BackTable / ENT / Podcast / Transcript #172

Podcast Transcript: HPV & Oropharyngeal Cancer: Evolving Insights & Implications

with Dr. Mihir Patel

In this episode, Dr. Mihir Patel, Professor of Otolaryngology at Emory University and expert in Transoral Robotic Surgery (TORS), discusses HPV-positive head and neck cancer with host Dr. Ashley Agan. You can read the full transcript below and listen to this episode here on BackTable.com.

(1) Dr. Mihir Patel's Journey from the Classroom to the Operating Room

(2) The HPV and Head & Neck Cancer Epidemic

(3) Primary Tumor Sites & Clinical Presentation of Oropharyngeal HPV

(4) Detecting & Diagnosing HPV Oropharyngeal Cancer with ctDNA, Narrow-Band Imaging & TORS

(5) Targeted Approaches to Identifying & Treating Unknown Primary HPV Cancers

(6) Managing Patients with Primary HPV Oropharyngeal Cancers Post-Surgery: cTDNA Biomarkers & Radiation Therapy

(7) Immunotherapy in HPV Head & Neck Cancer

(8) Counseling Head & Neck Cancer Patients on HPV: Transmission, Vaccine, and Surveillance

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Ep 172 HPV & Oropharyngeal Cancer: Evolving Insights & Implications with Dr. Mihir Patel

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[Dr. Ashley Agan]
Hi, everybody. Welcome to the BackTable ENT podcast. We're a podcast that focuses on all things otolaryngology and we've got a really great show for you today. Thanks for stopping by. I'll be your host today. My name is Ashley Agan. I am a general ENT, and today we're going to talk about oropharyngeal squamous cell carcinoma. Here with me to dive in deep on this topic, we have Dr. Mihir Patel. Welcome to the show, Mihir.

[Dr. Mihir Patel]
Thanks for having me. It's just an honor and pleasure to be here.

[Dr. Ashley Agan]
Oh, thank you. Let me give you a proper introduction for our guests who don't already know you. Dr. Mihir Patel is a professor in the Department of Otolaryngology at Emory University School of Medicine, and is the co-director of the Head and Neck Clinical Trials Working Group at Winship Cancer Institute. He specializes in transoral robotic surgery, also known as TORS. Welcome to the show, Mihir. Before we get started, we always like to toss it over to you to tell us about yourself and your background, and your practice specialty.

(1) Dr. Mihir Patel's Journey from the Classroom to the Operating Room

[Dr. Mihir Patel]
Sure. Before I got into medicine, interestingly, I was a teacher in Brooklyn. Brooklyn was a very different place then, and I would say it was more inner city. My students and a couple of coworkers that had been there for many years in that community in Bushwick, where I taught, inspired me to be present, to be in the moment, to be accountable in a different way that I was really used to.

I'll say that they taught me about loyalty and commitment and integrity in a way that was really critical for me in my life in my early 20s. That's what actually reinvigorated me to go to medical school. I went back to North Carolina, and it's where I grew up, and attended UNC for medical school and residency training. I think the rest was history after that.

[Dr. Ashley Agan]
Yes, that's amazing. When you were teaching, did you know you would eventually go to medical school, or was it in that environment that you were inspired to go do medicine?

[Dr. Mihir Patel]
It was really in that environment. I think it was the opportunity where I just saw what it took to build a community and how much pride my students had in their families and themselves and in their community with really not much in the way of resources. That was really phenomenal for me to see.

That's probably what led me to think, "Oh, maybe there's more that I can do." The great thing about academic medicine, as you can imagine, which is a type of practice I'm in now, is you get to teach, you get to build teams, build community. It really just fits right in with my daily passion, speaks to me very much.

[Dr. Ashley Agan]
Yes, that's beautiful. It sounds like a really nice practice environment. Your expertise is in head and neck cancer, specifically transoral robotic surgery. Tell me more about that. How did you find your way into that specifically?

[Dr. Mihir Patel]
Yes, that's a pretty funny story here, actually. What happened was I did not think-- I had my mindset on a particular fellowship, actually, at the time. Then I went to Penn. I just remember going there during interviews, and I just witnessed a robotic case. That was part of the process. It was early 2012, maybe, so this was early when TORS was slowly taking off. I was just impressed by the efficiency, and I was enamored by the technology.

At that point in time, I just knew that this is where I wanted to be. I remember coming home and talking to my wife about it and saying, "This is going to be something." Who knew? The way our practice is now, most of what I treat is head and neck cancer. Almost all of what I treat is head and neck cancer, and it's mostly squamous cell cancer. The way our team is set up is we just have an incredible team. Within that, we're subspecialized, and I just happen to be one of those that is focused on TORS.

[Dr. Ashley Agan]
I remember the first time I got to sit in that robot console. The optics, you really feel like it's a whole other dimension of surgery. I can imagine that being pretty memorable. Today we're going to dive in specifically to speak on HPV-related oropharyngeal cancer. Maybe just set the stage for us as far as HPV and its role in head and neck cancer prevalence, that sort of thing.

(2) The HPV and Head & Neck Cancer Epidemic

[Dr. Mihir Patel]
Today, HPV oropharynx cancers, that's what we see the most in terms of our mix of head and neck subsites or sites. More than oral cavity, more than larynx. I remember as a PGY2, so about 20 years ago, Maura Gillison, who is one of the clinicians credited for linking the association of HPV to squam cell cancers, which at the time were considered stage 4 cancers, she linked that to the human papillomavirus. The reason she was invited to speak was actually in the School of Public Health at Chapel Hill.

I just remember that there were only about 10 people there. There were very few I know. I just remember thinking of how incredible her research was and the fact that she was persistent and made these observations. This critically and ultimately changed and led to awareness of how people are even vaccinated today. What I'm getting at is what she noted was that these patients were younger, 55, 60-year-olds. They were mostly white males, no smoking history.

We know that's the most common risk for head and neck cancers. A lot of them were graduates of college, well-educated. She noted that many of them had more than five intimate lifetime partners throughout their life. That is how all of this transpired. That's what we see today. It has just taken off as an epidemic in some way or form, if you want to think about it. Because in 2018, the incidence of HPV-driven cancers in men surpassed HPV-driven cancers in women. It was primarily driven by oropharynx cancers. Yes.

[Dr. Ashley Agan]
Meaning that HPV-associated cancers, now the most common site would be in the oropharynx and not the cervix. That's what you mean by that.

[Dr. Mihir Patel]
Exactly.

[Dr. Ashley Agan]
That's pretty mind-blowing. Even myself, like when I think HPV, like I think that association with cervical cancer happens sometimes, as the bigger heading. Oropharynx cancer is the big one now. Is that because we don't have a way to screen for it the way they do in the cervix? Is the incidence just really growing? We don't know?

[Dr. Mihir Patel]
It's multifactorial. That's a great question. There's pretty good research to show that a number of these patients have HPV antibodies many years before they actually develop cancer. We're talking about infections from years ago that likely have developed. What makes this tricky is that it is very difficult to screen the tonsil area. More than 90% of the people in the population have had an HPV infection at some point in time. Only a few of them cause cancer out of the hundreds of types or over 100 types of HPV subtypes, only about 12 of them can cause cancer.

How do you screen for all those people? That's what makes it tough. There are some very interesting liquid biopsies coming down the road, ways to think about possibly screening. At one time, people were looking at swabs to try and do that, but that also is very difficult. The swabs are similar to what you would do for strep throat. The reason that's difficult is when the cancer develops, it develops not on the surface of the tonsil, but near the bottom of the tonsil or the deep part of the tonsil.

[Dr. Ashley Agan]
It's tucked in there. As far as the pathophysiology, the thought is, and update me because it's been a little while since I've gone down that road. The patients, as you mentioned, over 90% of the population has had an HPV infection, have been exposed to the virus, but their immune system has cleared it. Potentially there's a subset of patients who are keeping it at bay, but it's not totally cleared. Then something happens over time and it rears up.

[Dr. Mihir Patel]
That's exactly right. I couldn't have said any better. That's what happens. Essentially, let's just call it a chronic infection that integrates-- or in the way I tell patients or talk to patients about, I basically say, "Well, the virus is just trying to replicate. It's trying to create more of itself. It gets into that tonsil. Then all of a sudden it is now replicating squamous cells." That is essentially what happens.

[Dr. Ashley Agan]
We don't necessarily know what the trigger changeover point is, right?

[Dr. Mihir Patel]
Not yet.

[Dr. Ashley Agan]
Yes. Working on it.

[Dr. Mihir Patel]
Working on it. There's some really interesting science behind that. I remember asking our collaborators. We, again, because we're at the academic center, we have a number of collaborators. One is Rafi Ahmed at the Vaccine Center, and Andreas Wieland who was there at the time, right now is at Ohio State. I asked them this question. It's like, "You don't want to figure this out? You still haven't."

(3) Primary Tumor Sites & Clinical Presentation of Oropharyngeal HPV

[Dr. Ashley Agan]
That probably means there's more than one thing that's happening. It's just too hard to pin it on one culprit. The HPV squamous cell cancers are usually in the tonsils or base of the tongue. Oropharynx is that primary subsite. Why is that the primary site and not larynx or hypopharynx or somewhere else in the head and neck?

[Dr. Mihir Patel]
This was a source of debate for some time because there were times when cancers from the tongue or the larynx were removed and they have p16 positivity, which was considered at that time, a circuit marker for HPV. If you ask HPV researchers, they're going to say, "It can't just be p16 positive. We need to know that there's HPV DNA in that specimen and we need to look at in situ hybridization." There's got to be really three ways to look at it to determine if it's truly HPV driven.

When you distill it down, we've come to realize that there's just something about the tonsil and the tongue base, specifically that histologically they're different. They are lymphoid tissue. Primarily it's an immune-rich environment where you would think a virus would like to be. What causes all of the quick spread, so to speak, is that there's really no basement membrane in those areas. That's why we often see a small cancer there, but that's not how they're noticed.

[Dr. Ashley Agan]
Yes, which is a good segue into the typical presentation for these patients.

[Dr. Mihir Patel]
Uniformly, I feel like it happens after some stressful one, whatever it may be, "Oh, I was going through some business thing or closing," or, "I was sick for a little bit and all of a sudden I had this node that I noticed in my neck when I was shaving." Got some antibiotics for a little bit because you thought it might be an infection, got a CT scan, got a fine needle aspiration of that node, and I can't believe I have cancer. That's usually what I hear.

[Dr. Ashley Agan]
That's where you probably meet patients most of the time since you're the tertiary referral center.

[Dr. Mihir Patel]
Yes. That's exactly when I see them. It's at that point and then results in a long discussion about treatment and treatment options and what to do next.

[Dr. Ashley Agan]
Finding the primary, which I guess is a good moment to pause and talk about the unknown primary, which I think was more common in the past. Now the situations that end up where there's truly an unknown is a lot less common because we're able to find it is my experience. I don't know. Tell me what your thoughts are.

[Dr. Mihir Patel]
Yes. This is really been a big interest of mine. I think it started essentially-- well, the unknown primaries always existed even if you go back a hundred years to Hayes Martin. The reasoning and the difference it was-- the reason why it was unknown is because they didn't have the technology optics. They didn't have scopes in the same way that we do now. Now the unknown primary is because they actually are really small. Now as we've gotten a better understanding of HPV and how it resides and where it goes, we are better at finding them.

Part of that, to be honest, is just using a protocol, whatever it is that you have to identify it. It takes a couple of things that helps me in my mind understand the unknown primary. One, you've got to know that you're dealing with an HPV cancer, and usually clinically there are a lot of things that help you determine that. Before p16 was sometimes positive, sometimes not. Clinically, you still have to really look at the patient and say, "Okay, is this someone who's likely to have an HPV-driven cancer?" That's one of the things that I would always think about in my mind.

The second thing that's new now is that we can actually do a liquid biopsy and get circulating tumor HPV DNA. If that's positive, that is highly sensitive and highly specific for knowing that you've got an HPV-driven cancer. Then I talk to patients and I tell them, "Look, this is likely in your tonsil or your tongue base, and we are going to do a real-time investigation to try and find it." That's where TORS has really helped. It's really helped us deescalate therapy for these patients and that's where I also tell them. We're not going to have to radiate your entire throat to try and treat this.

What we're going to do is we're going to take out the tonsil. We're going to go look at it at pathology, and if pathology sees it then we will clear the margins. If not, we'll transition to removing the tonsil off the back of your tongue or the tongue base. If we see it, clear the margin. If we don't see it, I don't want you to be disconcerted because the chance of it coming back is very low. In our series, we haven't seen that happen yet. Now because they present with a neck node, the majority of these patients are going to get radiation. In fact, all of them do.

Because of the size of the lymph node or there tends to be multiple lymph nodes, we also remove those at the time of surgery. They've gotten completed treatment for what we call an unknown primary. The nice thing now is you can also get a circulating tumor DNA level after surgery. If it goes to non-detectable, that's another way of telling the patient, "Look, I believe we have cleared this surgically and now we need to continue with our standard of care postoperative radiation treatment."

(4) Detecting & Diagnosing HPV Oropharyngeal Cancer with ctDNA, Narrow-Band Imaging & TORS

[Dr. Ashley Agan]
Yes, that ctDNA, I feel like that's newer. I don't remember us having that when I was in training. Can you talk about that just a little bit more?

[Dr. Mihir Patel]
Absolutely. Their ctDNA is essentially what happens is that the tumor is shedding in the bloodstream and HPV has tagged it. We can look at specific sequences to determine that it's an HPV-driven cancer. Essentially that's what's being done. It's taking pieces of tumor that have been released into the bloodstream, and identifying and linking that to HPV virus. This isn't uncommon. There are other cancer diseases that do this, including lymph colon cancer. I think they're working on this in lung cancer. We are a few steps behind, but we're there and it's emerging.

[Dr. Ashley Agan]
Would that ctDNA look the same for someone who has HPV cervical cancer?

[Dr. Mihir Patel]
It does work for cervical and anal cancer as well.

[Dr. Ashley Agan]
If a patient had a co-occurring cervical or anal cancer that was HPV, that could also make that positive. It's not specific for the site. It's just specific for HPV.

[Dr. Mihir Patel]
Exactly.

[Dr. Ashley Agan]
The patient that presents to you with the new neck mass, they all get the ctDNA up front.

[Dr. Mihir Patel]
Yes.

[Dr. Ashley Agan]
If it's an HPV-associated cancer, that'll be positive. That helps you know as you're going in, if you're looking for the primary, you have a good sense that this is going to be in the tonsil or base of tongue.

[Dr. Mihir Patel]
Yes. Because, before this test, p16-positive cancers that were a large neck node could also be a skin cancer. About 20 to 30% of skin cancers will be p16 positive.

[Dr. Ashley Agan]
Patients usually come in with a CT, as you mentioned. As far as further workup, do you also get PET scans?

[Dr. Mihir Patel]
That's our standard. We do.

[Dr. Ashley Agan]
Everybody gets a PET. How often are you finding the primary on PET?

[Dr. Mihir Patel]
That's a great question. When you think about the algorithm on this, there was a recent study that looked at this with a meta-analysis. Looking at how often you can identify the tumor, and the different modalities of tests that we can use to help us identify it. A CT scan will find the cancer, let's say the primary specific, about 23% of the time in a PET scan on the order of 40 to 50%.

If you take a patient for a direct laryngoscopy and biopsy, you can increase that to about 55 to maybe 60%. Now if it's a true unknown and you have no idea of where it is after all these imaging modalities, using TORs can help increase that from 50 to 60 to potentially 70, 80, 85. I think most institutions report about 80 to 85% identification rate, which is really remarkable when you think about it.

[Dr. Ashley Agan]
Because it used to be so much lower?

[Dr. Mihir Patel]
Because it used to be so much lower, and then what it really does is it changes the treatment options for those patients. Even if that patient doesn't have full-on surgery, and even if they go to chemotherapy and radiation, our radiation oncology colleagues can really limit the volume and target where the cancer was actually identified rather than trying to treat the other lingual tonsils or palatine tonsils.

[Dr. Ashley Agan]
I think that's worth expanding on because there's some patients that stand out in my mind who were treated for an unknown primary maybe 20 years ago. The radiation morbidity, like their treatment morbidity is significant. The two that come to mind both have non-functioning larynx, can't really swallow. It's really significant if you can't find where that primary tumor is. I'm sure you can speak to how the radiation protocols have changed, but I think in the past the thought was everything from the nasopharynx down to the larynx needs to be just blasted.

[Dr. Mihir Patel]
That's exactly how it was in the early 2000s. Those were the patients that we see with dysfunctional larynx. Then as the association of HPV was linked to this cancer, then for the most part, most radiation oncologists will tell you that they are going to radiate the tongue base, the tonsil, and the retropharyngeal nodal basin. When you think about that, that's still a lot of the oropharynx for what in reality is likely a T1 cancer. There are some places that may just treat the neck low, but there are fewer far between.

[Dr. Ashley Agan]
Wow. Just not treat the primary side, just treat the neck and then just wait and see kind of thing?

[Dr. Mihir Patel]
That's right. Again, this was done back at MD Anderson. If you look at some of the literature from the '80s. This was one option that was presented at the time as a treatment algorithm for unknown primary. Again those were typical squamous cell cancers, smokers. In this setting, when you think about it, when you are delivering radiation intensity to the neck, let's say 70 or 60 gray.

There is going to be some radiation that does get to the tonsil and tongue base anyway. Maybe it's 50 gray, maybe it's 60 gray, just depends on the initial intensity to the neck. That could potentially treat that. There are some doses that have been experimented with to see if they could treat that initial primary and the neck. It's gotten as low to 36 gray depending on the situation.

[Dr. Ashley Agan]
For the primary?

[Dr. Mihir Patel]
For all of it.

[Dr. Ashley Agan]
For all of it?

[Dr. Mihir Patel]
For all of it.

[Dr. Ashley Agan]
As primary treatment or as adjuvant?

[Dr. Mihir Patel]
As primary treatment.

[Dr. Ashley Agan]
Okay. Interesting. In thinking about the patient that presents with the neck mass, it seems, and an unknown primary, maybe you've gotten the CT and the PET and it's not quite obvious where the primary is. The tonsils like to light up on PET scans incidentally all the time. We see patients who've gotten their PET scan for their melanoma or something else.

They just end up in your office to have things checked out because things are lighting up in the oropharynx. Are there other things you do during your exam to try to help you get an idea of where you're going in your TORS case, looking for areas that might be suspicious, helping you figure out where to target your biopsies?

[Dr. Mihir Patel]
That is really a great question because there are some opportunities that we can use at the time of our flexible laryngoscopy. Some scopes have narrow-band imaging, which is basically a combination of blue-green light and it causes the mucosa to look a little different than white light. You can see slight and subtle variations in the mucosa and ulcers that you might not see otherwise. This is something that has been developed and studied in the GI literature, which is what they use to look for dysplasia or polyps or things of that nature.

I learned this from one of my laryngology colleagues, Adam Klein, who basically said, "Look, I use this in the clinic to try and look at dysplasia in the larynx." I said, "Let me try using this on the tongue base and see what we can find out. "In fact, it does help us localize it sometimes. If you have an idea of where a tumor is, then the chance of finding it goes from 80 to 85% to almost 90 to 95%. It does help.

[Dr. Ashley Agan]
Do patients commonly present with any sort of symptoms other than this painless neck mass? How often do they have a sore throat or globus or anything?

[Dr. Mihir Patel]
Very rarely. I think the ones that present with a sore throat tend not to have a neck mass so much, but those are the more rare cases. Majority, I'd say 80% of the patients we see, maybe even more, have a neck mass.

[Dr. Ashley Agan]
Yes. That's the classic vignette is that painless neck mass. For the workup, we've talked about your laryngoscopy with MBI. We talked about PET scans. We talked about the ctDNA. Anything else you do before you take these patients to surgery?

[Dr. Mihir Patel]
No. I don't do nothing more than that. There are some things that we look at to try and make sure they're good candidates, but clinically if it looks like the tonsil is removable safely, then we'll do that.

(5) Targeted Approaches to Identifying & Treating Unknown Primary HPV Cancers

[Dr. Ashley Agan]
When you're taking patients to the OR in the unknown primary situation, the goal of surgery is finding the primary. Then potentially if you find it, getting a good excision, yes?

[Dr. Mihir Patel]
Yes. The goal is to find it and in fact just treat it completely. I think it just depends on the degree of how aggressive the neck nodes are. If they're really aggressive or they're on both sides, I typically don't tackle that. If it's just four nodes or less, then we'll tackle the neck at the same time. The majority of times that's what we're doing when we take patients back for an unknown primary.

[Dr. Ashley Agan]
Do you do the neck first?

[Dr. Mihir Patel]
I do not. I do the neck second.

[Dr. Ashley Agan]
There's the debate about being able to clip the lingual and depending on how aggressive you're going to be in the base of tongue. I don't know. What's your rationale?

[Dr. Mihir Patel]
I could probably speak to this in many different ways. You opened up this box now. The evolution of my practice has changed dramatically. Initially I started actually doing the neck first, waiting a week, and then doing the transoral robotics part. That was because of block time and a number of other things. That's how I was taught. Then over time, particularly the pandemic and patients needing to be tested, I did not want them getting tested twice.

Operative efficiency then changed again, and we had a number of logistical things that made it such that I was going to do all these in one day. The reason I do the transoral robotics portion first is because we send that specimen to pathology to be analyzed for margins and getting real time data. While they are doing that, then we transition to removing the lymph nodes of the neck. It just helps with efficiency.

[Dr. Ashley Agan]
Yes, that makes sense.

[Dr. Mihir Patel]
That's why. I've also done the neck first and the transoral robotics portion second on the same day as well. In the instance when the lymph node biopsy comes back as non-diagnostic, clinically you're suspicious. In that situation, we'll take out the one lymph node that we think is cancer to confirm it's cancer. At that point, we're going to finish the neck dissection and then go back and look for the primary or remove the primary.

[Dr. Ashley Agan]
Got you. When you're looking for your unknown primary, do you have a system as far as, I do ipsilateral tonsil first, and then I move on to basal tongue. Let's say you're going in and you really have no preoperative hints as to where it might be. How do you start that search?

[Dr. Mihir Patel]
I always start with the tonsil. 60% of the time, it's going to be there. If they've had a tonsillectomy, obviously it makes it a lot easier. You start with the tongue base. One of the things that has changed my practice was that meta-analysis I referred to before that essentially noted that the risk of the contralateral tongue base having the primary, so contralateral to the neck node, is only 3%.

I just didn't feel like it was worth the risk of causing, even though you're taking a small amount of tissue, there's pretty good data and slick literature to show that even a lingual tonsil does because some dysphagia permanently.

[Dr. Ashley Agan]
Do you do ipsilateral tonsil, ipsilateral tongue base, contralateral tonsil?

[Dr. Mihir Patel]
No.

[Dr. Ashley Agan]
No?

[Dr. Mihir Patel]
The chance of it being in the contralateral tonsils is near 0%, very unlikely.

[Dr. Ashley Agan]
They don't need to match? You don't need to have--

[Dr. Mihir Patel]
I don't match them. I know. The patients, they always ask, "Just take them both out?" I'm like, "Not doing that."

[Dr. Ashley Agan]
Got it. Got it. Okay. Basically that sets your limit as far as if we're looking for it, we're going to remove the ipsilateral tonsil, we're going to remove the ipsilateral lingual tonsil, and that's it. If it's not there, then it's going to stay in the unknown primary category, but we're not going to add morbidity searching for it on the other side of the base of the tongue.

[Dr. Mihir Patel]
Yes, that's exactly right. We're going to try and maximize therapeutics and minimize morbidity, and that's now where we are at. We haven't had any unknown primaries recur to date. We've been quite remarkably fortunate, but at the same time it's the disease. You're talking about small-volume disease, and with appropriate treatment and adjuvant therapy, you're still talking about greater than 90% cure rates.

[Dr. Ashley Agan]
Yes. Just because of the disease itself, right? It's very different than our other squamous cell carcinoma in the head and neck.

[Dr. Mihir Patel]
Yes.

[Dr. Ashley Agan]
Let's think of a couple of different scenarios. For the patient who has their TORs, and let's say it's the small percentage where you don't find it. I guess, can we unpack a little bit of how pathology is looking at the tonsils and the lingual tonsils. They're doing some frozens at the time of surgery, but then they're also going to do some permanent sections too, right?

[Dr. Mihir Patel]
They will. They will. We are very fortunate to have dedicated head and neck pathology faculty for every single one of our frozen sections. The first thing is that this whole process requires a team from not only the oncologists, but even within the OR, and they are instrumental. I never really understood how important pathology was until I was an attending. I realized that we had just developed a system and working with them is how we came across this. We [unintelligible 00:35:11] the tonsils and we pick a few spots.

[Dr. Ashley Agan]
Are you doing that specifically? Are you doing that yourself or the pathologists are doing it?

[Dr. Mihir Patel]
The pathologists are doing that.

[Dr. Ashley Agan]
Okay. You send the whole thing?

[Dr. Mihir Patel]
I send the whole thing. We label it based on anatomical location so that we know where the tonsil and how it was sitting within the fossa. I usually sit there and watch them do it, and look under the microscope while they're looking. Again, they'll take maybe three or four slices. Areas that they think grossly might have or be housing the cancer, and then we'll look. It's a long process. It extends the day dramatically. We can't move to the lingual tonsil until we've gotten an answer on the tonsil.

Once we take out the lingual tonsil, typically we'll just check the edges. Then we'll just do what we call shave margins, look at the edge to make sure that we haven't cut across cancer. If all that's clear, we typically don't always bread loaf the remaining tissue. We just wait for the permanent pathology. Because if it's a two or three millimeter cancer, which I have seen, when you run a frozen section, you are at risk of losing that tissue when you're doing the frozen section. Find balance.

[Dr. Ashley Agan]
Yes, it's tough. Imagine such a tiny primary and not having a lot of visual or tactile feedback in the specimen or when you're looking in the surgical field to know, okay, I think I've got everything. I think it's that unique situation where looking at it super close under the microscope like that is a really important part of the success of everything. Back to our patient who is still in the unknown primary category. That small group of patients who have had ipsilateral tonsillectomy, ipsilateral lingual tonsillectomy, and we still don't have a primary site. What does their treatment pathway look like from there?

(6) Managing Patients with Primary HPV Oropharyngeal Cancers Post-Surgery: cTDNA Biomarkers & Radiation Therapy

[Dr. Mihir Patel]
We've already removed the lymph nodes of the neck.

[Dr. Ashley Agan]
Right.

[Dr. Mihir Patel]
At that point, when we talk to them at their postoperative visit, I tell them, "I know you're going to be worried about this, but you just got to understand that we've likely removed it. Or there is a possibility that it transitioned into the neck when it spread." Either way, I don't have an answer as to where it is directly. What I can tell you is that for us, and the way we would treat this is we would just radiate your neck on. Typically because the primary in theory could be from the tongue base, both necks get radiated.

When you radiate patients with typical IMRT, they are going to receive about, let's say, 30, 50 gray to the oropharynx, somewhere in that range, even if you're only radiating the necks. I tell them, "We're only going to radiate the necks. The oropharynx will get some radiation dose. All I can tell you is that we haven't seen any comeback, but we'll follow you for five years." Again, now that we have the ctDNA options, that gives them a little bit more security about their prognosis and how to deal with this.

[Dr. Ashley Agan]
When you say could have, talking about the primary transitioning into the neck. Does that mean that the actual primary tumor as it's spreading just moves and is not in the primary site anymore?

[Dr. Mihir Patel]
That's one of the theories.

[Dr. Ashley Agan]
Interesting. Okay. Then when do you recheck that ctDNA? Does that happen before they start their radiation or do you wait?

[Dr. Mihir Patel]
We do it before. We do. We now use that as a biomarker for looking at the degree or the intensity of radiation. We have now cut back. Dr. Bates is one of our lead radiation oncologists, and he is championing this trial where we actually lower the dose to 36 gray. Three weeks of radiation, 36 gray for any patient that has a non-detectable ctDNA after surgery.

As you can imagine, a number of these patients are these unknown primary patients. That's a far departure from the standard 60 grade that patients would get after surgery. The side effects are minimal. Again, this is on a clinical trial and this is where I was getting at, we are finding ways to lower doses meaningfully and studying it, but it takes a large randomized control trial to really understand the implications or change practice.

[Dr. Ashley Agan]
Yes. Do you expect for patients to-- is it typical for them to go down to undetectable ctDNA levels after surgery? Do you have to wait a period before you dry? Do you wait a week and then draw that?

[Dr. Mihir Patel]
You can draw it as early. We have some pretty good studies on these kinetics from Boston that have looked at this and you can draw as early as 24 hours. We typically wait to their postoperative visit at two to three weeks.

[Dr. Ashley Agan]
Yes. Most of the time you see it drop to undetectable levels? Is that like the --

[Dr. Mihir Patel]
Most of the time we see it drop to undetectable levels. The patients that have not, in our series, have been patients that have high risk disease. More than five [unintelligible 00:41:26]

[Dr. Ashley Agan]
Okay. Do you have patients that say, "I've got undetectable levels. I don't want radiation. It's not there anymore. Can I just skip that?"

[Dr. Mihir Patel]
Yes, we have. I do caution them about that because we have seen recurrences. There's pretty good data to show that there is a worse hazard ratio in the event that you have no positive disease that likely warrants radiation. It's until we get a better understanding of the biomarkers to determine when we can back off radiation completely. I would never advocate that to a patient.

[Dr. Ashley Agan]
Yes. Right. Right now it's just trying to maybe de-intensify lower doses, like you mentioned, so that you can decrease the morbidity associated with radiation.

[Dr. Mihir Patel]
Yes.

[Dr. Ashley Agan]
Then I assume that the pathway, if we're talking about our patient where we did find the primary, it's a similar pathway, except they've got that additional information to be able to focus on where the primary was.

[Dr. Mihir Patel]
Yes. In fact, it still makes for some interesting discussion because in those situations, when you're talking about a very small primary, if we have two millimeter margins or greater at our institution, we won't even radiate the primary site. That's our standard workflow, but Penn has done it as a trial, in a clinical trial to show that you can avoid, it's called the avoid trial, you can avoid the primary site in situations that-- and so it's been studied in a meaningful way.

[Dr. Ashley Agan]
That's as long as you have two millimeter margins?

[Dr. Mihir Patel]
That's what we use. I don't recall their criteria for avoiding the primary, but it's definitely a trial worth looking at.

[Dr. Ashley Agan]
Yes. If you feel like you found the primary, you got two millimeter margins, the disease is not there anymore. It's not necessary to radiate that area. It's just going to add morbidity?

[Dr. Mihir Patel]
Yes. Here's the thing is that head and neck cancer really is one of those cancers that requires exquisite communication teamwork between radiation and medical oncology. We are just fortunate enough to have very like-minded, progressive, thoughtful radiation and medical oncologists that are willing to consider various treatment options and de-escalations without causing harm. I think we've been able to do that in a meaningful way. We study it, we study what we're doing. Again, these are going to be smaller numbers compared to what it really takes to move the needle. We are fortunate to have the group we have.

[Dr. Ashley Agan]
Yes. A multidisciplinary team is a huge benefit for your patients as well, to be able to have doctors who are talking about them and working together. Is there a patient that is eligible for single modality treatment? If you have like a T1 tumor and you've operated on the neck and you found the primary, you have two millimeter margins, is that patient done? Their ctDNA is undetectable.

[Dr. Mihir Patel]
That is possible. If the lymph node is small enough and there's a single isolated lymph node that's less than three centimeters, then these patients, again, do very well, greater than 90% five-year disease-free survival. I'm going to take this a step back since you asked that question, because I can't go without talking about ECOG 3311, which is where this data has been borne out in a large randomized phase II trial. When we think about the standard of care for oropharynx cancers, it has been 70 gray with cisplatin in chemo radiation therapy.

In 2011 or '12, when this trial was being discussed, TOR is now and has emerged as a standard because of this trial. In all honesty, it's a revolutionary trial when you consider the political climate at that time. I think a tremendous amount of credit has to go to Bob Farris and Barbara Burtness for moving this forward and seeing it through because now we have incredible data about how surgery impacts this cancer. Not only that, we have really have some meaningful evidence that surgery to date has been the only way that we've been able to deescalate therapy in a large clinical trial setting.

That's with the radiation dose. I think it just speaks to the entire head and neck oncology discipline. It just shows that how when we work together, we just really can move the needle for patients. I think that's what I really learned from all that.

[Dr. Ashley Agan]
Yes. It's not a small thing to be able to offer lower doses of radiation for these patients. You're basically saying that that's because of TORs.

[Dr. Mihir Patel]
Exactly. Not only that, there's some data that shows HPV-driven cancers who had greater than 10-pack year history of smoking, those patients were considered or thought to do worse. Whereas we're not seeing that in the surgical patients within ECOG 3311. Ronny Mara is working on a trial of looking at this even further and potentially randomizing patients to TORs with adjuvant therapy versus chemoradiation at 70 gray with cisplatin.

[Dr. Ashley Agan]
Got you. For advanced disease, that's the conversation that you're having with people. If you want to do a combination of surgery with post-op radiation, it should be usually TORs followed by radiation or just chemoradiation from the start.

[Dr. Mihir Patel]
Yes. We tell patients, at least when I go talk to them, I say, look, you have a couple of options if they actually have a cancer that is resectable with surgery. A smaller T1, T2 primary, I'll tell them, you have two good options and it's really up to you in how you want to manage this. We will discuss the benefits and the side effects of each one. Thankfully, I'm able to do this with our medical and radiation oncologists in real time. We all work together and talk to the patient together to help them understand a little bit.

It can be overwhelming for patients. Some of them just say, "Look, tell me what you want us to do." We'll do that in that setting as well. It's a balance of understanding the patient and helping them understand what's going on with them, and letting them know what the reality is, is you have a stage one disease. What used to be called a stage four disease is actually now stage one disease. Now we're just trying to understand how we can minimize the morbidity for the next potentially 20 to 30 years of your life. That's usually what the discussion is centered around.

[Dr. Ashley Agan]
Yes. I think that's so nice too, that you guys do that multidisciplinary clinic model so that the patient isn't going here and there. "Okay. I've got my appointment with my surgeon this day. Okay. Now I'm going to meet with oncology. Then I got to meet with radiation. I got to get my teeth pulled and then I'm going to get a PET scan." I think to be able to see you guys all together is really lovely. I'm sure your patients really appreciate that.

[Dr. Mihir Patel]
Yes. We're super lucky to have this option for them at Winship. It's not even just the oncologists that are there, it's our speech and language pathologists. Nutrition is there, dental's there, social work. We all go into their rooms and we center the care around them.

[Dr. Ashley Agan]
Yes. I think there's the disease part of it, but then there's also the patient part of it, like sometimes just like logistics. If I live way out, like I'm not going to be able to drive to radiation, or I don't have transportation to go to radiation every day for six weeks, or there's the, surgical risk of it. There's so many things to factor into treatment outside of the complicated part of just deciding what's going to-- we're just talking about the tumor. It's nice for you guys too, to be able to talk to each other in real time with the patient there, to be able to make that plan. For chemotherapy, is it still like cisplatin? Is there a new chemo on the block or?

(7) Immunotherapy in HPV Head & Neck Cancer

[Dr. Mihir Patel]
I love it. I love how you put that. It's still cisplatin and NRG has a trial that's currently open with it's HN005 and that is a three arm study, was a three arm study, now is a two arm study, but the arm that dropped, and that's why I'd mentioned surgery was really so far to date the only way to de escalate, is the arm that dropped was the 60 gray and cisplatin arm. Now what's currently being tested is 70 gray and cisplatin versus 60 gray and Nivolumab or checkpoint inhibitor. We'll have to see how that shakes out.

[Dr. Ashley Agan]
What are your thoughts on the immune checkpoint inhibitors? We're talking about primary, right? We're not talking about treatment for recurrence. We're talking about upfront treatment?

[Dr. Mihir Patel]
We're talking about upfront treatment, absolutely. Previously untreated treatment. The thoughts on immune checkpoint inhibitors, I would think based on some of the work that I've been fortunate to be a part of, you would think that in an immune-rich environment with an infection and you have some drug that can potentially modulate the immune system to turn it on and activate and find cancer, this would be perfect for it. You would think that, let's give some immune checkpoint inhibitors before, see what happens. Hopefully this whole thing just melts away.

The reality is, is that the major pathologic response when immune checkpoint inhibitors are given before surgery, and there've been a number of trials have done this, I think seven or eight, the response rate, the major response rate, meaning only 10% of viable tumors left or less. The response rate is anywhere between like three and 30%. It ranges. We're not sure why. The question is, is how can we really understand that? What can we do to figure out why and what theoretically might be a phenomenal use of checkpoint inhibitors?

Why is this functionally not happening when in vitro we see it potentially happening? We are actually opening up a trial soon that looks at giving checkpoint inhibitors before surgery, then taking the blood and the lymphocytes and then looking at that in a functional way, again, through the vaccine center with Rafi and Andreas to better understand and see what is the discrepancy? Why is there a difference? Hopefully we'll get some meaningful data. It's just a window of opportunity trial with 20 patients, but we are hopeful with their expertise. They're just so smart. They're so good that we can really understand and maybe get a better idea of why this isn't translating.

[Dr. Ashley Agan]
More to come?

[Dr. Mihir Patel]
More to come.

(8) Counseling Head & Neck Cancer Patients on HPV: Transmission, Vaccine, and Surveillance

[Dr. Ashley Agan]
Before I let you go, I wanted to just ask you a couple of things about talking to patients about HPV transmission in the patient who presents with cancer. Frequently for me, sometimes I'll have patients who maybe have a papilloma on their palate or something, but as we start talking about like, what is this? Then, oh, you say HPV and then they go, "Oh, I've heard of HPV. Isn't HPV an STD? Oh, wait, now are we allowed to kiss?" The conversation always devolves into that. I'm just curious how you counsel your patients about that.

[Dr. Mihir Patel]
Navigating that is a challenge. There's no doubt about it. The patients that get papillomas, I do worry about those patients because papillomas are, while they are considered the low-risk types, I worry about patients that, those patients in particular, if they get a high-risk HPV infection, then I do think they are at risk because for whatever reason, their immune system has not been able to take care of the infection. Those patients I would even consider for vaccination.

Now, getting back to transmission in partners, as we talked about earlier, this was likely an infection that happened years ago, chronic infection, something that may be there, may not be there, may not be in the saliva, but in the tonsil hiding. I tell patients that, look, the chance that you've already had an HPV infection is already very high, and the chance that you've cleared it is also pretty high. Now, for your partner, obviously that wasn't the case, but for you, it's unlikely that this is going to develop or turn into a cancer.

Now that's what I tell them. Now there are ways to potentially even say, "Look, we could test your ctDNA or take your blood, do a liquid biopsy, and see if the ctDNA is positive. One of the studies out of Boston from that same group looked at that, and they noted that there are a few patients that will have a positive ctDNA before they even ever present with HPV head and neck cancer. It starts to get interesting, like are these patients worthwhile to investigate further? I don't know because, just clinically and anecdotally, I have only seen this happen once out of thousands of patients we treated.

[Dr. Ashley Agan]
Is there a thought that ctDNA would eventually be used for screening in the way they do like with PSAing and stuff like that?

[Dr. Mihir Patel]
That's one of the proposals, not only for screening, but even for surveillance. Currently we image our patients every six months for the first two years, so neck and chest. Everyone has a different protocol, but that's ours, and there are thoughts that you could just do a liquid biopsy and maybe not even expose the patient to unnecessary CT scans. Again, you're talking about a disease with a 90% disease-free survival and cure rate after five years.

[Dr. Ashley Agan]
Yes, because if it's zero or if it's undetectable, then the chances that you're going to find something on your CT scan is really low.

[Dr. Mihir Patel]
Yes, exactly. Then there are studies to show that the ctDNA level, when it's elevated, actually finds or is an earlier way to detect a recurrence.

[Dr. Ashley Agan]
Okay, so how often, for your protocol at your institution, how often are you guys checking your ctDNA in the surveillance setting?

[Dr. Mihir Patel]
We check it every six months, so based on their follow-up schedule.

[Dr. Ashley Agan]
Okay. If it looks like it went from undetectable to, "Oh, it bumped up a little bit," then you start imaging and PET scan, whatever?

[Dr. Mihir Patel]
I'll tell them that we're going to want to get a second test to confirm. Usually we'll do that. We'll do an early second test within six weeks to three months, and then we'll image early.

[Dr. Ashley Agan]
Okay.

[Dr. Mihir Patel]
We'll image at a sequence.

[Dr. Ashley Agan]
Okay. Is that because sometimes when you see that little bump, it's just too early to pull out all the testing because it might be negative too early?

[Dr. Mihir Patel]
You can get a false positive. Yes, you can get a false positive. The number's low, and I don't remember the exact number, but that can happen.

[Dr. Ashley Agan]
Okay. Interesting. Before I let you go, you mentioned the vaccine. How do you talk to your patients about the HPV vaccine? From an age standpoint, is there an age where it's like, oh, it's probably not worth getting it at this point? What are your thoughts?

[Dr. Mihir Patel]
Such an interesting question, only because I just think about the evolution of the vaccine. My wife was one of the first to get the vaccine when it was released around 2008, and she was right at the age limit. At that time it was only for females 26 and younger, so she was 26 at the time. Then it started to include boys and girls, maybe like six, seven years later, again at age 26. I remember thinking to myself, I was beyond that age and I was thinking, gosh, I really wouldn't mind getting this vaccine.

I feel like I'm exposed to it all the time. I just paid for it out of pocket, I guess when I was around 40 years old or so. Interestingly, now the age has bumped up to 45, 46 years old where it's covered. I just tell patients that story a little bit. I say, "I don't know what the answer is here. I would highly recommend, first and foremost, that you get your children vaccinated. This is not a vaccine that's associated with sexual promiscuity. This is a cancer vaccine. I would highly encourage you get your children and your family members that are younger vaccinated. For you, I don't know how much benefit it's going to provide.

It's something that you can do if you like to, you might have to pay for it out of pocket depending on their age." I tell them that and I say, "I just don't have any evidence to support doing it at this time. What's really important is to think about that next generation. There is some thought in the HPV science world and those that track population science that we may see this disease start to decline around 2050 and potentially go down to much smaller numbers around 2070." The impact of the vaccine is tremendous if we can get that message out there.

[Dr. Ashley Agan]
Yes. I think with us in the ENT world, when you see head and neck cancer and the toll that it takes, the morbidity of treatment, the thought is like, why not? Even if I'm getting it at 40 and it doesn't work, what's the downside? Maybe if it does give me a little bit of protection, yes. Thank you for weighing in on that. I think I saw a headline recently about the efficacy that they really seen that it's in patients who are vaccinated, that there's like no cancers. I don't remember what the headline was, but it's an effective vaccine.

[Dr. Mihir Patel]
Absolutely.

[Dr. Ashley Agan]
Awesome. This has been fun. I've really learned a lot. I appreciate you taking the time. Is there anything that we've missed that you want to-- or is there a little cherry that you want to put on top of the conversation to end it with?

[Dr. Mihir Patel]
No, I think that the vaccine, that's the icing on the cake. I think that it's not just the icing, it actually should probably be the appetizer and the main course. It really is. No, this has just been so much fun. I've just had a great time and I love that you all are doing this and I need to get one of those footies.

[Dr. Ashley Agan]
Yes, you do. We'll get you one.

[Dr. Mihir Patel]
I think it's just wonderful to be able to have this platform and to be able to do what you're doing. I'm really thankful and I think our community is really appreciative.

[Dr. Ashley Agan]
Yes. Thank you. Thank you so much. Thank you for your commitment and integrity and passion for this patient population, really. I think your patients are very lucky to have you. If people want to either reach out to you or learn more about you, is there a website or a social media or any sort of place you would like to send them?

[Dr. Mihir Patel]
Yes, I don't have any social media outlet, but if you just Google Winship and my name, that website will show up and I'm happy for anyone to email me. It's just my first name, middle initial and last name with the dots in between the initial and the names @Emory.edu.

[Dr. Ashley Agan]
Wonderful. Very good. Thank you so much for taking the time. Have a great rest of your day.

[Dr. Mihir Patel]
Thanks, Ashley. Have fun.

Podcast Contributors

Dr. Mihir Patel

Dr. Mihir Patel is an otolaryngologist head and neck surgeon and assistant professor with Emory Healthcare in Atlanta, Georgia.

Dr. Ashley Agan

Dr. Ashley Agan is an otolaryngologist in Dallas, TX.

Cite This Podcast

BackTable, LLC (Producer). (2024, May 21). Ep. 172 – HPV & Oropharyngeal Cancer: Evolving Insights & Implications [Audio podcast]. Retrieved from https://www.backtable.com

Disclaimer: The Materials available on BackTable.com are for informational and educational purposes only and are not a substitute for the professional judgment of a healthcare professional in diagnosing and treating patients. The opinions expressed by participants of the BackTable Podcast belong solely to the participants, and do not necessarily reflect the views of BackTable.