Introduction: Head and Neck Squamous Cell Cancer and HPV: A Different Animal
Antonio Jimeno, MD, PhD
University of Colorado Cancer Center and Charles C. Gates Center for Regenerative Medicine and Stem Cell Biology
Human papillomavirus (HPV) types 16 and 18 are the etiologic cause of an increasing percentage of head and neck squamous cell cancer (HNSCC).1,2
This subtype of HNSCC typically affects younger, healthier patients, who have a potentially longer time at risk for recurrence than the “classic” patient with HNSCC. The epidermal growth factor receptor (EGFR) inhibitor cetuximab is the only targeted drug
HPV-positive and HPV-negative HNSCC have a different biology5
; while HPV-positive HNSCC seems to have higher susceptibility to radiation and DNA-targeting agents than HPV-negative HNSCC, data are starting to emerge questioning the role of EGFR inhibitors in HPV-positive HNSCC. A retrospective study showed that patients who are HPV-positive have worse outcomes after cetuximab plus radiation compared to cisplatin and radiation.6
Investigators recently presented the results of the randomized phase III SPECTRUM trial that evaluated the safety and efficacy of panitumumab (a fully human monoclonal antibody targeting EGFR) combined with platinum-
based chemotherapy compared with chemotherapy alone in patients with relapsed or metastatic HNSCC.7
Patients with HPV-negative HNSCC had improved outcomes when treated with panitumumab compared with chemotherapy alone, whereas no improvement was observed in patients with HPV-positive tumors. This may be secondary to lower expression of EGFR in HPV-positive HNSCC,8,9
but the precise reason is unknown.
This dual problem (increasing incidence and potentially lower efficacy of existing therapies) highlights the need for further action in both implementing prevention strategies and researching novel treatment approaches that reflect this changing landscape.
Dr. Jimeno is an Associate Professor of Medicine/Oncology and Otolaryngology, Director of the Head and Neck Cancer Medical Oncology Program, and Director of the Cancer Stem Cell-directed Clinical Trials Program at the University of Colorado Cancer Center and Charles C. Gates Center for Regenerative Medicine and Stem Cell Biology. He has been an ASCO member since 2003.
- Gillison ML, Koch WM, Capone RB, et al. J Natl Cancer Inst. 2000;92:709-20.
- Kreimer AR, Clifford GM, Boyle P, et al. Cancer Epidemiol Biomarkers Prev. 2005;14:467-75.
- Bonner JA, Harari PM, Giralt J, et al. N Engl J Med. 2006;354:567-78.
- Vermorken JB, Mesia R, Rivera F, et al. N Engl J Med. 2008;359:1116-27.
- Agrawal N, Frederick MJ, Pickering CR, et al. Science. 2011;333:1154-7.
- Koutcher LD, Sherman E, Carlson D, et al. 2010 ASTRO Annual Meeting. Abstract 133.
- Stoehlmacher-Williams J, Villanueva C, Foa P, et al. J Clin Oncol. 2012;30 (suppl; abstr 5504).
- Reimers N, Kasper HU, Weissenborn SJ, et al. Int J Cancer. 2007;120:1731-8.
- Kumar B, Cordell KG, Lee JS, et al. J Clin Oncol. 2008;26:3128-37.
HPV Vaccination for Males: Clinical Trials and Social Tribulations
Gregory A. Masters, MD, FACP
Helen F. Graham Cancer Center
In debating the societal value of a medical intervention, one must consider multiple angles. Thus considered, I believe it is time to support universal vaccination of both boys and girls (young men and women) against the human papillomavirus (HPV) for the following reasons: 1) The sexually transmitted virus HPV is associated with, and probably causes many types of, morbid and potentially fatal cancer; 2) We have a highly effective vaccine for the prevention of HPV infection in both males and females; 3) Although we must acknowledge the need for prospective research to substantiate the hypothesis that HPV vaccination can prevent HPV-associated cancers and reduce overall mortality, it is up to us as cancer care leaders to educate and opine on the value of these interventions so that primary care physicians and individual patients can make an appropriate choice regarding participation in these vaccination programs, and so the public and government representatives can make informed decisions on public funding of this care.
HPV has been implicated as a cause of many virally induced diseases: genital warts, recurrent respiratory papillomatosis, and numerous malignancies, including those of the cervix, vagina, vulva, penis, anus, oral cavity, and oral pharynx. This virus is currently thought to be the most common sexually transmitted disease, with 20 million people infected in the United States, and 6.2 million new infections annually.1 Exposure to this virus is nearly ubiquitous among sexually active individuals.
Increasing sexual activity is associated with a higher risk of HPV infection. The prevalence of HPV among girls and women is 26.8%.1 Infections often occur soon after the onset of sexual activity. Specific sexual behavior may influence the transmission of HPV and thus affect sites of infection and subsequent malignancy.2 Studies suggest that HPV prevalence in the oral pharynx is three times higher in men than women,3 so their risk of oral pharynx cancer may be higher. HPV subtypes 16 and 18 are strongly implicated in most cervical cancers, most anal cancers, many penile cancers, and some oropharynx cancer. Up to 70% of cervical cancer cases are associated with these viral subtypes.4 Recent data suggests that the incidence of HPV-associated oropharynx cancer is on the rise, accounting for only 16% of oral cancers in the 1980s compared with 72% of these cancers diagnosed between 2000 and 2004.5
Two vaccines have been developed that demonstrate activity in controlling viral infection and decreasing viral associated morbidity from HPV. The two vaccines in clinical use include the bivalent vaccine HPV2 (Cervarix®, GlaxoSmithKline), effective against oncogenic HPV types 16 and 18, and a quadrivalent vaccine HPV4 (Gardasil®, Merck), effective against HPV types 6, 11, 16, and 18.
These vaccines have shown significant efficacy in reducing HPV-associated disease such as genital warts and premalignant lesions. One study of HPV4 showed a 90% reduction in development of external genital lesions in male patients without prior infection who received the vaccine.6
Because of the morbidity, both physical and psychologic, that this virus causes, FDA approval was granted in 2006 for the HPV vaccine in females to prevent cervical cancer. The vaccine was approved for use in males in 2009 to prevent genital warts.
Reflecting the FDA approval, both the American Academy of Pediatrics and the Centers for Disease Control and Prevention’s Advisory Committee on Immunization Practices have updated their recommendations for HPV vaccination to include boys and young men. These clinical guidelines now include a recommendation for HPV vaccination in boys and men age 11 to 26, in addition to previous recommendations
for vaccination of girls and women
age 11 to 26.
Clinical trial evidence supporting the reduction in invasive cancer incidence or mortality has not yet been shown, in part because of the significant lag time associated with the development of malignancy from initial HPV infection. Nonetheless, it is reasonable to assume that reducing HPV infection rates will ultimately lead to fewer cancers and thus a reduced mortality from HPV-associated malignancies. The magnitude of that benefit can still be debated.
Public education needed
Despite these benefits, public acceptance of the HPV vaccine has been slow, and adherence to the clinical guidelines impotent. This has been a subject of debate, with discussion involving clinicians and scientists with a scientific background in infectious disease, public health, and oncology, as well as political candidates, who may or may not be well educated and informed on the topic. This has not served the public well. The focus on government mandates has been a distraction: we should not support government mandates in this area. Few people want to be told what they have to do in health-related activities, and required vaccination would not be realistic with our limited resources to enforce such a mandate. Rather, progress will be best achieved through education.
The barriers we face in moving forward with a more universal HPV vaccination program include both social and financial barriers, but the potential benefits of HPV vaccination in males include societal benefits, such as herd immunity, decreased morbidity and mortality, and lower societal cost for the care of HPV-related diseases.
Should ASCO take a position on HPV vaccination in males? If so, how can we implement such a strategy? And what can we as clinicians do to help our patients most effectively?
These are ongoing questions that will need to be addressed in this debate. This is an issue that is not going away soon. The public health impact of HPV infection and the potential benefits of HPV vaccination will continue to occupy headlines until an appropriate strategy has been developed that maximizes our ability to control infection and reduce morbidity and mortality from this preventable disease.
We oncologists spend a lot of time treating patients with advanced disease: redirecting some of our efforts to earlier interventions that can prevent morbidity and mortality may have a greater societal impact and may be a more cost-effective strategy.
Dr. Masters is a lung cancer specialist and Director of Medical Oncology Fellowship at Helen F. Graham Cancer Center. An ASCO member since 1996, he currently serves on the Cancer Communications Committee and as Chair of the Test Materials Development Committee.
- Dunne EF, Unger ER, Sternberg M, et al. JAMA. 2007;297:813-9.
- D’Souza G, Kreimar A, Viscidi R, et al. N Engl
J Med. 2007;356:1944-56.
- Gillison ML, Broutian T, Pickard RK, et al. JAMA. 2012;307:693-703.
- Schiffman M, Castle PE, Jeronimo J, et al. Lancet. 2007;370:890-907.
- Chaturvedi AK, Engels EA, Pfeiffer RM, et al.
J Clin Oncol. 2001;29:4294-301.
- Giuliano AR, Palefsky JM, Goldstone S, et al.
N Engl J Med. 2011; 364:401-11.
The views and opinions expressed in Current Insights in Oncology are those of the authors alone. They do not necessarily reflect the views or positions of the Editor or of the American Society of Clinical Oncology.
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