HPV and Head and Neck Cancer

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), <50 years, with no
history of alcohol or tobacco use, has been recorded over the past decade. These
cancers have an improved prognosis and survival in comparison to other head and
neck cancers (5) – see table 1 for comparison of general epidemiology.
Table 1: Comparison of the general epidemiology of HPV related and unrelated head
and neck cancers (HNC)(6)
HPV-related HNC
HPV-unrelated HNC
Incidence trend
Increasing
Decreasing/stable
Anatomic location
Primarily tonsil and All head and neck sites
base of tongue
Median age (y) at diagnosis
54
60
Socioeconomic status
Higher
Lower
Primary risk factors
Sexual exposure to Tobacco
oral HPV
exposure
Survival
Better
Worse
3-y oropharyngeal survival (%)
93%
57%
and
alcohol
What are the risk factors for HPV-related Head and Neck Cancer?
HPV is a family of more than 100 virus types that can live in the flat, thin cells on the
surface of the skin, cervix, vagina, anus, vulva, penis, mouth, and throat. A lot
remains unknown about the natural history of this viral infection that spreads through
contact with infected skin, mucous membranes, and bodily fluids. Epidemiologic
studies show that there are several notable differences in the demographics of patients
who develop HPV-related head and neck cancers compared to traditional head and
neck cancer patients. HPV-related patients tend to have had more active sex lives(7):
•
Earlier age of sexual debut
•
Higher number of lifetime vaginal sex partners
•
Higher number of lifetime oral sex partners
As all sexual behaviours are colinear (people who have a higher number of partners
for 1 sexual act tend to have a higher number of partners for other sexual acts as well),
it is difficult to differentiate which sexual behaviours are associated with oral HPV
transmission. It most be stressed that HPV is very common with 75% of the sexually
active population in the US having the virus at some stage in their life. The vast, vast
majority of infections (90-99%) are cleared without any problems. For some
reason, possible linked to smoking and more probably linked to a deficiency in
the immune system, people are not able to clear the virus in the oral cavity and
develop cancer in the oropharynx region (it is thought that tonsillar crypts, the
site of initial HPV infection, may be an immune privileged site). A review
reported that higher oral HPV prevalence has been reported among select groups
such as individuals infected with the human immunodeficiency virus (33%), current
smokers (10%) and people with >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.