OncologySTAT Editorial Team

Dr. Maura Gillison is Professor of Medicine, Epidemiology, and Otolaryngology at Ohio State University in Columbus.

OncologySTAT: The results of the Radiation Therapy Oncology Group (RTOG) 0129 trial showed that the human papillomavirus (HPV) is an independent prognostic factor in oropharyngeal cancer. Could you tell us about the rationale for this study?

Dr. Gillison: Over the last 10 years, our research has shown that cancers of the oropharynx are actually 2 completely different diseases that can look quite similar. One subset is caused HPV infection, and the other is more closely associated with long-term use of alcohol and tobacco.

Initial studies suggested that the presence of HPV in a patient’s tumor had prognostic significance, but study limitations made that conclusion dubious. We set out to determine whether or not HPV was indeed an independent prognostic factor in head and neck cancer. To show whether there was a direct relationship between HPV infection and head and neck cancer, we needed to prospectively study a uniformly treated and uniformly staged patient population. Thus, we used the study population from the trial conducted by the RTOG. We divided the patients into 2 groups—those whose tumors were caused by HPV and those whose tumors were not—and we compared survival outcomes for the 2 groups.

The results showed that HPV status was the single most important predictor of patient outcome, even more so than disease stage and other well-known prognostic factors such as performance status and presence of anemia. In fact, after accounting for 6 other nonprognostic factors, patients with HPV-positive cancer had less than half the risk of dying from their cancer as did patients whose cancer was HPV negative. At 5 years, that translated into a 30% absolute difference in survival.

On the basis of these results, we can state definitively that HPV is a strong and independent prognostic factor for oropharynx cancers. Currently, tumor HPV status is determined for all patients with head and neck cancer prior to enrollment into a clinical trial. I believe that HPV-positive oropharynx cancer is a completely different disease from traditional head and neck cancer, to the extent that we need to design separate clinical trials that are specific for the HPV-positive patient, as distinct from the HPV-negative patients.

Unfortunately, we have not made true progress over the last 15 to 20 years in therapy for patients with head and neck cancer. The major advances have been in our understanding of the underlying etiology of the disease and its inherent biologic responsiveness. Patients with HPV-negative head and neck cancer, in particular, are still doing extraordinarily poorly. Even with the use of intense, concurrent chemoradiation, as was done in the RTOG trial, 5-year survival is only about 30%.

OncologySTAT: Now that we can stratify patients by HPV status, it will be possible to separate out people who have head and neck cancer related to tobacco use and conduct separate trials on those patients, or investigate different therapies for them.

Dr. Gillison: Exactly. Our data indicate that patients with HPV-positive tumors do extraordinarily well. Some still do die of their cancer, but about 80% are alive and doing well 5 years later. Many of these patients are quite young; it’s not unusual to see patients in their 30s or 40s. If they’re expected to survive their cancer, then they will have to deal with the consequences of the therapy for 30, 40, or 50 years.

OncologySTAT: Are they surviving longer?

Dr. Gillison: They are surviving longer. Now we need to focus on improving their outcomes. The more aggressive approaches being used in head and neck cancer, such as combination therapy with multiple agents, together with standard chemotherapy, biologics, and radiation therapy, all should be studied in HPV-negative patients. The increased toxicity of combined therapies may be warranted in terms of the risk-benefit analysis because these patients have such poor survival. At present, it would be inappropriate to use such therapies for the HPV-positive group.

OncologySTAT: Will you be following the HPV-positive patients over the long term? Patients with head and neck cancer are at risk for second cancers later on.

Dr. Gillison: We analyzed second cancers in our trial and found that they were significantly less likely to occur in HPV-positive patients than in HPV-negative patients. The difference was largely explained by a difference in rates of smoking in the 2 groups of patients. The rate of second cancers is approximately 20% among HPV-negative patients, whereas it’s about 5% in the HPV-positive group.

OncologySTAT: Are there any follow-up studies planned or underway right now?

Dr. Gillison: The National Cancer Institute (NCI) steering committee has adopted my recommendation to design separate clinical trials for HPV-positive and HPV-negative patients. We also hope to conduct clinical trials with the European Organisation for Research and Treatment of Cancer (EORTC) and the French Head and Neck Oncology and Radiotherapy Group. This work will focus on how best to treat patients with HPV-positive head and neck cancer. We don’t know the best treatment strategy, because HPV-positive cancer wasn’t recognized until recently as a unique disease entity.

In the United States, incidence rates of HPV-positive cancer are rising dramatically. NCI data for 2000 put the incidence at 10% per year, but this rate is expected to double in the current decade. Thus, in the future, the alcohol- and tobacco-related cancers are going to be the rare cancers.

We need to figure out as rapidly as possible the standard of care for this cancer. Together with RTOG and the Eastern Cooperative Oncology Group (ECOG), we are in the process of designing a large, randomized phase II study specific to HPV-positive patients. We estimate enrolling 800 to 1,000 patients. Endpoints will include quality of life and toxicity outcomes. Because HPV-positive patients respond so well to therapy, the question now is whether we can reduce the use of intense therapy and thereby decrease the long-term consequences of the therapy. Some therapies used during the last 15 years for head and neck cancer have yielded only a 5% to 8% absolute benefit in 5-year survival, but they have contributed to a 500% increase in morbidity over the long term. Many patients end up not being able to swallow food and are therefore dependent on gastrostomy tubes, which has significant social and quality-of-life implications.

So the goal of that trial is to compare standard-of-care therapy, as it was developed in RTOG 0129, with 2 other treatment algorithms involving reduced-intensity therapy. Hopefully, we will find that reduced-intensity therapy does not compromise survival. We hope we can get answers sooner rather than later.

OncologySTAT: Do you think vaccination is going to have a role in reducing the incidence of HPV-related head and neck cancers over time?

Dr. Gillison: I certainly hope so. Half of my research program involves work on oral HPV infection, looking at its prevalence in the US population, predictors, and the natural history. Soon we will be starting a clinical trial that evaluates whether the currently approved HPV vaccines can more effectively prevent oral HPV infections. We hope to have answers in 5 years.

HPV vaccines are extraordinarily effective (nearly 100%) in preventing cervical dysplasia and cancer among women. Both the Food and Drug Administration and the Centers for Disease Control and Prevention report virtually no evidence of any severe toxicities or negative outcomes from the vaccine. However, only 1 out of 4 parents in the United States have made the decision to have their daughters vaccinated.

OncologySTAT: Pediatricians appear to be proponents of vaccination against HPV.

Dr. Gillison: Yes. I understand that there are social implications to the vaccine, as well as cost-benefit considerations, because the vaccine is expensive. However, my patients look at it this way: If they had the option, in retrospect, of getting 3 vaccines in their teens instead of having to deal with the consequences of a cancer diagnosis for themselves and their families later on, they say it would have been an easy decision.

For HPV-related cancers, we’ve found the Achilles heel, in that HPV is necessary for these cancers, causing about 20,000 cases in the United States every year. The vaccine appears to be fairly effective at every site where it’s been tested. My concern is that, if we can’t make the appropriate decisions on a policy level that could eliminate a cancer for which we’ve identified a single cause, what will we do for all these other cancers, the genetics of which are much more complex? Cancers such as colon cancer and breast cancer are tremendously heterogeneous in terms of genetic predisposition. There’s probably not going to be an Achilles heel for those cancers. In my opinion, potentially 20,000 US families are affected each year by a cancer for which the HPV vaccine holds promise. Worldwide, that’s more than a million cases.

OncologySTAT: What are the implications of your results for community-based oncologists?

Dr. Gillison: The patient population that gets HPV-related head and neck cancer is highly educated; they tend to be of high socioeconomic status. This is a different population than head and neck cancer patients in the past, who, because of their protracted alcohol and tobacco abuse, maybe didn’t advance as well in society as these patients, who tend not to smoke and drink. Patients we see tend to be Internet savvy, and when they read about the profound prognostic significance of the HPV test, they demand it.

If you knew that you had been diagnosed with a cancer for which there was a test that could determine whether you had an 85% chance of 5-year survival as opposed to a 30% chance, you’d probably demand it, too, because you’d want to make plans for your life. Community oncologists should be aware of these data, because any patient with an oropharynx cancer who does not have traditional risk factors probably has an HPV-related cancer.

Unfortunately, a lot of medical oncologists in the community are still unaware of the relationship between HPV and oropharynx cancer. They need to be made aware of the relationship so that they can counsel their patients appropriately. Many patients are completely stumped as to why they’ve gotten this cancer. Community oncologists need to know that HPV testing is available in at least 2 institutions, Johns Hopkins and Ohio State University.

All clinical trials conducted by ECOG and RTOG will now require determination of HPV status for eligibility. Oncologists in the community who refer patients for clinical trials need to be aware of this and know how to counsel their patients when the results come back. There is still a social stigma to having a cancer caused by a sexually transmitted infection, and community oncologists need to be sensitive to that. In my clinical practice, I’ve seen marriages dissolve over the blame game, and relationships strained because of guilt feelings in one partner or the other. Community oncologists need to educate themselves about HPV so that they can handle this difficult counseling.

OncologySTAT: That’s an interesting aspect that we don’t often think about in terms of participation in a clinical trial.

Dr. Gillison: Telling someone that they have a cancer caused by a sexually transmitted infection can have social implications. In my opinion, there should be no stigma associated with it. As an HPV biologist, I recognize that 80% of individuals will have an HPV infection at some point in their life. That may even be an underestimation, as it is based solely on data for cervical cancer. Anal HPV infection and oral HPV infection didn’t factor into those previous estimates.

I see HPV infection as a consequence of being human. Nearly all people who get an HPV infection can handle it immunologically, without developing any health consequences. We don’t know what’s different about the 0.01% of people who develop cancer from the virus and those who don’t. I try to educate people about the high prevalence of HPV infection. Education can help remove the social stigma.

A lot of my patients feel relieved when I tell them how common the infection is. There’s also a perception that HPV infection is an indication of promiscuity, which is not correct. A study done at the University of Washington followed college-aged women from their freshman year forward to assess the incidence of HPV infection. The analysis was restricted to women who were virgins at entry into the study. The women were followed only through their first sexual partner, after which they were censored. By the end of 1 year, 25% of the women had contracted an HPV infection. By the end of 2 years, the incidence had risen to one-third. Men are remarkable reservoirs for HPV infection. An estimated 63% of men in the United States have a genital HPV infection.

So it’s best to think of HPV infection as a consequence of being human and having evolved with the virus for a long time. With this viewpoint, people won’t attach such a stigma to it.

OncologySTAT: It will also be important to determine which patients can have good outcomes despite receiving less aggressive therapy. This could spare them some of the speech and eating problems that result from head and neck cancer.

Dr. Gillison: As the principal investigator on the planned RTOG study, I know some of the comparisons we will be looking at. Less intensive radiation is one option for less aggressive therapy. Most of the complications from therapy are related to patients’ receiving chemotherapy and radiation at the same time; an alternative approach might be to administer these treatments sequentially. Or, if given together, they could be given at lower doses. These are some of the different options being considered for this study.

This news story was resourced by the Oral Cancer Foundation, and vetted for appropriateness and accuracy.

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