Melanie Cole, MS (Host): Welcome to Better Edge, a Northwestern Medicine podcast for physicians. I'm Melanie Cole, and joining me today to talk about the changing epidemiology of oral cavity cancer is Dr. Katelyn Stepan. She's an Assistant Professor of Otolaryngology, Head and Neck Surgery at Northwestern Medicine. Dr. Stepan, it's a pleasure to have you join us today, and I'd like you to start by providing a bit of an overview of significant changes in the incidence and prevalence of oral cavity cancer in recent years. How has that landscape changed over the course of your career?

Katelyn Stepan, MD: Sure. Well, thank you so much for having me. So over time, we've seen a decline in tobacco-associated cancers, including oral cavity cancers as a whole. And just to clarify, you know, when we're talking about oral cavity cancer, we're referring to the specific anatomic subsites. So, that includes the lip, anterior two-thirds of the tongue, floor of mouth, buccal mucosa, gums or gingiva, hard palate, and retromolar trigone. Thinking about all of these subsites that comprise the oral cavity, while we've seen an overall decrease in the incidence of oral cavity cancer over the past several decades, the rates of oral tongue cancer specifically are increasing. In particular, previous studies have found those rates to be increasing among younger patients and women, and many without traditional factors such as alcohol or tobacco use. However, more recent data, including a study we just very recently published utilizing the U.S. Cancer Statistics Public Use Database, which captures 97% of newly diagnosed cancers, suggests that the rates of oral tongue cancer categorically are actually increasing among both men and women across all ages. And furthermore, we are really predominantly seeing this increase among white patients and not across other races or ethnicities. And so while this trend is not entirely universal, this increasing incidence of oral tongue cancer is not isolated to the U.S., but is actually being seen in several areas across the globe.

Melanie Cole, MS: That's fascinating. I'd like you to speak about the changes in the prevalence of HPV-related oral cavity cancer and how that relates to the non-HPV-related cases. But before we get to that, and these might coincide these questions to what do you attribute this rise in tongue cancer globally?

Katelyn Stepan, MD: Yeah. So, in this instance, specifically talking about oral tongue cancer, which is that anterior two-thirds of the tongue, traditionally the predominant risk factors have included heavy alcohol use, smoking or tobacco, including smokeless tobacco, as well as things like betel nut use. However, the recent rise in oral tongue cancer is unlikely to be related to tobacco and alcohol, given declines in consumption across the U.S. population. So as you can imagine, this is a very active area of investigation in terms of figuring out what's causing this rise in oral tongue cancer.

At this point, unfortunately, we don't really have any clear answers. It's hypothesized that a combination of genetic predisposition and environmental exposures may portend a higher risk for these patients. And the genetic or molecular landscape of these tumors is being investigated. You know, and we talk about, and I think we'll talk more about this, but HPV has been associated with base of tongue or that posterior one third of the tongue cancers arising there. But several studies have looked at the role of HPV, as well as many other viruses in oral tongue cancer, and there really just has not been found to be a clear association.

So, there is some thought that things such as the oral microbiome may play a role. There's also speculation regarding things such as dental trauma or hardware that could play some role in development of these oral tongue cancers, but these are still areas that are being looked into.

Melanie Cole, MS: Wow, that's so interesting. So now, expand a little on the HPV-related oral cancers. Speak about what you're seeing with those and the trends.

Katelyn Stepan, MD: Sure. So as I mentioned, you know, HPV has no significant etiologic role in oral cavity or oral tongue cancer, meaning the anterior two-thirds of the tongue. However, HPV does play a very large role in oropharynx cancer or those cancers involving the tonsils or base of tongue, meaning that posterior one-third of the tongue. And so, again, we've seen that despite decreases in tobacco use, rates of oropharyngeal cancer have been rising. And this is very largely due to HPV-related disease. So, in the United States and some other Western countries, the majority of oropharyngeal cancers are now believed to be HPV-related, estimated to be around 70-80% of oropharyngeal squamous cell carcinoma. Generally speaking, HPV-related oropharynx cancer has a better prognosis and tends to do better overall than those cases not related to HPV.

Melanie Cole, MS: So, as we look at the continuum of screening and diagnostic criteria, and we think of HPV and these other risk factors that you've mentioned, speak about screening and any advances that are going that might impact early diagnosis rate. Because now, I mean, obviously, we've got Gardasil, we've got things, more awareness of HPV. However, as you see, some of these rates coincide with each other. Speak about what we're doing now with screening for this.

Katelyn Stepan, MD: Sure. I think one really exciting new area is that we have a blood test that's now available that is able to detect circulating tumor or HPV DNA in a patient's blood. This is, you know, of course, specific to HPV-related disease. We have currently, at least here at Northwestern, now integrated this into our surveillance protocol with evidence suggesting that this can help us catch any cancer recurrences earlier than we would otherwise typically be able to do clinically. But as you can imagine, I think this has great promise in the future for utility as a screening tool. And we're still kind of working I think on some of that data and how that would kind of be implemented in an efficacious way.

Melanie Cole, MS: Where do dentists fit into this screening?

Katelyn Stepan, MD: Great question. I will say, practically speaking, I think one of the most important aspects of screening is simply routine followup with your dentist. So, seeing a dentist every six months ensures that you're getting a regular oral cavity exam and can certainly contribute to catching some worrisome changes early on. I get a lot of referrals for oral cavity lesions from dentists and I'll say many times, you know, a dentist is really the first line provider that recognizes something small and worrisome in a patient's mouth. And if we're able to catch those early, you know, in general, they're very treatable. And so, that gives us a huge advantage.

You know, there are other things on the horizon, but that haven't really been routinely implemented into our practice, but could potentially show promise in the future. These are things like salivary biomarkers, or looking for specific molecular and genetic changes associated with cancer that can be detected in a patient's saliva. There are things like optical imaging technologies, such as narrow-band imaging and fluorescence imaging, which could allow for better visualization or abnormalities in the oral cavity. And so, as I said, you know, these aren't routinely performed yet in our practice, but could be exciting things to look for in the future.

Melanie Cole, MS: What about exciting changes in the treatment landscape that have impacted the epidemiology? Because this is challenging and unique, these cancers. And they have some possible devastating effects for patients that have advanced cancers of these types. So, speak about some of the treatments that you're seeing and what's exciting in your field right now.

Katelyn Stepan, MD: Yeah, absolutely. So, I would say, regarding oropharynx cancer, I think one of the most exciting advancements is the HPV vaccine. And recognizing its relationship to oropharynx cancer and routine HPV vaccination is now recommended in the U.S. for all adolescents at the age of 11 to 12 years old. It can even be done as early as nine years old. And in the U.S., the HPV vaccine is approved through age 45, I believe. So hopefully, you know, in future generations, if we're really able to implement this across that younger population, I mean, you could imagine that could hopefully nearly eradicate the disease down the line.

 Specifically regarding HPV-related disease, there have been a number of clinical trials looking at de-escalation therapy for HPV-related disease. So, in specific instances, of course, on a case by case basis, we're able to offer lower doses of adjuvant radiation or even forego, you know, chemotherapy based on some promising relatively new clinical trial data from ECOG 3311. And as you can imagine, this is associated with decreased toxicity and side effects that come with that treatment.

Melanie Cole, MS: It's a pretty exciting time in your field, Dr. Stepan. Discuss for us the importance of having a robust care team when treating oral cavity cancers and the introduction of therapy involvement of multiple subspecialists. Speak a little bit about that multidisciplinary approach.

Katelyn Stepan, MD: Yeah, absolutely. I think multidisciplinary care of these cancer cases is really so critical to achieving the best long-term outcome in terms of both disease control and long-term function. As part of that team, the surgical oncology team, the radiation oncology team, and the medical oncology team, really, it's important to kind of get everyone involved early on, and then typically continue to follow the patient through the course of their treatment and beyond for surveillance.

Additionally, things like, you know, setting patients up with early swallow therapy and physical therapy, lymphedema therapy, things like that really help us optimize our functional outcomes. And in an age where we do have exciting advances in clinical trials on the horizon, you know, having that multidisciplinary approach really allows us to make sure that we are capturing all the opportunities available for any given patient and making sure they have access to that.

Melanie Cole, MS: This is a really interesting topic and it's been a great discussion. Dr. Stepan, as we wrap up, any research or clinical trials that are on the horizon for future research in this field? Where do you see it going in the next 10 or 20 years? Give us a little blueprint.

Katelyn Stepan, MD: Sure. Well, I will say there are a couple of exciting trials that we have open here currently. As a lot of people know, involved in clinical trials, you know, to get really meaningful answers, these things take a long time just to ensure the integrity of the data and the followup and everything like that.

 One of these is for oral cavity cancer regarding sentinel lymph node biopsies. And sentinel lymph node biopsies are an accepted alternative to elective neck dissection, that are actually in our NCCN treatment guidelines for early stage T1 or T2 disease in those with a clinically node-negative neck. However, we currently don't have any phase III data to compare the two treatments. And so HN006, a trial we have open here, is an international multi institutional phase II/III prospective trial looking at sentinel lymph node biopsies compared to elective neck dissections in this population. So, I think this is a really exciting area that anyone who treats oral cavity will be really, you know, eager to see these results and how that changes care down the line.

Additionally, for HPV-related oropharynx cancer, we have a trial open called the SELECT trial. This is a phase III randomized controlled trial looking at SPECT-CT-guided elective contralateral neck treatment for patients with lateralized oropharyngeal cancer. So, essentially, we're seeing if we can use lymphatic mapping pretreatment to avoid contralateral neck radiation in certain patients who have a clinically node-negative contralateral neck disease. And this is where the current paradigm is to treat bilateral necks. So again, this is just really exciting kind of in that de-escalation realm for HPV-specific disease. This is again one of those questions that I think we all grapple with as providers, you know, surgical oncologists, medical oncologists, and radiation oncologists, and understanding these outcomes will not only help us understand the disease better, but treat patients more specifically and hopefully with the long term goal of, you know, giving them sufficient treatment to obtain the disease control that we want, but really minimizing those side effects associated with treatment.

Melanie Cole, MS: Thank you so much, Dr. Stepan, for joining us and telling us really the exciting things going on in your field and future research. Thank you again. To refer your patient or for more information, please visit our website at breakthroughsforphysicians.nm.org/ent to get connected with one of our providers. That concludes this episode of Better Edge, a Northwestern Medicine podcast for physicians. Please always remember to subscribe, rate, and review this podcast and all the other Northwestern Medicine podcasts. I'm Melanie Cole. Thanks so much for joining us today.