Cancer Professional: Autumn 2013; Vol 7, (3)
HPV and Head and Neck Cancer Clinical and Public Policy Updates from an international symposium held at NUI Galway on May 17th
Prof. Ivan Keogh: Head of the Academic Department of Otorhinolaryngology, NUI Galway and Consultant Otolaryngologist, Galway University Hospitals.
Mr. Tony O'Connor: Consultant Otolaryngologist, Bon Secours Hospital, Galway & Academic Department of Otorlaryngology, NUI Galway.
Diarmuid Coughlan: HRB/NCI Health Economics Fellow in Cancer Prevention. School of Economics, NUI Galway. * Corresponding Author:
Diarmuid Coughlan –
[email protected] In June 2013, Hollywood actor Michael Douglas, in an interview with the Guardian newspaper, spoke frankly about a subset of head and neck cancers that
has been branded as an ‘epidemic’ in the medical literature(1). These cancers
are considered to be a distinct epidemiologic, clinical and molecular entity(2)
and are linked to oral sex. A symposium on May 17th in NUI Galway was held to discuss the causal role of the Human Papilloma Virus (HPV) in head and neck
cancers. This was the first formal dialogue on this subject by Irish clinicians and public health professionals. The Health Research Board (HRB) sponsored this symposium as part of their Knowledge Exchange and Dissemination Scheme
(KEDS) grant funding. A “NUI Galway Millennium Fund” was also awarded to support the symposium. Over 140 delegates listened attentively and debated with 13 national and international experts. A webinar and various social media
components were utilised to disseminate information. Speakers’ video presentations and slides are available online via the following website: http://www.nuigalway.ie/health-economics/hpvsymposium/
Epidemiology on HPV-related Head and Neck Cancer: Head and neck Cancer is a heterogeneous group (17 different sites) of neoplasms that share a common anatomic origin. Research over the past 15 years has shown that HPV causes a subset of head and neck cancers, primarily oropharyngeal squamous cell carcinomas (OPSCC). Although most head and neck cancers are still caused by excessive tobacco and alcohol use, the incidence of HPV-related OPSCC is increasing in the United States(3) and parts of Western Europe, most notable in Sweden(4). Greater than 90% are due to a single HPV type: HPV-16 (1). The increasing incidence of HPV-related OPSCC, particularly in men (3:1 vs. women), 5 lifetime sexual partners (7.4%) (6). Signs and symptoms of HPV-related Head and Neck Cancer: Tobacco and alcohol related oral cancers, present with visible symptoms such as
white lesions (leukoplakia), red plaques (erythroplakia) or persistent ulcers. HPV-related cancers are associated with lymph tissue in the oropharynx
(palatine tonsils and lingual tonsils). The oropharynx is an anatomic site, which is difficult to visualise and palpate. Patients may present with difficulty
swallowing, chronic hoarseness, persistent sore throat or painless swelling in the neck (usually an enlarged lymph gland).
What is happening in HPV & Head and Neck Cancer in Ireland? Dr. Linda Sharp (Senior Epidemiologist, National Cancer Registry Ireland) set the scene at the symposium by stating that as a group, head and neck cancer were
the 6th most common cancer in men and the 16th most common cancer in women
on the island of Ireland. Each year, on average 438 men and 170 women are
diagnosed with a head and neck cancer. The number that is truly HPV-related is
currently unknown. However, in autumn 2013, the CERVIVA research collaboration funded by the HRB, in partnership with surgeons and pathologists around Ireland, will embark on a major investigation of HPV of the oropharynx,
oral cavity and larynx diagnosed since 1994. This will provide the first population-based data on the epidemiology of HPV infection in head and neck cancer in Ireland.
How to detect HPV-related Head and Neck Cancer? One of the evolving developments in characterising this cancer has been the
indiscriminate and non-standardised testing of clinical samples. HPV infection is strongly correlated with the oropharynx region and in particular the base of
tongue, palatine and lingual tonsils (See Figure 1). Professor William Westra (Johns Hopkins) stated at the symposium that no single test has been universally
accepted as best practice. The crux of establishing gold standard HPV testing is
to differentiate an incidental virus (e.g. passenger virus or vial contaminant) from an active oncologic agent. Evidence for transcriptional activation of the
viral oncoproteins E6 and E7 is generally regarded as the gold standard for clinically relevant HPV.
Most diagnostic laboratories that perform routine
testing of clinical samples use 1 of the 2 methods for HPV detection: 1. PCR-based amplification.
2. DNA in situ hybridization.
However, another detection method that is increasing in popularity is the
immunohistochemical detection of the cellular protein p16 as a practical
alternative or complimentary procedure for HPV testing (8). This is based on the high correlation between HPV detection and p16 overexpression(9).
Figure 1: Anatomical distribution of HPV-related head and neck cancer (Taken with permission from Prof. Westra’s presentation on May 17th) Treatment of HPV-positive Head and Neck Cancer The common consensus among the experts at the symposium was that given the better survival (cure rate) of the HPV-positive patients; de-intensification treatment regimes (Radiotherapy, Chemotherapy), with the aim of maintaining
current survival whilst mitigating long term adverse events is the goal. Keynote
speaker from the US, Professor Sara Pai (Johns Hopkins) and from the UK, Professor Terry Jones (Liverpool), both pointed to randomised controlled trials
that are ongoing in their jurisdictions that are focused on the reduction of morbidity including therapeutic vaccine.
Current treatment strategies, typically involving concurrent cisplatin based
chemoradiotherapy are associated with high rates of acute and long-term
toxicity, particularly with respect to long-term swallowing function. What was
evident from the case-studies discussion, led by Mr. Paul O’Neill & Ms Helena
Rowley (Mater, Dublin) was that all treatment options: Surgery, radiation therapy,
concurrent
chemoradiotherapy,
chemoradiotherapy,
surgery
followed
by
surgery
radiotherapy
followed
and
by
induction
chemotherapy with concurrent chemoradiotherapy all may have a place in treatment depending on the patient’s clinical, demographic and smoking status.
Professor Pai elaborated on the multi-disciplinary management offered by the
head and neck cancer clinic at Hopkins where patients meet with head and neck
surgeons, medical oncologists, radiation oncologists, and speech and language pathologists in one clinic visit. After review of medical records, pathology,
imaging studies and physical examination, a consensus opinion regarding
management is given. This process allows patients to have open discussion of the pros and cons of various treatment options with all disciplines present. Implications for the spouse:
What was unfortunate with the treatment of Michael Douglas’s comments about
throat cancer in the social media era was the slanderous innuendo directed at his wife. There is still so much unknown about the natural history of oral HPV and it
is likely that HPV-associated head and neck cancers are due to legacy infections that take 10-40 years to develop into a cancer tumour.
Evidence from Sweden suggests that husbands’ of wives with invasive cervical cancer or in-situ cervical cancer had at least twice the expected rate of tonsil
cancer(10). Preliminary US findings showed that spouses and long-term partners of patients diagnosed with HPV-positive oropharyngeal cancer were no
more likely to test positive for oral HPV infection than people in the general population and have a low risk of HPV-related oropharyngeal cancer(11).
Should boys be vaccinated against HPV? The last session at the symposium focused on the public policy implications of
HPV-related head and neck cancer and in particular the case for vaccinating boys against HPV. The HPV-quadrivalent vaccine (Gardasil®) protects against HPV –
type 6,11, 16 & 18 and is however only licensed for use for prevention of genital warts in men in Europe. It will take decades before we know whether the vaccine
is effective against HPV-related cancers in men (HPV causes penile and anal cancer too at much lower rates than in the oropharynx). The benefit of adding
boys to a school-wide program is dependent on coverage in girls. Consider that the 3-dose uptake of HPV vaccine of girls in the US is only 35% where as in
Ireland it is 82%. Recently, in Australia, where the 3-dose vaccination uptake is 73% there was a 82% decline in genital warts in heterosexual men attributable
to herd immunity with no genital warts in vaccinated women(12). Another consideration is that sexual networks are not bounded by jurisdiction and there will be plenty of females that are not vaccinated in the world. Moreover, there is an equity question, as homosexual men would not be protected against the virus. What is evident now in the US is that HPV-associated head and neck cancers have now surpassed cervical cancer in incidence cases (13). In France, the
estimated annual costs of treating HPV-associated HNC in men (€94.6million) is greater than invasive cervical cancer (€83.9million) in women(14). This has
implications for how HPV vaccination is portrayed to the public, as Gardasil is
not a direct cervical cancer prevention vaccine; it is a quadrivalent HPV vaccine that hopefully prevents all HPV-related cancers and not just 70% of cervical
cancer attributable to HPV-type 16. In essence, only time will tell, but for the next 30-40 years men will be disproportionately inflicted with the scourge of this
virus. Ireland should see more cases given the changes in sexual norms over the past 20 years. Hopefully, trial results will help doctors prescribe safe and
effective treatment that will reduce the debilitating adverse effects associated
with treating this cancer. Finally, the intended consequence of the symposium
was to foster and develop multidisciplinary and multi-centred research on the
island of Ireland. As stated so eloquently by Professor Sara Pai that: “Within each patient there is an opportunity to learn more about the disease. We should not
only treat the patient but advance the field by enrolling patients in studies, be they epidemiological or clinical trials”. References: 1. 2. 3. 4. 5. 6. 7. 8.
9.
Marur S, D’Souza G, Westra WH, Forastiere AA. HPV-associated head and neck cancer: a virus-related cancer epidemic. Lancet Oncol. 2010 Aug;11(8):781–9. Gillison ML. Human papillomavirus-associated head and neck cancer is a distinct epidemiologic, clinical, and molecular entity. Semin. Oncol. 2004 Dec;31(6):744–54.
Chaturvedi AK, Engels EA, Pfeiffer RM, Hernandez BY, Xiao W, Kim E, et al. Human Papillomavirus and Rising Oropharyngeal Cancer Incidence in the United States. J. Clin. Oncol. 2011; 29(32): 4294-301
Attner P, Du J, Näsman A, Hammarstedt L, Ramqvist T, Lindholm J, et al. The role of human papillomavirus in the increased incidence of base of tongue cancer. Int. J. Cancer J. Int. Cancer. 2010; 126(12): 2879–84. O’Rorke MA, Ellison MV, Murray LJ, Moran M, James J, Anderson LA. Human papillomavirus related head and neck cancer survival: A systematic review and meta-analysis. Oral Oncol. 2012; 48(12): 1191–201.
Joseph AW, D’Souza G. Epidemiology of human papillomavirus-related head and neck cancer. Otolaryngol. Clin. North Am. 2012; 45(4): 739–64.
D’Souza G, Kreimer AR, Viscidi R, Pawlita M, Fakhry C, Koch WM, et al. Casecontrol study of human papillomavirus and oropharyngeal cancer. N. Engl. J. Med. 2007; 356(19): 1944–56. Westra WH. Detection of human papillomavirus in clinical samples. Otolaryngol. Clin. North Am. 2012; 45(4): 765–77.
Hoffmann M, Ihloff AS, Görögh T, Weise JB, Fazel A, Krams M, et al. p16(INK4a) overexpression predicts translational active human papillomavirus infection in tonsillar cancer. Int. J. Cancer 2010; 127(7): 1595–602.
10. Hemminki K, Dong C, Frisch M. Tonsillar and other upper aerodigestive tract cancers among cervical cancer patients and their husbands. Eur. J. Cancer Prev. Off. J. Eur. Cancer Prev. Organ. Ecp. 2000; 9(6):433–7.
11. D'Souza G. Pai SI, Hadddad RI. Gillison M, Posner R. Oral HPV infection in HPV-positive oropharyngeal cancer cases and their spouses. J Clin Oncol,
2013 (suppl; abstr CRA6031) Available from: http://meetinglibrary.asco.org/content/111185-132
12. Ali H, Donovan B, Wand H, Read TRH, Regan DG, Grulich AE, et al. Genital warts in young Australians five years into national human papillomavirus vaccination programme: national surveillance data. BMJ. 2013; 346: 20-32.
13. Jemal A, Simard EP, Dorell C, Noone A-M, Markowitz LE, Kohler B, et al. Annual Report to the Nation on the Status of Cancer, 1975–2009, Featuring the Burden and Trends in Human Papillomavirus (HPV)–Associated Cancers and HPV Vaccination Coverage Levels. J. Natl. Cancer Inst. 2013; 105(3): 175-201
14. Borget I, Abramowitz L, Mathevet P. Economic burden of HPV-related cancers in France. Vaccine. 2011; 29(32):5 245–9. Pictures from Symposium:
1. Opening address - HPV and Head and Neck Cancer Symposium – May 17th 2012 Aula Maxima NUI Galway.
2. Prof. Ivan Keogh - Head of the Academic Department of Otorlaryngology, NUIG and Consultant Otolaryngologist, Galway University Hospitals
3. Prof. William Westra - Professor of Pathology, Oncology and Otolaryngology/ Head and Neck Surgery at the Johns Hopkins University School of Medicine
4. Prof. Sara Pai - Associate Professor of Otolaryngology, Head and Neck Surgery and Oncology at the Johns Hopkins University School of Medicine.
