Human papillomavirus infection and cancers of the oropharynx

Source: www.ajho.com
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.

1. Haddad RI, Shin DM. Recent advances in head and neck cancer. N Engl J Med. 2008;359(11):1143-1154.
2. Gillison ML, Koch WM, Capone RB, et al. Evidence for a causal association between human papillomavirus and a subset of head and neck cancers. J Natl Cancer Inst. 2000;92(9):709-720.
3. D’Souza G, Kreimer AR, Viscidi R, et al. Case-control study of human papillomavirus and oropharyngeal cancer. N Engl J Med. 2007;356(19):1944-1956.
4. Gillison ML, Lowy DR. A causal role for human papillomavirus in head and neck cancer. Lancet. 2004;363(9420): 1488-1489.
5. Chaturvedi AK, Engels EA, Anderson WF, Gillison ML. Incidence trends for human papillomavirus-related and -unrelated oral squamous cell carcinomas in the United States. J Clin Oncol. 2008;26(4):612-619.
6. Settle K, Posner MR, Schumaker LM, et al. Racial survival disparity in head and neck cancer results from low prevalence of human papillomavirus infection in black oropharyngeal cancer patients. Cancer Prev Res (Phila Pa). 2009 Jul 29 [Epub ahead of print].
7. Fakhry C, Westra WH, Li S, et al. Improved survival of patients with human papillomavirus-positive head and neck squamous cell carcinoma in a prospective clinical trial. J Natl Cancer Inst. 2008;100(4):261-269.
8. Lassen P, Eriksen JG, Hamilton-Dutoit S, et al. Effect of HPV-associated p16INK4A expression on response to radiotherapy and survival in squamous cell carcinoma of the head and neck. J Clin Oncol. 2009;27(12):1992-1998.
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.

October, 2009|Oral Cancer News|

Port Coquitlam dentist hopes to save a life with a Velscope

Source: www.bclocalnews.com
Author: Diane Strandberg

A Port Coquitlam dentist is offering to do more than fix cavities and polish teeth. Dr. Glenn Keryluk wants to save a life.

He’s purchased an oral cancer screening device he expects will shortly become standard equipment in all dentist offices and he is offering to screen patients referred to by local doctors.

“It’s the latest and greatest in cancer detection,” Keryluk says of the Velscope, a hand-held device that shines a blue light on oral lesions that could be cancerous.

Manufactured by a White Rock-based company, the Velscope can show abnormal tissue below the surface, even before it becomes apparent to the clinicians’ eye. Healthy tissue glows green under the light but cancerous tissue looks black. Being able to detect oral cancer early is key to surviving the disease because the longer the cancer is around the more likely it will spread to nearby organs.

Keryluk held a free screening day for patients at his office at 2099 Lougheed Highway recently and is cutting standard fees for the procedure or waving them entirely for people without dental coverage. The procedure is painless, takes only a few minutes and a photograph of the lesion taken by the machine can be sent to a physician for follow-up.

“If you catch it early it could be that a person’s life is saved. I just want people to be aware of the technology out there,” Keryluk said.

He’s only seen two cases of oral cancer in 20 years as a dentist but the Velscope may increase his chances of spotting the disease.

Oral cancer is more common in men than women and age, tobacco use and heavy drinking are risks. But Keryluk said younger people have been diagnosed with oral cancer and the disease is on the rise. Human papillomavirus associated with cervical cancer has also been linked to oral cancer so it’s not just a disease of older people who drink and smoke.

“The day I save somebody’s life for early detection, I’ll give you a call,” Keryluk said.

September, 2009|Oral Cancer News|

More evidence links alcohol, cancer in women

Source: apnews.myway.com
Author: staff

A study of nearly 1.3 million British women offers yet more evidence that moderate alcohol consumption increases the risk of a handful of cancers. British researchers surveyed middle-aged women at breast cancer screening clinics about their drinking habits, and tracked their health for seven years.

A quarter of the women reported no alcohol use. Nearly all the rest reported fewer than three drinks a day; the average was one drink a day. Researchers compared the lightest drinkers – two or fewer drinks a week – with people who drank more.

Each extra drink per day increased the risk of breast, rectal and liver cancer, University of Oxford researchers reported Tuesday in the Journal of the National Cancer Institute. The type of alcohol – wine, beer or liquor – didn’t matter.

That supports earlier research, but the new wrinkle: Alcohol consumption was linked to esophageal and oral cancers only when smokers drank.

Also, moderate drinkers actually had a lower risk of thyroid cancer, non-Hodgkin’s lymphoma and renal cell cancer.

For an individual woman, the overall alcohol risk is small. In developed countries, about 118 of every 1,000 women develop any of these cancers, and each extra daily drink added 11 breast cancers and four of the other types to that rate, the study found.

But population-wide, 13 percent of those cancers in Britain may be attributable to alcohol, the researchers concluded.

Moderate alcohol use has long been thought to be heart-healthy, something the new research doesn’t address but that prompts repeated debate about safe levels. U.S. health guidelines already recommend that women consume no more than one drink a day; two a day for men, who metabolize alcohol differently.

“You have to balance all those things out,” said Dr. Philip J. Brooks, who researches alcohol and cancer at the National Institutes of Health. “This kind of information is important for people to know and to consult with their physician about the various risk factors they have.”

February, 2009|Oral Cancer News|

Smoking and drinking linked to throat and stomach cancer

Source: uk.reuters.com
Author: Michael Kahn

Drinking alcohol and smoking cigarettes appear to increase the risk of certain common throat and stomach cancers, Dutch researchers reported on Monday.

The findings, presented at an American Association for Cancer Research meeting in Washington, underline other health recommendations for people to follow a healthy lifestyle and drink and smoke only in moderation.

“It appeared that current smokers have the highest risks, and former smokers have an intermediate risk compared with never smokers,” Jessie Steevens, an epidemiologist at Maastricht University in the Netherlands, said in a statement.

The incidence of stomach cancer has fallen dramatically in the United States and western Europe over the past 60 years but the disease remains a serious problem in much of the rest of the world, where it is a leading cause of cancer death, according to the Mayo Clinic.

Oesophageal, or throat, cancer is a form of cancer that starts in the inner layer of the oesophagus, the 10-inch-long tube that connects the throat to the stomach.

The researchers followed more than 120,000 Dutch residents for more than two decades to investigate risk factors for oesophageal adenocarcinoma and gastric cardia adenocarcinoma — a type of stomach cancer — as well as oesophageal squamous cell carcinoma, which resembles head and neck cancer.

Other studies have linked oesophageal cancer in general to drinking and smoking, but Steevens and colleagues wanted to refine the risk of the different types of the tumours.

They found that for oesophageal squamous cell carcinoma — which accounts for about half of throat cancers — people who consumed four glasses of alcohol each day had five times the risk of developing the cancer of non-drinkers.

Smoking was associated with an increased risk of all three cancers with the risks of the more common throat cancer higher than the other two cancers, Steevens said.

“These are the results when no other aspects of smoking were considered, such as the amount of cigarettes smoked per day and the number of years a person smoked,” Steevens said.

“When we took into account the smoking duration and frequency, it appeared that the difference in risk between former smokers and current smokers could partly be explained by these other aspects of smoking.”

Reporting by Michael Kahn; editing by Julie Steenhuysen and Tim Pearce

November, 2008|Oral Cancer News|

Younger people suffering from mouth cancer

Source: www.rochdaleonline.co.uk
Author: staff

People in their 20s are being urged to look out for the symptoms of mouth cancer. The disease is usually found in older people who have smoked and drunk alcohol over a long period of time. Now mouth cancer specialists are reporting cases of people in their 20s and 30s with non-healing ulcers, white and red patches or a lump, which are all possible signs and symptoms of the disease.

Mr Andrew Baldwin, a consultant oral and maxillofacial surgeon, believes that there is still a lack of awareness about mouth cancer in the general population.

“People who smoke and drink alcohol for a number of years tend to be those who suffer the most from mouth cancer. However, in the last few years we have seen a minority of people in their mid 20’s developing the disease.

There can also be other causes so people who don’t necessarily smoke and drink heavily but have the symptoms should not dismiss mouth cancer.”

Mr Robert Woodwards, a consultant oral and maxillofacial surgeon, insists early detection of the disease prevents people from being permanently disfigured.

“Whilst typically associated with smoking and drinking can be related to other causes and the key to a successful outcome for treatment for mouth cancer is to catch the disease when it is early and the lesion is small.

“Smaller mouth cancers are much easier to treat and the results of surgery can be limited so that alteration in a patient’s appearance is not necessarily the result of treatment.”

Emma Riley, oral health practitioner at Pennine Acute Trust, believes Mouth Cancer Action Week, starting on Monday 17 November, can save lives.

“Sadly, we’re seeing a rise in the number of cases of mouth cancer. It’s a familiar story really, unfortunately we’re smoking too much, drinking too much and don’t have the diet we should.”

“Many people simply don’t know the risks of mouth cancer, and we hope that the help Mr Baldwin, Mr Woodwards and their colleague Mr Ewen Thomson are offering during the awareness week will help with that.”

November, 2008|Oral Cancer News|