Dr. Hayes is not completely convinced that the increase is related to changing sexual practices. "Unlike other STDs, this appears to have a quite long latency period. The mean age of most of the patients we see is in their 50s, with some in their 40s. We see very few patients in their 30s."
Even among HPV-positive patients, the story is probably more complex than simply the viral component in the tumor, he said. "This story is also about smoking. Patients with HPV-associated tumors and a significant smoking history don’t tend to have the same favorable outcomes."
This thought is backed up by a recent study of 743 patients with oropharyngeal squamous cell carcinomas published in the New England Journal of Medicine. Of the 323 patients who had HPV typing, 206 were positive for the virus. After HPV status, smoking was the largest predictor of mortality, with the risk of death significantly increased with each additional pack-year of tobacco smoking (N. Engl. J. Med. 2010;363:24-35). "Smoking is associated with a lot of things: worse overall health on many fronts, heart and vascular disease and stroke, but it’s also probably with a change in the biology of the disease," Dr. Hayes said. "It appears that smoking and nonsmoking lung cancer, for example, have a very different underlying biology."
Patients who were nonsmokers in that study did very well in the setting of one of the most aggressive treatment regimens, Dr. Hayes noted. "Does this mean we want to continue that because it’s successful, or decrease the intensity of the treatment because it works but has lots of side effects? There is a big incentive to decrease the toxicity right now, but it’s tough to know what to do next.
Again, no data have shown just how smoking might relate to HPV status and survival in oropharyngeal cancer, both experts said.
Only prospective studies will answer all – or any – of these questions, they agreed. "This should really be tested in prospective clinical trials before we alter any management for any of these patients," Dr. Cohen said.
A few prospective studies to answer some of these questions are already in progress. Dr. Cohen is a primary investigator in one of these. "Our study will be a radiation-sparing trial for patients with HPV-positive cancers. Those who have a good response to induction chemotherapy will get a much narrower radiation field, which should lower long-term toxicity dramatically. It will be a 110 patient study."
Another phase II trial is studying paclitaxel, cisplatin, and cetuximab to see how well they work when followed by cetuximab and two different doses of intensity-modulated radiation therapy (IMRT) in patients with HPV-associated stage III or stage IV oropharyngeal cancers that can be resected. Sponsored by ECOG, the trial will divide patients into two groups. One group will undergo low-dose IMRT 5 days per week for approximately 5 weeks (27 fractions) and also receive cetuximab IV for 1-2 hours once weekly for 6 weeks.
Those in the second study group will undergo standard-dose IMRT 5 days per week for approximately 6 weeks (33 fractions), as well as cetuximab IV over 1-2 hours once weekly for 7 weeks.
The second trial, sponsored by the comprehensive cancer center at Ohio State University in Columbus, is a phase I study of the side effects and best dose of vorinostat when given together with cisplatin and radiation therapy in patients with stage III or stage IVA squamous cell cancer of the oropharynx, either unresectable or borderline resectable.
Patients will receive oral vorinostat on days 0-2 and cisplatin IV on days 7, 21, and 35. They will also undergo radiotherapy 5 days a week beginning on day 7, with concurrent oral vorinostat along with the radiotherapy 3 days per week
A third prospective study, sponsored by the comprehensive cancer center at Case Western Reserve University in Cleveland, intends to examine how well erlotinib given with docetaxel and radiation therapy might work in treating patients with stage III or stage IV squamous cell carcinoma of the head and neck.
All of these trials will stratify patients by HPV positivity or negativity, potentially providing much of the information oncologists need to decide whether those with the HPV advantage can continue to experience excellent outcomes while undergoing less-intensive treatment.
In the meantime, both experts reiterated, it makes no sense to issue blanket treatment recommendations based on HPV tumor status. However, they added, looking at an individual’s risk factors – including HPV status, smoking status, age, and general health – may influence what track treatment can take.