
A small subset of people are not able to clear the acute infection, however. It takes about two to three decades for the chronic infection to transform the cells. A typical cancer patient presents in their 50s. Why some people go from acute to chronic infection remains unknown. There are some hypotheses related to the immune response to HPV, but a test has yet to be developed.
Most people who have infections will never ever get cancer, Dr. Zevallos said. The challenge is capturing that subset of people who have infections. This has led to a rethinking of treatment.
Clinical Presentation
Typically, there are no symptoms until the tumor gets quite large. An asymptomatic neck mass (Level II/III) is common. Cancers arise deep in the tonsil crypts, with minimal dysphagia/odynophagia.
“The reason we think there’s a dramatic difference in how they present is the cancers of HPV arise not on the surface but deep in the crypts,” Dr. Zevallos said. “They grow there for some time and could even spread to the lymph nodes before they break through the surface of the throat.”
P16 immunohistochemistry (IHC) has really been the only biomarker in clinical practice. It is prognostic but a very good surrogate.
HPV and Rising Oropharyngeal Cancer Incidence in the U.S.
An important paper published in 2011 in the Journal of Clinical Oncology found there was a 28% increase in all OPSCC, a 225% increase in HPV+ OPSCC, and a 50% decrease in HPV- OPSSC. It is now the most common HPV-associated malignancy in the U.S., surpassing cervical cancer.
“Rates continue to increase and will likely increase by even more over the next 20 years until vaccination,” Dr. Zevallos said. “This is a clear and present problem that we’re facing on a daily basis in our clinics and across the country.”
Worldwide Incidence OPSCC
OPSCC is primarily a problem in developed nations like the U.S. and Europe, though it is beginning in underdeveloped nations. Rural areas are just not as tested.
Oral HPV Infection in the U.S.
The actual infection happens 20-30 years earlier. An important study measured infection with HPV (not cancer) in adult men and women. People were in their 20s and in 60s. Both men and women had it, but it was primarily significant in men. The initial peak is explained by people becoming sexually active and exposed for the first time.
The second peak in 50s is unclear at this point. It is not due to a midlife crisis or anything. As we get older, our immune response becomes diminished. The number of sexual partners (lifetime) is directly correlated with risk of HPV.
Oral HPV Infection and Transmission
- Oral HPV is not casually transmitted (i.e. by sharing drinks, ksis on cheek)
- Partners have likely already shared any infections
- With new partners, discuss protection methods (e.g. condoms, barrier protection)
- Exposure does not equal cancer
What to Tell Partner(s) of HPV+ OPSCC Cancer Patients
- Cancer risk is similar to general population
- Former and current partners have already been exposed
- Exposure does not mean cancer
- Sexual life with partners should continue
- Consider protection with new partners
- Cervical cancer screening guidelines – no additional recommendations
HPV Vaccination
Many of the HPV- cancers caused by smoking and drinking are preventable. What are the options for vaccination? The schedule and dosing change constantly. Currently there are three vaccines available for HPV designed for certain types: The bivalent and quadrivalent, and the latest – the 9-valent, which covers nine different subtypes of HPV, including high and low risk.
In terms of schedule and dosing, a routine vaccination is given at age 11-12 years, and can be started at nine years. A catch-up vaccination is given at age 13-26 years if not adequately vaccinated. Shared clinical decision making is done with some adults age 27-45 years if not adequately vaccinated.
About 85% of people will get an HPV infection in their lifetime. Vaccinating all 11–12-year-olds can protect them long before they are ever exposed. The CDC recommends two doses of HPV vaccine for all adolescents at age 11 or 12 years.
HPV Vaccine Safety
- The most common adverse events reported were considered mild
- For serious adverse events reported, no unusual pattern or clustering that would suggest that the events were caused by the HPV vaccine
- These findings are similar to the safety reviews of MCV4 and Tdap vaccines
- 57 million doses of HPV vaccine distributed in the U.S. since 2006
The rate of vaccination across the U.S. varies among 13–17-year-olds. It ranges from 20% all the way up to 70-80% in the northeast. People age 18-26 have similar patterns.
HPV Vaccine Impact: High HPV Vaccine Coverage in Australia
- 80% of school age girls in Australia are fully vaccinated
- High-grade cervical lesions have declined in women less than 18 years of age
- For vaccine eligible females, the proportion of genital warts cases declined dramatically by 93%
- Genital warts have declined by 82% among males of the same age, indicating herd immunity
Vaccination Rates
The vaccination rate among 18–26-year-old adults varies by sex and race/ethnicity. There is a significant decrease when it comes to racial/ethnic groups. “This is something that requires an increase in awareness among all communities to have the benefit of vaccination,” Dr. Zevallos said.
HPV vaccination in eligible veterans is poor. Per a study:
- Vaccination rates among US veterans age 18-26 is <50% of civilian population
- Striking differences by race/ethnicity, SES, and branch of service
- Pressing need to implement vaccination among active-duty military
- Females: 30%, males: 17%
HPV will shorten the lives of a significant number of veterans, yet it can be prevented. “Hopefully this study will draw attention that we need more guidance and vaccination from our military community,” said Dr. Zevallos.
Treatment of HPV+ OPSCC
- Since 1990s, treatment of pharyngeal cancer has been largely non-surgical
- Oncologic outcomes equivalent in surgery vs non-surgery
- Open surgery had unacceptable morbidity
- Standard of care definitive radiation and chemo is the gold standard
- Transoral robotic surgery (TORS) has emerged as an alternative
- Increasing evidence supports Treatment De-intensification for HPV+ OPSCC
Phase II Trial of De-intensified Chemoradiotherapy
- Definitive treatment with 60 Gy =/- weekly cisplatin based on pathologic features
- Excellent 2-year LRC 95% and OS 95%
- Global QoL returned to baseline
- Dry mouth was most common toxicity
Reemergence of Surgery Using Transoral Robotic Approaches
- TORS has become an important tool in management
- Institutional treatment patterns (and biases) differ significantly
- What is the role of surgery in the treatment deintensification landscape
TORS for Oropharyngeal Squamous Cell Carcinoma: Indications
- T1-T2, N0-N2 squamous cell carcinoma of the tonsil, base of tongue, pharyngeal walls
- Concurrent neck dissection is performed at the time of TORS
- Treatment deintensification
Phase II Randomized Trial of TORS +
Dr. Ferris conducted a randomized trial of TORS +50 Gy vs. 60 Gy for intermediate risk of HPV+ OPSCC. There were excellent oncologic and functional outcomes. It also showed the importance of surgeon credentialling. This study has led to new studies where current clinical trials will be built upon.
Not every patient deserves deintensification, Dr. Zevallos said.
Summary
- HPV+ OPSCC has dramatically altered the epidemiology, demographics, and outcomes in HNC
- TORS may offer appropriate treatment de-escalation and quality of life in select patients
- T1-T2, NO and N1
- Unknown primary patients
- Deintensification of radiation and chemo also possible