Virally Related Head and Neck Cancers: The Quiet Epidemic

Podcast Transcript

Dale Shepard, MD, PhD: Cancer Advances, a Cleveland Clinic podcast for medical professionals, exploring the latest, innovative research and clinical advances in the field of oncology. Thank you for joining us for another episode of Cancer Advances. I'm your host, Dr. Dale Shepard, a medical oncologist here at Cleveland Clinic overseeing our Taussig Phase I and Sarcoma Programs. Today, I'm happy to be joined by Dr. Eric Lamarre, a head and neck surgeon in the Cleveland Clinic Head and Neck Institute. Dr. Lamarre is here today to talk to us about HPV related head and neck cancers. Welcome Eric.

Eric Lamarre, MD: Thank you. And thank you for having me.

Dale Shepard, MD, PhD: Absolutely. Maybe to start out, tell us a little bit about your role here at Cleveland Clinic.

Eric Lamarre, MD: I'm the interim section head for head and neck oncologic surgery and reconstruction within the Head and Neck Institute at Cleveland Clinic. And so I'm a practicing surgeon and deal predominantly with cancers of the head and neck.

Dale Shepard, MD, PhD: Certainly what we're going to talk about today involves the head and neck and that's HPV related cancer. Maybe we have a very diverse group that might be listening in. Can you maybe give us a little bit of an overview of what HPV related head and neck cancers is all about?

Eric Lamarre, MD: I think this is a great topic because we're seeing almost an epidemic within malignancies of this type. The first thing to start off with is what type of anatomy we're dealing with. And so I think it's important to distinguish oral pharynx from oral cavity cancers. And so when we think about oral pharynx, it typically starts at the back portion of the oral cavity and so we encompass areas such as the base of tongue, tonsillar area, as well as the soft palate and the posterior pharynx. That's predominantly what we're talking about today. And that's in distinction from more of the mobile tongue and the palate, which we consider as the oral cavity.

Maybe about three or four decades ago, oropharyngeal cancers were largely associated with heavy tobacco and alcohol exposure. And so in the 1960s, smoking rates were somewhere on the order of 40% and with the assistance of public health education, it currently has fallen to about 20%. And so you would have expected kind of a concomitant decrement in oropharyngeal cancers associated with it. But in fact, we've seen a slight uptick of oropharyngeal cancers. And within the last two decades or so, we've started to appreciate that this has been largely related to HPV infections, so HPV derived oropharyngeal cancers. And associated with that, we've seen kind of a shift of demographics. And so the conventional HPV negative malignancy, which we now designate, which is more associated with heavy tobacco and alcohol use, tended to occur more in the 60 plus age range, affected both women and men and largely African-American males, more so than white males.

But what we've seen particularly in the last decade is kind of a shift in the demographics more towards 40 to 59 age range. It's this population, particularly white men, that we've seen an increase in oropharyngeal cancers. Almost say a 10% annual increase in incidence since the year 2000. And again, the principal etiology of what's thought to be responsible for this is human papilloma virus. As we all know, HPV transmission is primarily through sexual contact and oral genital contact, which can lead to oral and oral pharyngeal infection. And an overwhelming majority of HPV and related cases are related to the subtype HPV 16. Exposure to the human papilloma virus is exceedingly common with an estimated point prevalence of anywhere from 43 to 62%. And it's been extrapolated that there's a lifetime prevalence of any anatomic site infection being anywhere from 65 to a 100%.

Men are more likely to have an oral infection than women and it has to do with the density of virus within the genital mucosa for women and then factors that have shown to lead to this increased incidence, particularly in men, has been over the last few decades, perhaps a decrease in the age of sexual debut and an increase in the number of partners, which may have contributed to a rise in exposures.

The risk of infection also increases with the number of oral and sexual partners. The locations that we tend to see are more along a tonsil and base of tongue and just an annual incidence has been shown somewhere around 2.6 per 100,000 patients in the year 2005. And we've seen a 5% increase in the percentage rate. It's really shifted how we've thought about the disease process and really led for us to educate other clinicians in terms of differing presentations, because it's been a slightly different disease process than what we've conventionally seen with the tobacco and alcohol related oropharyngeal cancers.

Dale Shepard, MD, PhD: In terms of those differences, maybe you can let us know about the difference in sort of the biology and the what stage they may present at, the likelihood that they're less of a local tumor versus a metastatic disease. How is that different for HPV associated head and neck cancers compared to the traditional tobacco and alcohol related?

Eric Lamarre, MD: Yeah, so on a more molecular level, the HPV negative cancers are thought to be mediated through a lot of alterations in the p53 tumor suppressor gene. Whereas p16 is over expression is thought to be responsible for the pathophysiology of HPV mediated oropharyngeal cancers. Along with that, we tend to see a difference in terms of clinical presentation. Where HPV negative cancers you'll often find a prominent primary tumor that's in the base of tongue or tonsil or palate and then that's associated with nodal disease in the neck, HPV positive disease in contrast, will have very, very small primaries. And so it's hard to identify the tonsil or primary or the base of tongue primary and how they will typically present will be with nodal metastases.

And so the characteristic of the nodal metastases will oftentimes be cystic and that can lead to kind of a diagnostic dilemma at times, because fine needle aspirates will sometimes be equivocal and that will need to escalate in order to get a definitive diagnosis. In general, the presentation has changed, but not only that, but the treatment responses have actually been more favorable. But we use essentially identical treatment modalities or both and what we've seen is actually an improved local regional control if you do have an HPV mediated malignancy.

Dale Shepard, MD, PhD: You mentioned about the nodal presentation. Is part of this a lack of awareness by patients' primary care providers being aware that this may be developing rather than getting that big, bulky tumor that we saw in the past?

Eric Lamarre, MD: Yeah, I think there certainly has been a learning curve in the last decade or so. And I think it's become more understood now, but there still remains some education in terms of how this disease evolves. As I instruct my trainees, particularly in adults over 25 or so, a significant lump in the neck is cancer until proven otherwise. And so I think there were other benign cysts for example, like a brachial plexus that were initially misconstrued as being benign cysts when in fact they were metastatic nodal disease. And so that's been educational for the fields to really raise awareness amongst other clinicians, what a significant lymph node can represent in this disease process.

Dale Shepard, MD, PhD: Certainly there's the vaccine for HPV. And is it too early to be seen an impact on that vaccine in the patients that are showing up in your clinics? Or has there been a difference at this point?

Eric Lamarre, MD: Yeah, absolutely. I think your first point is right on in that the vaccine itself has only been approved since 2006 and so the time span from the infection of the HPV to evolution to a cancer is thought to be decade, even longer than that. It remains to be determined what the impact will be with respect to the vaccine. But I think another issue makes it a little bit more challenging in that the compliance rates for the vaccine are actually not ideal. When you look at the teens, for example. The vaccine is indicated for as early as nine, but typically recommended 11 to 12 with the vaccine and then subsequently a vaccine six to 12 months after that. When you look at compliance rates, it's anywhere on the order of 60% of receiving one dose and almost 45% of having both doses. And so when scientists looked at what it would take for kind of a community immunity, it's on the order of 80%. Those rates are well below that. It's not only that the infection precedes evolution to a cancer, but it's also I think we're still struggling with optimizing compliance rates.

Dale Shepard, MD, PhD: And then the initial focus was on vaccination of girls but then can you weigh in on sort of the vaccination of boys as well?

Eric Lamarre, MD: Yeah, I think the initial indication was for females and that was a kind of a bivalent vaccine and then Gardasil, which is a quadrivalent, or there's actually nine different targets that Gardasil now has, is now FDA approved for both. And so the age range is anywhere from nine to 26 where it's recommended. And then beyond that, it's at the discretion of the doctor in conjunction with the patient up to 45 years old. But certainly I think that led to initial perhaps misperception of the virus itself. But I think public health information has started to say that this is equally important for males as it is for females.

Dale Shepard, MD, PhD: All right. It sounds like vaccinating males and females and just getting the vaccine is going to be an important continued push. If we shift gears a little bit, maybe you can talk to us a little bit about what are the treatment options? What does treatment of this look like?

Eric Lamarre, MD: We use the three conventional modalities, surgery, radiation and chemotherapy in varying combinations. For early stage cancers and it's interesting, when we talk about staging, the staging system has evolved in 2018 and it has made a separate designation for HPV related malignancy. Not to say that it changes how we address the cancer from a treatment standpoint, but we've recognized it as a distinct disease process, which has historically had better response rates to our conventional treatments. I'll kind of take you through the evolution in terms of treatments initially.

I would say a couple of decades ago, surgery was part of the mainstay. This was before the 1990s or so, but it was quite morbid. It would require a mandibulotomy and very extensive. Would affect swallowing and quite a morbid operation. And that was initially followed by radiation. But then with the onset of other sites within the head and neck, such as the larynx, we saw the utility of organ preservation trials and that's in the way of concurrent treatment. That was combined cisplatin with radiation and that data served as kind of a focal point that was extrapolated to the oropharynx. And so then we started to employ them for base of tongue and tonsil cancers. And that's where we were in the kind of the beginning of 2000 or so.

And then somewhere around 2009, the FDA approved transoral robotic surgery. That's brought surgery back into the forefront a little bit and that's been the topic of a clinical trial presently. That's the general shift in paradigm. I would say we generally treat early stage oropharyngeal cancers with radiation alone or surgery alone and that's done robotically and then kind of advanced stage is treated with concomitant chemoradiation or you can use surgery and we're trying to tease out what that role will be in HPV related disease through a surgical clinical trial.

Dale Shepard, MD, PhD: And so you mentioned the clinical trial and you mentioned robotics. Is the robotic surgery just to clarify, is that only through a trial mechanism at this point? Or is that also into some elements of standard of care?

Eric Lamarre, MD: It is within standard of care at present. Transoral robotic is FDA approved for tonsillar malignancies and base of tongue malignancies.

Dale Shepard, MD, PhD: And specifically in HPV as well?

Eric Lamarre, MD: Yep. Yes, but where the clinical trial is involved is to see how those patients are risk stratified afterwards. To determine a low risk, intermediate risk and high risk and looking at what adjuvant treatments are necessary afterwards.

Dale Shepard, MD, PhD: And I guess speaking of adjuvant therapies, you mentioned the differences in terms of nodal presentation, oftentimes. Is what is the change in terms of adjuvant therapies at this point?

Eric Lamarre, MD: We've used cisplatin in terms of the chemotherapy for years and that still is widely used. Other clinical trials have looked at cituximab in comparison to cisplatin. Radiation therapy has evolved. Initially we were doing the external beam and certainly IMRT has really refined treatment and made it a lot more focal. And so those are commonly used adjuvant treatments, but where it becomes kind of interesting is what I'll give you an example. What has been widely viewed in head and neck cancer is the notion that when a lymph node has a cancer that spreads outside of the lymph node, we commonly employ chemotherapy in an adjuvant setting in conjunction with radiation therapy. And those results have been extrapolated to HPV positive related malignancies, but we're starting to maybe recognize that that doesn't have as much import for HPV related malignancies. That's been the topic of some clinical trials moving forward and be curious to see how that evolves in comparison to the more conventional HPV negative related head and neck malignancies.

Dale Shepard, MD, PhD: What about screening? What kind of efforts are underway in terms of trying to find this at an early stage?

Eric Lamarre, MD: That's where a lot of work remains to be done, I believe. There is no recommended screening as of this time. I think it would have been nice to have something comparable to screen for cervical cancers like pap smears, but the challenge within HPV oropharyngeal infections is just infection itself doesn't necessarily imply causality. And so you could have the infection cleared away and as I mentioned before, the incidence of infections are very high. And so we haven't really identified a test that is truly indicative of a malignancy to initiate screening. Another point is cervical cancers tend to go through a whole series of molecular and pathologic changes where they'll start from a dysplasia and evolve to frank carcinoma. And we haven't quite identified a corollary in the oropharynx to go along with that. If we were to do that, I think it would perhaps lead to similar screening mechanisms that are used in cervical cancers, but such a change has not been identified thus far.

Dale Shepard, MD, PhD: To the physicians that are listening to the podcast, what type of patients should be considered for a referral to the Cleveland Clinic for evaluation?

Eric Lamarre, MD: I would say particularly males, but also females that are 40 and above. And I've seen them even earlier than 40, but 40 and above with a persistent neck mass that has been present for at least a few weeks. And so that's the typical patient that we see. They may not necessarily have other risk factors such as tobacco use or alcohol use. And so those patients really need to see us for a biopsy and or appropriate workup otherwise.

As I mentioned beforehand, the fact that these HPV related cancers have small primaries, it's hard to detect them from the standpoint of where their initial tumor has arisen from. That tends to be less symptomatic, but if it were to progress, that is to say that if the base of tongue cancers or the tonsil cancers were enlarged, you may have some issues with swallowing that could be subtle or drastic. When you look at someone's tonsils, you may have asymmetric tonsil, which sometimes could be indicative of a malignancy. And so those are tips that I instruct my residents to keep an eye on and also discuss with clinicians in the community.

Dale Shepard, MD, PhD: This is certainly a potentially serious disease. You mentioned early that the incidence is increasing, what are the biggest gaps?

Eric Lamarre, MD: I think the one gap we've spent a bit time addressing is education to clinicians that initially what was perceived as a brachial plexus could be more concerning in a patient that we conventionally did not think of being at risk for malignancy. There's also the gap in vaccines. I think that has the potential for mitigating risk of this in the future and just a continued generalized education for both medical professionals, as well as community on the importance of preventative measures and vaccination measures for HPV and how it could lead to oropharyngeal cancers.

Dale Shepard, MD, PhD: Well, I thank you for your insight on this really important disease, Eric, and I appreciate you being with us today.

Eric Lamarre, MD: Thank you for your time. I appreciate the opportunity.

Dale Shepard, MD, PhD: This concludes this episode of Cancer Advances. You will find additional podcast episodes on our website, clevelandclinic.org/canceradvancespodcast. Subscribe to the podcast on iTunes, Google Play, Spotify, SoundCloud or wherever you listen to podcasts. And don't forget you can access real time updates from Cleveland Clinic's Cancer Center experts on our Consult QD website at consultqd.clevelandclinic.org/cancer. Thank you for listening. Please join us again soon.