Expert Differentiates Carcinogen-Induced and Virally Associated HNSCC

Kathryn A. Gold, MD

Head and neck squamous cell carcinoma (HNSCC) consists of 2 biologically and clinically different diseases, according to Kathryn A. Gold, MD. The first of which is carcinogen induced, caused by tobacco or alcohol use, and the second being virally associated through the contraction of the human papilloma virus (HPV).

The recent rise in HPV has directly affected the increase in HNSCC cases, namely oropharyngeal cancer in men. Patients with HPV-positive present with a different set of prognostic factors and symptoms, says Gold, and should be treated with therapies that differ from those used in carcinogen-induced HNSCC.

OncLive: Can you provide an overview of your presentation on virally mediated head and neck cancer?

During her talk at the 2017 OncLive^® State of the Science Summit™ on Advanced HNSCC and Thyroid Cancer, Gold, a medical oncologist and associate professor of medicine at University of California, San Diego Heath, discussed HPV status and prognosis of these patients, as well recognizing risk factors of virally-associated HNSCC. In an interview during the meeting, Gold emphasized the need for differentiated treatment, as well as the realistic opportunity to prevent cancer through vaccination.Gold: In the clinic, we are increasingly recognizing that more of our patients are coming in without the traditional risk factors that we think of for head and neck cancer. Traditionally, we think of head and neck cancer as being a disease of older men and those with tobacco or alcohol exposure. Some of our younger patients do not have any of those exposures. It is becoming increasingly recognized that HPV is the cause of their head and neck cancer.

How should we approach HPV-positive patients differently?

This seems to be very clinically important. These patients are younger and healthier than our HPV-negative patients and the treatment outcomes do tend to be different, as well.We know that HPV-positive patients tend to have a better prognosis. If a patient who is HPV positive comes in with locally advanced disease, there is a good chance that I can cure their cancer. Right now, we are not using that as a factor to select treatment options, but we will in the future. As we learn more about this cancer, we may be able to dial back a little bit on the treatment for these patients and possibly spare them some of the long-term toxicities that we see with head and neck cancer therapy.

What are the clinical characteristics that are seen with this population?

Can you provide some insight into the treatment of HPV-related oropharyngeal cancer?

We now know that HPV is prognostic. For patients who come in with locally advanced disease, we typically treat them with chemoradiation—which are the vast majority of patients that I see in my clinic. Chemoradiation of HPV-negative cancer does not have great overall survival; it is only about 40% at 5 years. For HPV-positive cancer—especially nonsmokers—we cure about 85% of those patients so the prognosis is very different. Even for HPV-positive patients, smoking affects this rate. If a patient is HPV positive and they are a smoker, their outcome in a more intermediate category than those who have never smoked. The clinical characteristics that we see in someone coming in with an HPV-positive head and neck cancer, firstly, is that the primary site tends to be in the base of the tongue or tonsils, while HPV-negative disease is more likely to be found in the oral cavity, larynx, or hypopharynx. HPV-positive patients also tend to be younger than those who present with HPV-negative. They are usually male; it’s about a 3:1 ratio of men to women with HPV-positive head and neck cancer. Pathologically, these tumors are more likely to be differentiated, non-keratinizing carcinoma. Oropharyngeal cancer typically presents locally advanced, meaning with a large primary tumor—or more often, with lymph node metastases. The textbook treatment for these is to combine chemotherapy with radiation, specifically, intensity-modulated radiotherapy with high-dose cisplatin at 100 mg/m² every 3 weeks. That is our typical treatment, and it leads to good outcomes; however, we also know that it is very hard to tolerate. It can leave people with lifelong swallowing difficulties, dry mouth, and neuropathy. Obviously, if that is the only way to cure the cancer, than most people would say that it is worth it. However, our goal is to cure them with less intensive therapy.

What challenges have you observed with the HPV vaccination?

We are looking at newer approaches. Surgery, specifically robotic surgery, is being more frequently used for these patients. The idea is that we can clear out most of their disease and then perhaps they can get a lower radiation dose and spare chemotherapy afterwards. We are also looking at the possibility of using only radiation therapy. We know that chemotherapy is necessary for HPV-negative tumors; however, for HPV-positive disease, we may be able to get away with using less or no chemotherapy. There are a lot of clinical trials focusing on that right now.I am a strong proponent of vaccination. I have 2 children, and I can tell you as soon as they are old enough I will be dragging them to the pediatrician’s office to get them their shot because this presents a very real opportunity to prevent cancer. It has gotten more press for preventing cervical cancer, but we also believe it will prevent most cases of oropharyngeal cancer related to HPV, as well.

The side effects of the vaccine are pretty mild. A sore arm is the thing complained of most often; however, if you look on the internet, you can see a lot of websites alleging other bad things will happen. The science hasn't really borne that out. Hopefully, the HPV vaccine will put me out of a job and force me to learn something else in 20 years.

Unfortunately, the uptake has been low. Less than 30% of eligible people across the country get the vaccination. More girls than boys get it, but boys need to be vaccinated, too. It protects them not only against oropharyngeal cancer, but against genital warts, and possibly penile and anal cancer.

What would you like your main message to be about HPV-related head and neck cancer?

One of the reasons that this vaccine hasn't been taken up too much is that there is an association of HPV as a sexually transmitted disease. There is a fear that we are giving our children mixed messages by vaccinating them at a young age against a disease that is sexually transmitted. I can understand that complaint, but at the same time I would do everything that I can to protect my children from getting cancer, and I don't think the squeamishness about them one day becoming sexually active should factor into that. HNSCC is 2 entirely different diseases. Biologically and clinically, HPV-negative squamous cell carcinoma is a very different disease than HPV-positive squamous cell carcinoma. Therefore, clinical trials in the future need to differentiate between them.

For HPV-negative disease, we need to focus on intensifying therapy and trying to get better outcomes. In the recurrent and metastatic setting, we need to focus on targeting things like CDK4/6 and other pathways that are possibly involved in cell cycle regulation.

On the other hand, in the locally advanced setting of HPV-positive disease, we need to focus on de-intensifying therapy and trying to spare patients from toxicities. In the metastatic setting, the focus might be a bit different, as well. Immunotherapy might be even more important for HPV-positive disease. Although it is important for both groups, we may have different opportunities to target pathways, such as PI3K. There is also an opportunity to study therapeutic vaccines in this group.

The biggest thing moving forward is that we need to treat these cancers like the 2 entirely different diseases that they are, and not group them together just because, geographically, they occur in the same areas.