Source: MedScape
Author: Zosia Chustecka

March 30, 2010 — The incidence of oropharyngeal carcinoma related to human papillomavirus (HPV) has been increasing in recent years, and there is speculation that this is the result of the “sexual revolution” of the 1960s.

This increase in the incidence of HPV-related oropharyngeal cancer has important public health implications, British experts warn in an editorial published online March 25 in the British Medical Journal.

HPV-related oropharyngeal carcinoma appears to be a new and distinct disease entity, with better survival than the classic non-HPV-related disease, they point out.

“These patients are typically younger and employed, and — because outcomes seem to be more favorable than for patients with non-HPV-related carcinoma — they will live longer with the functional and psychological sequelae of their treatment. Consequently, they need prolonged support from health, social, and other services, and may require help returning to work,” write the authors, headed by Hisham Mehanna, BMedSc, MB ChB, FRCS, director of the Institute of Head and Neck Studies and Education at University Hospital in Coventry, United Kingdom.

However, currently, there is no good evidence to support managing patients with HPV-related head and neck cancer differently from those whose tumors are not HPV-related, the researchers write.

Several studies are being planned to evaluate different treatment options, and Dr. Mehanna and colleagues urge clinicians to offer all patients with oropharyngeal cancer the opportunity to enroll in a clinical trial. However, until data from those trials are available, “we suggest that clinicians should not change their current treatment policies.”

Maura Gillison, MD, PhD, professor of medicine, epidemiology, and otolaryngology at Ohio State University in Columbus, who was approached for independent comment, toldMedscape Oncology that she agrees.

Currently, patients should be treated the same, whether they are HPV positive or negative, she said, but they should be “strongly encouraged” to participate in trials.

Increase Linked to Sexual Behavior?

As evidence for the increasing incidence of HPV-related oropharyngeal carcinoma, the researchers cite several studies. One of these, conducted in Stockholm, Sweden, found a progressive proportional increase in HPV detected in biopsies taken to diagnose oropharyngeal cancer, from 23.3% in the 1970s, to 29% in the 1980s, 57% in the 1990s, 68% in 2000 to 2002, 77% in 2003 to 2205, and 93% in 2006 and 2007 (Int J Cancer. 2009:125:362-366).

One reason for this increase could be the sexual transmission of HPV, primarily through orogenital intercourse, Dr. Mehanna and colleagues write.

They also cite a recently published pooled analysis of 8 multinational studies conducted by the International Head and Neck Cancer Epidemiology (INHANCE) consortium (Int J Epidemiol. 2010;39:166-181). Using pooled data, this group compared 5642 patients with head and neck cancer and 6069 control subjects, and found that the risk of developing oropharyngeal carcinoma was associated with a history of 6 or more lifetime sexual partners, 4 or more lifetime oral sex partners, and — for men — an earlier age at first sexual intercourse.

The association between HPV-related oropharyngeal cancers and sexual behavior — having several sexual partners, and with oral sex and “French kissing” — has been reported in previous studies. Last year, American experts highlighting the increase in HPV-related oropharyngeal cancer suggested an association with an increase in the practice of oral sex among white, younger Americans, as reported previously by Medscape Oncology.

Dr. Gillison told Medscape Oncology that “it is clear that the strongest behavioral risk for [HPV-related oropharyngeal cancer] is the lifetime number of oral sex partners.”

“However, there are no data to specifically link the increase in disease incidence to changes in oral sexual behaviors over time,” she added, pointing out that sexual-behavior surveys in the United States did not collect this type of information before the 1990s.

“This is something that I have looked at carefully,” Dr. Gillison said, and she believes that the available data suggest that the sharp increase in HPV-related oropharyngeal cancer is a result of the sexual revolution of the 1960s.

Legacy of the Sexual Revolution

“Our own work, using the [Surveillance, Epidemiology, and End Results] database, shows a strong cohort effect, which means the greatest determinant of risk in any age group is the year that you were born,” Dr. Gillison reported.

“These cohort effects are largely driven by societal changes, and they tend to affect people first who are younger, because they are the people leading the behavioral changes,” she explained.

During the 1960s, teenagers and young adults were more active sexually than previous generations, and having multiple sexual partners became more acceptable. “The more sexual partners you have, the greater the risk of contracting any sexually transmitted disease, including HPV,” Dr. Gillison pointed out.

The time lag between an oral HPV infection and the development of HPV-related oropharyngeal cancer is between 15 and 30 years, and the age at which this cancer is usually diagnosed is 50 years or more.

So the increase in this cancer that was seen in the 1990s and the 2000s is likely to be the result of young people participating in increased sexual activity in the 1960s and 1970s, Dr. Gillison suggested.

“We saw a really sharp climb in the incidence in 2000,” Dr. Gillison noted. “So you have to think: What were these people [now 50 or more years old] doing 20 to 30 years ago?”

Dr. Mehanna told Medscape Oncology that he “totally agrees.”

The time line of the sudden increase in these cancers seen in the past decade and the 20 to 30 years that it takes for HPV-related cancer to develop points to changes in sexual behaviors that began in the 1960s and 1970s, he said. “The time frame fits,” he said, although he added that “this is conjecture.”

However, there are many points that are backed up with data. “What we know for sure is that HPV causes oropharyngeal cancer, and we understand the molecular mechanisms involved, so we know how it causes it,” Dr. Mehanna explained. “We also know that patients who have HPV-related oropharyngeal cancers are more likely to have had 6 or more sexual partners or 4 or more oral sex partners,” he said, and men are more likely to have started having sex at an earlier age. This [fits] with data for cervical cancer, also caused by HPV, which is more likely in women who become sexually active at an earlier age, he noted.

Rethink on HPV Vaccination?

Because a vaccine against HPV is already marketed for use in girls and young women to prevent cervical cancer, and was recently approved for use in boys to prevent genital warts, there has been speculation about whether this vaccine will also protect against HPV-related oropharyngeal cancer.

Dr. Gillison points out that there is no scientific evidence, as yet, to show that HPV vaccination does protect against HPV-related orophageal cancer. “It ought to,” she explained, because this cancer is mainly associated with HPV type 16, and this is one of the virus types that the vaccines contain. “But science can be surprising, and things don’t always work out as we expect,” she warned. She pointed out that the oral cavity is very different from the genital area, and the differences in mucosal surfaces and in the antibodies in saliva and genital secretions might alter the response to vaccination.

“Whether the currently available HPV vaccines have the potential to prevent oral HPV infections that lead to cancer, and thereby reverse the current upward incidence trends documented now in the United States, the United Kingdom, and Sweden, is an important and unanswered question,” Dr. Gillison commented.

“Unfortunately, the studies designed to evaluate this question that were slated to start next month in young men have recently been cancelled by the pharmaceutical sponsors,” she added.

In their editorial, Dr. Mehanna and colleagues suggest that the recent rapid rise in HPV-related oropharyngeal carcinoma might alter some of the cost-effectiveness considerations about this vaccine and, in particular, its use in boys before they become sexually active.

The HPV vaccination of boys was judged to be not cost-effective in a recent analysis (BMJ 2009;339:b3884), but this decision was made on the basis of old data, Dr. Mehanna explained to Medscape Oncology. The data in that cost-effectiveness study only go up to 2003, but there has been a considerable increase — a doubling, in fact — since then, he said. There are data from 2009 that suggest that about 70% of oropharyngeal cancer is HPV-positive, compared with about 35% in 2003, he noted.

Hence, that study underestimated the incidence of HPV-related oropharyngeal cancer, Dr. Mehanna said, and a new cost-effectiveness analysis needs to be carried out to take these new incidence data into account. “It may well turn out to be cost-effective,” he added.

Dr. Mehanna is director of the Institute of Head and Neck Studies and Education, which does contract work for GlaxoSmithKline. One of his coauthors, Terence Jones, from the Liverpool CR-UK Cancer Centre, School of Cancer Studies, Division of Surgery and Oncology, in the United Kingdom, is involved in a clinical trial in patients with HPV-related oropharyngeal carcinoma with a therapeutic vaccine that the manufacturer (Advaxis) is providing free of charge.

BMJ. 2010;340:c1439. Abstract