Author: Robert Haddad, MD
Dana Farber Cancer Institute, Boston, MA
The author was invited to contribute his thoughts on the topic of human papillomavirus and cancers of the oropharynx.
Squamous cell carcinoma of the head and neck (SCCHN) is a major public health problem, affecting nearly half a million individuals worldwide each year. These cancers can arise from the oral cavity, oropharynx, nasopharynx, hypopharynx and larynx.1 Treatment of head and neck cancer is often multidisciplinary, involving chemotherapy, radiation therapy, and surgery. Patient symptoms can include a sore throat, ear pain, odynophagia, or hoarseness. Most patients will present with stage III or IV disease. The major risk factors are smoking tobacco and alcohol abuse. A large number of patients diagnosed with oropharynx cancer, however, have no history of smoking or drinking, and increasing epidemiological, molecular, and clinical evidence suggests that high-risk human papillomavirus (HPV), especially HPV-16, account for the development of these cancers.2-5 Most individuals are unaware of their infection and have no symptoms.
HPV is one of the more common virus groups in the world, and more than 80 types of HPV have been identified. Some types (eg, HPV 6 and 11) are known to cause benign conditions such as genital warts, while other types (eg, HPV 16 and 18) are known to be associated with malignant, cancerous transformation. Although different types of HPV are known to infect different parts of the body, HPV usually infects the epithelial cells of skin and mucosa. The epithelial surfaces include all areas covered by skin and/or mucosa such as the tonsil, tongue base, vagina, penis, and anus. Transfer of the virus between individuals can occur with any type of skin-to-skin or skin-to-mucosa contact. HPV infection is known to be a necessary infection for the development of cervical cancer in women and is a risk factor for the development of anal, penile, and vulvar cancer. It is noteworthy that the site mainly associated with HPV infection in the head and neck area is the oropharynx, particularly the tonsils and tongue base. Other sites, including the oral cavity and larynx, are not. Nasopharynx cancer is associated with another type of virus, Epstein Barr Virus (EBV). It is not clear why the oropharynx is more susceptible to HPV transformation. It is well established that the transmission of genital HPV infections is associated with sexual contact and its prevalence increases among individuals with multiple sexual partners. The means by which HPV is transmitted to the oral cavity is less well understood at this stage but sexual behavior and practices are one possible mode of transmission.3 Oropharynx cancer can be placed in the category of “virally mediated cancers” along with cervical cancer, anal cancer, vulvar cancer, and penile cancer (all associated with HPV), and nasopharyngeal cancer and lymphomas (both associated with EBV).
There is an emerging consensus that 2 pathways exist in oropharynx cancer’s development, one caused by smoking and/or alcohol and another caused by HPV infection. The absence of genetic changes in HPV-positive head and neck cancer contrasts to what is observed in HPV-negative head and neck cancer. In the typical squamous cell carcinomas not caused by HPV, p53 mutations are frequently present. In contrast, HPV-related carcinomas usually do not contain any p53 mutations, and predominantly occur in patients with no excessive tobacco and/or alcohol consumption history, implying that HPV-positive and HPVnegative head and neck cancer represent distinct entities. Furthermore, it has been shown that the outcome of patients with HPV-related tumors is better compared to those with a smoking-related tumor. Indeed, we have enough evidence at this stage to support the notion that patients who have an oropharynx cancer related to HPV will have a longer survival than those whose cancer is not related to HPV. This is likely due to a higher response to chemotherapy and radiation than is seen with HPV-associated tumors. Recently, new evidence has emerged showing that African Americans have a lower incidence of HPV infection, likely accounting for the worse prognosis seen in head and neck cancer affecting these patients.6
The first prospective report of improved outcome in HPV-positive SCCHN comes from the Eastern Cooperative Oncology group (ECOG).7 In a single-arm phase 2 study performed by ECOG, 96 patients with stages III or IV oropharynx or larynx cancer received induction chemotherapy with carboplatin and paclitaxel followed by concurrent chemoradiotherapy with weekly carboplatin and paclitaxel and standard radiation. The presence or absence of HPV oncogenic types in tumors was determined by multiplex polymerase chain reaction (PCR) and in situ hybridization. The authors were able to show that patients with HPV-positive tumors had higher response rates after induction chemotherapy (82% vs 55%) and after chemoradiation treatment (84% vs 57%) compared with patients with HPV-negative tumors. After a median follow-up of more than 3 years, patients with HPV-positive tumors had significantly improved overall survival (2-year overall survival, 95% vs 62%) and, after adjustment for age, tumor stage, and ECOG performance status, lower risks of progression and death from any cause than those with HPV-negative tumors.
A surrogate for HPV infection, p16 positivity, has also recently been found to have a major impact on treatment response and survival in patients treated with radiotherapy alone in the Denmark. Indeed, patients with p16 positive tumors had a 5-year survival of 62%; the survival for those with p16 negative tumors was only 26%.8
RTOG 0129 is a large randomized study comparing chemoradiotherapy with 2 different radiation fractionation schedules. A correlative study presented at the 2009 American Society of Clinical Oncology meeting looked at the association of tumor HPV status and survival for the oropharynx group in this phase 3 study.9 HPV status was evaluable for 73% of oropharynx cases and 60% were HPV16 positive. After median follow-up of 4.4 years, cases with HPV-positive oropharynx cancer had better overall survival (2 year, 87.5% vs 67.2%) and progression-free survival (2 year, 71.9% vs 51.2%). Overall, patients with HPV-positive cancer had a 59% reduction in risk of death and a 46% reduction in risk of progression or death. Second primary tumors were less common among HPV-positive cases and patterns of first failure were similar. Another interesting finding from this study is that smoking status is important for patients with HPV-positive tumors. Mortality was higher for those patients that were smokers compared with nonsmokers in the HPV-positive group. It is likely, based on recent data, that 3 categories of oropharynx cancer patients exist:
Group 1: Oropharynx cancer, HPV positive, no active or prior smoking history. These patients have an excellent prognosis and the vast majority of those are cured with radiation-based therapy. Cure rate: 80% to 90%.
Group 2: Oropharynx cancer, HPV positive, current or former smoker. This is considered an intermediaterisk group with survival that is better than the HPV negative group but inferior to group 1. Cure rate: 50% to 60%.
Group 3: Oropharynx cancer, HPV negative. This group has a poor prognosis and is clearly different than the first 2 groups. Cure rate: 30% to 40%.
The findings regarding HPV and head and neck cancer have yet to be translated into clinical practice. Indeed, treatment recommendations have not changed so far and chemotherapy/radiation therapy and surgery remain mainstays of therapy. Currently, we do not recommend that treatment be tailored to HPV status unless this is done as part of a clinical trial. Going forward, HPV stratification should and would be required in all head and neck cancer clinical trials. There will also be HPV-related oropharynx trials where only patients with this entity are enrolled. This is important since this group is clearly distinct for the HPV-negative group and has a different prognosis. The most interesting option will be “dose de-intensification” for chemotherapy, radiation therapy, or both. Many imminent clinical trials will be looking at a lowered radiotherapy dose or at a radiation therapy alone option (without chemotherapy) for patients. The implications are significant in term of side effects and quality of life. Decreasing the radiation dose will have significant positive impact for patients. It will be crucial as these trials develop to make sure that the high cure rates for these patients are not compromised. HPV-related oropharynx cancer could be the equivalent of Hodgkin disease, for which radiation dose has been lowered significantly or even eliminated from treatment paradigms. Until this is studied in prospective, well-designed clinical trials, oncologists should continue to treat patients with the current standards and only use HPV status as a prognostic factor. Testing for HPV is rapidly becoming a standard approach with oropharynx cancer and in situ hybridization (ISH) appears to be the preferred method, even though a much simpler and more easily performed test (p16 immunohistochemistry) is likely to be as reliable as ISH.
Finally, HPV vaccination is an important tool in fighting cervical cancer in women and undoubtedly will become a tool in the fight against oropharyngeal cancer. Clinical trials looking at expanding vaccination strategies to boys and girls will be crucial in this fight.
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9. Gillison ML, Harris J, Westra W, et al. Survival outcomes by tumor human papillomavirus (HPV) status in stage III-IV oropharyngeal cancer (OPC) in RTOG 0129. J Clin Oncol. 2009;27:15(suppl;abstr6003).
Author disclosures: No relationships with industry were reported.